(hetero)ARYL and indolinyl NRF2 protein degraders

Abstract

The present disclosure provides compounds represented by Formula (IV): (IV), and the salts or solvates thereof, wherein R1, R2a, R2b, R2c, R3, Y, M, and Z1 are as defined in the specification. Compounds having Formula (IV) are nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitors and / or degraders useful for the treatment of cancer and other diseases.

Description

(HETERO)ARYL AND INDOLINYL NRF2 PROTEIN DEGRADERS BACKGROUND Field

[0001] The present disclosure provides nuclear factor erythroid 2 related factor 2 (Nrf2) protein inhibitors and heterobifunctional small molecule Nrf2 protein degraders. Nrf2 inhibitors and degraders are useful for the treatment of cancer and other diseases. Background

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

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

[0004] The Nrf2 pathway also plays a role in neurodegeneration, diabetes, cardiovascular disease, kidney disease, and liver disease. Nrf2 levels vary significantly depending on physiological, temporal 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 thus suppress tumor growth, prevent metastasis, and / or increase sensitivity to chemotherapy. There is a need in the art for Nrf2 inhibitors and degraders to treat cancer and other diseases.BRIEF SUMMARY

[0005] In one aspect, the present disclosure provides small molecules represented by any one of Formulae (I)-(III), and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof. These compounds, and the salts and solvates thereof, are collectively referred to herein as "Compounds of the Disclosure" or individually as a "Compound of the Disclosure." Compounds of the Disclosure are Nrf2 inhibitors, Nrf2 degraders, and / or synthetic intermediates used to prepare Nrf2 degraders. Nrf2 inhibitors and / or degraders are useful in treating diseases or conditions wherein inhibition and / or degradation of the Nrf2 protein provides a therapeutic benefit to a subject.

[0006] In another aspect, the present disclosure provides methods of treating a condition or disease by administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., a human cancer patient, in need thereof. The disease or condition treatable by inhibition and / or degradation of Nrf2 is, for example, a cancer, a neurodegenerative disease, diabetes, a cardiovascular disease, a kidney disease, or a liver disease.

[0007] In another aspect, the present disclosure provides a method of inhibiting Nrf2 protein in a subject in need thereof, the method comprising administering to the subject an effective amount of a Compound of the Disclosure.

[0008] In another aspect, the present disclosure provides a method of degrading, e.g., 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 Disclosure.

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

[0010] In another aspect, the present disclosure provides a composition comprising a Compound of the Disclosure and an excipient and / or pharmaceutically acceptable carrier for use treating diseases or conditions wherein inhibition and / or degradation of the Nrf2 provides a benefit, e.g., cancer.

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

[0012] In another aspect, the present disclosure provides a Compound of the Disclosure for use in treatment of a disease or condition of interest, e.g., cancer.

[0013] In another aspect, the present disclosure provides a use of a Compound of the Disclosure for the manufacture of a medicament for treating a disease or condition of interest, e.g., cancer.

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

[0015] In another aspect, the present disclosure provides methods of preparing Compounds of the Disclosure.

[0016] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed. DETAILED DESCRIPTION I. Compounds of the Disclosure

[0017] In one embodiment, Compounds of the Disclosure are compounds having Formula (I):, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0018] R1is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

[0019] R2a, R2b, and R2care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0020] R3is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0021] Y is -CH2-J-, wherein J is attached to the thiazole;

[0022] J is selected from the group consisting of optionally substituted 5-membered heteroarylenyl and;

[0023] v is 1 or 2;

[0024] R4a, R4b, R4c, and R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; or

[0025] R4aand R4bare taken together with the carbon atoms to which they are attached to form a 5- to 7-membered optionally substituted heterocyclo or an optionally substituted C5-C7 cycloalkyl; and

[0026] R4cand R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, - S(=O)2CH3, and halo;

[0027] R4eis selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, halo, hydroxy, -O-L-X1, and -O-L-X-B1;

[0028] X1is selected from the group consisting of -OR10and -NR11aR11b;

[0029] R10is hydrogen;

[0030] R11ais selected from the group consisting of hydrogen and -C(=O)OC(CH3)3;

[0031] R11bis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0032] L is selected from the group consisting of -(CH2)m-, -*(CH2)n(OCH2CH2)o-, and -(CH2)p-Z-(CH2)q-; wherein the carbon marked with an "*" is attached to X;

[0033] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0034] n is 2, 3, or 4;

[0035] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0036] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

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

[0038] Z is selected from the group consisting of -(CR6aR6b)- and -N(R7)-;

[0039] R6ais selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, substituted optionally C4-C8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

[0040] R6bis selected from the group consisting of hydrogen and C1-C6alkyl;

[0041] R7is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl;

[0042] X is selected from the group consisting of -O-, -NH-,

[0043] B1is selected from the group consisting of: ,

[0044] R5a, R5b, and R5care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

[0045] In some embodiments, Compounds of the Disclosure are compounds having Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4eisselected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, halo, and hydroxy. In some embodiments, Compounds of the Disclosure wherein R4eis selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, halo, and hydroxy are useful as Nrf2 inhibitors and / or as synthetic intermediates for preparing Nrf2 degraders.

[0046] In some embodiments, Compounds of the Disclosure are compounds having Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4eis -O-L-X1. In some embodiments, Compounds of the Disclosure wherein R4eis -O-L-X1are useful as synthetic intermediates for preparing Nrf2 degraders.

[0047] In some embodiments, Compounds of the Disclosure are compounds having Formula (II):or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2a, R2b, R2c, R3, R4a, R4b, R4c, R4d, J, L, X, and B1are as defined in connection with Formula (I). In some embodiments, Compounds of the Disclosure having Formula (II) are useful as Nrf2 degraders.

[0048] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C3-C8cycloalkyl. In some embodiments, R1is cyclopropyl.

[0049] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted phenyl.

[0050] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0051] R1is:

[0052] R1a, R1b, R1c, R1d, and R1eare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

[0053] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1b, R1c, R1d, and R1eare hydrogen.

[0054] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1ais C1-C4 alkyl. In some embodiments, R1ais methyl.

[0055] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted 5- to 9-membered heteroaryl. In some embodiments, R1is optionally substituted imidazole. In some embodiments, R1is:.

[0056] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2a, R2b, and R2care hydrogen.

[0057] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C4alkyl. In some embodiments, R3is methyl.

[0058] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4ais selected from the group consisting of hydrogen and fluoro. In some embodiments, R4ais hydrogen. In some embodiments, R4ais fluoro.

[0059] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4bis selected from the group consisting of hydrogen and fluoro. In some embodiments, R4bis hydrogen. In some embodiments, R4bis fluoro.

[0060] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4cis selected from the group consisting of hydrogen and fluoro. In some embodiments, R4cis hydrogen. In some embodiments, R4cis fluoro.

[0061] In some embodiments, Compounds of the Disclosure are compounds having Formula (I) or (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4b, R4c, and R4dare hydrogen.

[0062] In some embodiments, Compounds of the Disclosure are compounds having Formula (III):, or a pharmaceutically acceptable salt or solvate thereof, R1, R4a, J, L, X, and B1are as defined in connection with Formula (I).

[0063] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is:.

[0064] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:,wherein the bond marked with an "*" is attached to the thiazole.

[0065] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the group consisting of -(CH2)m- and -*(CH2)n(OCH2CH2)o-.

[0066] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), 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.

[0067] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), 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.

[0068] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), 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 anotherembodiment, 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.

[0069] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -(CR6aR6b)-.

[0070] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is:.

[0071] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is:.

[0072] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III) or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R7)-.

[0073] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6ais halo. In another embodiment, R6ais hydroxyl. In another embodiment, R6ais C1-C6 alkyl. In another embodiment, R6ais C1-C4 haloalkyl. In another embodiment, R6ais an optionally substituted C3-C8 cycloalkyl. In another embodiment, R6ais an optionally substituted C4-C8 heterocyclo. In another embodiment, R6ais an optionally substituted phenyl. In another embodiment, R6ais an optionally substituted 5- to 9- membered heteroaryl.

[0074] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6bis hydrogen. In another embodiment, R6bis C1-C6 alkyl.

[0075] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof,wherein R7is hydrogen. In another embodiment, R7is C1-C6 alkyl. In another embodiment, R7is C1-C4 haloalkyl.

[0076] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0077] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

[0078] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is:.

[0079] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(III), or a pharmaceutically acceptable salt or solvate thereof, wherein X is:

[0080] In some embodiments, Compounds of the Disclosure are compounds having Formula (IV):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0081] R1is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, (amino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, optionally substituted 4- to 8-membered heterocyclo, and -CH(R12a)N(R12b)(R12c);

[0082] R2a, R2b, and R2care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0083] R3is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0084] Y is -W1-J-, wherein J is attached to the thiazole;

[0085] W1is C1-C4 alkylenyl;

[0086] J is selected from the group consisting of 5-membered heteroarylenyl and;

[0087] v is 1 or 2;

[0088] M is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl;

[0089] Z1is selected from the group consisting of -O-L-X1and -O-L-X-B1, and -X3-L1-X4-B1;

[0090] X1is selected from the group consisting of -OR10and -NR11aR11b;

[0091] R10is hydrogen;

[0092] R11ais selected from the group consisting of hydrogen and -C(=O)OC(CH3)3;

[0093] R11bis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0094] L is selected from the group consisting of -(CH2)m-, -*(CH2)n(OCH2CH2)o-, and -(CH2)p-Z-(CH2)q-;

[0095] wherein the carbon marked with an "*" is attached to X;

[0096] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0097] n is 2, 3, or 4;

[0098] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0099] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0100] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0101] Z is selected from the group consisting of -(CR6aR6b)- and -N(R7)-;

[0102] R6ais selected from the group consisting of halo, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, substituted optionally C4-C8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

[0103] R6bis selected from the group consisting of hydrogen and C1-C6 alkyl;

[0104] R7is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl; and

[0105] X is selected from the group consisting of -O-, -NH-,

[0106] X3is absent; or

[0107] X3is selected from the group consisting of -CH2-, -O-, -N(R9a)-, and 5- or 6- membered heterocyclenyl;

[0108] R9ais selected from the group consisting of hydrogen and C1-C4 alkyl;

[0109] L1is -J1-J2-J3-J4-;

[0110] wherein J1is attached to X3;

[0111] J1is absent; or

[0112] J1selected from the group consisting of C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12-membered heterocyclenyl, phenylenyl, and 4- to 9- membered heteroarylenyl;

[0113] J2is absent; or

[0114] J2is selected from the group consisting of -O-, -N(R7a)-, -C(=O)-, -C(=O)N(R7a)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;

[0115] R7ais selected from the group consisting of hydrogen and C1-C4 alkyl;

[0116] J3is absent; or

[0117] J3is selected from the group consisting of -O-, -N(R7b)-, -C(=O)-, -C(=O)N(R7b)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;

[0118] R7bis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0119] J4is absent; or

[0120] J4is selected from the group consisting of -O-, -N(R7c)-, -C(=O)-, -C(=O)N(R7c)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;

[0121] R7cis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0122] X4is absent; or

[0123] X4is selected from the group consisting of -CH2-, -CH=CH-, -C≡C-, -O- , -N(R8a)-, and 4-to 8-membered heterocyclenyl;

[0124] R8ais selected from the group consisting of hydrogen and C1-C4 alkyl;

[0125] with the provisos that (i) at least one of J1, J2, J3, or J4is present; and (ii) L1comprises a combinbation of stable covalent bonds;

[0126] B1is selected from the group consisting of: ,

[0127] R5a, R5b, and R5care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0128] R12ais selected from the group consisting of substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocylco, optionally substituted aryl, optionally substituted heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (carboxamido)alkyl, and mercaptoalkyl;

[0129] R12bis selected from the group consisting of hydrogen and C1-C4 alkyl; and

[0130] R12cis selected from the group consisting of hydrogen and C1-C4 alkyl; or

[0131] R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo.

[0132] In some embodiments, Compounds of the Disclosure are compounds having Formula (V):or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2a, R2b, R2c, R3, J, W1, M, X3, L1, X4, and B1are as defined in connection with Formula (IV).

[0133] In some embodiments, Compounds of the Disclosure are compounds having Formula (IV) or (V), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0134] M is selected from the group consisting of: ,,

[0135] R4a, R4b, R4c, and R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; or

[0136] R4aand R4bare taken together with the carbon atoms to which they are attached to form a 5- to 7-membered optionally substituted heterocyclo or an optionally substituted C5-C7 cycloalkyl; and

[0137] R4cand R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; and

[0138] the bond marked with an "*" is attached to W1.

[0139] In some embodiments, Compounds of the Disclosure are compounds having Formula (VI):(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2a, R2b, R2c, R3, J, R4a, R4b, R4c, R4d, X3, L1, X4, and B1are as defined in connection with Formula (IV).

[0140] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C3-C8 cycloalkyl. In some embodiments, R1is cyclopropyl.

[0141] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted phenyl.

[0142] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0143] R1is:

[0144] R1a, R1b, R1c, R1d, and R1eare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo. In some embodiments, R1b, R1c, R1d, and R1eare hydrogen. In some embodiments, R1ais C1-C4 alkyl.

[0145] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted 5- to 9-membered heteroaryl. In some embodiments, R1is optionally substituted imidazole.

[0146] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is (amino)alkyl.

[0147] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted 4- to 8-membered heterocyclo.

[0148] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein is -CH(R12a)N(R12b)(R12c).

[0149] In another embodiment, Compounds of the Disclosure are compounds having Formula (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

[0150] In another embodiment, Compounds of the Disclosure are compounds having Formula (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0151] R1is selected from the group consisting of:

[0152] R12band R12care methyl; or

[0153] R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclo.

[0154] In another embodiment, Compounds of the Disclosure are compounds having Formula (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

[0155] In another embodiment, Compounds of the Disclosure are compounds having Formula IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0156] R1is selected from the group consisting of:

[0157] R12band R12care methyl; or

[0158] R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclo.

[0159] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, R1is selected from any one or more of the groups of Table 7. Table 7

[0160] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2a, R2b, and R2care hydrogen.

[0161] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C4 alkyl. In some embodiments, R3is methyl.

[0162] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4ais selected from the group consisting of hydrogen and fluoro.

[0163] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4bis selected from the group consisting of hydrogen and fluoro.

[0164] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4cis selected from the group consisting of hydrogen and fluoro.

[0165] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R4b, R4c, and R4dare hydrogen.

[0166] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J is:

[0167] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:wherein the bond marked with an "*" is attached to the thiazole.

[0168] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:, wherein the bond marked with an "*" is attached to the thiazole.

[0169] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is -O-.

[0170] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is -NH-.

[0171] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X3is 6-membered heterocyclenyl.

[0172] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J4is absent.

[0173] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J4is C1-C3 alkylenyl.

[0174] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J3is absent.

[0175] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J2is absent.

[0176] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J2is selected from the group consisting of 3- to 8-membered cycloalkeylenyl and 4- to 12-membered heterocyclenyl.

[0177] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C1-C8 alkylenyl.

[0178] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C3-C6 heteroalkylenyl.

[0179] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C1-C8 alkylenyl; J2is absent; or J2is selected from the group consisting of -O- and -N(R7a)-; J3is absent; or J3is C1-C8 alkylenyl; and J4is absent.

[0180] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein L1is any one or more of the groups of Table 8, wherein the bond marked with an "*" is attached to X4. Table 8

[0181] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -O-.

[0182] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -NH-.

[0183] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -C≡C-.

[0184] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X4is 4-to 8-membered heterocyclenyl.

[0185] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (IV)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X4is absent.

[0186] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-1.

[0187] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI) or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-2.

[0188] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-3.

[0189] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-4.

[0190] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-5.

[0191] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-6.

[0192] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R5a, R5b, and R5care hydrogen.

[0193] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is selected from the group consisting of:

[0194] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is selected from the group consisting of:

[0195] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is selected from the group consisting of:

[0196] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is:.

[0197] In some embodiments, Compounds of the Disclosure are compounds having any one of Formulae (I)-(VI), or a pharmaceutically acceptable salt or solvate thereof, wherein B1is:.

[0198] In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof. Table 11: The bond marked with an "*" is attached to the thiazole.

[0199] In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Table 1-A, or a pharmaceutically acceptable salt or solvate thereof.Table 1-A

[0200] In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Table 1 and Table 2, or a pharmaceutically acceptable salt or solvate thereof.

[0201] In another embodiment, the disclosure provides any one or more of the compounds of Table 2, or a pharmaceutically acceptable salt or solvate thereof. Table 2

[0202] In another embodiment, the disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier or excipient.

[0203] Compounds of the Disclosure may contain an asymmetric carbon atom. In some embodiments, Compounds of the Disclosure are racemic compounds. In other embodiments, Compounds of the Disclosure are enantiomerically enriched, e.g., 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%.

[0204] In another embodiment, the cereblon binding portion of a Compound of the Disclosure, i.e., B1, is enantiomerically enriched. In another embodiment, the cereblon binding portion of the molecule is racemic. The present disclosure encompasses all possible stereoisomeric, e.g., diastereomeric, forms of Compounds of the Disclosure. When a Compound of the Disclosure is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the Compounds of the Disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.

[0205] The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure, including pharmaceutically acceptable salts. As used herein, the "pharmaceutically acceptable salt" refers to non-toxic salt forms of Compounds of the Disclosure. See e.g., Gupta et al., Molecules 23:1719 (2018). Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitablecation. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference Compounds of the Disclosure appearing herein is intended to include the actual compound as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0206] The present disclosure also encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term "solvate" as used herein is a combination, physical association and / or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, "solvate" encompasses both solution-phase andisolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A "hydrate" relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. 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. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by 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). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures 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 the solvent in a crystal of the solvate.

[0207] Compounds of the Disclosure can be prepared using the general synthetic methods shown in Schemes 1-4.Scheme 1Scheme 2

[0208] Compounds of the Disclosure can also be prepared using procedures similar to those disclosed in International Appl. No. PCT / US2023 / 069147, which is hereby incorporated by reference in its entirety.II. Therapeutic Methods of the Disclosure

[0209] Compounds of the Disclosure inhibit and / or degrade Nrf2 protein and are thus useful in the treatment of a variety of diseases and conditions. In particular, Compounds of the Disclosure are useful in methods of treating a disease or condition wherein inhibition and / or degradation of Nrf2 proteins provides a benefit, for example, cancers and proliferative diseases. Compounds of the Disclosure are also useful in methods of treating a neurodegenerative disease, diabetes, a cardiovascular disease, a kidney disease, or a liver disease in a subject.

[0210] The therapeutic methods of the disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., a cancer patient, in need thereof. The present methods also encompass administering a second therapeutic agent to the subject in combination with the Compound of the Disclosure. The second therapeutic agent is selected from drugs known as useful in treating the disease or condition afflicting the individual in need thereof, e.g., a chemotherapeutic agent and / or radiation known as useful in treating a particular cancer.

[0211] The present disclosure provides certain Compounds of the Disclosure as Nrf2 protein inhibitors for the treatment of diseases and conditions wherein inhibition of Nrf2 proteins has a beneficial effect. These compounds typically have IC50 (the drug concentration that results in 50% Nrf2 protein inhibition) values of less than 100 μM, e.g., less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 µM, less than about 0.5 µM, or less than about 0.1 µM.

[0212] The present disclosure provides certain Compounds of the Disclosure as Nrf2 protein degraders for the treatment of diseases and conditions wherein degradation of Nrf2 proteins has a beneficial effect. These compounds typically have DC50 (the drug concentration that results in 50% Nrf2 protein degradation) values of less than 100 μM, e.g., less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 µM, less than about 0.5 µM, or less than about 0.1 µM.

[0213] In one embodiment, the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein degradation of Nrf2 protein provides a benefit comprising administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need thereof. Since Compounds of the Disclosure are degraders of Nrf2 protein, a number of diseases and conditions mediated by or genetically associated with Nrf2 can be treated by employing these compounds.The present disclosure is thus directed generally 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 Disclosure.

[0214] The present disclosure is further directed to a method of inhibiting Nrf2 protein in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one Compound of the Disclosure.

[0215] The present disclosure is further directed to a method of degrading Nrf2 protein in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one Compound of the Disclosure.

[0216] 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 Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure treat cancer by degrading Nrf2. Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table 3. Table 3

[0217] In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 4. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia. Table 4

[0218] In another embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous 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 a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a 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.

[0219] In another embodiment, the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous 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, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

[0220] In another embodiment, Compounds of the Disclosure are 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.

[0221] In another aspect, the present disclosure provides a method of treating autoimmune disease, respiratory disease, digestive disease, cardiovascular disease, metabolic disease, or neurodegenerative disease in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure treat these diseases by degrading Nrf2.

[0222] In another aspect, the present disclosure provides a method of treating neurodegenerative disease in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure.

[0223] In another aspect, the present disclosure provides a method of treating diabetes in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure.

[0224] In another aspect, the present disclosure provides a method of treating cardiovascular disease in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure.

[0225] In another aspect, the present disclosure provides a method of treating kidney disease in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure.

[0226] In another aspect, the present disclosure provides a method of treating liver disease in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure.

[0227] The methods of the present disclosure can be accomplished by administering a Compound of the Disclosure as the neat compound or as a pharmaceutical composition. Administration of a pharmaceutical composition, or neat Compound of the Disclosure, can be performed during or after the onset of the disease or condition of interest. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.

[0228] In one embodiment, a Compound of the Disclosure is administered as a single agent to treat a disease or condition wherein degradation of Nrf2 protein provides a benefit. In another embodiment, a Compound of the Disclosure is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein degradation of Nrf2 protein provides a benefit. The second therapeuticagent is different from the Compound of the Disclosure. A Compound of the Disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the Compound of the Disclosure and second therapeutic agent can be administered as a single pharmaceutical composition or two separate pharmaceutical compositions.

[0229] 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.

[0230] A Compound of the Disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the Compound of the Disclosure is administered before the second therapeutic agent or vice versa. One or more doses of the Compound of the Disclosure and / or one or more doses of the second therapeutic agent can be administered. The Compound of the Disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.

[0231] In methods of the present disclosure, a therapeutically effective amount of a Compound of the Disclosure, typically formulated in accordance with pharmaceutical practice, is administered to a subject, e.g., a human cancer patient, in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and / or malfunctions that are present, the risks of developing particular signs, symptoms and / or malfunctions, and other factors.

[0232] A Compound of the Disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and / or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.

[0233] Pharmaceutical compositions include those wherein a Compound of the Disclosure is administered in an effective amount to achieve its intended purpose. Theexact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure that is sufficient to maintain therapeutic effects.

[0234] Toxicity and therapeutic efficacy of the Compounds of the Disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which is defined as the highest tolerated dose of a chemical that can be administered to animals without causing severe toxicity or mortality. The dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0235] A therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the Nrf2 protein inhibitor and / or degrader that are sufficient to maintain the desired therapeutic effects. The desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required. For example, a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d x 4); four doses delivered as one dose per day at three-day intervals (q3d x 4); one dose delivered per day at five-day intervals (qd x 5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5 / 2 / 5); or, any dose regimen determined to be appropriate for the circumstance.

[0236] A Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 1000 milligrams per dose, about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a Compound of the Disclosure can be administered, per dose, 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 milligrams, including all doses between 0.005 and 500 milligrams.

[0237] The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, can be from about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 μg / kg. The dosage of a composition may be at 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, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, or more. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient.

[0238] As stated above, a Compound of the Disclosure can be administered in combination with a second therapeutically active agent. In some 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 the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

[0239] In another embodiment, chemotherapeutic agents or other anti-proliferative agents can be combined with Compound of the Disclosure to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with Compounds of the Disclosure include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved chemotherapeutic drug.

[0240] Examples of antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an anti-estrogen; an anti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; a MEK inhibitor; an antitumor antibiotic; a nitrosourea; a compound targeting / decreasing protein or lipid kinase activity, a compound targeting / decreasing protein or lipid phosphatase activity, or any further anti-angiogenic compound.

[0241] Nonlimiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.

[0242] Nonlimiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

[0243] Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 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 podophillotoxines, such as etoposide and teniposide.

[0244] Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin 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; discodermolides; cochicine and epothilones and derivatives thereof.

[0245] Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.

[0246] Exemplary nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

[0247] Exemplary nonlimiting matrix metalloproteinase inhibitors ("MMP inhibitors") include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.

[0248] Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.

[0249] Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.

[0250] Exemplary nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.

[0251] Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.

[0252] Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

[0253] Exemplary nonlimiting antiproliferative antibodies include trastuzumab, trastuzumab-DMl, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term “antibody" is meant 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.

[0254] Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.

[0255] The term "an inhibitor of Ras oncogenic isoforms," such as H-Ras, K-Ras, or N-Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.

[0256] Exemplary nonlimiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.

[0257] Exemplary nonlimiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.

[0258] The phrase "compounds used in the treatment of hematologic malignancies" as used herein includes FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, Ι-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds which target, decrease, or inhibit anaplastic lymphoma kinase.

[0259] Exemplary nonlimiting Flt-3 inhibitors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.

[0260] Exemplary nonlimiting HSP90 inhibitors include compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[0261] The phrase "a compound targeting / decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or any further anti-angiogenic compound" as used herein includes a protein tyrosine kinase and / or serine and / or threonine kinase inhibitor or lipid kinase inhibitor, such as a) a compound targeting, decreasing, or inhibiting the activity of the platelet- derived growth factor-receptors (PDGFR), such as a compoundthat targets, decreases, or inhibits the activity of PDGFR, such as an N-phenyl-2- pyrimidine-amine derivatives, such as imatinib, SUlOl, SU6668, and GFB-111; b) a compound targeting, decreasing, or inhibiting the activity of the fibroblast growth factor- receptors (FGFR); c) a compound targeting, decreasing, or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as a compound that targets, decreases, or inhibits the activity of IGF-IR; d) a compound targeting, decreasing, or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) a compound targeting, decreasing, or inhibiting the activity of the Axl receptor tyrosine kinase family; f) a compound targeting, decreasing, or inhibiting the activity of the Ret receptor tyrosine kinase; g) a compound targeting, decreasing, or inhibiting the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) a compound targeting, decreasing, or inhibiting the activity of the c-Kit receptor tyrosine kinases, such as imatinib; i) a compound targeting, decreasing, or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. Bcr-Abl kinase) and mutants, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB / Akt, and Ras / MAPK family members, and / or members of the cyclin-dependent kinase family (CDK), such as a staurosporine derivative disclosed in U.S. Patent No.5,093,330, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521 ; LY333531 / LY379196; a isochinoline compound; a farnesyl transferase inhibitor; PD184352 or QAN697, or AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23 / RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) a compound targeting, decreasing, or inhibiting 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 El.l, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and 7H-pyrrolo- [2,3-d]pyrimidine derivatives; and m) a compound targeting, decreasing, or inhibiting the activity of the c-Met receptor.

[0262] 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.

[0263] Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.

[0264] Additional, nonlimiting, exemplary chemotherapeutic compounds, one or more of which may be used in combination with a Compound of the Disclosure, include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivatives, 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 amides, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-a- epihydrocotisol, cortex olone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, a plant alkaloid, a hormonal compound and / or antagonist, a biological response modifier, such as a lymphokine or interferon, an antisense oligonucleotide or oligonucleotide derivative, shRNA, and siRNA.

[0265] Other examples of second therapeutic agents, one or more of which a Compound of the Disclosure also can be combined, include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine; a treatment for Parkinson's Disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor, such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti- Parkinson's agent; an agent for treating cardiovascular disease, such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver disease, such as a corticosteroid, cholestyramine, an interferon, and an anti- viral agent; an agent for treating blood disorders, such as a corticosteroid, an anti- leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders, such as gamma globulin.

[0266] In another embodiment, the second therapeutically active agent is an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors. Thus, in one embodiment, a Compound of the Disclosure is administered in combination with an immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor.

[0267] In another embodiment, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-L1, a ligand of PD-1, enhances immune function and mediates antitumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies of anti-PD-1 antibodies, see U.S.2013 / 0309250, U.S.6,808,710, U.S.7,595,048, U.S.8,008,449, U.S.8,728,474, U.S. 8,779,105, U.S. 8,952,136, U.S. 8,900,587, U.S. 9,073,994, U.S. 9,084,776, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0268] 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. Particular anti-PD-L1 antibodies include, but are not limitedto, avelumab, atezolizumab, durvalumab, and BMS-936559. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. 8,217,149, U.S. 2014 / 0341917, U.S. 2013 / 0071403, WO 2015036499, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

[0269] 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 costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. For a general discussion of the availability, methods of production, 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).

[0270] In another embodiment, the immune checkpoint inhibitor is a LAG3 inhibitor. LAG3, Lymphocyte Activation Gene 3, is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation. In addition, LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule- organizing center, and only induced following antigen specific T cell activation. U.S.2014 / 0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781. For a general discussion of the availability, methods of production, mechanism of action, and studies, see, U.S. 2011 / 0150892, U.S. 2014 / 0093511, U.S.20150259420, and Huang et al., Immunity 21:503-13 (2004).

[0271] 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 the duration and magnitude of TH1 and TC1 T-cell responses. The TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8+T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology Research 2:393-98 (2014). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. For a general discussion of the availability, methods ofproduction, mechanism of action, and studies 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).

[0272] In another embodiment, the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E.R., PNAS 110:10886-87 (2013).

[0273] The term "antibody" is meant 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 meant to include soluble receptors that do not possess the Fc portion of the antibody. In one embodiment, the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.

[0274] Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction. Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat.8,114,845.

[0275] Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat.8,907,053.

[0276] Another class of immune checkpoint inhibitors include 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 inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions. Pardoll, Nature Reviews. Cancer 12:252-64 (2012); Löb, Cancer Immunol Immunother 58:153-57 (2009). Particular IDO blocking agents include, but are not limited to, levo-1-methyl typtophan (L-1MT) and 1-methyl-tryptophan (1MT). Qian et al., Cancer Res 69:5498-504 (2009); and Löb et al., Cancer Immunol Immunother 58:153-7 (2009).

[0277] 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

[0278] Other examples of second therapeutic agents, one or more of which a Compound of the Disclosure also can be combined, include glutamine antagonists. Suitable glutamine antagonists are disclosed, for example, in WO 2017 / 023774 and WO 2019 / 071110. Particular glutamine antagonists include, but are not limited to, isopropyl (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-6-diazo-5- oxohexanoate, or a pharmaceutically acceptable salt thereof, isopropyl (S)-2-((S)-6- acetamido-2-((3S,5S,7S)-adamantane-1-carboxamido)hexanamido)-6-diazo-5- oxohexanoate, or a pharmaceutically acceptable salt thereof, (S)-2-((S)-2-acetamido-3- (1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoic acid, or a pharmaceutically acceptable salt thereof, or 6-diazo-5-oxo-L-norleucine, or a pharmaceutically acceptable salt thereof.

[0279] In one embodiment, the second therapeutic agent comprises one of the anti-cancer drugs or anti-cancer drug combinations listed in Table 5. Table 5

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

[0281] The above-mentioned second therapeutically active agents, one or more of which can be used in combination with a Compound of the Disclosure, are prepared and administered as described in the art.

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

[0283] These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a Compound of the Disclosure. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, 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 Disclosure.

[0284] When a therapeutically effective amount of a Compound of the 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, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.

[0285] Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees,capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.

[0286] Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Buffers and pH modifiers can also be added to stabilize the pharmaceutical composition.

[0287] Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0288] Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0289] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions. 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 also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0290] Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the Compound of the Disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.

[0291] In particular, the Compounds of the 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, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Compound of the Disclosure are typically used in the form of a sterile aqueous solution that can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.

[0292] The disclosure provides the following particular embodiments in connection with treating a disease in a subject with a Compound of the Disclosure.

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

[0294] Embodiment II. The method Embodiment I, wherein the subject has cancer, e.g., any one of more of the cancers of Table 3 or Table 4.

[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, e.g., NSCLC.

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

[0298] Embodiment VI. The method of any one of Embodiments I-V further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition, e.g., an immune checkpoint inhibitor or other anticancer agent.

[0299] Embodiment VII. A pharmaceutical composition comprising a Compound of the 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, e.g., NSCLC.

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

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

[0305] Embodiment XIII. The compound of Embodiment XIII for use in treating cancer.

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

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

[0308] Embodiment XVI. Use of a Compound of the Disclosure for the manufacture of a medicament for treatment of cancer, neurodegenerative disease, diabetes, cardiovascular disease, kidney disease, or liver disease.

[0309] Embodiment XVII. The use of Embodiment XVI for the treatment of 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, e.g., 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 within a cell of a subject in need thereof, the method comprising administering to the subject a Compound of the Disclosure. In one embodiment, the Nrf2 protein is reduced by about 50% or less, e.g., 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, e.g., 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 Embodiments I or VI, wherein the subject has neurodegenerative disease.

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

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

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

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

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

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

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

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

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

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

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

[0333] Embodiment XLI. The use of Embodiment XVI, wherein the subject has liver disease. III. Kits of the Disclosure

[0334] In another embodiment, the present disclosure provides kits that comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates its use to practice methods of the present disclosure. In one embodiment, the kit includes 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, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of thedisclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration. IV. Definitions

[0335] The phrase "a disease or condition wherein inhibition and / or degradation of Nrf2 provides a benefit" and the like pertains to a disease or condition in which Nrf2 is important or necessary, e.g., for the onset, progress, expression of that disease or condition, or a disease or a condition that is known to be treated by a Nrf2 inhibitor or degrader. Examples of such diseases or conditions include, but are not limited to, cancer, neurodegenerative disease, 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 is readily able to determine whether a compound treats a disease or condition mediated by an Nrf2 inhibitor or degrader for any particular cell type, for example, by assays that conveniently can be used to assess the activity of particular compounds.

[0336] The term "Nrf2 degrader" and the like refer to a heterobifunctional small molecule that degrades Nrf2 protein. Nrf2 degraders contain a first ligand that binds to Nrf2 protein, a second ligand for an E3 ligase system, and a chemical linker that tethers the first and second ligands. Representative Compounds of the Disclosure that degrade Nrf2 protein are disclosed in Tables 1-A and 1-B.

[0337] The term "second therapeutic agent" refers to a therapeutic agent different from a Compound of the Disclosure and that is known to treat the disease or condition of interest. For example, when a cancer is the disease or condition of interest, the second therapeutic agent can be a known chemotherapeutic drug, like taxol, or radiation, for example.

[0338] The term "disease" or “condition” denotes disturbances and / or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and / or malfunctions. Compounds of the Disclosure are inhibitors and / or degraders of Nrf2 and can be used in treating or preventing diseases and conditions wherein inhibition or degradation of Nrf2 provides a benefit.

[0339] As used herein, the terms "treat," "treating," "treatment," and the like refer to eliminating, reducing, or ameliorating a disease or condition, and / or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term "treat" and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

[0340] As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of preventing the onset of a disease or condition and / or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent," "preventing," and "prevention" also include delaying the onset of a disease and / or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms "prevent," "preventing" and "prevention" may include "prophylactic treatment," which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously- controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.

[0341] The term "therapeutically effective amount" or "effective dose" as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to a subject in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent or stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent or stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and / or kills existing cancer cells, it may be cytostatic and / or cytotoxic.

[0342] The term "container" means any receptacle and closure therefore suitable for storing, shipping, dispensing, and / or handling a pharmaceutical product.

[0343] The term "insert" means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the "label" for a pharmaceutical product.

[0344] "Concurrent administration," "administered in combination," "simultaneous administration," and similar phrases mean that two or more agents are administered concurrently to the subject being treated. By "concurrently," it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to a subject in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert. For example, a Compound of the Disclosure can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent. A Compound of the Disclosure and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route. When a Compound of the Disclosure and the second therapeutic agent are not administered concurrently, it is understood that they can be administered in any order to a subject in need thereof. 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 subsequent 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 after) the administration of a second therapeutic agent treatment modality (e.g., radiotherapy), to a subject in need thereof. In various embodiments, a 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 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours 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 therapies are administered at about 1 minute to about 24 hours apart.

[0345] The use of the terms "a", "an", "the", and similar referents in the context of describing the disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0346] The term "halo" as used herein by itself or as part of another group refers to -Cl, -F, -Br, or -I.

[0347] The term "nitro" as used herein by itself or as part of another group refers to -NO2.

[0348] The term "cyano" as used herein by itself or as part of another group refers to -CN.

[0349] The term "hydroxy" as herein used by itself or as part of another group refers to -OH.

[0350] The term "alkyl" as used herein by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C1-C12 alkyl, or the number of carbon atoms designated, e.g., a C1 alkyl such as methyl, a C2 alkyl such as ethyl, etc. In one embodiment, the alkyl is a C1-C10 alkyl. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1-C3 alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C1-C12 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0351] The term "optionally substituted alkyl" as used herein by itself or as part of another group refers to an alkyl group that is either unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl,carboxyalkyl, -N(R56a)C(=O)R56b, -N(R56c)S(=O)2R56d,- S(=O)2R58; wherein:

[0352] R56ais hydrogen or alkyl;

[0353] R56bis 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-C10 aryl, or optionally substituted heteroaryl;

[0354] R56cis hydrogen or alkyl;

[0355] R56dis 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-C10 aryl, or optionally substituted heteroaryl;

[0356] R56eis 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-C10 aryl, or optionally substituted heteroaryl;

[0357] R57is 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

[0358] R58is 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.

[0359] The term "alkylenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted alkyl group. In one embodiment, the alkylenyl is a divalent form of a C1-12 alkyl, i.e., a C1-C12 alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C1-10 alkyl, i.e., a C1-C10 alkylenyl. In one embodiment,the alkylenyl is a divalent form of a C1-8 alkyl, i.e., a C1-C8 alkylenyl. In one embodiment, the alkylenyl is a divalent form of an C1-6 alkyl, i.e., a C1-C6 alkylenyl. In another embodiment, the alkylenyl is a divalent form of an C1-4 alkyl, i.e., a C1-C4 alkylenyl. In some embodiments, the alkylenyl is unsubstituted. In some embodiments, the alkylenyl is substituted, e.g., with one, two, or three substituents. In some embodiments, the substituent(s) is / are halo. Non-limiting exemplary alkylenyl groups include, but are not limited to, -CH2-, -CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, - CH2(CH2)2CH2-, -CH2(CH2)3CH2-, -CH2(CH2)4CH2-, -CH2(CH2)5CH2- , -CH2(CH2)6CH2-, -CH(CH3)CH2-, -CH2C(CH3)2CH2-, and -CH(CH3)CH2CH2-.

[0360] The term "alkenyl" as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C2-C6 alkenyl group. In another embodiment, the alkenyl group is a C2-C4 alkenyl group. In another embodiment, the alkenyl group has one carbon-to-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0361] The term "optionally substituted alkenyl" as used herein by itself or as part of another refers to an alkenyl group that is either unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting exemplary optionally substituted alkenyl groups include -CH=CHPh.

[0362] The term "alkynyl" as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-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-to-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0363] The term "optionally substituted alkynyl" as used herein by itself or as part of another group refers to an alkynyl group that is either unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently halo, nitro,cyano, hydroxy, amino, e.g., alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting exemplary optionally substituted alkynyl groups include -C≡CPh and -CH(Ph)C≡CH.

[0364] The term "haloalkyl" as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and / or iodine atoms. In one embodiment, the alkyl is substituted by one, two, or three fluorine and / or chlorine atoms. In another embodiment, the alkyl is substituted by one, two, or three fluorine atoms. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl. 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.

[0365] The terms "hydroxyalkyl" or "(hydroxy)alkyl" as used herein by themselves or as part of another group refer to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting exemplary (hydroxyl)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3- hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3- dihydroxyprop-2-yl.

[0366] The term "alkoxy" as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C1-C6 alkyl and resulting alkoxy is thus referred to as a "C1-C6 alkoxy." In another embodiment, the alkyl is a C1-C4 alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0367] The term "haloalkoxy" as used herein by itself or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C1-C6 haloalkyl. 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.

[0368] The term "alkylthio" as used herein by itself 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.

[0369] The terms "alkoxyalkyl" or "(alkoxy)alkyl" as used herein by themselves or as part of another group refers to an alkyl group substituted with one alkoxy group. In one embodiment, the alkoxy is a C1-C6 alkoxy. In another embodiment, the alkoxy is a C1-C4 alkoxy. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec- butoxymethyl, and pentyloxymethyl.

[0370] The term "heteroalkyl" as used by itself or part of another group refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing from three to twenty chain atoms, i.e., 3- to 20-membered heteroalkyl, or the number of chain atoms designated, wherein at least one -CH2- is replaced with at least one of -O-, -N(H)-, -N(C1- C4 alkyl)-, or -S-. The - O-, -N(H)-, -N(C1-C4 alkyl)-, or -S- can independently be placed at any position of the aliphatic hydrocarbon chain so 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 with one -O- group. In another embodiment, two -CH2- groups are replaced with two -O- groups. In another embodiment, three -CH2- groups are replaced with three -O- groups. In another embodiment, four -CH2- groups are replaced with four -O- groups. In another embodiment, one -CH2- group is replaced with one -NH- group. Non-limiting exemplary heteroalkyl groups include CH2OCH3, -CH2OCH2CH- 2CH3, -CH2CH2CH2OCH3, -NHCH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH- 2CH2OCH2CH3, - CH2CH2OCH2CH2OCH2CH2OCH2CH3, and -NHCH2CH2CH2CH3.

[0371] The term "heteroalkylenyl" as used herein by itself or part of another group refers to a divalent form of a heteroalkyl group. In one embodiment, the heteroalkylenyl is a divalent form of a 3- to 12-membered heteroalkyl, i.e., a 3- to 12-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- to 10-membered heteroalkyl, i.e., a 3- to 10-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- to 8-membered heteroalkyl, i.e., a 3- to 8-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- to 6-membered heteroalkyl, i.e., a 3- to 6-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- or 4-membered heteroalkyl, i.e., a 3- or 4-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a radical of the formula -(CH2)n1(OCH2CH2)n2-, wherein n1 is 2, 3, or 4; and n2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In another embodiment, the heteroalkylenyl is a radical of the formula -(CH2)p1-Za-CH2)p2-, wherein Z is selected from the group consisting of -(CRa6Rb6)- and -N(Ra7)-; Ra6is selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, substituted optionally C4-C8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; Rb6is selected from the group consisting of hydrogen and C1-C6 alkyl; Ra7is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl; p1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and p2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the sum of p1 + q1 is at least 2. Non-limiting exemplary heteroalkylenyl groups include, , but are not limited to, -CH2OCH2-, -CH2CH2OCH2CH2-, -CH2CH2N(H)CH2CH2-, - CH2OCH2CH2CH2-, -CH2CH2OCH2CH2OCH2CH2-, -NHCH2CH2OCH2CH2-, - N(CH3)CH2CH2OCH2CH2-, -NHCH2CH2CH2CH2-, -NHCH2CH2CH2CH2CH2CH2- , -NHCH2CH2CH2NH-, and -NHCH2CH2CH2CH2NH-.

[0372] The term "cycloalkyl" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C3-12 cycloalkyl, or the number of carbons designated, e.g., a C3 cycloalkyl such a cyclopropyl, a C4 cycloalkyl such as cyclobutyl, etc. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl is a C3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C5 cycloalkyl, i.e., cyclopentyl or cyclopentenyl. In another embodiment, the cycloalkyl is a C6 cycloalkyl, i.e., cyclohexyl or cyclohexenyl. Non-limiting exemplary C3-12 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 by itself or as part of another group refers to a cycloalkyl group that is either unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl,- S(=O)2R58, or -OR59, wherein R56a, R56b, R56c, R56d, R56e, R57, and R58are as defined in connection with the term "optionally substituted alkyl" and R59is (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] The term "cycloalkylenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted cycloalkyl group. In one embodiment, the cycloalkylenyl is a C3-C8 cycloalkylenyl. In one embodiment, the cycloalkylenyl is a C3- C6 cycloalkylenyl. In some embodiments, the cycloalkylenyl is unsubstituted. In some embodiments, the cycloalkylenyl is substituted, e.g., with one, two, or three substituents. In some embodiments, the substituents are each independently C1-C4 alkyl or halo. Non- limiting exemplary groups include:.

[0375] The term "heterocyclo" as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to eighteen ring members, i.e., a 3- to 18-membered heterocyclo, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide, i.e., S(=O), or sulfone, i.e., S(=O)2. The term heterocyclo includes groups wherein one or more -CH2- groups is replaced with one or more -C(=O)- groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one. The term heterocyclo also includes groups having 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]azepin-2-one.

[0376] In one embodiment, the heterocyclo group is a 4- to 8-membered cyclic group containing one ring and one or two oxygen atoms, e.g., tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, e.g., pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, e.g., morpholine, and, optionally, one -CH2- group is replaced with one -C(=O)- group, e.g., pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one -CH2- group is replaced with one -C(=O)- group. In another embodiment, the heterocyclo group is a 8- to12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include:.

[0377] The term "optionally substituted heterocyclo" as used herein by itself or part of another group refers to a heterocyclo group that is either unsubstituted or substituted with one to four substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, - N(R56a)C(=O)R56b, -N(R56c)S(=O)2R56d, -C(=O)R57, -S(=O)R56e, -S(=O)2R58, or -OR59, wherein R56a, R56b, R56c, R56d, R56e, R57, R58, and R59are as defined in connection with the term "optionally substituted cycloalkyl." Substitution may occur on any available carbon or nitrogen atom of the heterocyclo group.

[0378] In one embodiment, the heterocyclo group is a spiroheterocyclo. The term "spiroheterocyclo" as used herein by itself or part of another group refers to an optionally substituted heterocyclo group containing seven to eighteen ring members, wherein:

[0379] (i) a first and second ring are connected through a quaternary carbon atom, i.e., a spirocarbon;

[0380] (ii) the first ring is an optionally substituted mono- or bicyclic heterocyclo containing a nitrogen atom; and

[0381] (iii) the second ring is either:

[0382] (a) an optionally substituted mono- or bicyclic cycloalkyl; or

[0383] (b) an optionally substituted mono- or bicyclic heterocyclo containing a nitrogen atom.

[0384] In one embodiment, the first ring is an optionally substituted monocyclic 4- to 9- membered heterocyclo containing a nitrogen atom. In another embodiment, the second ring is an optionally substituted monocyclic C3-C8 cycloalkyl. In another embodiment, the second ring is a monocyclic C3-C8 cycloalkyl substituted with a hydroxy group. In another embodiment, the second ring is an optionally substituted monocyclic 4- to 9- membered heterocyclo containing a nitrogen atom. Non limiting exemplary spiroheterocyclo groups include:.

[0385] The term "heterocyclenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted heterocyclo group. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted 4- to 12-membered heterocyclo group. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted 4- to 8-membered heterocyclo group. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted azetidine. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted piperidinyl. In some embodiments, the heterocyclenyl is unsubstituted. In some embodiments, the heterocyclenyl is substituted, e.g., with one, two, or three substituents. In some embodiments, the substituents are each independently C1-C4 alkyl or halo. Non-limiting exemplary heterocyclenyl groups include, but are not limited to:.

[0386] The term "spiroheterocyclenyl" as used herein by itself or part of another group refers to a divalent form of a spiroheterocyclo. Non-limiting exemplary spiroheterocyclenyl groups include:

[0387] The term "aryl" as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C6-C14 aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

[0388] The term "optionally substituted aryl" as used herein by itself or as part of another group refers to aryl that is either unsubstituted or substituted with one to five substituents, wherein the substituents are each independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R56a)C(=O)R56b, -N(R56c)S(=O)2R56d, - C(=O)R57, -S(=O)R56e, -S(=O)2R58, or -OR59, wherein R56a, R56b, R56c, R56d, R56e, R57, R58, and R59are as defined in connection with the term "optionally substituted cycloalkyl."

[0389] 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-limiting exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3- fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro- 4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclo groups. Non-limiting xamples include: 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin- 2-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and 2-oxo-2,3,4,5-tetrahydro-1H- benzo[d]azepin-1-yl.

[0390] The term "phenylenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted phenyl group. In some embodiments, the phenylenyl is unsubstituted. In some embodiments, the phenylenyl is substituted, e.g., with one, two, or three substituents. In some embodiments, the substituents are each independently C1-C4 alkyl or halo, e.g. fluoro. Non-limiting examples include, but are not limited to:.

[0391] The term "heteroaryl" as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to 14 fourteen ring members, i.e., a 5- to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, 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, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H- imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl),pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2- yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3- yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non- limiting exemplary N-oxide is pyridyl N-oxide.

[0392] The term "optionally substituted heteroaryl" as used herein by itself or as part of another group refers to a heteroaryl that is either unsubstituted or substituted with one to four substituents, wherein the substituents are independently halo, nitro, cyano, hydroxy, amino, (e.g., -NH2, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, -N(R56a)C(=O)R56b, - N(R56c)S(=O)2R56d, -C(=O)R57, -S(=O)R56e, -S(=O)2R58, or -OR59, wherein R56a, R56b, R56c, R56d, R56e, R57, R58, and R59are as defined in connection with the term "optionally substituted cycloalkyl."

[0393] 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.

[0394] The term " heteroarylenyl" as used herein by itself or part of another group refers to a divalent form of an optionally substituted heteroaryl group. In one embodiment, the heteroarylenyl is a 5-membered heteroaryleneyl, e.g., heteroarylenyl derived from pyrrole, imidazole, thiazole, furan, oxazole, or isooxazole. In one embodiment, the heteroarylenyl is an optionally substituted 6-membered heteroarylenyl, e.g., heteroarylenyl derived from pyridine, pyrimidine, pyrazine, or pyridazine. In some embodiments, the heteroarylenyl is unsubstituted. In some embodiments, the heteroarylenyl is substituted, e.g., with one, two, or three substituents. In some embodiments, the substituents are each independently C1-C4 alkyl or halo, e.g., fluoro. Exemplary non-limiting exemplary 5-membered heteroarylenyl groups include:.

[0395] The term "aryloxy" as used herein by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.

[0396] The term "heteroaryloxy" as used herein by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is pyridyl-O-.

[0397] The term "aralkyloxy" as used herein by itself or as part of another group refers to an aralkyl attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH2O-.

[0398] The term "(cyano)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one, two, or three cyano groups. In one embodiment, the alkyl is substituted with one cyano group. In another embodiment, the alkyl is a C1-C6 alkyl In another embodiment, the alkyl is a C1-C4 alkyl. Non-limiting exemplary (cyano)alkyl groups include -CH2CH2CN and -CH2CH2CH2CN.

[0399] The term "(cycloalkyl)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group(s) is an optionally substituted C3-C6 cycloalkyl. In another embodiment, the alkyl is a C1-C6alkyl. In another embodiment, the alkyl is a C1- C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl)alkyl groups include:.

[0400] The term "sulfonamido" as used herein by itself or as part of another group refers to a radical of the formula -SO2NR50aR50b, wherein R50aand R50bare each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R50aand R50btaken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary sulfonamido groups include -SO2NH2, -SO2N(H)CH3, and -SO2N(H)Ph.

[0401] The term "(carboxamido)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with a carboxamido group. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (carboxamido)alkyl groups include -CH2C(=O)NH2, -CH2C(=O)N(CH3)2, and -CH2CH2C(=O)NH2.

[0402] The term "alkylcarbonyl" as used herein by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an alkyl group. In one embodiment, the alkyl is a C1-C4 alkyl. A non-limiting exemplary alkylcarbonyl group is -COCH3.

[0403] The term "arylcarbonyl" as used herein by itself or as part of another group refers to a carbonyl group, i.e., -C(=O)-, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is -COPh.

[0404] The term "alkylsulfonyl" as used herein by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by an alkyl group. A non-limiting exemplary alkylsulfonyl group is -SO2CH3.

[0405] The term "arylsulfonyl" as used herein by itself or as part of another group refers to a sulfonyl group, i.e., -SO2-, substituted by an optionally substituted aryl group. A non-limiting exemplary arylsulfonyl group is -SO2Ph.

[0406] The term "mercaptoalkyl" as used herein by itself or as part of another group refers to an alkyl substituted by a -SH group.

[0407] The term "carboxy" as used by itself or as part of another group refers to a radical of the formula -C(=O)OH.

[0408] The term "ureido" as used herein by itself or as part of another group refers to a radical of the formula -NR51a-C(=O)-NR51bR51c, wherein R51ais hydrogen or alkyl; and R51band R51care each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substitutedheteroaryl, or R51band R51ctaken together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary ureido groups include -NH-C(C=O)-NH2 and -NH-C(C=O)-NHCH3.

[0409] The term "guanidino" as used herein by itself or as part of another group refers to a radical of the formula -NR52a-C(=NR53)-NR52bR52c, wherein R52ais hydrogen or alkyl; R52band R53care each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R52band R52ctaken together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclo group; and R53is 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.

[0410] The term "(heterocyclo)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the alkyl is substituted with one optionally substituted 5- to 8-membered heterocyclo group. In another embodiment, alkyl is a C1-C6 alkyl. In another embodiment, alkyl is a C1-C4 alkyl. The heterocyclo group can be linked to the alkyl group through a carbon or nitrogen atom.

[0411] The term "carbamate" as used herein by itself or as part of another group refers to a radical of the formula -NR54a-C(=O)-OR54b, wherein R54ais hydrogen or alkyl, and R54bis hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting exemplary carbamate group is -NH-(C=O)-OtBu.

[0412] The term "(heteroaryl)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one or two 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 optionallysubstituted 5- or 6-membered heteroaryl groups. In one embodiment, the alkyl group is a C1-C6 alkyl. In another embodiment, the alkyl group is a C1-C4 alkyl. In another embodiment, the alkyl group is a C1 or C2 alkyl.

[0413] The terms "aralkyl" or "(aryl)alkyl" as used herein by themselves or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. In another embodiment, the alkyl is a C1 or C2 alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, -CHPh2, and -CH(4-F-Ph)2.

[0414] The terms "amido" or "carboxamido" as used herein by itself or as part of another group refers to a radical of formula -C(=O)NR60aR60b, wherein R60aand R60bare each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl; or R60aand R60btaken together with the nitrogen to which they are attached from a 4- to 8-membered optionally substituted heterocyclo group. In one embodiment, R60aand R60bare each independently hydrogen or C1-C6 alkyl. Non-limiting exemplary carboxamido groups include -C(=O)NH2, -C(=O)N(H)CH3, and -C(=O)N(H)Ph.

[0415] The term "amino" as used by itself or as part of another group refers to a radical of the formula -NR55aR55b, wherein R55aand R55bare independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl.

[0416] In one embodiment, the amino is -NH2.

[0417] In another embodiment, the amino is an "alkylamino," i.e., an amino group wherein R55ais C1-6 alkyl and R55bis hydrogen. In one embodiment, R55ais C1-C4 alkyl. Non-limiting exemplary alkylamino groups include -N(H)CH3 and -N(H)CH2CH3.

[0418] In another embodiment, the amino is a "dialkylamino," i.e., an amino group wherein R55aand R55bare each independently C1-6 alkyl. In one embodiment, R55aand R55bare each independently C1-C4 alkyl. Non-limiting exemplary dialkylamino groups include -N(CH3)2 and -N(CH3)CH2CH(CH3)2.

[0419] In another embodiment, the amino is a "hydroxyalkylamino," i.e., an amino group wherein R55ais (hydroxyl)alkyl and R55bis hydrogen or C1-C4alkyl.

[0420] In another embodiment, the amino is a "cycloalkylamino," i.e., an amino group wherein R55ais optionally substituted cycloalkyl and R55bis hydrogen or C1-C4 alkyl.

[0421] In another embodiment, the amino is a "aralkylamino," i.e., an amino group wherein R55ais aralkyl and R55bis hydrogen or C1-C4 alkyl. Non-limiting exemplary aralkylamino groups include -N(H)CH2Ph, -N(H)CHPh2, and -N(CH3)CH2Ph.

[0422] The term "(amino)alkyl" as used herein by itself or as part of another group refers to an alkyl substituted with one amino group. In one embodiment, the amino group is - NH2. In one embodiment, the amino group is an alkylamino. In another embodiment, the amino group is a dialkylamino. In another embodiment, the alkyl is a C1-C6 alkyl. In another embodiment, the alkyl is a C1-C4 alkyl. 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).

[0423] The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom 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, phosphorous, fluorine and chlorine, such as2H (or deuterium (D)),3H, 11C,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36Cl, respectively, e.g.,3H,11C, and14C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a positionwith an atom having a different atomic mass or mass number." Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

[0424] As noted above, Compounds of the Disclosure contain one or more asymmetric carbon atoms and may thus give rise to 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. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure. All conformational isomers, i.e., stereoisomers produced by rotation about a σ bond, are also encompassed by the present disclosure.

[0425] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules 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).

[0426] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0427] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the 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.

[0428] The term "racemic" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic.

[0429] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0430] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0431] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as │ │*100, where R and S are the respectivemole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([^]obs / [^]max)*100, where [^]obs is the optical rotation of the mixture of enantiomers and [^]max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

[0432] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11. V. Particular Embodiments

[0433] The disclosure provides the following particular embodiments.

[0434] Embodiment 1. A compound having Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0435] R1is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

[0436] R2a, R2b, and R2care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0437] R3is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0438] Y is -CH2-J-, wherein J is attached to the thiazole;

[0439] J is selected from the group consisting of optionally substituted 5-membered heteroarylenyl and

[0440] v is 1 or 2;

[0441] R4a, R4b, R4c, and R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; or

[0442] R4aand R4bare taken together with the carbon atoms to which they are attached to form a 5- to 7-membered optionally substituted heterocyclo or an optionally substituted C5-C7 cycloalkyl; and

[0443] R4cand R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, - S(=O)2CH3, and halo;

[0444] R4eis selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, halo, hydroxy, -O-L-X1, and -O-L-X-B1;

[0445] X1is selected from the group consisting of -OR10and -NR11aR11b;

[0446] R10is hydrogen;

[0447] R11ais selected from the group consisting of hydrogen and -C(=O)OC(CH3)3;

[0448] R11bis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0449] L is selected from the group consisting of -(CH2)m-, -*(CH2)n(OCH2CH2)o-, and -(CH2)p-Z-(CH2)q-; wherein the carbon marked with an "*" is attached to X;

[0450] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0451] n is 2, 3, or 4;

[0452] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0453] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0454] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0455] Z is selected from the group consisting of -(CR6aR6b)- and -N(R7)-;

[0456] R6ais selected from the group consisting of halo, hydroxyl, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, substituted optionally C4-C8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

[0457] R6bis selected from the group consisting of hydrogen and C1-C6 alkyl;

[0458] R7is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl;

[0459] X is selected from the group consisting of -O-, -NH-,

[0460] B1is selected from the group consisting of: ,

[0461] R5a, R5b, and R5care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

[0462] Embodiment 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R4eis selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, halo, and hydroxy.

[0463] Embodiment 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R4eis -O-L-X1.

[0464] Embodiment 4. The compound of Embodiment 1, having Formula (II):or a pharmaceutically acceptable salt or solvate thereof.

[0465] Embodiment 5. The compound of any of Embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C3-C8 cycloalkyl.

[0466] Embodiment 6. The compound of Embodiment 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is cyclopropyl.

[0467] Embodiment 7. The compound of any of Embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted phenyl.

[0468] Embodiment 8. The compound of Embodiment 7, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0469] R1is:

[0470] R1a, R1b, R1c, R1d, and R1eare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

[0471] Embodiment 9. The compound of Embodiment 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1b, R1c, R1d, and R1eare hydrogen.

[0472] Embodiment 10. The compound of Embodiments 8 or 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1ais C1-C4 alkyl.

[0473] Embodiment 11. The compound of any of Embodiments 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted 5- to 9-membered heteroaryl.

[0474] Embodiment 12. The compound of Embodiment 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted imidazole.

[0475] Embodiment 13. The compound of Embodiment 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

[0476] Embodiment 14. The compound of any one of Embodiments 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R2a, R2b, and R2care hydrogen.

[0477] Embodiment 15. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C4 alkyl.

[0478] Embodiment 16. The compound of Embodiment 15, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is methyl.

[0479] Embodiment 17. The compound of any one of Embodiments 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R4ais selected from the group consisting of hydrogen and fluoro.

[0480] Embodiment 18. The compound of any one of Embodiments 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein R4bis selected from the group consisting of hydrogen and fluoro.

[0481] Embodiment 19. The compound of any one of Embodiments 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R4cis selected from the group consisting of hydrogen and fluoro.

[0482] Embodiment 20. The compound of any one of Embodiments 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R4b, R4c, and R4dare hydrogen.

[0483] Embodiment 21. The compound of any one of Embodiments 4-13 or 17 having Formula (III):(III), or a pharmaceutically acceptable salt or solvate thereof.

[0484] Embodiment 22. The compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein J is:.

[0485] Embodiment 23. The compound of any one of Embodiments 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:wherein the bond marked with an "*" is attached to the thiazole.

[0486] Embodiment 24. The compound of any one of Embodiments 1 or 3-23, or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the group consisting of -(CH2)m- and -*(CH2)n(OCH2CH2)o-.

[0487] Embodiment 25. The compound of Embodiment 24, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2)m-.

[0488] Embodiment 26. The compound of Embodiment 24, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -*(CH2)n(OCH2CH2)o-.

[0489] Embodiment 27. The compound of any one of Embodiments 1 or 3-23, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -(CH2)p-Z-(CH2)q-.

[0490] Embodiment 28. The compound of Embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -(CR6aR6b)-.

[0491] Embodiment 29. The compound of Embodiment 27, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -N(R7)-.

[0492] Embodiment 30. The compound of any one of Embodiments 1 or 3-29, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -O-.

[0493] Embodiment 31. The compound of any one of Embodiments 1 or 3-29, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -NH-.

[0494] Embodiment 32. The compound of any one of Embodiments 1 or 3-29, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:.

[0495] Embodiment 33. The compound of any one of Embodiments 1 or 3-29, or a pharmaceutically acceptable salt or solvate thereof, wherein X is:.

[0496] Embodiment 34. The compound of any one of Embodiments 1 or 3-33, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-1.

[0497] Embodiment 35. The compound of any one of Embodiments 1 or 3-33, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-2.

[0498] Embodiment 36. The compound of any one of Embodiments 1 or 3-33, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-3.

[0499] Embodiment 37. The compound of any one of Embodiments 1 or 3-33, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-4.

[0500] Embodiment 38. The compound of any one of Embodiments 1 or 3-33, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-5.

[0501] Embodiment 39. The compound of any one of Embodiments 1 or 3-33, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-6.

[0502] Embodiment 40. The compound of any one of Embodiments 34-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care independently selected from the group consisting of hydrogen and fluoro.

[0503] Embodiment 41. The compound of Embodiment 40, or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care hydrogen.

[0504] Embodiment 42. 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.

[0505] Embodiment 43. 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 2.

[0506] Embodiment 44. A pharmaceutical composition comprising the compound of any one of Embodiments 1-43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0507] Embodiment 45. 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 a therapeutically effective amount of the compound of any one of Embodiments 1-43, or a pharmaceutically acceptable salt thereof, to the subject.

[0508] Embodiment 46. The method of Embodiment 45 further comprising administering a second therapeutic agent to the subject.

[0509] Embodiment 47. The method of Embodiments 45 or 46 for treating cancer in a subject in need thereof.

[0510] Embodiment 48. The method of Embodiments 45 or 46, wherein the cancer is a solid tumor.

[0511] Embodiment 49. The method of Embodiments 45 or 46, wherein the cancer is a hematological cancer.

[0512] Embodiment 50. The method of Embodiments 45 or 46, wherein the cancer is one or more of the cancers of Table 3.

[0513] Embodiment 51. A method of reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein within a cell of a subject, the method comprising administering to the subject a compound of any one of Embodiments 4-42, or a pharmaceutically acceptable salt or solvate thereof.

[0514] Embodiment 52. The method of Embodiment 51, wherein the subject has cancer.

[0515] Embodiment 53. A kit comprising the compound of any one of Embodiments 1-43, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt thereof, to a subject having cancer.

[0516] The disclosure provides the following particular embodiments.

[0517] Embodiment* 1. A compound having Formula (IV):(IV), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0518] R1is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, (amino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, optionally substituted 4- to 8-membered heterocyclo, and -CH(R12a)N(R12b)(R12c);

[0519] R2a, R2b, and R2care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0520] R3is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0521] Y is -W1-J-, wherein J is attached to the thiazole;

[0522] W1is C1-C4 alkylenyl;

[0523] J is selected from the group consisting of 5-membered heteroarylenyl and

[0524] v is 1 or 2;

[0525] M is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl;

[0526] (i) Z1is selected from the group consisting of -O-L-X1and -O-L-X-B1, wherein:

[0527] X1is selected from the group consisting of -OR10and -NR11aR11b;

[0528] R10is hydrogen;

[0529] R11ais selected from the group consisting of hydrogen and -C(=O)OC(CH3)3;

[0530] R11bis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0531] L is selected from the group consisting of -(CH2)m-, -*(CH2)n(OCH2CH2)o-, and -(CH2)p-Z-(CH2)q-;

[0532] wherein the carbon marked with an "*" is attached to X;

[0533] m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0534] n is 2, 3, or 4;

[0535] o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0536] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0537] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0538] Z is selected from the group consisting of -(CR6aR6b)- and -N(R7)-;

[0539] R6ais selected from the group consisting of halo, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, substituted optionally C4-C8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

[0540] R6bis selected from the group consisting of hydrogen and C1-C6 alkyl;

[0541] R7is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl; and

[0542] X is selected from the group consisting of -O-, -NH-,

[0543] (ii) Z1is -X3-L1-X4-B1, wherein:

[0544] X3is absent; or

[0545] X3is selected from the group consisting of -CH2-, -O-, -N(R9a)-, and 5- or 6- membered heterocyclenyl;

[0546] R9ais selected from the group consisting of hydrogen and C1-C4 alkyl;

[0547] L1is -J1-J2-J3-J4-;

[0548] wherein J1is attached to X3;

[0549] J1is absent; or

[0550] J1selected from the group consisting of C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12-membered heterocyclenyl, phenylenyl, and 4- to 9- membered heteroarylenyl;

[0551] J2is absent; or

[0552] J2is selected from the group consisting of -O-, -N(R7a)-, -C(=O)-, -C(=O)N(R7a)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;

[0553] R7ais selected from the group consisting of hydrogen and C1-C4 alkyl;

[0554] J3is absent; or

[0555] J3is selected from the group consisting of -O-, -N(R7b)-, -C(=O)-, -C(=O)N(R7b)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;

[0556] R7bis selected from the group consisting of hydrogen and C1-C4 alkyl;

[0557] J4is absent; or

[0558] J4is selected from the group consisting of -O-, -N(R7c)-, -C(=O)-, -C(=O)N(R7c)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;

[0559] R7cis selected from the group consisting of hydrogen and C1-C4alkyl;

[0560] X4is absent; or

[0561] X4is selected from the group consisting of -CH2-, -CH=CH-, -C≡C-, -O- , -N(R8a)-, and 4-to 8-membered heterocyclenyl;

[0562] R8ais selected from the group consisting of hydrogen and C1-C4 alkyl;

[0563] with the provisos that (i) at least one of J1, J2, J3, or J4is present; and (ii) L1comprises a combinbation of stable covalent bonds;

[0564] B1is selected from the group consisting of B-1, B-2, B-3, B-4, B-5, and B-6, wherein

[0565] R5a, R5b, and R5care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo;

[0566] R12ais selected from the group consisting of substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocylco, optionally substituted aryl, optionally substituted heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (carboxamido)alkyl, and mercaptoalkyl;

[0567] R12bis selected from the group consisting of hydrogen and C1-C4 alkyl; and

[0568] R12cis selected from the group consisting of hydrogen and C1-C4 alkyl; or

[0569] R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo.

[0570] Embodiment* 2. The compound of Embodiment* 1, or a pharmaceutically acceptable salt or solvate thereof, having Formula (V):

[0571] Embodiment* 3. The compound of Embodiments* 1 or 2, wherein:

[0572] M is selected from the group consisting of M-1, M-2, M-3, M-4, and M-5;

[0573] R4a, R4b, R4c, and R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; or

[0574] R4aand R4bare taken together with the carbon atoms to which they are attached to form a 5- to 7-membered optionally substituted heterocyclo or an optionally substituted C5-C7 cycloalkyl; and

[0575] R4cand R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; and

[0576] the bond marked with an "*" is attached to W1.

[0577] Embodiment* 4. The compound of Embodiment* 3, or a pharmaceutically acceptable salt or solvate thereof, having Formula (VI):

[0578] Embodiment* 5. The compound of any of Embodiments* 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C3-C8 cycloalkyl.

[0579] Embodiment* 6. The compound of Embodiment* 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is cyclopropyl.

[0580] Embodiment* 7. The compound of any of Embodiments* 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted phenyl.

[0581] Embodiment* 8. The compound of Embodiment* 7, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0582] R1is:

[0583] R1a, R1b, R1c, R1d, and R1eare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

[0584] Embodiment* 9. The compound of Embodiment* 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1b, R1c, R1d, and R1eare hydrogen.

[0585] Embodiment* 10. The compound of Embodiments* 8 or 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1ais C1-C4 alkyl.

[0586] Embodiment* 11. The compound of any of Embodiments* 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted 5- to 9-membered heteroaryl.

[0587] Embodiment* 12. The compound of Embodiment* 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted imidazole.

[0588] Embodiment* 13. The compound of any of Embodiments* 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from the group consisting of (amino)alkyl, optionally substituted 4- to 8-membered heterocyclo, and -CH(R12a)N(R12b)(R12c).

[0589] Embodiment* 14. The compound of any of Embodiments* 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from any one or more of the groups of Table 7.

[0590] Embodiment* 15. The compound of any one of Embodiments* 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R2a, R2b, and R2care hydrogen.

[0591] Embodiment* 16. The compound of any one of Embodiments* 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C4 alkyl.

[0592] Embodiment* 17. The compound of Embodiment* 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is methyl.

[0593] Embodiment* 18. The compound of any one of Embodiments* 3-17, or a pharmaceutically acceptable salt or solvate thereof, wherein R4ais selected from the group consisting of hydrogen and fluoro.

[0594] Embodiment* 19. The compound of any one of Embodiments* 3-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R4bis selected from the group consisting of hydrogen and fluoro.

[0595] Embodiment* 20. The compound of any one of Embodiments* 3-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R4cis selected from the group consisting of hydrogen and fluoro.

[0596] Embodiment* 21. The compound of any one of Embodiments* 3-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R4b, R4c, and R4dare hydrogen.

[0597] Embodiment* 22. The compound of any one of Embodiments* 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein J is:.

[0598] Embodiment* 23. The compound of any one of Embodiments* 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:, wherein the bond marked with an "*" is attached to the thiazole.

[0599] Embodiment* 24. The compound of Embodiment* 23, or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:, wherein the bond marked with an "*" is attached to the thiazole.

[0600] Embodiment* 25. The compound of any one of Embodiments* 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is -O-.

[0601] Embodiment* 26. The compound of any one of Embodiments* 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is -NH-.

[0602] Embodiment* 27. The compound of any one of Embodiments* 1-24, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is 6-membered heterocyclenyl.

[0603] Embodiment* 28. The compound of any one of Embodiments* 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein J4is absent.

[0604] Embodiment* 29. The compound of any one of Embodiments* 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein J4is C1-C3 alkylenyl.

[0605] Embodiment* 30. The compound of any one of Embodiments* 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein J3is absent.

[0606] Embodiment* 31. The compound of any one of Embodiments* 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein J2is absent.

[0607] Embodiment* 32. The compound of any one of Embodiments* 1-30, or a pharmaceutically acceptable salt or solvate thereof, wherein J2is selected from the group consisting of 3- to 8-membered cycloalkeylenyl and 4- to 12-membered heterocyclenyl.

[0608] Embodiment* 33. The compound of any one of Embodiments* 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C1-C8 alkylenyl.

[0609] Embodiment* 34. The compound of any one of Embodiments* 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C3-C6 heteroalkylenyl.

[0610] Embodiment* 35. The compound of any one of Embodiments* 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0611] J1is C1-C8 alkylenyl;

[0612] J2is absent; or

[0613] J2is selected from the group consisting of -O- and -N(R7a)-;

[0614] J3is absent; or

[0615] J3is C1-C8alkylenyl; and

[0616] J4is absent.

[0617] Embodiment* 36. The compound of Embodiments* 1-27, or a pharmaceutically acceptable salt or solvate thereof, wherein L1is any one or more of the groups of Table 8, wherein the bond marked with an "*" is attached to X4.

[0618] Embodiment* 37. The compound of any one of Embodiments* 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -O-.

[0619] Embodiment* 38. The compound of any one of Embodiments* 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -NH-.

[0620] Embodiment* 39. The compound of any one of Embodiments* 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -C≡C-.

[0621] Embodiment* 40. The compound of any one of Embodiments* 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is 4-to 8-membered heterocyclenyl.

[0622] Embodiment* 41. The compound of any one of Embodiments* 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-1.

[0623] Embodiment* 42. The compound of any one of Embodiments* 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-2.

[0624] Embodiment* 43. The compound of any one of Embodiments* 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-3.

[0625] Embodiment* 44. The compound of any one of Embodiments* 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-4.

[0626] Embodiment* 45. The compound of any one of Embodiments* 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-5.

[0627] Embodiment* 46. The compound of any one of Embodiments* 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-6.

[0628] Embodiment* 47. The compound of any one of Embodiments* 41-46, or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care independently selected from the group consisting of hydrogen and fluoro.

[0629] Embodiment* 48. The compound of Embodiment* 47, or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care hydrogen.

[0630] Embodiment* 49. 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.

[0631] Embodiment* 50. 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-A

[0632] Embodiment* 51. A pharmaceutical composition comprising the compound of any one of Embodiments* 1-50 or 61-64, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0633] Embodiment* 52. 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 a therapeutically effective amount of the compound of any one of Embodiments* 1-50 or 61-64, or a pharmaceutically acceptable salt thereof, to the subject.

[0634] Embodiment* 53. The method of Embodiment* 52 further comprising administering a second therapeutic agent to the subject.

[0635] Embodiment* 54. The method of Embodiments* 52 or 53 for treating cancer in a subject in need thereof.

[0636] Embodiment* 55. The method of Embodiments* 52 or 53, wherein the cancer is a solid tumor.

[0637] Embodiment* 56. The method of Embodiments* 52 or 53, wherein the cancer is a hematological cancer.

[0638] Embodiment* 57. The method of Embodiments* 52 or 53, wherein the cancer is one or more of the cancers of Table 3.

[0639] Embodiment* 58. A method of reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein within a cell of a subject, the method comprising administering tothe subject a compound of any one of Embodiments* 1-50 or 61-64, or a pharmaceutically acceptable salt or solvate thereof.

[0640] Embodiment* 59. The method of Embodiment* 58, wherein the subject has cancer.

[0641] Embodiment* 60. A kit comprising the compound of any one of Embodiments* 1-50 or 61-64, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt thereof, to a subject having cancer.

[0642] Embodiment* 61. The compound of Embodiment* 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

[0643] Embodiment* 62. The compound of Embodiment* 61, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0644] R1is selected from the group consisting of:

[0645] R12band R12care methyl; or

[0646] R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclo.

[0647] Embodiment* 63. The compound of Embodiment* 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

[0648] Embodiment* 64. The compound of Embodiment* 63, or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0649] R1is selected from the group consisting of:

[0650] R12band R12care methyl; or

[0651] R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclo. EXAMPLES EXAMPLE 1 Synthesis of 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(4-(1-(cyclopropanecarbonyl)indolin- 5-yl)-5-methylthiazol-2-yl)imidazolidin-2-one (Compound A-1)Step 1.1-(2-chloroethyl)-3-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2- yl)urea

[0652] solution of (5-(2-amino-5-methylthiazol-4-yl)indolin-1- yl)(cyclopropyl)methanone (1.00 g, 3.34 mmol) and 1-chloro-2-isocyanatoethane (0.53 g,5.0 mmol) in tetrahydrofuran (40 mL) was stirred at 70 °C for 24 hrs. The solvent was removed in vacuo. The residue was purified by flash column chromatography (ethyl acetate) to give crude 1-(2-chloroethyl)-3-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5- methylthiazol-2-yl)urea (0.70 g, 52% yield) as a white solid. MS (ESI) m / z: 405.1 [M+H]+. Step 2. 1-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)imidazolidin- 2-one

[0653] A solution of 1-(2-chloroethyl)-3-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5- methylthiazol-2-yl)urea (0.70 g, 1.7 mmol), tetrabutylammonium bromide (28.0 mg, 0.09 mmol) and potassium carbonate (0.72 g, 5.2 mmol) in tetrahydrofuran (45 mL) was stirred at 70 °C for 48 hrs. The mixture was cooled to room temperature and filtered. The filter cake was washed with N,N-dimethylformamide (15 mL x 2) and dried to give 1-(4- (1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2-yl)imidazolidin-2-one (0.31 g, 49% yield) as a white solid. MS (ESI) m / z: 369.2 [M+H]+. Step 3. 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(4-(1-(cyclopropanecarbonyl)indolin-5- yl)-5-methylthiazol-2-yl)imidazolidin-2-one (Compound A-1)

[0654] A solution of 1-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5-methylthiazol-2- yl)imidazolidin-2-one (0.15 g, 0.41 mmol), 5-(chloromethyl)benzo[d][1,3]dioxole (0.14 g, 0.82 mmol) and potassium carbonate (0.23 g, 1.6 mmol) in N,N-dimethylformamide (15 mL) was stirred at 60 °C for 18 hrs. The mixture was cooled to room temperature, diluted with water (20 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 Pre-HPLC (Column: Welch Xtimate 21.2*250mm C18, 10 um, Mobile Phase: A: water (10 mmol / L ammonium bicarbonate) B: acetonitrile; B%: 30%-70% in 15 min) to give 1-(benzo[d][1,3]dioxol-5-ylmethyl)-3-(4-(1- (cyclopropanecarbonyl) indolin-5-yl)-5-methylthiazol-2-yl)imidazolidin-2-one (6.0 mg,3% yield) as a white solid.1H NMR (500 MHz, DMSO-d6): δ 8.04 (d, J = 7.5 Hz, 1 H), 7.51 (s, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 6.90 - 6.87 (m, 2 H), 6.80 (dd, J = 8.0 Hz, 1.5 Hz, 1 H), 6.00 (s, 2 H), 4.33 (m, 4 H), 4.00 (t, J = 8.5 Hz, 2 H), 3.43 (t, J = 8.0 Hz, 2 H), 3.24 (t, J = 8.0 Hz, 2 H), 2.43 (s, 3 H), 1.97 (brs, 1 H), 0.88 - 0.85 (m, 4 H). MS (ESI) m / z: 503.2 [M+H]+. EXAMPLE 2 Synthesis of (5-(2-(2-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-imidazol-5-yl)-5- methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (Compound A-2)Step 1.2-(benzo[d][1,3]dioxol-5-yl)acetonitrile

[0655] A solution of 5-(chloromethyl)benzo[d][1,3]dioxole (0.80 g, 4.69 mmol), potassium cyanide (0.61 g, 9.4 mmol) and 18-crown-6 (0.15 g, 0.47 mmol) in chloroform (20 mL) and water (10 mL) was stirred at 45 °C for 4 hrs. The mixture was cooled to room temperature, diluted with water (20 mL), extracted with chloroform (30 mL), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate / petroleum ether = 1 / 7) to give 2-(benzo[d][1,3]dioxol-5-yl)acetonitrile (0.72 g, 95% yield) as a white solid. MS (ESI) m / z: 162.0 [M+H]+. Step 2.2-(benzo[d][1,3]dioxol-5-yl)acetamidine dihydrochloride

[0656] To a solution of 2-(benzo[d][1,3]dioxol-5-yl)acetonitrile (0.50 g, 3.10 mmol) in ethanol (3 mL), was added acetyl chloride (2.44 g, 31.0 mmol) at 0 °C. After addition, the mixture was stirred at room temperature for 48 hrs. The solvent was removed in vacuo. The residue was dissolved in ammonia (7 M in methanol, 8 mL), and then the solution was stirred at room temperature for 18 hrs. The solvent was removed in vacuo to give 2-(benzo[d][1,3]dioxol-5-yl)acetamidine dihydrochloride (0.41 g, 53% yield) as a white solid. MS (ESI) m / z: 179.1 [M+H]+. Step 3. (5-(2-(2-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-imidazol-5-yl)-5-methylthiazol-4- yl)indolin -1-yl)(cyclopropyl)methanone (Compound A-2)

[0657] A solution of 2-bromo-1-(4-(1-(cyclopropanecarbonyl)indolin-5-yl)-5- methylthiazol-2-yl)ethanone (0.20 g, 0.49 mmol), 2-(benzo[d][1,3]dioxol-5- yl)acetamidine dihydrochloride (0.37 g, 1.48 mmol) and sodium bicarbonate (0.33 g, 3.9 mmol) in N,N-dimethylformamide (3 mL) was stirred at 50 °C for 18 hrs. The reaction was quenched with water (10 mL), extracted with dichloromethane (25 mL x 2), washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Column: Welch Xtimate 21.2*250mm C18, 10 um, Mobile Phase: A: water (0.01% formic acid aqueous solution) B: acetonitrile; B%: 30%-70% in 15 min) to give (5-(2-(2-(benzo[d][1,3]dioxol-5-ylmethyl)- 1H-imidazol-5-yl)- 5-methylthiazol-4-yl)indolin-1-yl)(cyclopropyl)methanone (10.4 mg, 4.4% yield) as a white solid.1H NMR (400 MHz, DMSO-d6): δ 12.25 (brs, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.59 (s, 1 H), 7.56 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 6.87 - 6.86 (m, 1 H), 6.84 (s, 1 H), 6.73 (dd, J = 8.0 Hz, 2 Hz, 1 H), 6.96 (s, 2 H), 4.33 (t, J = 7.6 Hz, 2 H), 3.92 (s, 2 H), 3.24 (t, J = 8.0 Hz, 2 H), 2.51 (s, 3 H), 1.99 (brs, 1 H), 0.89 - 0.86 (m, 4 H). MS (ESI) m / z: 484.9 [M+H]+. EXAMPLE 4 Synthesis of 4-[(2-{2-[3-({5-[4-(1-cyclopropanecarbonyl-2,3-dihydro-1H-indol-5-yl)-5- methyl-1,3-thiazol-2-yl]-1,3-oxazol-2-yl}methyl)phenoxy]ethoxy}ethyl)amino]-2-(2,6- dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (Cpd. No.74)

[0658] N-{2-[4-(1-cyclopropanecarbonyl-2,3-dihydro-1H-indol-5-yl)-5-methyl-1,3- thiazol-2-yl]-2-oxoethyl}-2-{3-[2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3- dihydro-1H-isoindol-4-yl]amino}ethoxy)ethoxy]phenyl}acetamide (0.037 g, 0.044 mmol, 1.0 eq) in Polyphosphoric acid (1.301 g, 13.28 mmol, 300.0 eq) was stirred at 100°C for 2.5 h. UPLC analysis showed full conversion. The mixture was diluted with water and then anhydrous NaHCO3 was added till pH ~ 9 was obtained. It was extracted 3x with DCM, dried over sodium sulphate and evaporated to dryness. Then it was purified by prep. HPLC (acidic conditions with 0.1% FA) to give 18 mg (49% yield) of the title compound as a yellow solid. LCMS: [C₄₃H₄₀N₆O₈S], desired mass = 800.89, observed mass = 801.2 [M+H]+,NMR (300 MHz, DMSO) δ 11.09 (s, 1H), 9.76 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.62 – 7.44 (m, 4H), 7.16 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 5.1 Hz, 1H), 7.07 – 6.98 (m, 2H), 6.94 (dd, J = 8.7, 2.6 Hz, 1H), 6.66 (t, J = 5.8 Hz, 1H), 5.06 (dd, J = 12.6, 5.4 Hz, 1H), 4.34 (t, 2H), 4.18 (t, J = 4.5 Hz, 2H), 3.83 (t, J = 5.3 Hz, 2H), 3.72 (t, J = 5.4 Hz, 2H), 3.55 – 3.44 (m, 4H), 3.23 (t, J = 8.5 Hz, 2H), 2.95 – 2.82 (m, 1H), 2.64 – 2.57 (m, 1H), 2.55 (s, 3H), 2.48 – 2.42 (m, 1H), 2.07 – 1.94 (m, 2H), 0.96 – 0.82 (m, 4H).EXAMPLE 3 Cancer Cell Viability

[0659] Representative Compounds of the Disclosure were tested in A549 (Vendor: ATCC; Cat# CCL-185; Description: lung, carcinoma) and / or LK-2 (Vendor: Riken; Cat# RCB1970; Description: lung, squamous cell carcinoma) cellular viability assays according to the following general protocol.

[0660] 1. Observed the cells under microscope.

[0661] 2. Aspirated the media and added 5 mL trypsin and incubate for 3 mins.

[0662] 3. Added 10 mL fresh media and harvested all the cells in to 15 mL tubes.

[0663] 4. Centrifuged the cells at 1000 rpm for 5 mins.

[0664] 5. Re-suspended the cells with 11 mL media and took 1 mL to determine the cell number and viability.

[0665] 6. Prepared cells suspension at 20 K / mL (A549) or 35 K / mL (LK-2).

[0666] 7. Seeded the cells into 96-well plate and incubated for overnight.

[0667] 8. Added compounds into each well with a HPD300 machine (nine three-fold dilutions typically starting at 30 µM final concentration) and incubated for 3 days.

[0668] 9. After 3 days, took out the plates from the incubator and observed the cells under microscope.

[0669] 10. Passed a film at the bottom of the plates.

[0670] 11. Equilibrated the plate and its contents at room temperature for approximately 30 minutes.

[0671] 12. Thawed the CellTiter-Glo® Buffer and equilibrated to room temperature prior to use.

[0672] 13. Equilibrated the lyophilized CellTiter-Glo® Substrate to room temperature prior to use.

[0673] 14. Transferred 100 ml of CellTiter-Glo® Buffer into the amber bottle containing CellTiter-Glo® Substrate to reconstituted the lyophilized enzyme / substrate mixture.

[0674] 15. Mixed by gently vortexing, swirling or inverting the contents to obtain a homogeneous solution.

[0675] 16. Added 100 µL CellTiter-Glo® Reagent into each well.

[0676] 17. Mixed contents for 15 minutes on an orbital shaker to induce cell lysis.

[0677] 18. Recorded luminescence with EnSpire machine.

[0678] 19. Passed the raw data into the file and analyzed the data with XLfit software.

[0679] The results are provided in Table 6. Table 6EXAMPLE 4 Protein Degradation Assay

[0680] Representative Compounds of the Disclosure are tested for protein degradation in huH1 cells (Vendor: JCRB: Cat# JCRB0199; Description: Human hepatoma) by Western blot analysis according to the following general protocol.

[0681] Cell treatment

[0682] Day 0: Plate the Huh1 cells into 10-cm dishes (1.5 x 106 / dish)

[0683] Day 1: Treat the cells with compounds at five concentrations, e.g., 0.01 µM, 0.04 µM, 0.11 µM, 0.33 µM and 1 µM; or 0.4 µM, 1.1 µM, 3.3 µM, 10 µM, and 30 µM.

[0684] Day 4: Harvest the cell pellets, spilt 1 / 3 of the pellet to extract RNA by Nucleospin RNA plus kit and measure Nrf2 and GPX2 by RT-PCR, the remaining 2 / 3 of the pellet to run Western blot analysis.

[0685] Western blot assay Procedure

[0686] Sample Preparation

[0687] a) Cell samples are lysed with lysis buffer (1x Cell lysis buffer added Protease inhibitor and phosphatase inhibitor) on ice for 5~10 min and spun at 15,000 rpm in an Eppendorf microfuge for 15 min at 4°C.

[0688] b) The protein supernatant is collected in a new 1.5 ml tube and the protein concentrations are determined by the Pierce BCA kit (Thermo #23225).

[0689] c) Mix protein sample with 5x SDS-PAGE loading buffer.

[0690] d) Boil for 5 min.

[0691] e) Cool at RT or on ice for 5 min.

[0692] f) Flash spin to bring down condensation prior to loading gel.

[0693] Running the gel

[0694] a) After flash spinning the samples, 20μg protein are loaded into the wells.

[0695] b) Use SDS-PAGE running buffer.

[0696] c) Run with constant voltage (70 V) for 1.5-2 hr.

[0697] Membrane transfer

[0698] a) Assemble "sandwich" for Invitrogen iBlot.

[0699] b) Transfer for 9 min using P0 program.

[0700] c) Immerse membrane in Odyssey blocking buffer or 5% BSA for at least 1 hr.

[0701] Antibody incubation and gel detection

[0702] a) Incubate with 1st Antibody 1:500 diluted in blocking buffer overnight at 4°C.

[0703] b) Wash 4 x 15 min with 0.05-0.1% Tween 20 in TBS.

[0704] c) Incubate with secondary antibody 1:10K diluted in blocking buffer for at least 1 hr at RT.

[0705] d) Wash 3 x 15 min with 0.05-0.1% Tween 20 in TBS.

[0706] e) Detect with ODYSSEY (Li-COR) EXAMPLE 5 Measurement of Nrf2 Degradation in A549 HiBiT Nrf2 cell using Nano-Glo HiBiT Lytic Detection System

[0707] A549 HiBiT-Nrf2 cells (Promega, Cat. No. CS3023219) are seeded into 384-well plates at cell density of 5,000 cells / well in 40 µL of cell culture medium (Ham's F-12 Nutrient Mix supplemented with 10% FBS and 1% antibiotic-antimycotic).

[0708] The next day, cells are treated with representative Compounds of the Disclosure and incubated for 6 h and 20 h at 37 ⁰C, 5% CO2. Staurosporine is used as a control.

[0709] At the end of incubation Nrf2 degradation (HiBiT readout) and cell viability (CellTiter-Glo readout) are determined. For HiBiT readout, Nano-Glo HiBiT Reagent mix (Promega, Cat. No. N3050) is added to wells, plates are incubated 2 min on an orbital shaker and are incubated at room temperature in the dark for additional 30 minutes. At the end of incubation luminescence is measured using ultrasensitive luminescence mode (Envision, Perkin Elmer).

[0710] For CellTiter-Glo readout, CellTiter-Glo reagent (Promega, Cat. No. G7573) is added to wells of parallel plates. Plates are incubated on orbital shaker for 2 minutes andare incubated at room temperature in the dark for additional 30 min. At the end of incubation luminescence is measured (EnVision, Perkin Elmer).

[0711] It is to be understood that the foregoing embodiments and exemplifications are not intended to be limiting in any respect to the scope of the disclosure, and that the claims presented herein are intended to encompass all embodiments and exemplifications whether or not explicitly presented herein

[0712] All patents and publications cited herein are fully incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:

1. A compound having Formula (IV):or a pharmaceutically acceptable salt or solvate thereof, wherein: R1is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted phenyl, optionally substituted 5- to 9-membered heteroaryl, (amino)alkyl, (heterocyclo)alkyl, (cycloalkyl)alkyl, optionally substituted 4- to 8-membered heterocyclo, and -CH(R12a)N(R12b)(R12c); R2a, R2b, and R2care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R3is selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; Y is -W1-J-, wherein J is attached to the thiazole; W1is C1-C4 alkylenyl; J is selected from the group consisting of 5-membered heteroarylenyl and; v is 1 or 2; M is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, and 6-membered heteroarylenyl; Z1is selected from the group consisting of -O-L-X1and -X3-L1-X4-B1; X1is selected from the group consisting of -OR10and -NR11aR11b; R10is hydrogen; R11ais selected from the group consisting of hydrogen and -C(=O)OC(CH3)3; R11bis selected from the group consisting of hydrogen and C1-C4 alkyl;L is selected from the group consisting of -(CH2)m-, -*(CH2)n(OCH2CH2)o-, and -(CH2)p-Z-(CH2)q-; wherein the carbon marked with an "*" 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 the group consisting of -(CR6aR6b)- and -N(R7)-; R6ais selected from the group consisting of halo, hydroxy, C1-C6 alkyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, substituted optionally C4-C8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl; R6bis selected from the group consisting of hydrogen and C1-C6 alkyl; R7is selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C4 haloalkyl; and X is selected from the group consisting of -O-, -NH-,X3is absent; or X3is selected from the group consisting of -CH2-, -O-, -N(R9a)-, and 5- or 6- membered heterocyclenyl; R9ais selected from the group consisting of hydrogen and C1-C4 alkyl; L1is -J1-J2-J3-J4-; wherein J1is attached to X3; J1is absent; or J1selected from the group consisting of C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12-membered heterocyclenyl, phenylenyl, and 4- to 9- membered heteroarylenyl; J2is absent; or J2is selected from the group consisting of -O-, -N(R7a)-, -C(=O)-, -C(=O)N(R7a)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl;R7ais selected from the group consisting of hydrogen and C1-C4 alkyl; J3is absent; or J3is selected from the group consisting of -O-, -N(R7b)-, -C(=O)-, -C(=O)N(R7b)- , -C(=O)O-, C1-C8 alkylenyl, C3-C12 heteroalkylenyl, C3-C8 cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl; R7bis selected from the group consisting of hydrogen and C1-C4 alkyl; J4is absent; or J4is selected from the group consisting of -O-, -N(R7c)-, -C(=O)-, -C(=O)N(R7c)- , -C(=O)O-, C1-C8alkylenyl, C3-C12heteroalkylenyl, C3-C8cycloalkylenyl, 4- to 12- membered heterocyclenyl, phenylenyl, and 4- to 9-membered heteroarylenyl; R7cis selected from the group consisting of hydrogen and C1-C4 alkyl; X4is absent; or X4is selected from the group consisting of -CH2-, -CH=CH-, -C≡C-, -O- , -N(R8a)-, and 4-to 8-membered heterocyclenyl; R8ais selected from the group consisting of hydrogen and C1-C4 alkyl; with the provisos that (i) at least one of J1, J2, J3, or J4is present; and (ii) L1comprises a combinbation of stable covalent bonds; B1is selected from the group consisting of: ,R5a, R5b, and R5care independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; R12ais selected from the group consisting of substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocylco, optionally substituted aryl, optionally substituted heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (carboxamido)alkyl, and mercaptoalkyl; R12bis selected from the group consisting of hydrogen and C1-C4alkyl; and R12cis selected from the group consisting of hydrogen and C1-C4 alkyl; or R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclo.

2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, having Formula (V):

3. The compound of claims 1 or 2, wherein: M is selected from the group consisting of:R4a, R4b, R4c, and R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; orR4aand R4bare taken together with the carbon atoms to which they are attached to form a 5- to 7-membered optionally substituted heterocyclo or an optionally substituted C5-C7 cycloalkyl; and R4cand R4dare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo; and the bond marked with an "*" is attached to W1.

4. The compound of claim 3, or a pharmaceutically acceptable salt or solvate thereof, having Formula (VI):(VI).

5. The compound of any of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted C3-C8 cycloalkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is cyclopropyl.

7. The compound of any of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted phenyl.

8. The compound of claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein: R1is:R1a, R1b, R1c, R1d, and R1eare independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, cyano, hydroxy, -S(=O)2CH3, and halo.

9. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R1b, R1c, R1d, and R1eare hydrogen.

10. The compound of claims 8 or 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R1ais C1-C4alkyl.

11. The compound of any of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted 5- to 9-membered heteroaryl.

12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is optionally substituted imidazole.

13. The compound of any of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from the group consisting of (amino)alkyl, optionally substituted 4- to 8-membered heterocyclo, and -CH(R12a)N(R12b)(R12c).

14. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

15. The compound of claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein: R1is selected from the group consisting of:R12band R12care methyl; or R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclo.

16. The compound of claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is:.

17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein: R1is selected from the group consisting of:R12band R12care methyl; or R12band R12ctaken together with the nitrogen atom to which they are attached form an optionally substituted 3-, 4-, 5-, or 6-membered heterocyclo.

18. The compound of any of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R1is selected from any one or more of the groups of Table 7.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R2a, R2b, and R2care hydrogen.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is C1-C4 alkyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt or solvate thereof, wherein R3is methyl.

22. The compound of any one of claims 3-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R4ais selected from the group consisting of hydrogen and fluoro.

23. The compound of any one of claims 3-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R4bis selected from the group consisting of hydrogen and fluoro.

24. The compound of any one of claims 3-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R4cis selected from the group consisting of hydrogen and fluoro.

25. The compound of any one of claims 3-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R4b, R4c, and R4dare hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein J is:

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:, wherein the bond marked with an "*" is attached to the thiazole.

28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein J is selected from the group consisting of:, wherein the bond marked with an "*" is attached to the thiazole.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is -O-.

30. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is -NH-.

31. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt or solvate thereof, wherein X3is 6-membered heterocyclenyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein J4is absent.

33. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein J4is C1-C3 alkylenyl.

34. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt or solvate thereof, wherein J3is absent.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein J2is absent.

36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt or solvate thereof, wherein J2is selected from the group consisting of 3- to 8-membered cycloalkeylenyl and 4- to 12-membered heterocyclenyl.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C1-C8 alkylenyl.

38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein J1is C3-C6 heteroalkylenyl.

39. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein: J1is C1-C8 alkylenyl; J2is absent; or J2is selected from the group consisting of -O- and -N(R7a)-; J3is absent; or J3is C1-C8 alkylenyl; and J4is absent.

40. The compound of claims 1-31, or a pharmaceutically acceptable salt or solvate thereof, wherein L1is any one or more of the groups of Table 8, wherein the bond marked with an "*" is attached to X4.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -O-.

42. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -NH-.

43. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is -C≡C-.

44. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt or solvate thereof, wherein X4is 4-to 8-membered heterocyclenyl.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-1.

46. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-2.

47. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-3.

48. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-4.

49. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-5.

50. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt or solvate thereof, wherein B1is B-6.

51. The compound of any one of claims 45-50, or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care independently selected from the group consisting of hydrogen and fluoro.

52. The compound of claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein R5a, R5b, and R5care hydrogen.

53. 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.

54. 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-A 55. A pharmaceutical composition comprising the compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

56. 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 a therapeutically effective amount of the compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, to the subject.

57. The method of claim 56 further comprising administering a second therapeutic agent to the subject.

58. The method of claims 56 or 57 for treating cancer in a subject in need thereof.

59. The method of claims 56 or 57, wherein the cancer is a solid tumor.

60. The method of claims 56 or 57, wherein the cancer is a hematological cancer.

61. The method of claims 56 or 57, wherein the cancer is one or more of the cancers of Table 3.

62. A method of reducing nuclear factor erythroid 2-related factor 2 (Nrf2) protein within a cell of a subject, the method comprising administering to the subject a compound of any one of claims 1-54, or a pharmaceutically acceptable salt or solvate thereof.

63. The method of claim 62, wherein the subject has cancer.

64. A kit comprising the compound of any one of claims 1-54, or a pharmaceutically acceptable salt thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt thereof, to a subject having cancer.

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