Degraders and uses thereof

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic protein.

Description

[0001] DEGRADERS AND USES THEREOF

[0002] CROSS-REFERENCE

[0003]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 595,640, filed November 2, 2023, U.S. Provisional Application No. 63 / 609,738, filed December 13, 2023, and U.S. Provisional Application No. 63 / 559,138, filed February 28, 2024, each incorporated herein by reference in its entirety.

[0004] SEQUENCE LISTING

[0005]

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on October 25, 2024, is named 56690_774_601_SL.xml and is 15,018 bytes in size.

[0006] BACKGROUND

[0007]

[0003] Cancer (e.g., tumor, neoplasm, metastases) is the second leading cause of death worldwide estimated to be responsible for about 10 million deaths each year. Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) are one of the most frequent Ras mutations detected in human cancers, including lung adenocarcinomas (LUADs) and pancreatic ductal adenocarcinoma (PDAC).

[0008]

[0004] Ras proteins have long been considered “undruggable,” due to, in part, high affinity to their substrate guanosine-5'-triphosphate (GTP) and / or their smooth surfaces without any obvious targeting region. The specific G12C Ras gene mutation has been identified as a druggable target to which a number of G12C specific inhibitors have been developed. However, such therapeutics are still of limited application, as the G12C mutation in Ras exhibits a much lower prevalence rate as compared to other known Ras mutations, such as G12D and G12V. Drug resistance and lack of durability impose further limitations to such therapeutics.

[0009] SUMMARY

[0010]

[0005] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically target Ras, including wildtype Ras, mutants and / or associated proteins of Ras to reduce Ras signaling output. Of particular interest are Ras inhibitors, including pan Ras inhibitors capable of inhibiting two or more Ras mutants and / or wildtype Ras, as well as mutant-selective inhibitors targeting mutant Ras proteins such as Ras G12D, G12C, G12S, G13D, and / or G12V, for the treatment of Ras-associated diseases (e.g., cancer). Of further interest are Ras-specific protein degrader compounds that are capable of binding to a Ras protein and enhancing the degradation of the Ras protein. Of additional interest are methods of synthesizing such Ras protein specific degraders along with new compounds that are useful in those synthetic methods. Such compositions and methods can be particularly useful for treating a variety of diseases including, but not limited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and / or treatment for a wide diversity of diseases.

[0011]

[0006] In an aspect is provided a compound of Formula (A0): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0012] Z1is selected from N and N(RBlb);

[0013] Z2is selected from C(RB2) and C(O);

[0014] ZB5is selected from C(RB9)2 and O;

[0015] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0016] Z7is selected from C(RB7) and N(RB7b);

[0017] Z8is selected from C(RB8), C(RB8)2, and N;

[0018] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0019] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0020] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0021] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0022] DG is a degradation enhancer; nl is selected from 1, 2, and 3;

[0023] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0024] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0025] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0026] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0027] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0028] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0029] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0030] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- 12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0031] RB23is independently selected at each occurrence from hydrogen and Ci-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0032] > indicates a single or double bond such that all valences are satisfied.

[0033]

[0007] In an aspect is provided a compound of Formula (A): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0034] Z1is selected from N and N(RBlb);

[0035] Z2is selected from C(RB2) and C(O);

[0036] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0037] Z7is selected from C(RB7) and N(RB7b);

[0038] Z8is selected from C(RB8), C(RB8)2, and N;

[0039] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0040] J1is selected from a bond, Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0041] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0042] J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0043] DG is a degradation enhancer; nl is selected from 1, 2, and 3;

[0044] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0045] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0046] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0047] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0048] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0049] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0050] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0051] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- 12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0052] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0053]

[0008] In an aspect is provided a compound of Formula (Al): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0054] Z1is selected from N and N(RBlb);

[0055] Z2is selected from C(RB2) and C(O);

[0056] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0057] Z7is selected from C(RB7) and N(RB7b);

[0058] Z8is selected from C(RB8), C(RB8)2, and N;

[0059] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0060] J1is selected from a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0061] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0062] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0063] DG is a degradation enhancer; nl is selected from 1, 2, and 3;

[0064] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl,

[0065] 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0066] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0067] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0068] RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0069] RB13is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0070] RB2° is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -

[0071] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0072] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0073] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0074]

[0009] In embodiments of a compound described herein (e.g., compound of Formula (A0), (A), and / or (Al)), or a salt or solvate thereof, the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4,

[0075] NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF 1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UB0X5, UBR5, VHL (von-Hippel- Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP 1 (cellular inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4,

[0076] FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.

[0077]

[0010] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof, the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2,

[0078] UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N,

[0079] UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

[0080] [OU] In embodiments of a compound described herein (e.g., compound of Formula (A0), (A), and / or (Al)), or a salt or solvate thereof, DG is a monovalent form of a degradation enhancer. In some embodiments, DG is selected wherein: J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10- membered heteroalkynylene are optionally substituted with one or more RB20; RB15is selected from hydrogen, Ci-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle, wherein C1-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one or more RB20; RB16is selected from hydrogen, C1-6 alkyl, -ORB12, - C(O)ORB12, and -C(O)RB12, wherein C1-6 alkyl is optionally substituted with one or more RB20; RB17is selected from halogen, -CN, C1-3 alkyl, C3.6 carbocycle, 4- to 6-membered heterocycle, and -S(O)2CH3, wherein C1-3 alkyl, C3.6 carbocycle, and 4- to 6-membered heterocycle are optionally substituted with one or more RB20; ol is selected from

[0081] 0, 1, and 2; pl and ql are independently selected from 1, 2, and 3; and X is selected from CH2 and C(O).

[0082]

[0012] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof, DG is selected from: ; wherein: J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to

[0083] 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene are optionally substituted with one or more RB20; RB15is selected from -CH(CH3)2 and -C(CH3)3; RB16is selected from hydrogen, - CH3, and -CH2OH; RB17is selected from methylthiazole and methylpyrazole; ol is selected from 0 and 1; pl and ql are independently selected from 1 and 2; and X is selected from CH2 and C(O).

[0084]

[0013] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a

[0085]

[0014] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof,

[0086]

[0015] In embodiments of a compound described herein (e.g., compound of Formula (A0), (A), and / or (Al)), or a salt or solvate thereof, DG comprises a monovalent form of a compound selected from

[0087]

[0016] In an aspect is provided a method of preparing a compound of Formula (AO): the method comprising:

[0088] (a) reacting a compound of Formula (a0): with a degradation enhancer under conditions to effect release of LG and production of the compound of Formula (AO), wherein:

[0089] Z1is selected from N and N(RBlb);

[0090] Z2is selected from C(RB2) and C(O);

[0091] ZB5is selected from C(RB9)2 and O;

[0092] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0093] Z7is selected from C(RB7) and N(RB7b);

[0094] Z8is selected from C(RB8), C(RB8)2, and N;

[0095] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0096] J1is selected from a bond, Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0097] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0098] J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0099] DG is a degradation enhancer;

[0100] LG is a leaving group; nl is selected from 1, 2, and 3;

[0101] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0102] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0103] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0104] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0105] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0106] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0107] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0108] RB22is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0109] RB23is independently selected at each occurrence from hydrogen and Ci-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0110]

[0017] In embodiments of a compound described herein (e.g., compound of Formula (AO) or (A)), or a salt or solvate thereof, the compound is a compound of Formula (A-l): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0111] Z6is selected from C(RB6) and N;

[0112] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB20;

[0113] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, and -C(O)N(RB12)-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB20;

[0114] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, and -C0-6 alkyl-(3- to 12-membered heterocycle)-, , wherein -C0-6 alkyl-(C3-12 carbocycle)- and -C0-6 alkyl-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0115] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, each of which is optionally substituted with one or more nl is 1;

[0116] RB2is -O(Ci-3 alkylene)(4- to 10-membered heterocycle), -O(Ci-3 alkylene)-(4- to 5-membered heterocycle)-(Ci-3 alkylene)-(4- to 10-membered heterocycle), or -O(Ci-3 alkylene)-(C3-4 cycloalkyl)-(Ci-3 alkylene)- (4- to 10-membered heterocycle), wherein alkylene, cycloalkyl, 4- to 5-membered heterocycle, and 4- to 10-membered heterocycle are each optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, -O-( cycloalkyl), -NH2, -NH(CI-3 alkyl), - N(CI-3alkyl)2, and =C(RB21)2;

[0117] RB6is halogen or haloalkyl; RB7is selected from Ce-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20;

[0118] RB8is halogen;

[0119] RB9is independently selected at each occurrence from hydrogen and methyl;

[0120] RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0121] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0122] RB21is independently selected at each occurrence from hydrogen, halogen, and alkyl;

[0123] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0124] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0125]

[0018] In an aspect is provided a method of preparing a compound of Formula (A): the method comprising:

[0126] (a) reacting a compound of Formula (a): with a degradation enhancer under conditions to effect release of LG and production of the compound of Formula (A), wherein:

[0127] Z1is selected from N and N(RBlb);

[0128] Z2is selected from C(RB2) and C(O);

[0129] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0130] Z7is selected from C(RB7) and N(RB7b);

[0131] Z8is selected from C(RB8), C(RB8)2, and N;

[0132] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0133] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0134] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0135] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0136] DG is a degradation enhancer;

[0137] LG is a leaving group; nl is selected from 1, 2, and 3;

[0138] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB 12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°; RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0139] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0140] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0141] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0142] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0143] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH; RB22is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0144] RB23is independently selected at each occurrence from hydrogen and Ci-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0145]

[0019] In embodiments of the method of preparing a compound of Formula (AO), (A), and / or (Al), the reaction mixture comprises a base. In embodiments of the method, the reaction mixture comprises 5- to 12-equivalents of the base relative to the amount of degradation enhancer. In embodiments of the method, the base is N,N- diisopropylethylamine. In embodiments of the method, the compound of Formula (a0), (a), and / or (al) and the degradation enhancer are heated to 40 to 100 °C for 2 to 48 hours. In embodiments of the method, the method further comprises (b) purifying the compound of Formula (A0), (A), and / or (Al). In embodiments of the method, the method may include the preparation of any embodiment of the compound of Formula (A0), (A), and / or (Al), including preparation of a compound of Formula (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (A-l), (A-2), (A- 3), (A-4), (A-5), (A-6), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), or (Al-6), or any embodiment thereof. In embodiments of the method, the method may include the use of any embodiment of the compound of Formula (a), including the use of a compound of Formula (a0-l), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (a-l), (a-2), (a-3), (a-4), (a- 5), (a-6), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), or any embodiment thereof.

[0146]

[0020] In an aspect is provided a compound of Formula (a0): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0147] Z1is selected from N and N(RBlb);

[0148] Z2is selected from C(RB2) and C(O);

[0149] ZB5is selected from C(RB9)2 and O;

[0150] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0151] Z7is selected from C(RB7) and N(RB7b);

[0152] Z8is selected from C(RB8), C(RB8)2, and N;

[0153] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0154] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0155] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0156] J3is selected from Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0157] LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;

[0158] RB4is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0159] RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0160] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0161] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0162] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0163] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB20;

[0164] RB20is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB20attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0165] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0166] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0167] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0168]

[0021] In an aspect is provided a compound of Formula (a): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0169] Z1is selected from N and N(RBlb);

[0170] Z2is selected from C(RB2) and C(O);

[0171] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0172] Z7is selected from C(RB7) and N(RB7b);

[0173] Z8is selected from C(RB8), C(RB8)2, and N;

[0174] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°; J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB20;

[0175] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0176] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0177] LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;

[0178] RB4is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0179] RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0180] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0181] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0182] RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0183] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0184] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0185] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0186] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0187] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0188]

[0022] In an aspect is provided a compound of Formula (al): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0189] Z1is selected from N and N(RBlb);

[0190] Z2is selected from C(RB2) and C(O);

[0191] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0192] Z7is selected from C(RB7) and N(RB7b);

[0193] Z8is selected from C(RB8), C(RB8)2, and N;

[0194] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0195] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0196] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0197] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0198] LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;

[0199] RB4is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0200] RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0201] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0202] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0203] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0204] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0205] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0206] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0207] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- 12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0208] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and

[0209] > indicates a single or double bond such that all valences are satisfied.

[0210]

[0023] In embodiments of a compound described herein (e.g., compound of Formula (a0) or (a)), or a salt or solvate thereof, the compound is a compound of Formula (a-1): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0211] Z6is selected from C(RB6) and N;

[0212] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB20;

[0213] J1is selected from a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, and -C(O)N(RB12)-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB20;

[0214] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, and -C0-6 alkyl-(3- to 12-membered heterocycle)-, , wherein -C0-6 alkyl-(C3-12 carbocycle)- and -C0-6 alkyl-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0215] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, each of which is optionally substituted with one or more RB20;

[0216] LG is selected from -OS(O)2RB4;

[0217] RB4is selected from C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20; nl is 1;

[0218] RB2is -O(Ci-3 alkylene)(4- to 10-membered heterocycle), -O(Ci-3 alkylene)-(4- to 5-membered heterocycle)-(Ci-3 alkylene)-(4- to 10-membered heterocycle), or -O(Ci-3 alkylene)-(C3-4 cycloalkyl)-(Ci-3 alkylene)- (4- to 10-membered heterocycle), wherein C1-3 alkylene, C3.4 cycloalkyl, 4- to 5-membered heterocycle, and 4- to 10-membered heterocycle are each optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, -O-( cycloalkyl), -NH2, -NH(CI-3 alkyl), - N(CI-3alkyl)2, and =C(RB21)2;

[0219] RB6is halogen or haloalkyl;

[0220] RB7is selected from Ce-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20;

[0221] RB8is halogen;

[0222] RB9is independently selected at each occurrence from hydrogen and methyl;

[0223] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0224] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0225] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0226] RB21is independently selected at each occurrence from hydrogen, halogen, and alkyl;

[0227] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0228] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0229]

[0024] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), or (a0-6)), ZB5is C(RB9)2. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), or (a0-6)), ZB5is O.

[0230]

[0025] In embodiments, nl is 1. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, Q2is 4- to 6-membered monocyclic heterocycloalkyl optionally substituted with one or more RB2°. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, Q2is 7- to 9- membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB2°. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, , each of which is optionally substituted with one or more RB20. In embodiments of a compound described herein (e.g., compound of Formula (A) or (a)), or a salt or solvate thereof, , which is optionally substituted with one or more RB2°.

[0231]

[0026] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, Z1is N, Z2is C(RB2), Z6is C(RB6), Z7is C(RB7), and Z8is C(RB8); Z1is N, Z2is C(RB2), Z6is N, Z7is C(RB7), and Z8is C(RB8); Z1is N, Z2is C(RB2), Z6is C(RB6)2, Z7is N(RB7b), and Z8is C(RB8)2; or Z1is N(RBlb), Z2is C(O), Z6is C(RB6), Z7is C(RB7), and Z8is N. In embodiments of a compound described herein (e.g., compound of Formula (a)), or a salt or solvate thereof, Z1is N, Z2is C(RB2), Z6is C(RB6), Z7is C(RB7), and Z8is C(RB8). In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), Z1is N, Z2is C(RB2), Z6is N, Z7is C(RB7), and Z8is C(RB8).

[0232]

[0027] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J1is selected from a bond, Ci-6 alkylene, 2- to 6-membered heteroalkylene, and -C(O)-, wherein Ci-6 alkylene and 2- to 6-membered heteroalkylene are optionally substituted with one or more RB2°. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J1is -C(O)-. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J2is selected from a bond, -C0-6 alkyl- (C2-i2carbocycle)-, and -C0-6 alkyl-(3- to 12-membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)- and - C0-6 alkyl-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J2is a bond. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J3is selected from Ci-6 alkylene, 2- to 6-membered heteroalkylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J3is selected from Ci-6 alkylene and 2- to 6- membered heteroalkylene, each of which is optionally substituted with one or more RB2°. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J3is selected from Ci-6 alkylene and 2- to 6-membered heteroalkylene. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J1is -C(O)-; J2is a bond; and J3is Ci-6 alkylene. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J1is a bond; J2is a bond; and J3is selected from Ci-6 alkylene and 2- to 6-membered heteroalkylene, each of which is optionally substituted with one or more RB20. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J1is -C(O)-; J2is 3- to 12-membered heterocycle optionally substituted with one or more RB20; and J3is Ci-6 alkylene. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, J3is selected from -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20. In embodiments, J3is selected from Ci-6 alkylene and 2- to 6-membered heteroalkylene, each of which is optionally substituted with one or more RB20. In embodiments, J3is selected from Ci-6 alkylene and 2- to 6- membered heteroalkylene.

[0233]

[0028] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB2is -O(Ci-3 alkylene)(4- to 10-membered heterocycle), wherein 4- to 10- membered heterocycle is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and =C(RB21, and wherein RB21is in )d2ependently selected at each occurrence from hydrogen, halogen, and C1-3 alkyl. In embodiments of a compound described herein (e.g., compound of

[0234] ed of a compound described herein (e.g., Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, . In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al),

[0235] (a0), (a), and / or (al)), RB2is selected from . In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al),

[0236] (a0), (a), and / or (al)), RB2is In embodiments of a compound described herein (e.g., compound of

[0237] Formula (AO), (A), (Al), (a0), (a), and / or (al)), RB2is selected from

[0238]

[0239]

[0029] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB6is selected from hydrogen, halogen, and C1-3 haloalkyl. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB6is halogen. In embodiments, RB6is halogen or C1-3 haloalkyl

[0240]

[0030] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB7is selected from Cg-i2 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, - ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH^CFk, -CF3, -C=CH, -OH, -NH2, and -cyclopropyl. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, embodiments of a compound described herein (e.g., compound embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), embodiments of a compound described herein (e.g., compound of Formula embodiments of a compound described

[0241]

[0031] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB8is independently selected from hydrogen and halogen. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB8is halogen.

[0242]

[0032] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, RB6is halogen; RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20; and RB8is halogen.

[0243]

[0033] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), halogen. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), compound described herein (e.g., compound of Formula (AO) or (A)), the compound has the formula: embodiments of a compound described herein (e.g., compound of Formula ((a0) and (a)), the compound has the , p .g., ,

[0244] (A), (Al), (A-7) (a0), (a), (al), or (a-7)), the compound is a compound selected from the compounds of Table 1.

[0245]

[0034] In an aspect is provided a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0246]

[0035] In an aspect is provided a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0247]

[0036] In an aspect is provided a method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a compound described herein, wherein the compound is characterized in that upon contacting the Ras mutant protein, said Ras mutant protein exhibits reduced Ras signaling output. In embodiments, the cancer is a solid tumor or a hematological cancer.

[0248]

[0037] In an aspect is provided a method of reducing signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the signaling output of the Ras protein. In embodiments, the compound binds covalently or non-covalently to the Ras protein, thereby reducing the signaling output of the Ras protein.

[0249]

[0038] In an aspect is provided a method of inhibiting cell growth, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.

[0250]

[0039] In embodiments, a method described herein includes administering an additional agent. In embodiments, the additional agent comprises (1) an inhibitor of MEK; (2) an inhibitor of epidermal growth factor receptor (EGFR) and / or mutants thereof; (3) an immunotherapeutic agent; (4) a taxane; (5) an anti -metabolite; (6) an inhibitor of FGFR1 and / or FGFR2 and / or FGFR3 and / or mutants thereof; (7) a mitotic kinase inhibitor; (8) an anti-angiogenic drug; (9) a topoisomerase inhibitor; (10) a platinum-containing compound; (11) an inhibitor of c-MET and / or mutants thereof; (12) an inhibitor of BCR-ABL and / or mutants thereof; (13) an inhibitor of ErbB2 (Her2) and / or mutants thereof; (14) an inhibitor of AXL and / or mutants thereof; (15) an inhibitor of NTRK1 and / or mutants thereof; (16) an inhibitor of RET and / or mutants thereof; (17) an inhibitor of A-Raf and / or B-Raf and / or C-Raf and / or mutants thereof; (18) an inhibitor of ERK and / or mutants thereof; (19) an MDM2 inhibitor; (20) an inhibitor of mTOR; (21) an inhibitor of IGF 1 / 2 and / or IGF1-R; (22) an inhibitor of CDK9; (23) an inhibitor of famesyl transferase; (24) an inhibitor of SHIP pathway; (25) an inhibitor of SRC; (26) an inhibitor of JAK; (27) a PARP inhibitor, (28) a ROS1 inhibitor; (29) an inhibitor of SHP pathway; (30) an inhibitor of Src, FLT3, HD AC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT; (31) an inhibitor of KRAS G12C; (32) an SHC inhibitor; (33) a GAB inhibitor;

[0251] (34) a PI-3 kinase inhibitor; (35) a MARPK inhibitor; (36) a CDK4 / 6 inhibitor; (37) a MAPK inhibitor; (38) a SHP2 inhibitor; (39) a checkpoint immune blockade agent; (40) a SOS1 inhibitor; or (41) a SOS2 inhibitor. In embodiments, the additional agent comprises an inhibitor of SHP2 selected RMC-4630, ERAS-601, TNO155, JAB- 3068, IACS-13909 / BBP-398, SHP099, and RMC-4550. In embodiments, the additional agent comprises an inhibitor of SOS selected from RMC-5845, BI-1701963, BI-3406, MRTX0902, and BAY-293.

[0252] INCORPORATION BY REFERENCE

[0253]

[0040] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0254] BRIEF DESCRIPTION OF THE DRAWINGS

[0255]

[0041] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0256]

[0042] FIG. 1 depicts a sequence alignment of various wild type Ras proteins including K-Ras, H-Ras, N-Ras, RalA, and RalB, from top to bottom.

[0257] DETAILED DESCRIPTION

[0258]

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Chemical structures are named herein according to IUPAC conventions as implemented in ChemDraw® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes”, and “included”, is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0259]

[0044] The term “Cx.y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx.yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups, that contain from x to y carbons in the chain.

[0260]

[0045] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (Ci-s alkyl) or one to six carbon atoms (C1-6 alkyl). Exemplary alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0261]

[0046] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2- fluoropropyl, and 1,2-dibromoethyL

[0262]

[0047] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2 12 alkenyl), such as two to eight carbon atoms (C2-8 alkenyl) or two to six carbon atoms (C2-6 alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l-enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0263]

[0048] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynyl groups, containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2- 12 alkynyl), such as two to eight carbon atoms (C2-8 alkynyl) or two to six carbon atoms (C2-6 alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0264]

[0049] “Alkylene” or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., C1-12 alkylene), such as one to eight carbon atoms (Ci-s alkylene) or one to six carbon atoms (C1-6 alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points of attachment of the alkylene, alkenylene or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0265]

[0050] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0266]

[0051] “Heteroalkylene”, “heteroalkenylene” and “heteroalkynylene” refer to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8- membered heteroalkylene group has a chain length of 3 to 8 atoms. The points of attachment of the heteroalkylene, heteroalkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, heteroalkenylene or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0267]

[0052] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbocycle may include C3-10 monocyclic rings, C5-12 bicyclic rings, C5-18 polycyclic rings, C5-12 spirocyclic rings, and C5-12 bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic carbocycle contains a number or rings equal to the minimum number of scissions required to convert the carbocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, the carbocycle is a Cg-i2 aryl group, such as Cg-io aryl. In some embodiments, the carbocycle is a C3-12 cycloalkyl group. In some embodiments, the carbocycle is a C5-12 cycloalkenyl group. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic rings, as valence permits, are included in the definition of carbocycle. A carbocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless state otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0268]

[0053] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2, 3, or 4 heteroatoms selected from O, S, P, and N. Heterocycle may include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic heterocycle contains a number or rings equal to the minimum number of scissions required to convert the heterocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocycloalkyl group. A heterocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, benzothienyl, benzoxazolyl, and quinolinyl. Unless stated otherwise specifically in the specification, a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0269]

[0054] “Heteroaryl” refers to an aromatic ring that comprises at least one heteroatom, for example 1, 2, 3, or 4 heteroatoms selected from O, S and N. Heteroaryl may include 5- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, 6- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12- membered bridged rings. As used herein, the heteroaryl ring may be selected from monocyclic, bicyclic, or polycyclic — including fused, spirocyclic and bridged ring systems — wherein at least one of the rings in the ring system is aromatic and comprises at least one heteroatom. A polycyclic heteroaryl contains a number or rings equal to the minimum number of scissions required to convert the heteroaryl into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heteroatom(s) in the heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0270]

[0055] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy the valence requirement.

[0271]

[0056] A waved line ” drawn across or at the end of a bond or a dashed bond are used interchangeably herein to denote where a bond disconnection or attachment occurs. For example, in the structure

[0272] RB7is 2-fluoro-6-hydroxyphenyl , then RB7may be depicted as ‘

[0273]

[0057] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0274]

[0058] A compound disclosed herein, such as a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0- 5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A- 8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from: halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two substituents attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12- membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0275] RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, alkyl, haloalkyl, and -OH;

[0276] RB22is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2- 6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein -C0-6 alkyl-(C3-12 carbocycle) and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl; and

[0277] RB23is independently selected at each occurrence from hydrogen and Ci-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0278]

[0059] In some embodiments, a compound disclosed herein, such as a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al- 4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from: halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), - C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, and -S(O)2N(RB22)(RB23)-, wherein Ci-6alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci-6haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, and =C(RB21)2;

[0279] RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, and Ci-6 haloalkyl; RB22is independently selected at each occurrence from hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C2.6 alkenyl, C2.

[0280] 6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein -C0-6 alkyl-(C3-i2carbocycle) and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and Ci-6 alkyl;

[0281] RB23is independently selected at each occurrence from hydrogen and Ci-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0282]

[0060] In some embodiments, a compound disclosed herein, such as a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al- 4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from halogen, oxo, =NH, -CN, -NO2, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), - OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, C3-10 carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, - CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0283]

[0061] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0284]

[0062] Where bivalent substituent groups are specified herein by their conventional chemical formulae, written from left to right, they are intended to encompass the isomer that would result from writing the structure from right to left, e.g., -CH2O- is also intended to encompass -OCH2-.

[0285]

[0063] “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, an “optionally substituted” group may be either unsubstituted or substituted.

[0286]

[0064] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0065] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to,2H,3H,13C,14C,15N,18O,170,35S,36C1, and18F. Of particular interest are compounds of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-l), (a-2), (a- 3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6) enriched in tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the disclosure enriched in deuterium — especially at a site of metabolism — resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (AO), (A0-1), (A0-2), (A0- 3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al- 5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6) enriched in a positron emitting isotope, such asnC,18F,15O and13N, which can be used, for example, in Positron Emission Topography (PET) studies. Isotopically- enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0287]

[0066] As used herein, the phrase “of the formula”, “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. For example, if one structure is depicted, it is understood that all stereoisomer and tautomer forms are encompassed, unless stated otherwise.

[0288]

[0067] Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or are enriched in a stereoisomeric form having such configuration. The compounds of the disclosure may be provided as racemic mixtures. Accordingly, the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When a chemical structure is depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structure. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the disclosure unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. Individual stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.

[0289]

[0068] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds described herein are included with the scope of the disclosure unless otherwise specified.

[0290]

[0069] The term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise unacceptable when used in the subject compositions and methods. For example, the term “pharmaceutically acceptable carrier” refers to a material — such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier — that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0291]

[0070] The terms “salt” and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid. Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids. In addition, when a compound contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term “salt” as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0292]

[0071] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts ofbasic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0293]

[0072] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,7V-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A’-melhy Iglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, A’-elhylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0294]

[0073] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0295]

[0074] As used herein, “treating” or “treatment” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (b) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (c) alleviating symptoms of the disease or medical condition in a subject. For example, “treating cancer” would include preventing cancer from reoccurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.

[0296]

[0075] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0297]

[0076] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., K-Ras). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0077] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[0078] The terms “subject” and “patient” refer to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, such as a human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and nondomestic animals such as wildlife and the like.

[0298]

[0079] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[0299]

[0080] The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0300]

[0081] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2 ’-fluoro, 2’-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0301]

[0082] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNA template (such as into an mRNA or other RNA transcript) and / or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0302]

[0083] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody. An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG” (or half antibody). Examples of modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL- CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., triabodies or tetrabodies).

[0303]

[0084] The term “antibody” and “antibodies” encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0304]

[0085] “Prodrug” is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein (e.g., a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al- 4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)). Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. In some aspects, a prodrug is inactive when administered to a subject but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press each of which is incorporated in full by reference herein). The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are typically prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of a hydroxy functional group, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound, and the like.

[0305]

[0086] The term “in vivo” refers to an event that takes place in a subject’s body. The term “ex vivo” refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0306]

[0087] The disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0307]

[0088] The term “Ras” or “RAS” refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (also used interchangeably herein as K-Ras, K-ras, or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0308]

[0089] The terms “mutant Ras” and “Ras mutant”, as used interchangeably herein, refer to a Ras protein with one or more amino acid mutations, such as with respect to a common reference sequence such as a wild-type (WT) sequence. In some embodiments, a mutant Ras is selected from a mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as from a mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, a mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, a mutation can be a substitution (e.g., a substituted amino acid), insertion (e.g., addition of one or more amino acids), or deletion (e.g., removal of one or more amino acids). In some embodiments, two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, a mutation can be present at any position of Ras. In some embodiments, a mutation can be present at position 12, 13, 62, 92, 95, 96 (e.g., Y96D), or any combination thereof of Ras relative to SEQ ID No. 1 when optimally aligned. In some embodiments, a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or fewer than 50 amino acids in length. In some embodiments, an amino acid of a mutation is a proteinogenic, natural, standard, non-standard, non- canonical, essential, non-essential, or non-natural amino acid. In some embodiments, an amino acid of a mutation has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, a mutation comprises a reactive moiety. In some embodiments, a substituted amino acid comprises a reactive moiety. In some embodiments, a mutant Ras can be further modified, such as by conjugation with a detectable label. In some embodiments, a mutant Ras is a full-length or truncated polypeptide. For example, a mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of a mutant RALA or mutant RALB).

[0309]

[0090] As used herein, the term “corresponding to” or “corresponds to” as applied to an amino acid residue in a polypeptide sequence refers to the correspondence of such amino acid relative to a reference sequence when optimally aligned (e.g., taking into consideration of gaps, insertions and mismatches; wherein alignment may be primary sequence alignment or three-dimensional structural alignment of the folded proteins). For instance, the serine residue in a K-Ras G12S mutant refers to the serine corresponding to residue 12 of SEQ ID No. 4, which can serve as a reference sequence. For instance, the aspartate residue in a K-Ras G12D mutant refers to the aspartate corresponding to residue 12 of SEQ ID No. 2, which can serve as a reference sequence. When an amino acid of a mutant Ras protein corresponds to an amino acid position in the WT Ras protein, it will be understood that although the mutant Ras protein amino acid may be a different amino acid (e.g., G12D, wherein the wildtype G at position 12 is replaced by an aspartate at position 12 of SEQ ID. No. 1), the mutant amino acid is at the position corresponding to the wildtype amino acid (e.g., of SEQ ID No. 1). In embodiments, a modified Ras mutant protein disclosed herein may comprise truncations at the C-terminus, or truncations at the N-terminal end preceding the serine residue. The serine residue in such N-terminal truncated modified mutant is still considered corresponding to position 12 of SEQ ID No. 1. In addition, an aspartate residue at position 12 of SEQ ID No. 2 finds a corresponding residue in SEQ ID Nos. 6 and 8.

[0310]

[0091] A “degradation enhancer” is a compound capable of binding a ubiquitin ligase protein (e.g., E3 ubiquitin ligase protein) or a compound capable of binding a protein that is capable of binding to a ubiquitin ligase protein to form a protein complex capable of conjugating a ubiquitin protein to a target protein. In some embodiments, the degradation enhancer is capable of binding to an E3 ubiquitin ligase protein or a protein complex comprising an E3 ubiquitin ligase protein. In some embodiments, the degradation enhancer is capable of binding to an E2 ubiquitin- conjugating enzyme. In some embodiments, the degradation enhancer is capable of binding to a protein complex comprising an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase protein.

[0311] Methods of Preparing Degrader Compounds

[0312]

[0092] In an aspect is provided a method of preparing a compound of Formula (AO): the method comprising:

[0313] (a) reacting a compound of Formula (a0): with a degradation enhancer under conditions to effect release of LG and production of the compound of Formula (AO), wherein:

[0314] Z1is selected from N and N(RBlb);

[0315] Z2is selected from C(RB2) and C(O);

[0316] ZB5is selected from C(RB9)2 and O;

[0317] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0318] Z7is selected from C(RB7) and N(RB7b); Z8is selected from C(RB8), C(RB8)2, and N;

[0319] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB20;

[0320] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB20;

[0321] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0322] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0323] DG is a degradation enhancer;

[0324] LG is a leaving group; nl is selected from 1, 2, and 3;

[0325] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0326] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°; RB9is independently selected at each occurrence from hydrogen and RB2°;

[0327] RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0328] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0329] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0330] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0331] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0332] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0333]

[0093] In an aspect is provided a method of preparing a compound of Formula (A): the method comprising:

[0334] (a) reacting a compound of Formula (a): with a degradation enhancer under conditions to effect release of LG and production of the compound of Formula (A), wherein:

[0335] Z1is selected from N and N(RBlb);

[0336] Z2is selected from C(RB2) and C(O);

[0337] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0338] Z7is selected from C(RB7) and N(RB7b);

[0339] Z8is selected from C(RB8), C(RB8)2, and N;

[0340] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0341] J1is selected from a bond, Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0342] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0343] J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0344] DG is a degradation enhancer;

[0345] LG is a leaving group; nl is selected from 1, 2, and 3;

[0346] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0347] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0348] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0349] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0350] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0351] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0352] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0353] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- 12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0354] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0355]

[0094] In an aspect is provided a method of preparing a compound of Formula (Al): the method comprising:

[0356] (a) reacting a compound of Formula (al): with a degradation enhancer under conditions to effect release of LG and production of the compound of Formula (Al), wherein:

[0357] Z1is selected from N and N(RBlb);

[0358] Z2is selected from C(RB2) and C(O);

[0359] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0360] Z7is selected from C(RB7) and N(RB7b);

[0361] Z8is selected from C(RB8), C(RB8)2, and N;

[0362] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0363] J1is selected from a bond, C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0364] J2is selected from a bond, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°; J3is selected from Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0365] DG is a degradation enhancer;

[0366] LG is a leaving group; nl is selected from 1, 2, and 3;

[0367] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0368] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0369] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0370] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0371] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0372] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB20attached to the same or adjacent atoms optionally join to form C2.i2carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6

[0373] RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0374] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0375] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0376]

[0095] In embodiments of the method of preparing a compound of Formula (AO), (A), and / or (Al), the reaction mixture comprises a base. In embodiments of the method of preparing a compound of Formula (AO), (A), and / or (Al), the reaction mixture comprises 5- to 12-equivalents of the base relative to the amount of degradation enhancer. In embodiments of the method of preparing a compound of Formula (AO), (A), and / or (Al), the base is N,N- diisopropylethylamine. In embodiments of the method of preparing a compound of Formula (AO), (A), and / or (Al), the compound of Formula (a0), (a), and / or (al) and the degradation enhancer are heated to 40 to 100 °C for 2 to 48 hours. In embodiments of the method of preparing a compound of Formula (A0), (A), and / or (Al), the method further comprises (b) purifying the compound of Formula (A0), (A), and / or (Al). In embodiments of the method of preparing a compound of Formula (A0), (A), and / or (Al), the method may include the preparation of any embodiment of the compound of Formula (A0), (A), and / or (Al), including preparation of a compound of Formula (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (Al-1), (Al-2), (Al-3), (A 1-4), (Al -5), (A 1-6), or any embodiment thereof. In embodiments of the method of preparing a compound of Formula (A0), (A), and / or (Al), the method may include the use of any embodiment of the compound of Formula (a0), (a), and / or (al) including the use of a compound of Formula (a0-l), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), or any embodiment thereof.

[0377]

[0096] In embodiments of the method of preparing a compound of Formula (A0), (A), and / or (Al), the degradation enhancer is selected from: wherein J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to

[0378] 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene are optionally substituted with one or more RB2°; RB15is selected from hydrogen, C1-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle, wherein Ci-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one or more RB20; RB16is selected from hydrogen, C1-6 alkyl, -ORB12, -C(O)ORB12, and -C(O)RB12, wherein C1-6 alkyl is optionally substituted with one or more RB20; RB17is selected from halogen, -CN, C1-3 alkyl, C3.6 carbocycle, 4- to

[0379] 6-membered heterocycle, and -S(O)2CH3, wherein C1-3 alkyl, C3.6 carbocycle, and 4- to 6-membered heterocycle are optionally substituted with one or more RB2°; ol is selected from 0, 1, and 2; pl and ql are independently selected from 1, 2, and 3; and X is selected from CH2 and C(O). In embodiments of the method of preparing a compound of

[0380] Formula (AO), (A), and / or (Al), DG is selected from wherein J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to

[0381] 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene are optionally substituted with one or more RB20; RB15is selected from hydrogen, C1-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle, wherein C1-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one or more RB20; RB16is selected from hydrogen, C1-6 alkyl, -ORB12, -C(O)ORB12, and -C(O)RB12, wherein C1-6 alkyl is optionally substituted with one or more RB20; RB17is selected from halogen, -CN, C1-3 alkyl, C3.6 carbocycle, 4- to 6-membered heterocycle, and -S(O)2CH3, wherein C1-3 alkyl, C3.6 carbocycle, and 4- to 6-membered heterocycle are optionally substituted with one or more RB20; ol is selected from 0, 1, and 2; pl and ql are independently selected from 1, 2, and 3; and X is selected from CH2 and C(O). In embodiments of the method of preparing a compound of Formula (AO), (A), and / or (Al), LG is selected from -Cl, -Br, -I, -OBt, -OS(O)2RB4and -OS(O)(NRB4b)RB4; RB4is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°; RB4bis selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°; and RB12)(RB13), and RB2° are as described for a compound of Formula (a0), (a), and / or (al) or embodiments thereof. The term “-OBt” is -O- benzotri azole.

[0382] Compounds

[0383]

[0097] In an aspect is provided a compound of Formula (AO): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0384] Z1is selected from N and N(RBlb);

[0385] Z2is selected from C(RB2) and C(O);

[0386] ZB5is selected from C(RB9)2 and O;

[0387] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0388] Z7is selected from C(RB7) and N(RB7b);

[0389] Z8is selected from C(RB8), C(RB8)2, and N;

[0390] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0391] J1is selected from a bond, Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0392] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0393] J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0394] DG is a degradation enhancer; nl is selected from 1, 2, and 3;

[0395] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0396] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;

[0397] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0398] RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0399] RB13is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0400] RB2° is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0401] RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0402] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0403] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0404]

[0098] In an aspect is provided a compound of Formula (A): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0405] Z1is selected from N and N(RBlb);

[0406] Z2is selected from C(RB2) and C(O);

[0407] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0408] Z7is selected from C(RB7) and N(RB7b);

[0409] Z8is selected from C(RB8), C(RB8)2, and N;

[0410] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0411] J1is selected from a bond, C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0412] J2is selected from a bond, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0413] J3is selected from C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0414] DG is a degradation enhancer; nl is selected from 1, 2, and 3;

[0415] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0416] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0417] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0418] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0419] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0420] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0421] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0422] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- 12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0423] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0424]

[0099] In an aspect is provided a compound of Formula (Al): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0425] Z1is selected from N and N(RBlb);

[0426] Z2is selected from C(RB2) and C(O);

[0427] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0428] Z7is selected from C(RB7) and N(RB7b);

[0429] Z8is selected from C(RB8), C(RB8)2, and N;

[0430] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0431] J1is selected from a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0432] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0433] J3is selected from Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0434] DG is a degradation enhancer; nl is selected from 1, 2, and 3;

[0435] RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0436] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0437] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0438] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0439] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0440] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB20atached to the same or adjacent atoms optionally join to form C2.i2carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6

[0441] RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0442] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0443] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23atached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0444]

[0100] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof, the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF 1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel- Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAP 1 (cellular inhibitor of apoptosis protein 1), APC / C (anaphase-promoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.

[0445]

[0101] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof, the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

[0446]

[0102] In embodiments of a compound described herein (e.g., compound of Formula (A0), (A), and / or (Al)), or a salt or solvate thereof, DG is selected from: ; wherein: J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to

[0447] 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene are optionally substituted with one or more RB20; RB15is selected from hydrogen, C1-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle, wherein Ci-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one or more RB20; RB16is selected from hydrogen, C1-6 alkyl, -ORB12, -C(O)ORB12, and -C(O)RB12, wherein C1-6 alkyl is optionally substituted with one or more RB20; RB17is selected from halogen, -CN, C1-3 alkyl, C3.6 carbocycle, 4- to

[0448] 6-membered heterocycle, and -S(O)2CH3, wherein C1-3 alkyl, C3.6 carbocycle, and 4- to 6-membered heterocycle are optionally substituted with one or more RB20; ol is selected from 0, 1, and 2; pl and ql are independently selected from 1, 2, and 3; and X is selected from CH2 and C(O).

[0449]

[0103] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof, DG is selected from: ; wherein: J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to

[0450] 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene are optionally substituted with one or more RB20; RB15is selected from -CH(CH3)2 and -C(CH3)3; RB16is selected from hydrogen, - CH3, and -CH2OH; RB17is selected from methylthiazole and methylpyrazole; ol is selected from 0 and 1; pl and ql are independently selected from 1 and 2; and X is selected from CH2 and C(O).

[0451]

[0104] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a

[0452]

[0105] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof,

[0453]

[0106] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), and / or (Al)), or a salt or solvate thereof, DG comprises a monovalent form of a compound selected from

[0454]

[0107] In an aspect is provided a compound of Formula (a0): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0455] Z1is selected from N and N(RBlb);

[0456] Z2is selected from C(RB2) and C(O);

[0457] ZB5is selected from C(RB9)2 and O;

[0458] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0459] Z7is selected from C(RB7) and N(RB7b);

[0460] Z8is selected from C(RB8), C(RB8)2, and N;

[0461] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0462] J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0463] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0464] J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;

[0465] LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;

[0466] RB4is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0467] RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0468] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0469] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0470] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0471] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0472] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6

[0473] RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0474] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0475] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0476]

[0108] In an aspect is provided a compound of Formula (a): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0477] Z1is selected from N and N(RBlb);

[0478] Z2is selected from C(RB2) and C(O);

[0479] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0480] Z7is selected from C(RB7) and N(RB7b);

[0481] Z8is selected from C(RB8), C(RB8)2, and N;

[0482] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0483] J1is selected from a bond, C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;

[0484] J2is selected from a bond, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;

[0485] J3is selected from C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0486] LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;

[0487] RB4is selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0488] RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0489] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0490] RB9is independently selected at each occurrence from hydrogen and RB2°;

[0491] RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0492] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0493] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB20attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0494] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0495] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0496] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0497]

[0109] In an aspect is provided a compound of Formula (al): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0498] Z1is selected from N and N(RBlb);

[0499] Z2is selected from C(RB2) and C(O);

[0500] Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);

[0501] Z7is selected from C(RB7) and N(RB7b);

[0502] Z8is selected from C(RB8), C(RB8)2, and N;

[0503] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0504] J1is selected from a bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -0S(0)2-, -0S(0)-, -OP(O)RB12-, -S(0)20-, -S(0)0-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB20;

[0505] J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;

[0506] J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;

[0507] LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;

[0508] RB4is selected from Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0509] RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;

[0510] RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°; RB9is independently selected at each occurrence from hydrogen and RB2°;

[0511] RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;

[0512] RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;

[0513] RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);

[0514] RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;

[0515] RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);

[0516] RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

[0517]

[0110] In embodiments of a compound described herein (e.g., compound of Formula (a0), (a), and / or (al)), or a salt or solvate thereof, LG is -OS(O)2RB4.

[0518] [HI] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, nl is 1. In embodiments, nl is 2. In embodiments, nl is 3. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, Q2is 4- to 6-membered monocyclic heterocycloalkyl optionally substituted with one or more RB2°. In embodiments, Q2is 7- to 9-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB2°. In embodiments of a compound

[0519] (a0), (a), and / or (al)), or a salt or solvate thereof, each of which is optionally substituted with one or more RB20. In embodiments of a compound described herein

[0520] (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, » is

[0521] H

[0522] 1 , each of which is optionally substituted with one or more RB20.

[0523]

[0112] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A), (Al), (a0), (a), and / or (al)), or a salt or solvate thereof, Z1is N, Z2is C(RB2), Z6is C(RB6), Z7is C(RB7), and Z8is C(RB8); Z1is N, Z2is C(RB2), Z6is N, Z7is C(RB7), and Z8is C(RB8); Z1is N, Z2is C(RB2), Z6is C(RB6)2, Z7is N(RB7b), and Z8is C(RB8)2; or Z1is N(RBlb), Z2is C(O), Z6is C(RB6), Z7is C(RB7), and Z8is N. In embodiments of a compound described herein (e.g., compound of Formula (a)), or a salt or solvate thereof, Z1is N, Z2is C(RB2), Z6is C(RB6), Z7is C(RB7), and Z8is C(RB8). In embodiments of a compound described herein (e.g., compound of Formula (a)), or a salt or solvate thereof, Z1is N, Z2is C(RB2), Z6is N, Z7is C(RB7), and Z8is C(RB8).

[0524]

[0113] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, J1is selected from a bond, Ci-6 alkylene, 2- to 6-membered heteroalkylene, and -C(O)-, wherein Ci-6 alkylene and 2- to 6-membered heteroalkylene are optionally substituted with one or more RB2°. In embodiments, J1is -C(O)-. In embodiments, J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, and -C0-6 alkyl-(3- to 12-membered heterocycle)-, wherein -C0-6 alkyl-(C3-i2carbocycle)- and -C0-6 alkyl-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°. In embodiments, J2is a bond. In embodiments, J3is selected from Ci-6 alkylene, 2- to 6-membered heteroalkylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°. In embodiments, J3is selected from Ci-6 alkylene and 2- to 6- membered heteroalkylene, each of which is optionally substituted with one or more RB2°. In embodiments, J3is selected from Ci-6 alkylene and 2- to 6-membered heteroalkylene. In embodiments, J3is selected from -C0-6 alkyl- (C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°.

[0525]

[0114] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, J1is -C(O)-; J2is a bond; and J3is Ci-6 alkylene. In embodiments, J1is a bond; J2is a bond; and J3is selected from Ci-6 alkylene and 2- to 6- membered heteroalkylene, each of which is optionally substituted with one or more RB20. In embodiments, J1is - C(O)-; J2is 3- to 12-membered heterocycle optionally substituted with one or more RB20; and J3is Ci-6 alkylene.

[0526]

[0115] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, RB2is -O(Ci-3 alkylene)(4- to 10-membered heterocycle), wherein 4- to 10-membered heterocycle is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and =C(RB21)2, and wherein RB21is independently selected at each occurrence from hydrogen, halogen, and C1-3 alkyl. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0- 2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-l), (a-2), (a-3),

[0527] compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0),

[0528] (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a-1), (a-

[0529] 2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (A

[0530] (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, RB2is selected from

[0531]

[0532]

[0116] In embodiments, RB2is -O-(Ci-3 alkylene)-(C3-4 carbocycle)-(Ci-3 alkylene)-(4- to 8-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from RB20; and RB20is as described in Formula (AO), (A0-1), (A0-2), (A0-3), (a0), (a0-1), (a0-2), (a0-3), (A), (A-l), (A-2), (A-3), (a), (a-l), (a-2), (a-3), or any embodiment thereof. In embodiments, RB2is -O-CH2-(cyclopropyl)-CH2-(4- to 8- membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from halogen, -CN, =C(RB21)2, C1-3 alkoxy, C1-3 haloalkoxy, and C1-3 alkyl optionally substituted with one or more substituents selected from halogen, -OH, and -NH2; and RB21is independently selected at each occurrence

[0533]

[0534]

[0117] In embodiments, RB2is jsindependently selected from hydrogen, halogen, -CN, -OH, -NH2, C1-3 alkoxy, and C1-3 haloalkoxy. In embodiments,

[0535]

[0118] In embodiments, RB2is -O-CH2-(cyclobutyl)-CH2-(5- to 8-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from halogen, -CN, =C(RB21)2, C1-3 alkoxy, C1-3 haloalkoxy, and C1-3 alkyl optionally substituted with one or more substituents selected from halogen, - OH, and -NH2; and RB21is independently selected at each occurrence from hydrogen and halogen. In embodiments,

[0536]

[0119] In embodiments, RB2is -O-CH2-(3- to 4-membered heterocycle)-CH2-(5- to 8-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from halogen, - CN, =C(RB21)2, C1-3 alkoxy, C1-3 haloalkoxy, and C1-3 alkyl optionally substituted with one or more substituents selected from halogen, -OH, and -NH2; and RB21is independently selected at each occurrence from hydrogen and halogen. In embodiments,

[0537]

[0120] In embodiments, RB2is -(4- to 7-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from RB2°; and RB2° is as described in Formula (AO), (A0-1), (A0- 2), (A0-3), (a0), (a0-1), (a0-2), (a0-3), (A), (A-l), (A-2), (A-3), (a), (a-l), (a-2), (a-3), or any embodiment thereof.

[0538] In embodiments, RB2is and RB24is independently selected from hydrogen, halogen, -CN, -OH, -NH2,

[0539] C1-3 alkoxy, and C1-3 haloalkoxy.

[0540]

[0121] In embodiments, RB2is -O-(Ci-3 alkylene)-(C4-6 carbocycle) optionally substituted with one or more substituents independently selected from RB20; and RB20is as described in Formula (AO), (A0-1), (A0-2), (A0-3), (a0), (a0-1), (a0-2), (a0-3), (A), (A r any embodiment thereof. In embodiments, RB2is selected from

[0541]

[0122] In embodiments, RB2is -O-CH2-(Cs carbocycle) optionally substituted with one or more substituents independently selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -ORB22, -N(RB22)(RB23), =NRB22, and =C(RB21)2; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, and -C0-6 alkyl-(C3-12 carbocycle) are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, and -N(RB22)(RB23); RB21is independently selected at each occurrence from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl; RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form

[0542] 3- to 10 membered heterocycle. In embodiments, RB2is selected from independently selected from hydrogen, halogen, -CN, -ORB22, -N(RB22)(RB23), C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0543] In embodiments, RB2is selected from

[0544]

[0123] In embodiments, RB2is -O-(Ci-3 alkylene)-(4- to 8-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from RB2°; and RB2° is as described in Formula (AO), (A0-1), (A0-2), (A0-3), (a0), (a0-1), (a0-2), (a0-3), (A), (A-l), (A-2), (A-3), (a), (a-l), (a-2), (a-3), or any embodiment thereof. In embodiments, RB2is -O-(Ci-3 alkylene)-(4- to 8-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -ORB22, -N(RB22)(RB23), =NRB22, and =C(RB21)2, wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12- membered heterocycle) are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, and -N(RB22)(RB23); RB21is independently selected at each occurrence from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl; RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle. In embodiments, RB2is selected from

[0545]

[0124] In embodiments, RB2is -O-(Ci-3 alkylene)-(4- to 8-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from halogen, -CN, =C(RB21)2, -ORB22, - N(RB22)(RB23), phenyl, 5 membered heteroaryl, and C1-3 alkyl optionally substituted with one or more substituents selected from halogen, -OH, and -NH2; RB21is independently selected at each occurrence from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl; RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form selected from hydrogen, halogen, -CN, -ORB22, -N(RB22)(RB23), =C(RB21)2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, Ci- 3 haloalkoxy, phenyl, and 5 membered heteroaryl; or two RB24are joined to form a C3.6 carbocycle or 3- to 5- membered heterocycle; RB21is independently selected at each occurrence from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl; RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10

[0546]

[0125] In embodiments, RB2is -O-(Ci-3 alkylene)-(8- to 10-membered nitrogen containing heterocycle) optionally substituted with one or more substituents independently selected from halogen, -CN, =C(RB21)2, -ORB22, - N(RB22)(RB23), phenyl, 5 membered heteroaryl, and C1-3 alkyl optionally substituted with one or more substituents selected from halogen, -OH, and -N(RB22)(RB23); RB21is independently selected at each occurrence from hydrogen, halogen, C1-3 alkyl, and C1-3 haloalkyl; RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle); and RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle. In embodiments, RB2is selected from , , , selected from . in embodiments, RB2is selected from . In embodiments, RB2is selected from

[0547] . In embodiments, RB2is selected from ' . In embodiments, RB2is selected from . In embodiments, RB2is selected from n embodiments, RB2is selected from . In embodiments, RB2is selected from embodiments, RB2is selected from . In embodiments, RB2is selected from In embodiments, RB2is selected from . In embodiments, RB2is selected from . In embodiments, RB2is selected from . In embodiments, RB2is selected from . In

[0548] F embodiments, RB2is selected from \ . In embodiments, R is selected from . In embodiments,

[0549] RB2is selected from

[0550]

[0126] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, RB6is selected from hydrogen, halogen, and C1-3 haloalkyl. In embodiments, RB6is halogen.

[0551]

[0127] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-1), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, RB7is selected from Cg-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20. In embodiments, RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20. In embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl. In embodiments, RB7is substituted with one, two, ,

[0552]

[0128] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-1), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, RB8is independently selected from hydrogen and halogen. In embodiments, RB8is halogen.

[0553]

[0129] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-1), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), or a salt or solvate thereof, RB6is halogen; RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20; and RB8is halogen.

[0554]

[0130] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A- 6), (A-7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5),

[0555]

[0131] In some embodiments, the present disclosure provides a compound of Formula (A0-1), (A0-2), or (A0-3):

[0556] (A0-3), or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula

[0557] (AO), or any embodiment thereof.

[0558]

[0132] In some embodiments, the present disclosure provides a compound of Formula (A-l), (A-2), or (A-3): or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula

[0559] (A), or any embodiment thereof.

[0560]

[0133] In some embodiments, the present disclosure provides a compound of Formula (Al-1), (Al-2), or (Al-3): (Al-3), or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (Al), or any embodiment thereof.

[0561]

[0134] In some embodiments, the present disclosure provides a compound of Formula (A0-1), (A0-2), (A0-3), (A- 1), (A-2), (A-3), (Al-1), (Al-2), or (Al-3), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0562] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0563] J1is selected from a bond, -C(O)-, -N(RB12)C(O)-, and Ci-6 alkylene, wherein Ci-6 alkylene is optionally substituted with one, two, or three RB20;

[0564] J2is selected from a bond, Ci-6 alkylene, and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0565] J3is selected from Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0566] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0567] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl;

[0568] RB8is halogen;

[0569] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0570] DG is as described for a compound of Formula (A).

[0571]

[0135] In some embodiments of a compound of Formula (A0-1), (A0-2), (A0-3), (A-l), (A-2), (A-3), (Al-1), (Al-

[0572] 2), or (Al-3), or a pharmaceutically acceptable salt or solvate thereof:

[0573] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0574] J1is selected from a bond, -N(RB12)C(O)-, and -C(O)-;

[0575] J2is a bond;

[0576] J3is selected from C1-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein C1-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB2°; RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl;

[0577] RB8is halogen;

[0578] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0579] DG is as described for a compound of Formula (A).

[0580]

[0136] In some embodiments, the present disclosure provides a compound of Formula (a0-1), (a0-2), or (a0-3):

[0581] (a0-3), or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula

[0582] (a0), or any embodiment thereof.

[0583]

[0137] In some embodiments, the present disclosure provides a compound of Formula (a-1), (a-2), or (a-3): or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (a), or any embodiment thereof.

[0584]

[0138] In some embodiments, the present disclosure provides a compound of Formula (al - 1), (al-2), or (al-3):

[0585] (al-3), or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (al), or any embodiment thereof.

[0586]

[0139] In some embodiments, the present disclosure provides a compound of Formula (a0-1), (a0-2), (a0-3), (a-1), (a-2), (a-3), (al-1), (al-2), or (al-3), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0587] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°; J1is selected from a bond, -C(O)-, -N(RB12)C(O)-, and Ci-6 alkylene, wherein Ci-6 alkylene is optionally substituted with one, two, or three RB20;

[0588] J2is selected from a bond, Ci-6 alkylene, and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0589] J3is selected from Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0590] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0591] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3-6 cycloalkyl;

[0592] RB8is halogen;

[0593] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0594] LG is as described for a compound of Formula (a).

[0595]

[0140] In some embodiments of a compound of Formula (a0-1), (a0-2), (a0-3), (a-1), (a-2), (a-3), (al-1), (al-2), or (al -3), or a pharmaceutically acceptable salt or solvate thereof:

[0596] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0597] J1is selected from a bond, -N(RB12)C(O)-, and -C(O)-;

[0598] J2is a bond;

[0599] J3is selected from C1-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein C1-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB2°;

[0600] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0601] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl;

[0602] RB8is halogen;

[0603] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and LG is as described for a compound of Formula (a).

[0604]

[0141] In some embodiments, the present disclosure provides a compound of Formula (A0-4), (A0-5), or (A0-6): or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula

[0605] (AO), or any embodiment thereof.

[0606]

[0142] In some embodiments, the present disclosure provides a compound of Formula (A-4), (A-5), or (A-6): or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (A), or any embodiment thereof.

[0607]

[0143] In some embodiments, the present disclosure provides a compound of Formula (Al-4), (Al-5), or (Al-6):

[0608] or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (Al), or any embodiment thereof.

[0609]

[0144] In some embodiments, the present disclosure provides a compound of Formula (A0-4), (A0-5), (A0-6), (A-

[0610] 4), (A-5), (A-6), (Al-4), (Al-5), or (Al-6), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0611] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB20;

[0612] J1is selected from a bond, -C(O)-, -N(RB12)C(O)-, and Ci-6 alkylene, wherein Ci-6 alkylene is optionally substituted with one, two, or three RB20;

[0613] J2is selected from a bond, Ci-6 alkylene, and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0614] J3is selected from Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0615] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0616] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3-6 cycloalkyl;

[0617] RB8is halogen;

[0618] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0619] DG is as described for a compound of Formula (A).

[0620]

[0145] In some embodiments of a compound of Formula (A0-4), (A0-5), (A0-6), (A-4), (A-5), (A-6), (Al-4), (Al- 5), or (A 1-6), or a pharmaceutically acceptable salt or solvate thereof:

[0621] B is selected from a 4- to 8-membered monocyclic heterocycle and 6- to 10-membered bridged bicyclic heterocycle, each of which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20;

[0622] J1is selected from a bond, -N(RB12)C(O)-, and -C(O)-;

[0623] J2is a bond;

[0624] J3is selected from C1-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0625] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0626] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3-6 cycloalkyl;

[0627] RB8is halogen;

[0628] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0629] DG is as described for a compound of Formula (A).

[0630]

[0146] In some embodiments, the present disclosure provides a compound of Formula (a0-4), (a0-5), or (a0-6): or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (a0), or any embodiment thereof.

[0631]

[0147] In some embodiments, the present disclosure provides a compound of Formula (a-4), (a-5), or (a-6):

[0632] (a-6), or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (a), or any embodiment thereof.

[0633]

[0148] In some embodiments, the present disclosure provides a compound of Formula (al-4), (al-5), or (al-6): or a pharmaceutically acceptable salt or solvate thereof, wherein all variables above are as described for Formula (al), or any embodiment thereof.

[0634]

[0149] In some embodiments of a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (a0), (a0-1), (a0-2), (a0-3),

[0635] (A), (A-l), (A-2), (A-3), (a), (a-1), (a-2), or (a-3), the compound has the formula wherein all variables of the formulae above are as described in Formula (AO), (A0-1), (A0-2), (A0-3), (a0), (a0-1), (a0-2), (a0-3), (A), (A-l), (A-2), (A-3), (a), (a-1), (a-2), (a-3), or any embodiment thereof. In some embodiments, the compound has formula (A-7). In some embodiments, the compound has formula (a-7). In some embodiments, the compound has formula (A-8). In some embodiments, the compound has formula (a-8).

[0636]

[0150] In some embodiments, the present disclosure provides a compound of Formula (a0-4), (a0-5), (a0-6), (a-4), (a-5), (a-6), (al-4), (al-5), or (al-6), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0637] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB20;

[0638] J1is selected from a bond, -C(O)-, -N(RB12)C(O)-, and Ci-6 alkylene, wherein Ci-6 alkylene is optionally substituted with one, two, or three RB20;

[0639] J2is selected from a bond, Ci-6 alkylene, and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0640] J3is selected from Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0641] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0642] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3-6 cycloalkyl;

[0643] RB8is halogen;

[0644] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0645] LG as described for a compound of Formula (a).

[0646]

[0151] In some embodiments of a compound of Formula (a0-4), (a0-5), (a0-6), (a-4), (a-5), (a-6), (al-4), (al-5), or (al-6), or a pharmaceutically acceptable salt or solvate thereof:

[0647] Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;

[0648] J1is selected from a bond, -N(RB12)C(O)-, and -C(O)-;

[0649] J2is a bond; J3is selected from Ci-6 alkylene and -C0-6 alkyl-(C3-12 carbocycle)-, wherein Ci-6 alkylene and -C0-6 alkyl- (C3-12 carbocycle)- are optionally substituted with one, two, or three RB20;

[0650] RB6is selected from hydrogen, halogen, and C1-3 haloalkyl.

[0651] RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl;

[0652] RB8is halogen;

[0653] RB9is independently selected at each occurrence from hydrogen and RB2°; nl is selected from 1, 2, and 3; and

[0654] LG is as described for a compound of Formula (a).

[0655]

[0152] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), or (a0-6)), ZB5is C(RB9)2. In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), or (a0-6)), ZB5is O.

[0656]

[0153] In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), RB6bis selected from hydrogen, -CN, C1-6 alkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°. In some embodiments, RB6bis selected from C1-6 alkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more RB2°. In some embodiments, RB6bis selected from C1-6 alkyl and C3-12 carbocycle, each of which is optionally substituted with one or more RB2°. In some embodiments, RB6bis C3-12 carbocycle, such as cyclopropyl.

[0657]

[0154] In embodiments of a compound described herein (e.g., compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A- 6), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al- 2), (al-3), (al-4), (al-5), or (al-6)), Z7is selected from C(RB7) and C(RB7)(RB7a). In some embodiments, Z7is C(RB7). In some embodiments, Z8is selected from C(RB8) and C(RB8)2. In some embodiments, Z8is C(RB8), such as CF. In some embodiments, RB7is selected from Ce-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB2°. In some embodiments, RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB2°. In some embodiments, RB7is benzothiophenyl optionally substituted with one or more RB2°. In some embodiments, RB8is selected from hydrogen and halogen. In some embodiments, RB8is halogen, such as fluorine. In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), RB6bis selected from C1-6 alkyl and C3-12 carbocycle, each of which is optionally substituted with one or more RB2°; Z7is C(RB7); Z8is C(RB8); RB7is selected from Ce-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20; and RB8is halogen.

[0658]

[0155] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-4), (a0), (a0-1), (a0-4), (A), (A-l), (A-4), (a), (a-l), (a-4), (Al), (Al-1), (Al-4), (al), (al-1), or (al-4)), Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b). In some embodiments, Z6is selected from C(RB6) and C(RB6)2. In some embodiments, Z6is selected from N and N(RB6b). In some embodiments, Z6is selected from C(RB6) and N. In some embodiments, Z6is selected from C(RB6)2and N(RB6b). In some embodiments, Z6is C(RB6). In some embodiments, Z6is C(RB6)2. In some embodiments, Z6is N. In some embodiments, Z6is N(RB6b).

[0659]

[0156] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al -6), Z7is selected from C(RB7) and N(RB7b). In some embodiments, Z7is C(RB7). In some embodiments, Z7is N(RB7b).

[0660]

[0157] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), Z8is selected from C(RB8), N, and C(RB8)2. In some embodiments, Z8is selected from C(RB8) and C(RB8)2. In some embodiments, Z8is C(RB8). In some embodiments, Z8is C(RB8)2. In some embodiments, Z8is N.

[0661]

[0158] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8), N, and C(RB8)2. In some embodiments, Z6is C(RB6); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z6is CC1; Z7is C(RB7); and Z8is CF. In some embodiments, Z6is CCF2; Z7is C(RB7); and Z8is CF. In some embodiments, Z6is N; Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z6is N; Z7is C(RB7); and Z8is CF. In some embodiments, Z6is C(RB6)2; Z7is N(RB7b); and Z8is C(RB8)2. In some embodiments, Z6is CH2; Z7is N(RB7b); and Z8is CH2. In some embodiments, Z6is N(RB6b); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z6is N(RB6b); Z7is C(RB7); and Z8is CF.

[0662]

[0159] In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), Z1is selected from N and N(RBlb); Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8), N, and C(RB8)2. In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), Z1is N; Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8), N, and C(RB8)2. In some embodiments, Z1is N; Z6is C(RB6); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z6is CC1; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z6is N; Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z6is N; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z6is C(RB6)2; Z7is N(RB7b); and Z8is C(RB8)2. In some embodiments, Z1is N; Z6is CH2; Z7is N(RB7b); and Z8is CH2. In some embodiments, Z1is N; Z6is N(RB6b); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z6is N(RB6b); Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N(RBlb); Z6is C(RB6); Z7is C(RB7); and Z8is N.

[0663]

[0160] In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), Z1is selected from N and N(RBlb); Z2is selected from C(RB2) and C(O); X3is N; Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8), N, and C(RB8)2. In some embodiments, Z1is N; Z2is C(RB2); Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8) and C(RB8)2. In some embodiments, Z1is N; Z2is C(RB2); Z6is C(RB6); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z2is C(RB2); Z6is CC1; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z2is C(RB2); Z6is N; Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z2is C(RB2); Z6is N; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z2is C(RB2); Z6is C(RB6)2; Z7is N(RB7b); and Z8is C(RB8)2. In some embodiments, Z1is N; Z2is C(RB2); Z6is CH2; Z7is N(RB7b); and Z8is CH2. In some embodiments, Z1is N; Z2is C(RB2); Z6is N(RB6b); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z2is C(RB2); Z6is N(RB6b); Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N(RBlb); Z2is C(O); Z6is C(RB6); Z7is C(RB7); and Z8is N.

[0664]

[0161] In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), Z1is N; Z2is selected from C(RB2) and C(O); Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8), N, and C(RB8)2. In some embodiments, Z1is N; Z2is C(RB2); Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b); Z7is selected from C(RB7) and N(RB7b); and Z8is selected from C(RB8) and C(RB8)2. In some embodiments, Z1is N; Z2is C(RB2); Z6is C(RB6); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z2is C(RB2); Z6is CC1; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z2is C(RB2); Z6is CCF3; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z2is C(RB2); Z6is N; Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z2is C(RB2); Z6is N; Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N; Z2is C(RB2); Z6is C(RB6)2; Z7is N(RB7b); and Z8is C(RB8)2. In some embodiments, Z1is N; Z2is C(RB2); Z6is CH2; Z7is N(RB7b); and Z8is CH2. In some embodiments, Z1is N; Z2is C(RB2); Z6is N(RB6b); Z7is C(RB7); and Z8is C(RB8). In some embodiments, Z1is N; Z2is C(RB2); Z6is N(RB6b); Z7is C(RB7); and Z8is CF. In some embodiments, Z1is N(RBlb); Z2is C(O); Z6is C(RB6); Z7is C(RB7); and Z8is N.

[0665]

[0162] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-4), (A0-5), (a0), (a0-1), (a0- 2), ] (a0-4), (a0-5), (A), (A-l), (A-2), (A-4), (A-5), (a), (a-l), (a-2), (a-4), (a-5), (Al), (Al-1), (Al-2), (Al-4), (Al- 5), (al), (al-1), (al-2), (al-4), or (al-5), RB6is selected from hydrogen, halogen, -CN, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -ORB12, and -N(RB12)(RB13), wherein C1-6 alkyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°. In some embodiments, RB6is selected from hydrogen, halogen, and alkyl. In some embodiments, RB6is selected from hydrogen and halogen. In some embodiments, RB6is hydrogen. In some embodiments, RB6is halogen, such as chlorine. In some embodiments, RB6is -Cl. In some embodiments, RB6is -F. In some embodiments, RB6is fluorine. In some embodiments, RB6is C1-6 alkyl optionally substituted with one or more independently selected halogen. In some embodiments, RB6is -CF3. In some embodiments, Z6is C(RB6)2 and each RB6is hydrogen.

[0666]

[0163] In some embodiments (e.g., a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), RB7is selected from C3 -12 carbocycle and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more RB2°; and RB7bis selected from C3-12 carbocycle, -C(O)-(C3- carbocycle), 6- to 12-membered heterocycle, and -C(O)-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more RB2°.

[0667]

[0164] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), RB7is selected from (A -12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20. In some embodiments, RB7is selected from Cio aryl and 9- membered heteroaryl, each of which is optionally substituted with one, two, or three RB20. In some embodiments, RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20. In some embodiments, RB7is selected from naphthalenyl and benzothiophenyl, each of which is optionally substituted with one, two, or three RB20. In some embodiments, RB7is selected from C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, Cg-io aryl, and 5- to 10-membered heteroaryl, each of which is optionally substituted with one, two, or three RB20. In some embodiments, RB7is selected from bicyclic C4-10 cycloalkyl, bicyclic 4- to 10-membered heterocycloalkyl, bicyclic C7-10 aryl, and bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one, two, or three RB20. In some embodiments, RB7is selected from bridged bicyclic C4-10 cycloalkyl, bridged bicyclic 4- to 10-membered heterocycloalkyl, bridged bicyclic C7-10 aryl, and bridged bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one, two, or three RB20. In some embodiments, RB7is selected from fused bicyclic C4-10 cycloalkyl, fused bicyclic 4- to 10-membered heterocycloalkyl, fused bicyclic C7-10 aryl, and fused bicyclic 7- to 10- membered heteroaryl, each of which is optionally substituted with one, two, or three RB20. In some embodiments, RB7is selected from Ce-io aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one, two, three, four, or five RB20. In some embodiments, RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20. In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl. In some embodiments, RB7is selected from G, aryl and 6-membered heteroaryl, each of which is substituted with one, two, three, four, or five RB20. In some embodiments, RB7is phenyl substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl. In some embodiments, RB7is phenyl substituted with one, two, three, or four substituents independently selected from -F, -Cl, -CN, -CH3, -CH2CH3, -CH-CH2, -CF3, -C=CH, -OH, -NH2, and - cyclopropyl. In some embodiments, RB7is optionally substituted with one or more RB20, such as one, two, three, four, five, six, or seven RB20.

[0668]

[0165] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1),

[0669] Q1, Q3, and Q5are independently selected from N and C(Rlq);

[0670] Q4and Q6are independently selected from O, S, C(Rlq)2, and N(Rlr);

[0671] Y4, Y5, Y6, Y9, and Y10are independently selected from C(Rlq) and N;

[0672] Y7and Y8are independently selected from C(Rlq), C(Rlq)2, N, and N(Rlr);

[0673] Y13is selected from a bond, C(Rlq), N, C(O), C(Rlq)2, C(O)C(Rlq)2, C(Rlq)2C(Rlq)2, C(Rlq)2N(Rlr), and N(Rlr);

[0674] Y14, Y15, Y17, and Y18are independently selected from C(O), C(Rlq), N, C(Rlq)2, and N(Rlr);

[0675] Y16is selected from C, N, and C(Rlq); each Rlqis independently selected from hydrogen, halogen, -CN, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to

[0676] 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, -N(RB12)(RB13), -C(O)ORB12, - OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, -N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, - OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, - S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, 2- to 6- membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB20; or two Rlqbonded to the same carbon are joined to form 3- to 10-membered heterocycle or C3-10 carbocycle, wherein 3- to 10-membered heterocycle and C3-10 carbocycle are optionally substituted with one, two, or three RB2°; or two Rlqbonded to adjacent atoms are joined to form 3- to 10-membered heterocycle or C3-10 carbocycle, wherein 3- to 10-membered heterocycle and C3-10 carbocycle are optionally substituted with one, two, or three RB2°; or one Rlqand one Rlrare joined to form 3- to 10-membered heterocycle or C3-10 carbocycle, wherein 3- to 10-membered heterocycle and C3-10 carbocycle are optionally substituted with one, two, or three RB20; each Rlris independently selected from hydrogen, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 3- to 10-membered heterocycle, and C3-10 carbocycle, wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 3- to 10-membered heterocycle, and C3-10 carbocycle are optionally substituted with one, two, or three RB20; and indicates a single or double bond such that all valences are satisfied.

[0677]

[0166] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1),

[0678]

[0679] NH2, NH2, NH2, NH2,ALK| NH2jn someembodiments, RB7is selected from

[0680] , , embodiments,

[0681]

[0167] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.6 cycloalkyl, -ORB22, -SRB22, and - N(RB22)(RB23), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3.6 cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -ORB22. In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3-6 cycloalkyl. In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C=CH, -OH, -NH2, and -cyclopropyl. In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from -F, -Cl, -CN, -CH3, -CH2CH3, -CH=CH2, - CF3, -C=CH, -OH, -NH2, and -cyclopropyl. In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, and - N(RB22)(RB23). In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -C=CH, -OH, and -NH2. In some embodiments, RB7is substituted with -F, -CN, and -NH2. In some embodiments, RB7is substituted with -F, -C=CH, and -OH. In some embodiments, RB7is substituted with -CF3, -CH3, and -NH2. In some embodiments, RB7is substituted with -CF3 and -NH2. In some embodiments, RB7is substituted with -CF3, -CH3, -F, and -NH2. In some embodiments, RB7is substituted with -CF3, -F, and -NH2. In some embodiments, RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C=CH, -OH, -NH2, and -cyclopropyl.

[0682]

[0168] In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), RB7bis selected from Cg-12 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB2°. In some embodiments, RB7bis selected from C10 aryl and 9-membered heteroaryl, each of which is optionally substituted with one, two, or three RB2°. In some embodiments, RB7bis selected from naphthalenyl and benzothiophenyl, each of which is optionally substituted with one, two, or three RB2°. In some embodiments, RB7bis selected from cycloalkyl, 3- to 10-membered heterocycloalkyl, Cg-io aryl, and 5- to 10-membered heteroaryl, each of which is optionally substituted with one, two, or three RB2°. In some embodiments, RB7bis selected from bicyclic cycloalkyl, bicyclic 4- to 10-membered heterocycloalkyl, bicyclic aryl, and bicyclic 7- to 10- membered heteroaryl, each of which is optionally substituted with one, two, or three RB2°. In some embodiments, RB7bis selected from bridged bicyclic cycloalkyl, bridged bicyclic 4- to 10-membered heterocycloalkyl, bridged bicyclic aryl, and bridged bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one, two, or three RB2°. In some embodiments, RB7bis selected from fused bicyclic cycloalkyl, fused bicyclic 4- to 10-membered heterocycloalkyl, fused bicyclic C7-10 aryl, and fused bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one, two, or three RB2°. In some embodiments, RB7bis selected from Ce-io aryl and 5- to 10-membered heteroaryl, each of which is optionally substituted with one, two, three, four, or five RB2°. In some embodiments, RB7bis selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20. In some embodiments, RB7bis substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl. In some embodiments, RB7bis selected from G, aryl and 6-membered heteroaryl, each of which is substituted with one, two, three, four, or five RB2°. In some embodiments, RB7bis optionally substituted with one or more RB2°, such as one, two, three, four, five, six, or seven RB2°.

[0683]

[0170] In some embodiments, for a compound of Formula (AO), (A), (Al), (a0), (a), and / or (al), RB7bis substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3.6 cycloalkyl, -ORB22, -SRB22, and -N(RB22)(RB23), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3.6 cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and -ORB22. In some embodiments, RB7bis substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, and - N(RB22)(RB23). In some embodiments, RB7bis substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -C=CH, -OH, and -NH2. In some embodiments, RB7bis substituted with -F, -CN, and -NH2. In some embodiments, RB7bis substituted with -F, -C=CH, and -OH. In some embodiments, RB7bis substituted with -CF3, -CH3, and -NH2. In some embodiments, RB7bis substituted with -CF3 and -NH2. In some embodiments, RB7bis substituted with -CF3, -CH3, -F, and -NH2. In some embodiments, RB7bis substituted with - CF3, -F, and -NH2. In some embodiments, RB7bis substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH-CH2, -CF3, -C=CH, -OH, -NH2, and -cyclopropyl. In some embodiments, RB7bis substituted with -Cl.

[0684]

[0171] In some embodiments, for a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (a), (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), RB8is selected from hydrogen, halogen, -CN, C1-6 alkyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -ORB12, and -N(RB12)(RB13), wherein C1-6 alkyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20. In some embodiments, RB8is selected from hydrogen, halogen, and C1-3 alkyl. In some embodiments, RB8is selected from hydrogen and halogen. In some embodiments, RB8is hydrogen. In some embodiments, RB8is halogen, such as chlorine. In some embodiments, RB8is -Cl. In some embodiments, RB8is -F. In some embodiments, RB8is -CF3. In some embodiments, RB8is C1-6 alkyl optionally substituted with one or more halogen. In some embodiments, RB8is fluorine. In some embodiments, Z8is C(RB8)2 and each RB8is hydrogen.

[0685]

[0172] In some embodiments (e.g., embodiments of a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A- 7), (A-8), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6)), for a compound described herein, RB6is halogen; RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20; and RB8is halogen.

[0686]

[0173] In some embodiments of a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6),

[0687] (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), Q2is 4- to 10-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 4-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 5-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 10-membered heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, a heterocycle recited in this paragraph is fully saturated or partially unsaturated. In some embodiments, a heterocycle recited in this paragraph is fully saturated. In some embodiments, a heterocycle recited in this paragraph is partially unsaturated. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring nitrogen atom. In some embodiments, a heterocycle recited in this paragraph comprises at least two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises exactly two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring oxygen atom. In some embodiments, a heterocycle recited in this paragraph comprises one ring nitrogen atom and one ring oxygen atom.

[0688]

[0174] In some embodiments of a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-l), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), Q2is 4- to 7-membered monocyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 4-membered monocyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 5-membered monocyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered monocyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered monocyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is 4- to 7-membered monocyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 4-

[0689] Ill membered monocyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 5-membered monocyclic heterocycloalkyl, which

[0690] (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered monocyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and

[0691] (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered monocyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is 4- to 7-membered monocyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 4- membered monocyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 5-membered monocyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered monocyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered monocyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, a heterocycle recited in this paragraph is fully saturated or partially unsaturated. In some embodiments, a heterocycle recited in this paragraph is fully saturated. In some embodiments, a heterocycle recited in this paragraph is partially unsaturated. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring nitrogen atom. In some embodiments, a heterocycle recited in this paragraph comprises at least two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises exactly two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring oxygen atom. In some embodiments, a heterocycle recited in this paragraph comprises one ring nitrogen atom and one ring oxygen atom.

[0692]

[0175] In some embodiments of a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6), (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (Al), (Al-1), (Al-2), (Al-3), (Al-4), (Al-5), (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or (al-6), Q2is 4- to 7-membered monocyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 4-membered monocyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 5-membered monocyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered monocyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered monocyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is 6- to 9- membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is 6- to 9-membered bridged bicyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered bridged bicyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered bridged bicyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered bridged bicyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered bridged bicyclic heterocycloalkyl, which (i) comprises only one ring heteroatom and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is 6- to 9-membered bridged bicyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered bridged bicyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered bridged bicyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered bridged bicyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered bridged bicyclic heterocycloalkyl, which (i) comprises at least two ring heteroatoms and (ii) is optionally substituted with one or more RB20. In some embodiments, a heterocycle recited in this paragraph is fully saturated or partially unsaturated. In some embodiments, a heterocycle recited in this paragraph is fully saturated. In some embodiments, a heterocycle recited in this paragraph is partially unsaturated. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring nitrogen atom. In some embodiments, a heterocycle recited in this paragraph comprises at least two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises exactly two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring oxygen atom. In some embodiments, a heterocycle recited in this paragraph comprises one ring nitrogen atom and one ring oxygen atom. In some embodiments, Q2is 6- to 9-membered bridged bicyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered bridged bicyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered bridged bicyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered bridged bicyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered bridged bicyclic heterocycloalkyl, which (i) comprises two ring nitrogen atoms and (ii) is optionally substituted with one or more RB20. In some embodiments, Q2is 6- to 10-membered fused bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered fused bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered fused bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered fused bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered fused bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 10-membered fused bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, a heterocycle recited in this paragraph is fully saturated or partially unsaturated. In some embodiments, a heterocycle recited in this paragraph is fully saturated. In some embodiments, a heterocycle recited in this paragraph is partially unsaturated. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring nitrogen atom. In some embodiments, a heterocycle recited in this paragraph comprises at least two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises exactly two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring oxygen atom. In some embodiments, a heterocycle recited in this paragraph comprises one ring nitrogen atom and one ring oxygen atom. In some embodiments, Q2is 6- to 12-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 6-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 7-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 8-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 9-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, Q2is a 10-membered spirocyclic bicyclic heterocycloalkyl optionally substituted with one or more RB20. In some embodiments, a heterocycle recited in this paragraph is fully saturated or partially unsaturated. In some embodiments, a heterocycle recited in this paragraph is fully saturated. In some embodiments, a heterocycle recited in this paragraph is partially unsaturated. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring nitrogen atom. In some embodiments, a heterocycle recited in this paragraph comprises at least two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises exactly two ring nitrogen atoms. In some embodiments, a heterocycle recited in this paragraph comprises at least one ring oxygen atom. In some embodiments, a heterocycle recited in this paragraph comprises one ring nitrogen atom and one ring oxygen atom.

[0693]

[0176] In some embodiments of a compound of Formula (AO), (A0-1), (A0-2), (A0-3), (A0-4), (A0-5), (A0-6),

[0694] (a0), (a0-1), (a0-2), (a0-3), (a0-4), (a0-5), (a0-6), (A), (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (a), (a-l), (a-2), (a-3),

[0695] (a-4), (a-5), (a-6), (Al), (A (Al-6), (al), (al-1), (al-2), (al-3), (al-4), (al-5), or

[0696] (al -6), Q2is selected from , each of which is optionally substituted with one or

[0697]

[0698]

[0177] In some embodiments, Q2is ■ , which is optionally substituted with one or more RB20. In some , which is optionally substituted with one or more RB20. In

[0699] ■ , which is optionally substituted with one or more RB20. In some embodiments, optionally substituted with one or more RB20. In some embodiments, Q2is , which is optionally substituted with one or more RB20. In some embodiments, Q2is , which is optionally substituted with one or more

[0700] RB20. In some embodiments, Q2is , which is optionally substituted with one or more RB20. In some embodiments, Q2is , which is optionally substituted with one or more RB20. In some embodiments, Q2is

[0701] 1 , which is optionally substituted with one or more RB20. In some embodiments, Q2is 1 , which is optionally substituted with one or more RB20. In some embodiments, , which is optionally substituted with one or more RB20. In some embodiments, , which is optionally substituted with one or more

[0702] RB20. In some embodiments, Q2is , which is optionally substituted with one or more RB20. In some , which is optionally substituted with one or more RB20. In

[0703] , which is optionally substituted with one or more RB20. In some embodiments, optional...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (AO):or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is selected from N and N(RBlb);Z2is selected from C(RB2) and C(O);ZB5is selected from C(RB9)2 and O;Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);Z7is selected from C(RB7) and N(RB7b);Z8is selected from C(RB8), C(RB8)2, and N;Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;J1is selected from a bond, C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or moreRB2°;J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;J3is selected from C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;DG is a degradation enhancer; nl is selected from 1, 2, and 3;RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13),wherein Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;RB9is independently selected at each occurrence from hydrogen and RB2°;RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and> indicates a single or double bond such that all valences are satisfied.

2. A compound of Formula (A):or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is selected from N and N(RBlb);Z2is selected from C(RB2) and C(O);Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);Z7is selected from C(RB7) and N(RB7b);Z8is selected from C(RB8), C(RB8)2, and N;Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;J1is selected from a bond, Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;DG is a degradation enhancer; nl is selected from 1, 2, and 3;RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB9is independently selected at each occurrence from hydrogen and RB2°;RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6alkoxy, Ci-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

3. The compound, salt, or solvate of any one of claims 1 to 2, wherein the degradation enhancer is capable of binding a protein selected from E3A, mdm2, APC, EDD1, SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECTD4, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HER5, HERC6, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE3D, UBE4A, UBE4B, UBOX5, UBR5, VHL (von-Hippel-Lindau ubiquitin ligase), WWP1, WWP2, Parkin, MKRN1, CMA (chaperon-mediated autophage), SCFb-TRCP (Skip-Cullin-F box (Beta-TRCP) ubiquitin complex), b-TRCP (b-transducing repeat-containing protein), cIAPl (cellular inhibitor of apoptosis protein 1), APC / C (anaphasepromoting complex / cyclosome), CRBN (cereblon), CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase, XIAP, IAP, KEAP1, DCAF15, RNF114, DCAF16, AhR, SOCS2, KLHL12, UBR2, SPOP, KLHL3, KLHL20, KLHDC2, SPSB1, SPSB2, SPSB4, SOCS6, FBXO4, FBXO31, BTRC, FBW7, CDC20, PML, TRIM21, TRIM24, TRIM33, GID4, avadomide, iberdomide, and CC-885.

4. The compound, salt, or solvate of any one of claims 1 to 2, wherein the degradation enhancer is capable of binding a protein selected from UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2DR, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2L1, UBE2L2, UBE2L4, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2W, UBE2Z, ATG3, BIRC6, and UFC1.

5. The compound, salt, or solvate of any one of the preceding claims, wherein DG is selected from:wherein:J4is selected from a bond, 2- to 10-membered heteroalkylene, 3- to 10-membered heteroalkenylene, and 3- to 10-membered heteroalkynylene, wherein 2- to 10-membered heteroalkylene, 3- to 10-memberedheteroalkenylene, and 3- to 10-membered heteroalkynylene are optionally substituted with one or more RB20;RB15is selected from hydrogen, Ci-6 alkyl, C3.8 carbocycle, and 3- to 8-membered heterocycle, wherein C1-6 alkyl, C3-8 carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one or more RB2°;RB16is selected from hydrogen, C1-6 alkyl, -ORB12, -C(O)ORB12, and -C(O)RB12, wherein C1-6 alkyl is optionally substituted with one or more RB20;RB17is selected from halogen, -CN, C1-3 alkyl, C3.6 carbocycle, 4- to 6-membered heterocycle, and - S(O)2CH3, wherein C1-3 alkyl, C3.6 carbocycle, and 4- to 6-membered heterocycle are optionally substituted with one or more RB20; ol is selected from 0, 1, and 2; pl and ql are independently selected from 1, 2, and 3; and X is selected from CH2and C(O).

6. The compound, salt, or solvate of any one of the preceding claims, wherein DG is7. A method of preparing a compound of Formula (AO):the method comprising:(a) reacting a compound of Formula (a0):with a degradation enhancer under conditions to effect release of LG and production of the compound of Formula (AO), wherein:Z1is selected from N and N(RBlb);Z2is selected from C(RB2) and C(O);ZB5is selected from C(RB9)2and O;Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);Z7is selected from C(RB7) and N(RB7b);Z8is selected from C(RB8), C(RB8)2, and N;Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;J1is selected from a bond, C1-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-memberedheteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB20;J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB20;J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB20;DG is a degradation enhancer;LG is a leaving group; nl is selected from 1, 2, and 3;RBlb, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, -C(O)N(RB12)(RB13), - C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB 12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB9is independently selected at each occurrence from hydrogen and RB2°;RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB13is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;RB2° is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), =NRB22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);RB21is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

8. A compound of Formula (a0):or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is selected from N and N(RBlb);Z2is selected from C(RB2) and C(O);ZB5is selected from C(RB9)2 and O;Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);Z7is selected from C(RB7) and N(RB7b);Z8is selected from C(RB8), C(RB8)2, and N;Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;J1is selected from a bond, Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;J3is selected from C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-12 carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;RB4is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-memberedheteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB20;RB9is independently selected at each occurrence from hydrogen and RB2°;RB12is independently selected at each occurrence from hydrogen, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB13is independently selected at each occurrence from hydrogen, Ci-6 alkyl, and Ci-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;RB2° is independently selected at each occurrence from halogen, oxo, -CN, Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, -ORB22, -SRB22, -N(RB22)(RB23), ~NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), - N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, -N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, - C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), -N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, - S(O)2N(RB22)(RB23), and -S(=O)(=NRB22)N(RB22)(RB23);RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);RB23is independently selected at each occurrence from hydrogen and Ci-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

9. A compound of Formula (a):or a pharmaceutically acceptable salt or solvate thereof, wherein:Z1is selected from N and N(RBlb);Z2is selected from C(RB2) and C(O);Z6is selected from C(RB6), C(RB6)2, N, and N(RB6b);Z7is selected from C(RB7) and N(RB7b);Z8is selected from C(RB8), C(RB8)2, and N;Q2is 4- to 12-membered heterocycle optionally substituted with one or more RB2°;J1is selected from a bond, Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -O-, -N(RB12)-, -C(O)-, - N(RB12)C(O)-, -C(O)N(RB12)-, -S-, -S(O)2-, -S(O)-, -P(O)RB12-, -N(RB12)S(O)2-, -N(RB12)S(O)-, -N(RB12)P(O)RB12-, - S(O)2N(RB12)-, -S(O)N(RB12)-, -P(O)RB12N(RB12)-, -OS(O)2-, -OS(O)-, -OP(O)RB12-, -S(O)2O-, -S(O)O-, and - P(O)RB12O-, wherein Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6- membered heteroalkenylene, and 3- to 6-membered heteroalkynylene are optionally substituted with one or more RB2°;J2is selected from a bond, -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle)-, wherein -C0-6 alkyl-(C3-12 carbocycle)-, -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle)- , -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)- are optionally substituted with one or more RB2°;J3is selected from Ci-6 alkylene, C2.6 alkenylene, C2.6 alkynylene, 2- to 6-membered heteroalkylene, 3- to 6-membered heteroalkenylene, 3- to 6-membered heteroalkynylene, -C0-6 alkyl-(C3-i2carbocycle)-, -(2- to 6- membered heteroalkyl)-(C3-i2carbocycle)-, -C0-6 alkyl-(3- to 12-membered heterocycle)-, and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle)-, each of which is optionally substituted with one or more RB2°;LG is selected from -OS(O)2RB4and -OS(O)(NRB4b)RB4; nl is selected from 1, 2, and 3;RB4is selected from Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), and -N(RB12)(RB13), wherein Ci-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3-i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RBlb, RB4b, RB6b, and RB7bare independently selected from hydrogen, -CN, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)ORB12, -C(O)RB12, - C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and - S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three RB2°;RB2, RB6, RB7, and RB8are independently selected at each occurrence from hydrogen, halogen, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB12, -SRB12, - N(RB12)(RB13), -C(O)ORB12, -OC(O)N(RB12)(RB13), -N(RB12)C(O)N(RB12)(RB13), -N(RB12)C(O)ORB12, - N(RB12)S(O)2RB12, -C(O)RB12, -S(O)RB12, -OC(O)RB12, -C(O)N(RB12)(RB13), -C(O)C(O)N(RB12)(RB13), - N(RB12)C(O)RB12, -S(O)2RB12, -S(O)(NRB12)RB12, -S(O)2N(RB12)(RB13), and -S(=O)(=NRB12)N(RB12)(RB13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB9is independently selected at each occurrence from hydrogen and RB2°;RB12is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -C0-6 alkyl-(C3-12 carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more RB2°;RB13is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl; or RB12and RB13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more RB2°;RB2° is independently selected at each occurrence from halogen, oxo, -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -ORB22, -SRB22, -N(RB22)(RB23), -NRli22, =C(RB21)2, -C(O)ORB22, -OC(O)N(RB22)(RB23), -N(RB22)C(O)N(RB22)(RB23), -N(RB22)C(O)ORB22, - N(RB22)S(O)2RB22, -C(O)RB22, -S(O)RB22, -OC(O)RB22, -C(O)N(RB22)(RB23), -C(O)C(O)N(RB22)(RB23), - N(RB22)C(O)RB22, -S(O)2RB22, -S(O)(NRB22)RB22, -S(O)2N(RB22)(RB23)-, and -S(=O)(=NRB22)N(RB22)(RB23); wherein two RB2° attached to the same or adjacent atoms optionally join to form C3-12 carbocycle or 3- to 12-membered heterocycle; wherein C1-6 alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-i2carbocycle), -(2- to 6-membered heteroalkyl)-(C3. i2carbocycle), -C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6RB21is independently selected at each occurrence from hydrogen, halogen, Ci-6 alkyl, Ci-6 haloalkyl, -C0-6 alkyl-(C3-i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle), or two RB21are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and -OH;RB22is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(C3- i2carbocycle), and -C0-6 alkyl-(3- to 12-membered heterocycle);RB23is independently selected at each occurrence from hydrogen and C1-6 alkyl; or RB22and RB23attached to the same nitrogen atom form 3- to 10 membered heterocycle; and indicates a single or double bond such that all valences are satisfied.

10. The compound, salt, solvate, or method of any one of claims 1 or 3 to 8, wherein ZB5is C(RB9)2.

11. The compound, salt, solvate, or method of any one of claims 1 to 10, wherein nl is 1.

12. The compound, salt, solvate, or method of any one of claims 1 to 11, wherein Q2is 7- to 9-membered bridged bicyclic heterocycloalkyl optionally substituted with one or more RB2°.

13. The compound, salt, solvate, or method of claim 12, wherein, which is optionally substituted with one or more RB20.

14. The compound, salt, solvate, or method of any one of the preceding claims, wherein:Z1is N, Z2is C(RB2), Z6is C(RB6), Z7is C(RB7), and Z8is C(RB8);Z1is N, Z2is C(RB2), Z6is N, Z7is C(RB7), and Z8is C(RB8);Z1is N, Z2is C(RB2), Z6is C(RB6)2, Z7is N(RB7b), and Z8is C(RB8)2; orZ1is N(RBlb), Z2is C(O), Z6is C(RB6), Z7is C(RB7), and Z8is N.

15. The compound, salt, solvate, or method of claim 14, wherein Z1is N, Z2is C(RB2), Z6is C(RB6), Z7is C(RB7), and Z8is C(RB8).

16. The compound, salt, solvate, or method of claim 14, wherein Z1is N, Z2is C(RB2), Z6is N, Z7is C(RB7), and Z8is C(RB8).

17. The compound, salt, solvate, or method of any one of the preceding claims, wherein J1is selected from a bond, Ci-6 alkylene, 2- to 6-membered heteroalkylene, and -C(O)-, wherein Ci-6 alkylene and 2- to 6-membered heteroalkylene are optionally substituted with one or more RB2°.

18. The compound, salt, solvate, or method of any one of the preceding claims, wherein J1is -C(O)-.

19. The compound, salt, solvate, or method of any one of the preceding claims, wherein J2is a bond.

20. The compound, salt, solvate, or method of any one of the preceding claims, wherein J3is selected from C1-6 alkylene and 2- to 6-membered heteroalkylene, each of which is optionally substituted with one or more RB20.

21. The compound, salt, solvate, or method of any one of claims 1 to 16, wherein:J1is -C(O)-;J2is a bond; andJ3is Ci-6 alkylene.

22. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB2is -O(Ci-3 alkylene)(4- to 10-membered heterocycle), wherein 4- to 10-membered heterocycle is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and =C(RB21)2, and wherein RB21is independently selected at each occurrence from hydrogen, halogen, and C1-3 alkyl.24. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB2is25. The compound, salt, solvate, or method of any one of claims 1 to 21, wherein RB2is selected from26. The compound, salt, solvate, or method of any one of claims 1 to 21, wherein RB2is27. The compound, salt, solvate, or method of any one of claims 1 to 21, wherein RB2is selected from28. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB6is halogen or C1-3 haloalkyl.

29. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB7is selected from Cg-i2 aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more RB20.

30. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB7is selected fromnaphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20.

31. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -ORB22, -N(RB22)(RB23), and C3.6 cycloalkyl.

32. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, - C=CH, -OH, -NH2, and -cyclopropyl.

33. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB7is selected from34. The compound, salt, solvate, or method of any one of the preceding claims,36. The compound, salt, solvate, or method of any one of claims 1 to 28, wherein37. The compound, salt, solvate, or method of any one of claims 1 to 28, whereinThe compound, salt, solvate, or method of any one of claims 1 to 28, wherein39. The compound, salt, solvate, or method of any one of claims 1 to 28, whereinThe compound, salt, solvate, or method of any one of claims 1 to 28, wherein41. The compound, salt, solvate, or method of any one of the preceding claims, wherein RB8is halogen.

42. The compound, salt, solvate, or method of any one of claims 1 to 28, wherein:RB6is halogen;RB7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more RB20; andRB8is halogen.

43. The compound, salt, solvate, or method of any one of claims 1 to 21, wherein:

44. The compound, salt, solvate, or method of any one of claims 1 to 21, wherein:RB2is selected fromRB6is halogen;RB8is halogen.

45. The compound, salt, solvate, or method of any one of claims 1, 2 and 7, having the formula:R46. The compound, salt, solvate, or method of any one of claims 7 to 9, having the formula:

47. The compound, salt, solvate, or method of claim 45 or 46, wherein48. The compound, salt, solvate, or method of claim 45 or 46, wherein49. The compound, salt, solvate, or method of claim 45 or 46, wherein50. The compound, salt, solvate, or method of claim 45 or 46, wherein RB7is51. The compound, salt, solvate, or method of claim 45 or 46, wherein52. The compound, salt, solvate, or method of any one of claims 45 to 51, wherein RB2is selected fromThe compound, salt, solvate, or method of any one of claims 45 to 51, wherein RB2isThe compound, salt, solvate, or method of any one of claims 45 to 51, whereinThe compound, salt, solvate, or method of any one of claims 45 to 51, wherein RB2is56. The compound, salt, solvate, or method of any one of claims 1, 7, and 8, wherein the compound is selected from a compound of Table 1.

57. A compound selected from99t.pharmaceutically acceptable salt or solvate thereof.A compound having the formulapharmaceutically acceptable salt or solvate thereof.of.

62. A pharmaceutical composition comprising a compound of any one of claims 1 to 6 or 8 to 61, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

63. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 6 or 8 to 61, or a pharmaceutically acceptable salt or solvate thereof.

64. A method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a compound of any one of claims 1 to 6 or 8 to 61, wherein the compound is characterized in that upon contacting the Ras mutant protein, said Ras mutant protein exhibits reduced Ras signaling output.

65. The method of claim 63 or 64, wherein the cancer is a solid tumor or a hematological cancer.

66. A method of reducing signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a compound of any one of claims 1 to 6 or 8 to 61, or a pharmaceutically acceptable salt or solvate thereof, thereby reducing the signaling output of the Ras protein.

67. The method of claim 66, wherein the compound binds covalently or non-covalently to the Ras protein,thereby reducing the signaling output of the Ras protein.

68. A method of inhibiting cell growth, comprising administering an effective amount of a compound of any one of claims 1 to 6 or 8 to 61, or a pharmaceutically acceptable salt or solvate thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.

69. The method of any one of claims 63 to 68, comprising administering an additional agent.

Images