WO2022271562A1 - Heterocycles and uses thereof - Google Patents

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 proteins.

Description

HETEROCYCLES AND USES THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/213,166, filed June 21, 2021, which is incorporated herein by reference in its entirety. BACKGROUND [0002] 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. [0003] Activated by guanine nucleotide exchange factors (GEFs), Ras in its GTP-bound state interacts with a number of effectors. Return to the inactive state is driven by GTPase-activating proteins (GAPs), which down- regulate active Ras by accelerating the weak intrinsic GTPase activity. For oncogenic Ras mutants, however, the GAP activity is impaired or greatly reduced, resulting in persistent activation, which drives the oncogenic Ras signaling through, e.g., the RAS-RAF-MEK-ERK and RAS-PI3K-PDK1-AKT pathways, both essential to cell survival and proliferation. [0004] The most-studied GEF for Ras is the protein Son of Sevenless (SOS) for which two human isoforms, SOS1 and SOS2, are known. SOS1 is a human homologue of the originally identified Drosophila protein Son of Sevenless. SOS1 has two binding sites for Ras proteins; a catalytic site that binds GDP-bound Ras proteins to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound Ras to further promote activation of Ras proteins. Son of Sevenless 2 (SOS2) is a homolog of SOS1 in mammalian cells. Double SOS1 and SOS2 knockout leads to rapid lethality in adult mice (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). [0005] Although Kras is known to be an oncogenic driver, there is no clinically approved targeted therapy for Ras mutant cancers thus far. Ras proteins have long been considered to be “undruggable,” due to, in part, high affinity to their substrate guanosine-5'-triphosphate (GTP) and/or their smooth surfaces without any obvious targeting region. Recently, a specific G12C Ras gene mutation has been identified as a druggable target. However, such therapeutic approach is still limiting, as the G12C mutation in Ras has a low prevalence rate (e.g., about 3% in pancreatic ductal adenocarcinoma) as compared to other known Ras mutations. SUMMARY [0006] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically inhibit Ras pathway signaling by, e.g., inhibiting a GEF such as a SOS protein. Such compositions and methods can be particularly useful for treating a variety of the 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 treatment for a wide diversity of diseases. [0007] In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Formula (I); wherein: R¹ is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R¹⁰; L¹ is a bond or C_1-6alkyl; R² is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(H)(R¹²), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), - CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3- 6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a; R³ is selected from halogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C₁- 9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -N(R¹⁴)S(O)R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), - C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(O)N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), -CH₂S(O)R¹⁵, -CH₂S(O)N(R¹²)(R¹³), -CH₂N(R¹²)S(O)(R¹³) and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b; R⁴ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁵ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁶ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_{2- 9}heterocycloalkyl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), - CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), -CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20c; R⁷ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_{2- 9}heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; each R¹⁰ is independently selected from halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d; each R¹² is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20e; each R¹³ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; or R¹² and R¹³, together with the nitrogen to which they are attached, form a C_2-9heterocycloalkyl ring optionally substituted with one, two, or three R^20f; each R¹⁴ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; each R¹⁵ is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_{6- 10}aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6- 10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20g; each R¹⁷ and each R^17a are independently selected from C_1-6alkyl and C_3-6cycloalkyl, wherein C_1-6alkyl and C3- 6cycloalkyl are optionally substituted with one, two or three of R^20h; or R¹⁷ and R^17a are combined to form a C_{2- 9}heterocycloalkyl ring; each R^20a, R^20b, R^20c, R^20d, R^20e, R^20f, R^20g, and R^20h is independently selected from halogen, oxo, =NH, -CN, C₁- 6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂-C₂- 9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, C_1-9heteroaryl, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², - C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), -OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, - N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, -S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), -OCH₂C(O)OR²², and -OC(O)R²⁵, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂- C_2-9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1- 6haloalkoxy, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², -C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), - OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, -N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, - S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), and -OC(O)R²⁵; each R²¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²² is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²³ is independently selected from H and C_1-6alkyl; each R²⁴ is independently selected from H and C_1-6alkyl; and each R²⁵ is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl, wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C_1-6alkyl, C_{1- 6}haloalkyl, C_1-6alkoxy, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl. [0008] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from hydrogen, C_1-6alkyl, C_3-6cycloalkyl, and C_2-9heterocycloalkyl, wherein C_1-6alkyl, C_3-6cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_1-6alkyl optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_1-6alkyl substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is -CH₃. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_3-6cycloalkyl optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_3-6cycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_2-9heterocycloalkyl substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from - N(R¹²)(R¹³), -C(O)R¹⁵, -C(O)N(R¹²)(R¹³), -SO2R¹⁵, -SO2N(R¹²)(R¹³), -P(O)(R¹⁷)(R^17a), C_1-6alkyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from - N(R¹²)(R¹³), C_1-6alkyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl, wherein C_1-6alkyl, C_3-10cycloalkyl, and C₂- 9heterocycloalkyl are optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_3-10cycloalkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_1-6alkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is -N(R¹²)(R¹³). In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is selected from hydrogen, halogen, C_1-6alkyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is independently selected from hydrogen, halogen, and unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is selected from hydrogen, halogen, C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3- 10cycloalkyl, C_2-9heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is independently selected from hydrogen, halogen, and unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is selected from C_1-6alkyl and C_{1- 6}haloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is -CH₃. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁴ is hydrogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L¹ is a bond. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 6-10 membered aryl ring substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one, two, or three R¹⁰. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, C3- 7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², and -N(R¹²)(R¹³), wherein C_1-6alkyl, C3- ₇cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, and -N(R¹²)(R¹³), wherein C_1-6alkyl is optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is halogen. [0009] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰; L¹ is a bond; R² is -CH₃; R³ is selected from -N(R¹²)(R¹³), C_1-6alkyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl, wherein C_1-6alkyl, C_3-10cycloalkyl, and C_{2- 9}heterocycloalkyl are optionally substituted with one, two, or three R^20b; R⁴ is hydrogen; R⁵ is -CH₃; R⁶ is hydrogen; and R⁷ is independently selected from hydrogen, halogen, and unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from C4-8cycloalkyl and C₂-7heterocycloalkyl, each of which is optionally substituted with one, two, or three R^20b; and R⁷ is -CH₃. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C₂-7heterocycloalkyl, and -OH, wherein C₂-7heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; and each R^20b is independently selected from halogen, oxo, and C_1-6alkyl, wherein C_{1- 6}alkyl is optionally substituted with one, two, or three groups selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R²⁵ is independently selected from C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl. [0010] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient. [0011] Also provided in the present disclosure is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is a solid tumor or a hematological cancer. [0012] Also provided herein is a method of reducing Ras signaling output comprising contacting a SOS1 protein with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, thereby reducing the Ras signaling output. In some embodiments is a method of reducing Ras signaling output of a SOS1 protein comprising contacting a SOS1 protein with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, thereby reducing the Ras signaling output. In some embodiments, a subject compound interferes or disrupts the interaction or binding between a SOS protein (e.g., SOS1) with a Ras protein (e.g., wildtype or a mutant Ras). [0013] Further provided herein is a method of inhibiting cell growth, comprising administering a cell expressing SOS1 with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, thereby inhibiting growth of said cells. The method may further comprise administering to the cell an additional agent. Where desired, the additional agent can be an inhibitor against one or more targets including but not limited to: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHC, GAB, GRB, PI3-kinase, MAPK, SHP1, SHP2, SHIP1, SHIP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, WT Ras (e.g., Kras), mutant Ras (KrasG12C, KrasG12D, KrasG13C, KrasG13D, KrasG12S, or KrasG12V), ROS1, CDK4/6, and a mutant of any target thereof. In some embodiments, the additional agent is a chemotherapeutic agent, a radioactive agent, or an immune modulator. [0014] Also provided herein is a modified SOS1 protein bound by a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein interaction of the SOS1 protein with a Ras protein is reduced as compared to a SOS1 protein unbound to said compound. INCORPORATION BY REFERENCE [0015] 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. DETAILED DESCRIPTION [0016] The practice of some embodiments disclosed herein employ, unless otherwise indicated, conventional techniques of immunology, biochemistry, chemistry, molecular biology, microbiology, cell biology, genomics and recombinant DNA, which are within the skill of the art. See for example Sambrook and Green, Molecular Cloning: A Laboratory Manual, 4th Edition (2012); the series Current Protocols in Molecular Biology (F. M. Ausubel, et al. eds.); the series Methods In Enzymology (Academic Press, Inc.), PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications, 6th Edition (R.I. Freshney, ed. (2010)). [0017] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood to which the claimed subject matter 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. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information. [0018] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. In this application, the use of “or” means “and/or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. [0019] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. [0020] Definition of standard chemistry terms may be found in reference works, including but not limited to, Carey and Sundberg “Advanced Organic Chemistry 4^th Ed.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology. [0021] Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those recognized in the field. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods and as described in various general and more specific references that are cited and discussed throughout the present specification. [0022] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein and as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, compositions described herein. [0023] As used herein, C₁-C_x includes C₁-C₂, C₁-C₃... C₁-C_x. C₁-C_x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). [0024] An “alkyl” group refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation. In some embodiments, the “alkyl” group may have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as “1 to 6” refers to each integer in the given range; e.g., “1 to 6 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group of the compounds described herein may be designated as “C₁- C₆alkyl” or similar designations. By way of example only, “C₁-C₆alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (i.e., an alkylene group). [0025] An “alkoxy” refers to a “-O-alkyl” group, where alkyl is as defined herein. [0026] The term “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond. Non-limiting examples of an alkenyl group include -CH=CH₂, -C(CH₃)=CH₂, -CH=CHCH₃, -CH=C(CH₃)₂ and –C(CH₃)=CHCH₃. In some embodiments, an alkenyl group may have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group). [0027] The term “alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond. Non-limiting examples of an alkynyl group include –C≡CH, -C≡CCH₃, –C≡CCH₂CH₃ and –C≡CCH₂CH₂CH₃. In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group). [0028] “Amino” refers to a -NH₂ group. [0029] The term “alkylamine” or “alkylamino” refers to the -N(alkyl)xHy group, where alkyl is as defined herein and x and y are selected from the group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, taken together with the nitrogen to which they are attached, can optionally form a cyclic ring system. “Dialkylamino” refers to an -N(alkyl)₂ group, where alkyl is as defined herein. [0030] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ electrons, where n is an integer. Aromatic rings can be formed from five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted. The term “aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl). [0031] As used herein, the term “aryl” refers to a monocyclic aromatic ring wherein each of the atoms forming the ring is a carbon atom (e.g., phenyl) or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic and aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic aromatic ring of the aryl ring system, and 3) the carbocyclic aromatic ring of the aryl ring system of 2) is not directly bonded (e.g., fused) to a heteroaryl ring in the polycyclic ring system. Aryl rings can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to phenyl, and naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). As used herein, the aryl radical is a monocyclic, bicyclic, or tricyclic ring system. In embodiments, an aryl is a monocyclic ring. In embodiments, an aryl is a fused ring polycyclic system. In embodiments, an aryl is a bridged ring polycyclic system. In some embodiments the aryl is a “fused ring aryl” wherein the aryl ring is fused with a cycloalkyl or a heterocycloalkyl ring. [0032] “Carboxy” refers to -CO₂H. In some embodiments, carboxy moieties may be replaced with a “carboxylic acid bioisostere”, which refers to a functional group or moiety that exhibits similar physical and/or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties to that of a carboxylic acid group. A compound with a carboxylic acid moiety can have the carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and/or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere would ionize at physiological pH to roughly the same extent as a carboxylic acid group. Examples of bioisosteres of a carboxylic acid include, but are not limited to,

and the like. [0033] The term “cycloalkyl” refers to a monocyclic carbocyclic saturated or partially unsaturated non-aromatic ring or a polycyclic carbocyclic (i.e., does not include heteroatom(s)) ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is carbocyclic saturated or partially unsaturated and non-aromatic, 2) a bond to the remainder of the compound is directly bonded to a carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system, and 3) the carbocyclic saturated or partially unsaturated non-aromatic ring of the ring system of 2) is not directly bonded (e.g., fused or spirocyclic) to a heterocycloalkyl ring in the polycyclic ring system. Cycloalkyls may be saturated or partially unsaturated. In some embodiments, a cycloalkyl ring is a spirocyclic cycloalkyl ring. In embodiments, a cycloalkyl is a monocyclic ring. In embodiments, a cycloalkyl is a fused ring polycyclic system. In embodiments, a cycloalkyl is a bridged ring polycyclic system. In embodiments, a cycloalkyl is a spirocyclic polycyclic ring system. In some embodiments, cycloalkyl groups include groups having from 3 to 10 ring atoms. Depending on the structure, a cycloalkyl group can be a monoradical or a diradical (i.e., a cycloalkylene group). [0034] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an monocyclic aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur; or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is aromatic and includes one or more heteroatoms selected from nitrogen, oxygen and sulfur and 2) a bond to the remainder of the compound is directly bonded to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur or an aromatic ring directly bonded (e.g., fused) to an aromatic ring including one or more heteroatoms selected from nitrogen, oxygen and sulfur, of the aryl ring system. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, or tricyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated (i.e., aromatic) and includes a heteroatom. In embodiments, a heteroaryl is a monocyclic ring. In embodiments, a heteroaryl is a fused ring polycyclic system. In embodiments, a heteroaryl is a bridged ring polycyclic system. In some embodiments is a “fused ring heteroaryl” wherein the heteroaryl ring is fused with a cycloalkyl, aryl, or heterocycloalkyl ring. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. Depending on the structure, a heteroaryl group can be a monoradical or a diradical (i.e., a heteroarylene group). [0035] A “heterocycloalkyl” group or “heteroalicyclic” group refers to a cycloalkyl group, wherein at least one skeletal ring atom of a saturated or partially unsaturated non-aromatic ring is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur. A heterocycloalkyl refers to a monocyclic saturated or partially unsaturated non- aromatic ring including one or more heteroatoms or a polycyclic ring system (e.g., bicyclic or tricyclic) wherein 1) at least one ring is saturated or partially unsaturated, non-aromatic, and includes one or more heteroatoms and 2) a bond to the remainder of the compound is directly bonded to a ring of the ring system that is a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms or a non-aromatic ring directly bonded (e.g., fused) to a saturated or partially unsaturated and non-aromatic ring that includes one or more heteroatoms of the ring system. Heterocycloalkyls may be saturated or partially unsaturated. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. In some embodiments, a heterocycloalkyl ring is a spirocyclic heterocycloalkyl ring. In embodiments, a heterocycloalkyl is a monocyclic ring. In embodiments, a heterocycloalkyl is a fused ring polycyclic system. In embodiments, a heterocycloalkyl is a bridged ring polycyclic system. In embodiments, a heterocycloalkyl is a spirocyclic polycyclic ring system. Unless otherwise noted, heterocycloalkyls have from 2 to 13 carbons in the ring or ring system. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Depending on the structure, a heterocycloalkyl group can be a monoradical or a diradical (i.e., a heterocycloalkylene group). [0036] The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromo and iodo. [0037] The term “haloalkyl” refers to an alkyl group that is substituted with one or more halogens. The halogens may the same or they may be different. Non-limiting examples of haloalkyls include -CH₂Cl, -CF₃, -CHF₂, - CH₂CF₃, -CF₂CF₃, and the like. [0038] The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyls include -CF₃, -CHF₂, -CH₂F, - CH₂CF₃, -CF₂CF₃, -CF₂CF₂CF₃, -CF(CH₃)₃, and the like. Non-limiting examples of fluoroalkoxy groups, include - OCF₃, -OCHF₂, -OCH₂F, -OCH₂CF₃, -OCF₂CF₃, -OCF₂CF₂CF₃, -OCF(CH₃)₂, and the like. [0039] The term “heteroalkyl” refers to an alkyl radical where one or more skeletal chain atoms is selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatom(s) may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH₂-O-CH₃, -CH₂-CH₂-O-CH₃, -CH₂-NH-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-N(CH₃)-CH₃, -CH₂-CH₂-NH-CH₃, - CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂-S(O)-CH₃, -CH₂-CH₂-S(O)₂-CH₃, -CH₂-NH-OCH₃, –CH₂-O- Si(CH₃)₃, -CH₂-CH=N-OCH₃, and -CH=CH-N(CH₃)-CH₃. In addition, up to two heteroatoms may be consecutive, such as, by way of example, -CH₂-NH-OCH₃ and -CH₂-O-Si(CH₃)₃. Excluding the number of heteroatoms, a “heteroalkyl” may have from 1 to 6 carbon atoms. [0040] The term “oxo” refers to the =O radical. [0041] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. [0042] A waved line “ ” drawn across a bond or a dashed bond “ ” are used interchangeably herein to denote

where a bond disconnection or attachment occurs. For example, in the structure ³

, if R is 1- cyclopropyl-1-carbonitrile as in

, then R³ may be depicted as

“ ” or “ ”. [0043] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. [0044] As used herein, the substituent “R” appearing by itself and without a number designation refers to a substituent selected from among from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl. [0045] “Optional” or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. [0046] The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, - CN, alkyne, C₁-C₆alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g. –NH2, -NHR, -N(R)₂), and the protected derivatives thereof. By way of example, an optional substituents may be L^sR^s, wherein each L^s is independently selected from a bond, - O-, -C(=O)-, -S-, -S(=O)-, -S(=O)₂-, -NH-, -NHC(O)-, -C(O)NH-, -S(=O)₂NH-, -NHS(=O)₂, -OC(O)NH-, - NHC(O)O-, -(C₁-C₆alkyl)-, or -(C₂-C₆alkenyl)-; and each R^s is independently selected from among H, (C₁-C₆alkyl), (C₃-C₈cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C₁-C₆heteroalkyl. The protecting groups that may form the protective derivatives of the above substituents are found in sources such as Greene and Wuts, above. [0047] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the heterocyclic LpxC inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. [0048] “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 of basic 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. [0049] “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, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra. [0050] “Prodrug” as used herein is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be 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). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are 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, may be 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. [0051] 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. [0052] The terms “polynucleotide”, “nucleotide”, “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 non- coding 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. [0053] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNA template (such as into and 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. [0054] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells, and their progeny of a biological entity obtained in vivo or cultured in vitro are also encompassed. [0055] 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. [0056] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant any therapeutically relevant improvement in or effect on one or more diseases, conditions, or symptoms under treatment. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more of the physiological symptoms of a disease, even though the disease, condition, or symptom may not have yet been manifested. Typically, prophylactic benefit includes reducing the incidence and/or worsening of one or more diseases, conditions, or symptoms under treatment (e.g. as between treated and untreated populations, or between treated and untreated states of a subject). [0057] 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. [0058] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody. [0059] 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, i.e., “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). [0060] 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. [0061] The term “in vivo” refers to an event that takes place in a subject's body. [0062] 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. [0063] 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. [0064] 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 (K-Ras or 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. [0065] 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, 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). Compounds [0066] The compounds of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, disclosed herein are SOS modulators and have a wide range of applications in therapeutics, diagnostics, and other biomedical research. [0067] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Formula (I); wherein: R¹ is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R¹⁰; L¹ is a bond or C_1-6alkyl; R² is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(H)(R¹²), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), - CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3- 6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a; R³ is selected from halogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_{1- 9}heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -N(R¹⁴)S(O)R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), - C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(O)N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), -CH₂S(O)R¹⁵, -CH₂S(O)N(R¹²)(R¹³), -CH₂N(R¹²)S(O)(R¹³) and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b; R⁴ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁵ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁶ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; R⁷ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; each R¹⁰ is independently selected from halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_{2- 9}heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d; each R¹² is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20e; each R¹³ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; or R¹² and R¹³, together with the nitrogen to which they are attached, form a C_2-9heterocycloalkyl ring optionally substituted with one, two, or three R^20f; each R¹⁴ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; each R¹⁵ is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6- 10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C6- 10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20g; each R¹⁷ and each R^17a are independently selected from C_1-6alkyl and C_3-6cycloalkyl, wherein C_1-6alkyl and C_{3- 6}cycloalkyl are optionally substituted with one, two or three of R^20h; or R¹⁷ and R^17a are combined to form a C_2- 9heterocycloalkyl ring; each R^20a, R^20b, R^20c, R^20d, R^20e, R^20f, R^20g, and R^20h is independently selected from halogen, oxo, =NH, -CN, C₁- 6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂-C_{2- 9}heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, C_1-9heteroaryl, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², - C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), -OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, - N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, -S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), -OCH₂C(O)OR²², and -OC(O)R²⁵, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂- C_2-9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C₁- 6haloalkoxy, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², -C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), - OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, -N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, - S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), and -OC(O)R²⁵; each R²¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²² is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²³ is independently selected from H and C_1-6alkyl; each R²⁴ is independently selected from H and C_1-6alkyl; and each R²⁵ is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_{1- 9}heteroaryl, wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C_1-6alkyl, C₁- 6haloalkyl, C_1-6alkoxy, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl. [0068] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Formula (I); wherein: R¹ is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R¹⁰; L¹ is a bond or C_1-6alkyl; R² is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(H)(R¹²), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), - CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3- 6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a; R³ is selected from halogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C₁- 9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -N(R¹⁴)S(O)R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), - C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(O)N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), -CH₂S(O)R¹⁵, -CH₂S(O)N(R¹²)(R¹³), -CH₂N(R¹²)S(O)(R¹³) and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b; R⁴ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁵ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁶ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_{2- 9}heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; R⁷ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_{2- 9}heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; each R¹⁰ is independently selected from halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d; each R¹² is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20e; each R¹³ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; or R¹² and R¹³, together with the nitrogen to which they are attached, form a C_2-9heterocycloalkyl ring optionally substituted with one, two, or three R^20f; each R¹⁴ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; each R¹⁵ is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_{6- 10}aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6- 10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20g; each R¹⁷ and each R^17a are independently selected from C_1-6alkyl and C_3-6cycloalkyl, wherein C_1-6alkyl and C3- 6cycloalkyl are optionally substituted with one, two or three of R^20h; or R¹⁷ and R^17a are combined to form a C_{2- 9}heterocycloalkyl ring; each R^20a, R^20b, R^20c, R^20d, R^20e, R^20f, R^20g, and R^20h is independently selected from halogen, oxo, =NH, -CN, C₁- 6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂- C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂-C₂- 9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, C_1-9heteroaryl, -CH₂-C_1-9heteroaryl, -OR²¹, -SR²¹, -N(R²²)(R²³), - C(O)OR²², -C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), -OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), - N(R²⁴)C(O)OR²⁵, -N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, -S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), -OCH₂C(O)OR²², and -OC(O)R²⁵, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C₂- 9heterocycloalkyl, -CH₂-C_2-9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, C_1-9heteroaryl, and -CH₂-C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², -C(O)N(R²²)(R²³), - C(O)C(O)N(R²²)(R²³), -OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, -N(R²⁴)C(O)R²⁵, - N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, -S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), and -OC(O)R²⁵; each R²¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²² is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²³ is independently selected from H and C_1-6alkyl; each R²⁴ is independently selected from H and C_1-6alkyl; and each R²⁵ is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C6- 10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C₁- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl. [0069] In some embodiments is a compound of Formula (I) having the structure of Formula (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Formula (I'). [0070] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from hydrogen, C_1-6alkyl, C_3-6cycloalkyl, and C_2-9heterocycloalkyl, wherein C_1-6alkyl, C_3-6cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_1-6alkyl optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_1- 6alkyl substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is -CH₃. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is -CH₂CH₃. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is -CH(CH₃)₂. [0071] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(H)(R¹²), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), - C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), - CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2- 6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from hydrogen, C_1-6alkyl, C_2-6alkenyl, C_{2- 6}alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6- 10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(H)(R¹²), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), - CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3- 6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a. [0072] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_3-6cycloalkyl optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_3-6cycloalkyl substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_3-6cycloalkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is cyclopropyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is cyclobutyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is cyclopentyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is cyclohexyl. [0073] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_2-9heterocycloalkyl substituted with one, two, or three R^20a. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_2-9heterocycloalkyl. [0074] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is hydrogen. [0075] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is C_1-6alkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is -CH₃. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is C₁- 6haloalkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is hydrogen. [0076] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁴ is hydrogen. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁴ is C_1-6alkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁴ is - CH₃. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁴ is C_1-6haloalkyl. [0077] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from -N(R¹²)(R¹³), -C(O)R¹⁵, -C(O)N(R¹²)(R¹³), -SO2R¹⁵, - SO₂N(R¹²)(R¹³), -P(O)(R¹⁷)(R^17a), C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from -N(R¹²)(R¹³), C_1-6alkyl, C_3-10cycloalkyl, and C₂- ₉heterocycloalkyl, wherein C_1-6alkyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20b. [0078] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from -OR¹², -N(R¹²)(R¹³), -C(O)R¹⁵, -C(O)N(R¹²)(R¹³), -SR¹², -SOR¹², - SO₂R¹⁵, -SO₂N(R¹²)(R¹³), -P(O)(R¹⁷)(R^17a), C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_{1- 9}heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b. [0079] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from -C(O)R¹⁵, -C(O)N(R¹²)(R¹³), C_2-9heterocycloalkyl, C_6-10aryl, and C_{1- 9}heteroaryl, wherein C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is selected from -C(O)R¹⁵. In some embodiments is a compound of Formula (I) or (I'), wherein R¹⁵ is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20g. [0080] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is C_2-9heterocycloalkyl substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is unsubstituted C_{2- 9}heterocycloalkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is spirocyclic C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is fused C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_6-10aryl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is fused C_6-10aryl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_1-9heteroaryl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is fused C_1-9heteroaryl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is -C(O)N(R¹²)(R¹³). [0081] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹⁵ is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20g. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹⁵ is spirocyclic C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20g. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹⁵ is fused C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20g. [0082] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_1-6alkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is C_1-6alkyl substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is unsubstituted C_1-6alkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is - OR¹². In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is -N(R¹²)(R¹³). In some embodiments is a compound of Formula (I) or (I'), wherein R³ is -N(R¹²)(R¹³) and R¹² and R¹³, together with the nitrogen to which they are attached, form a C_2-9heterocycloalkyl ring optionally substituted with one, two, or three R^20f. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is halogen. [0083] In some embodiments is a compound of Formula (I) or (I'), wherein R³ is C_3-10cycloalkyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is C_3-10cycloalkyl substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), wherein R³ is unsubstituted C_3-10cycloalkyl. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is cyclopropyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is cyclobutyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is cyclopentyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is cyclohexyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is aziridinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is azetidinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyrrolidinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is piperidinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is piperizinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is morpholinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is oxetanyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is tetrahydrofuranyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is tetrahydropyranyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyridinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyrazinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyrimidinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyridazinyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is phenyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyrazolyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is pyrrolyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is thiophenyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is thianyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is 1,3-imidazolyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is thiazolyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is oxepanyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is azepanyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is 1,4-dioxapanyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is 1,4-oxazepanyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is 2,6-diazaspiro[3.3]heptanyl optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is 2-oxa-6-azaspiro[3.3]heptanyl optionally substituted with one, two, or three R^20b. [0084] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0085] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0086] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

. [0087] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0088] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0089] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0090] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0091] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0092] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0093] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0094] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0095] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0096] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0097] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0098] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[0099] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[00100] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from C4-8cycloalkyl and C₂-7heterocycloalkyl, each of which is optionally substituted with one, two, or three R^20b. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

or each of which is optionally substituted with

one or more R^20b, such as one, two, or three R^20b. In some embodiments, each R^20b is independently selected from halogen, oxo, and C_1-6alkyl, wherein C_1-6alkyl is optionally substituted with one, two, or three groups selected from halogen. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is

[00101] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is selected from hydrogen, C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is selected from hydrogen and C_1-6alkyl optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is C_1-6alkyl optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is methyl. [00102] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is selected from hydrogen, C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is selected from hydrogen and C_1-6alkyl optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is C_1-6alkyl optionally substituted with one, two, or three R^20c. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is hydrogen. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is methyl. [00103] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L¹ is a bond. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L¹ is C_1-6alkyl. [00104] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 6-10 membered aryl ring optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 6-10 membered aryl ring substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a phenyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, C3- 7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², and -N(R¹²)(R¹³), wherein C_1-6alkyl, C3- ₇cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, and -N(R¹²)(R¹³), wherein C_1-6alkyl is optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is halogen. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is halogen or -OH. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from -F and C_1-6alkyl, wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is -F or -OH. [00105] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one, two, or three R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², and -N(R¹²)(R¹³), wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, and -N(R¹²)(R¹³), wherein C_1-6alkyl is optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one, two, or three R¹⁰, wherein each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is halogen. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is an unsubstituted 5-10 membered heteroaryl ring. [00106] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², and -N(R¹²)(R¹³), wherein C_1-6alkyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, and -N(R¹²)(R¹³), wherein C_1-6alkyl is optionally substituted with one, two, or three R^20d. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, and -N(R¹²)(R¹³), wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is halogen. [00107] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is benzothiazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is 1H- benzo[d]imidazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is benzo[c]thiophenyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is benzo[b]thiophenyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is indanyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is indenyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is tetralinyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is coumaranyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is furanyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is thiophenyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is oxazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is thiazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is 1H-indazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is imidazo[1,2- a]pyridinyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is pyrazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is 1H-indolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is pyridinyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is pyrimidinyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is pyrizinyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is 1H-imidazolyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is 1,4-benzodioxanyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is 3,4-dihydrobenzo[1,4]oxazinyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is benzo[b]furanyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is benzo[c]furanyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is phenyl optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is naphthalenyl optionally substituted with one or more R¹⁰. [00108] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is (benzo[d][1,3]dioxol-4-yl, 1,8a- dihydroimidazo[1,2-a]pyridin-8-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-inden- 4-yl, 1H-inden-5-yl, 1H-inden-6-yl, 1H-inden-7-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 2,3- dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydrobenzo[b][1,4]dioxin-6-yl, 2,3-dihydrobenzofuran-4-yl, 2,3- dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, 3,4-dihydro-2H- benzo[b][1,4]oxazin-5-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl, 3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, 3,4- dihydro-2H-benzo[b][1,4]oxazin-8-yl, 4-(benzo[d][1,3]dioxol-5-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8- tetrahydronaphthalen-2-yl, benzo[b]thiophen-4-yl, benzo[b]thiophen-5-yl, benzo[b]thiophen-6-yl, benzo[b]thiophen-7-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-5-yl, benzo[d]thiazol-6-yl, benzo[d]thiazol-7-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl, chroman-5-yl, chroman-6-yl, chroman-7-yl, chroman-8-yl, furan-2-yl, furan-3-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin- 7-yl, naphthalen-1-yl, naphthalen-2-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, or thiophen-3-yl, any of which is optionally substituted with one or more R¹⁰. [00109] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00110] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

. [00111] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is [00112] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00113] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00114] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00115] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00116] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00117] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00118] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00119] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00120] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00121] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00122] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00123] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00124] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00125] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is

[00126] In some embodiments is a compound of Formula (I) or (I'), wherein R¹ is or

such as R¹ is or

In some embodiments, each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C1-6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C2- 7heterocycloalkyl, and -OH, wherein C2-7heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl. [00127] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 3-12 membered cycloalkyl ring optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 3-12 membered cycloalkyl ring substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is an unsubstituted 3-12 membered cycloalkyl ring. [00128] In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 3-12 membered heterocycloalkyl ring optionally substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 3-12 membered heterocycloalkyl ring substituted with one or more R¹⁰. In some embodiments is a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is an unsubstituted 3-12 membered heterocycloalkyl ring. [00129] In some embodiments, the compound of Formula (I) is a compound of the formula

or

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [00130] In some embodiments is a compound selected from:

and ; or a pharmaceutically acceptable salt, solvate, or

prodrug thereof. Further Forms of Compounds Disclosed Herein Isomers [00131] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. Labeled compounds [00132] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as ²H, ³H, ¹³C, ¹⁴C, ^l5N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds described herein, and pharmaceutically acceptable salts, esters, solvate, hydrates, prodrugs, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i. e., ³H and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., ²H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, prodrugs, or derivative thereof is prepared by any suitable method. [00133] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Pharmaceutically acceptable salts [00134] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. [00135] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed. Solvates [00136] In some embodiments, the compounds described herein exist as solvates. In some embodiments are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions. [00137] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Synthesis of Compounds [00138] In some embodiments, the synthesis of compounds described herein are accomplished using means described in the chemical literature, using the methods described herein, or by a combination thereof. In addition, solvents, temperatures and other reaction conditions presented herein may vary. [00139] In other embodiments, the starting materials and reagents used for the synthesis of the compounds described herein are synthesized or are obtained from commercial sources, such as, but not limited to, Sigma- Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics. [00140] In further embodiments, the compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein as well as those that are recognized in the field, such as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4^th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4^th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3^rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as disclosed herein may be derived from reactions and the reactions may be modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formulae as provided herein. In some embodiments, the following synthetic methods may be utilized. Scheme 1

Scheme 2

Scheme 3 Scheme 4 Scheme 5

[00141] In some embodiments, the compounds of the present invention exhibit one or more functional characteristics disclosed herein. For example, a subject compound is capable of reducing Ras signaling output. In some instances, a subject compound is capable of disrupting Ras-SOS interaction, including disrupting interaction or binding between a mutant Kras (e.g., Kras G12C) and SOS1, or between a wildtype Kras and SOS1, thereby reducing Ras signaling output. In some embodiments, a subject compound binds specifically to a SOS protein, including SOS1. In some embodiments, the IC50 of a subject compound disclosed herein for a SOS protein is less than about less than about 5 µM, less than about 1 µM, less than about 50 nM, less than about 10 nM, less than about 1 nM, less than about 0.5 nM, less than about 100 pM, or less than about 50 pM, as measured in an in vitro assay known in the art or exemplified herein. [00142] A reduction in Ras signaling output can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP-bound Ras protein; (ii) a reduction of phosphorylated AKTs473, (iii) a reduction of phosphorylated ERKT202/y204, (iv) a reduction of phosphorylated S6S235/236, (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein), and (vi) an interference or disruption of the interaction or binding between a SOS protein (e.g., SOS1) with a Ras protein such as a wildtype or a mutant Ras. In some cases, the reduction in Ras signaling output can be evidenced by two, three, four, five, or all of (i)-(vi) above. Methods [00143] In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is a solid tumor or a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is a solid tumor. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is selected from prostate cancer, brain cancer, colon cancer, rectal cancer, renal-cell carcinoma, liver cancer, non- small cell carcinoma of the lung, cancer of the small intestine, cancer of the esophagus, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers, combinations of said cancers, and metastatic lesions of said cancers. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is a hematological cancer. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is a hematological cancer selected from one or more of chronic lymphocytic leukemia (CLL), acute leukemias, acute lymphoid leukemia (ALL), B-cell acute lymphoid leukemia (B-ALL), T- cell acute lymphoid leukemia (T-ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and pre-leukemia. In some embodiments is a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the cancer is one or more cancers selected from the group consisting of chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B cell acute lymphoblastic leukemia (B-ALL), and acute lymphoblastic leukemia (ALL). [00144] Any of the treatment methods disclosed herein can be administered alone or in combination or in conjunction with another therapy or another agent. By “combination” it is meant to include (a) formulating a subject composition containing a subject compound together with another agent, and (b) using the subject composition separate from the another agent as an overall treatment regimen. By “conjunction” it is meant that the another therapy or agent is administered either simultaneously, concurrently or sequentially with a subject composition comprising a compound disclosed herein, with no specific time limits, wherein such conjunctive administration provides a therapeutic effect. [00145] In some embodiments, a subject treatment method is combined with surgery, cellular therapy, chemotherapy, radiation, and/or immunosuppressive agents. Additionally, compositions of the present disclosure can be combined with other therapeutic agents, such as other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, immunostimulants, and combinations thereof. [00146] In one embodiment, a subject treatment method is combined with a chemotherapeutic agent. [00147] Exemplary chemotherapeutic agents include an anthracycline (e.g., doxorubicin (e.g., liposomal doxorubicin)), a vinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine), an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), an immune cell antibody (e.g., alemtuzamab, gemtuzumab, rituximab, ofatumumab, tositumomab, brentuximab), an antimetabolite (including, e.g., folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), a TNFR glucocorticoid induced TNFR related protein (GITR) agonist, a proteasome inhibitor (e.g., aclacinomycin A, gliotoxin or bortezomib), an immunomodulator such as thalidomide or a thalidomide derivative (e.g., lenalidomide). Additional chemotherapeutic agents contemplated for use in combination include busulfan (Myleran®), busulfan injection (Busulfex®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), daunorubicin hydrochloride (Cerubidine®), daunorubicin citrate liposome injection (DaunoXome®), dexamethasone, doxorubicin hydrochloride (Adriamycin®, Rubex®), etoposide (Vepesid®), fludarabine phosphate (Fludara®), hydroxyurea (Hydrea®), Idarubicin (Idamycin®), mitoxantrone (Novantrone®), Gemtuzumab Ozogamicin (Mylotarg®), anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), dacarbazine (DTIC-Dome®), dactinomycin (Actinomycin D, Cosmegan), dexamethasone, docetaxel (Taxotere®), 5-fluorouracil (Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine (difluorodeoxycitidine), ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine (Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®), mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate (Nolvadex®), teniposide (Vumon®), 6- thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®). [00148] Anti-cancer agents of particular interest for combinations with a compound of the present disclosure include: anthracyclines; alkylating agents; antimetabolites; drugs that inhibit either the calcium dependent phosphatase calcineurin or the p70S6 kinase FK506 or inhibit the p70S6 kinase; mTOR inhibitors; immunomodulators; vinca alkaloids; proteosome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; a CDK4 kinase inhibitor; a BTK inhibitor; a MKN kinase inhibitor; a DGK kinase inhibitor; or an oncolytic virus. [00149] Exemplary antimetabolites include, without limitation, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors): methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), floxuridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®)), 6-thioguanine (Thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), azacitidine (Vidaza®), decitabine and gemcitabine (Gemzar®). Preferred antimetabolites include, cytarabine, clofarabine and fludarabine. [00150] Exemplary alkylating agents include, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional exemplary alkylating agents include, without limitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® and Temodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®); Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan (Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (also known as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® and Neosar®); Dacarbazine (also known as DTIC, DIC and imidazole carboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine (Matulane®); Mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA, Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and Bendamustine HCl (Treanda®). [00151] In an aspect, compositions provided herein can be administered in combination with radiotherapy such as radiation. Whole body radiation may be administered at 12 Gy. A radiation dose may comprise a cumulative dose of 12 Gy to the whole body, including healthy tissues. A radiation dose may comprise from 5 Gy to 20 Gy. A radiation dose may be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12, Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. Radiation may be whole body radiation or partial body radiation. In the case that radiation is whole body radiation it may be uniform or not uniform. For example, when radiation may not be uniform, narrower regions of a body such as the neck may receive a higher dose than broader regions such as the hips. [00152] Where desirable, an immunosuppressive agent can be used in conjunction with a subject treatment method. Exemplary immunosuppressive agents include but are not limited to cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytoxin, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and irradiation, peptide vaccine, and any combination thereof. In accordance with the presently disclosed subject matter, the above-described various methods can comprise administering at least one immunomodulatory agent. In certain embodiments, the at least one immunomodulatory agent is selected from the group consisting of immunostimulatory agents, checkpoint immune blockade agents (e.g., blockade agents or inhibitors of immune checkpoint genes, such as, for example, PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIRs and CD39), radiation therapy agents, chemotherapy agents, and combinations thereof. In some embodiments, the immunostimulatory agents are selected from the group consisting of IL-12, an agonist costimulatory monoclonal antibody, and combinations thereof. In one embodiment, the immunostimulatory agent is IL-12. In some embodiments, the agonist costimulatory monoclonal antibody is selected from the group consisting of an anti-4-lBB antibody (e.g., urelumab, PF-05082566), an anti-OX40 antibody (pogalizumab, tavolixizumab, PF-04518600), an anti-ICOS antibody (BMS986226, MEDI-570, GSK3359609, JTX- 2011), and combinations thereof. In one embodiment, the agonist costimulatory monoclonal antibody is an anti-4-l BB antibody. In some embodiments, the checkpoint immune blockade agents are selected from the group consisting of anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof. In one embodiment, the checkpoint immune blockade agent is an anti-PD-Ll antibody. In some cases, a compound of the present disclosure can be administered to a subject in conjunction with (e.g., before, simultaneously or following) bone marrow transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In some cases, expanded cells can be administered before or following surgery. Alternatively, compositions comprising a compound described herein can be administered with immunostimulants. Immunostimulants can be vaccines, colony stimulating agents, interferons, interleukins, viruses, antigens, co- stimulatory agents, immunogenicity agents, immunomodulators, or immunotherapeutic agents. An immunostimulant can be a cytokine such as an interleukin. One or more cytokines can be introduced with modified cells provided herein. Cytokines can be utilized to boost function of modified T lymphocytes (including adoptively transferred tumor-specific cytotoxic T lymphocytes) to expand within a tumor microenvironment. In some cases, IL-2 can be used to facilitate expansion of the modified cells described herein. Cytokines such as IL-15 can also be employed. Other relevant cytokines in the field of immunotherapy can also be utilized, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof. An interleukin can be IL-2, or aldesleukin. Aldesleukin can be administered in low dose or high dose. A high dose aldesleukin regimen can involve administering aldesleukin intravenously every 8 hours, as tolerated, for up to about 14 doses at about 0.037 mg/kg (600,000 IU/kg). An immunostimulant (e.g., aldesleukin) can be administered within 24 hours after a cellular administration. An immunostimulant (e.g., aldesleukin) can be administered in as an infusion over about 15 minutes about every 8 hours for up to about 4 days after a cellular infusion. An immunostimulant (e.g., aldesleukin) can be administered at a dose from about 100,000 IU/kg, 200,000 IU/kg, 300,000 IU/kg, 400,000 IU/kg, 500,000 IU/kg, 600,000 IU/kg, 700,000 IU/kg, 800,000 IU/kg, 900,000 IU/kg, or up to about 1,000,000 IU/kg. In some cases, aldesleukin can be administered at a dose from about 100,000 IU/kg to 300,000 IU/kg, from 300,000 IU/kg to 500,000 IU/kg, from 500,000 IU/kg to 700,000 IU/kg, from 700,000 IU/kg to about 1,000,000 IU/kg. [00153] In some other embodiments, any of the compounds herein that is capable of modulating a SOS protein (e.g., SOS1) to reduce Ras signaling output may be administered in combination or in conjunction with one or more pharmacologically active agents including but not limited to: (1) an inhibitor of MEK (e.g., MEK1, MEK2) or of mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib, AZD6244); (2) an inhibitor of epidermal growth factor receptor (EGFR) and/or of mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab panitumumab, osimertinib, olmutinib, EGF-816); (3) an immunotherapeutic agent (e.g., checkpoint immune blockade agents, as disclosed herein); (4) a taxane (e.g., paclitaxel, docetaxel); (5) an anti-metabolite (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogues, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); (6) an inhibitor of FGFR1 and/or FGFR2 and/or FGFR3 and/or of mutants thereof (e.g., nintedanib); (7) a mitotic kinase inhibitor (e.g., a CDK4/6 inhibitor, such as, for example, palbociclib, ribociclib, abemaciclib); (8) an anti-angiogenic drug (e.g., an anti-VEGF antibody, such as, for example, bevacizumab); (9) a topoisomerase inhibitor (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) a platinum-containing compound (e.g. cisplatin, oxaliplatin, carboplatin); (11) an inhibitor of ALK and/or of mutants thereof (e.g. crizotinib, alectinib, entrectinib, brigatinib); (12) an inhibitor of c-MET and/or of mutants thereof (e.g., K252a, SU11274, PHA665752, PF2341066); (13) an inhibitor of BCR-ABL and/or of mutants thereof (e.g., imatinib, dasatinib, nilotinib); (14) an inhibitor of ErbB2 (Her2) and/or of mutants thereof (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) an inhibitor of AXL and/or of mutants thereof (e.g., R428, amuvatinib, XL-880); (16) an inhibitor of NTRK1 and/or of mutants thereof (e.g., Merestinib); (17) an inhibitor of RET and/or of mutants thereof (e.g., BLU-667, Lenvatinib); (18) an inhibitor of A-Raf, B-Raf (e.g., Sorafenib, Vemurafenib, Debrafenib, Encorafenib) and/or C-Raf and/or of mutants thereof (RAF-709, LY-3009120); (19) an inhibitor of ERK and/or of mutants thereof (e.g., ulixertinib); (20) an MDM2 inhibitor (e.g., HDM-201 , NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) an inhibitor of mTOR (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) an inhibitor of BET (e.g., I-BET 151, I-BET 762, OTX-015, TEN- 010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) an inhibitor of IGF1/2 and/or of IGF1-R (e.g., xentuzumab, MEDI-573); (24) an inhibitor of CDK9 (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) an inhibitor of farnesyl transferase (e.g., tipifarnib); (26) an inhibitor of SHIP pathway including SHIP2 inhibitor (e.g., AS1928909), as well as SHIP1 inhibitors; (27) an inhibitor of SRC (e.g., dasatinib); (28) an inhibitor of JAK (e.g., tofacitinib); (29) a PARP inhibitor (e.g. Olaparib, Rucaparib, Niraparib, Talazoparib), (30) a BTK inhibitor (e.g. Ibrutinib, Acalabrutinib, Zanubrutinib), (31) a ROS1 inhibitor (e.g., entrectinib), (32) an inhibitor of FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT, (33) an inhibitor of Kras12C mutant (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors binding to the cysteine residue 12 of Kras, the structures of these compounds are publicly known) (e.g., an inhibitor of Ras G12C as described in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US20180273523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, WO2019051291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, WO2020047192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO2020027083, WO2020027084, WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338, or related patents and applications, each of which is incorporated by reference in its entirety), (34) a SHC inhibitor (e.g., PP2, AID371185), (35) a GAB inhibitor (e.g., GAB-0001), (36) a GRB inhibitor, (37) a PI-3 kinase inhibitor (e.g., Idelalisib, Copanlisib, Duvelisib, Alpelisib, Taselisib, Perifosine, Buparlisib, Umbralisib, NVP-BEZ235-AN), (38) a MARPK inhibitor, (39) CDK4/6 (e.g., palbociclib, ribociclib, abemaciclib), (40) MAPK inhibitor (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH- 797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197), (41) an inhibitor of SHP pathway including SHP2 inhibitor (e.g., 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2- amine, RMC-4630, TNO155 JAB-3068 ( IACS-13909/BBP-398

, SHP099 ERAS-601, and RMC-4550

( ), as well as SHP1 inhibitors; or (42) an inhibitor of a wildtype Kras or a Kras mutant (e.g., Kras G12D including a compound described in WO2021041671, Kras G12C, Kras G12D, Kras G12S, Kras G12V, Kras G13D, Kras G13C, or Kras G13V). Inhibitors of any of the exemplary targets are applicable to the corresponding mutant targets having one or more mutations therein. In some embodiments, any of the compounds herein that is capable of inhibiting a SOS protein (e.g., SOS1) to reduce Ras signaling output may be administered in combination or in conjunction with one or more checkpoint immune blockade agents (e.g., anti-PD- 1 and/or anti-PD-L1 antibody, anti-CLTA-4 antibody). [00154] In combination therapy, a compound provided herein and another anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient. [00155] In some embodiments, a compound of the present disclosure and the other anti-cancer agent(s) are generally administered sequentially in any order by infusion or orally. The dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination. The compound of the present invention and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment. In addition, the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug. [00156] An antibiotic can be administered to a subject as part of a therapeutic regime. An antibiotic can be administered at a therapeutically effective dose. An antibiotic can kill or inhibit growth of bacteria. An antibiotic can be a broad spectrum antibiotic that can target a wide range of bacteria. Broad spectrum antibiotics, either a 3^rd or 4^th generation, can be cephalosporin or a quinolone. An antibiotic can also be a narrow spectrum antibiotic that can target specific types of bacteria. An antibiotic can target a bacterial cell wall such as penicillins and cephalosporins. An antibiotic can target a cellular membrane such as polymyxins. An antibiotic can interfere with essential bacterial enzymes such as antibiotics: rifamycins, lipiarmycins, quinolones, and sulfonamides. An antibiotic can also be a protein synthesis inhibitor such as macrolides, lincosamides, and tetracyclines. An antibiotic can also be a cyclic lipopeptide such as daptomycin, glycylcyclines such as tigecycline, oxazolidiones such as linezolid, and lipiarmycins such as fidaxomicin. In some cases, an antibiotic can be 1^st generation, 2^nd generation, 3^rd generation, 4th generation, or 5^th generation. A first-generation antibiotic can have a narrow spectrum. Examples of 1^st generation antibiotics can be penicillins (Penicillin G or Penicillin V), Cephalosporins (Cephazolin, Cephalothin, Cephapirin, Cephalethin, Cephradin, or Cephadroxin). In some cases, an antibiotic can be 2^nd generation.2^nd generation antibiotics can be a penicillin (Amoxicillin or Ampicillin), Cephalosporin (Cefuroxime, Cephamandole, Cephoxitin, Cephaclor, Cephrozil, Loracarbef). In some cases, an antibiotic can be 3^rd generation. A 3^rd generation antibiotic can be penicillin (carbenicillin and ticarcillin) or cephalosporin (Cephixime, Cephtriaxone, Cephotaxime, Cephtizoxime, and Cephtazidime). An antibiotic can also be a 4^th generation antibiotic. A 4^th generation antibiotic can be Cephipime. An antibiotic can also be 5^th generation.5^th generation antibiotics can be Cephtaroline or Cephtobiprole. [00157] In some cases, an anti-viral agent may be administered as part of a treatment regime. In some cases, a herpes virus prophylaxis can be administered to a subject as part of a treatment regime. A herpes virus prophylaxis can be valacyclovir (Valtrex). Valtrex can be used orally to prevent the occurrence of herpes virus infections in subjects with positive HSV serology. It can be supplied in 500 mg tablets. Valacyclovir can be administered at a therapeutically effective amount. [00158] In some cases, a treatment regime may be dosed according to a body weight of a subject. In subjects who are determined obese (BMI > 35) a practical weight may need to be utilized. BMI is calculated by: BMI = weight (kg)/ [height (m)] ². [00159] Body weight may be calculated for men as 50 kg+2.3*(number of inches over 60 inches) or for women 45.5kg + 2.3 (number of inches over 60 inches). An adjusted body weight may be calculated for subjects who are more than 20% of their ideal body weight. An adjusted body weight may be the sum of an ideal body weight + (0.4 x (Actual body weight – ideal body weight)). In some cases, a body surface area may be utilized to calculate a dosage. A body surface area (BSA) may be calculated by: BSA (m2) =√Height (cm) ∗Weight (kg)/3600. [00160] In some embodiments is a method of reducing Ras signaling output, comprising contacting a SOS protein (e.g., SOS1) with an effective amount of a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, thereby reducing the Ras signaling output. In some embodiments is a method of reducing Ras signaling output, comprising contacting a SOS protein (e.g., SOS1) with an effective amount of a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein said the compound inhibits the SOS1 protein activity or disrupt interaction or binding between a SOS1 protein and a Ras protein. In some embodiments, a compound of Formula (I) or (I') inhibits SOS1 or disrupts interaction or binding between SOS1 and one or more of the following: a K-Ras protein including wildtype and any mutant thereof. In some embodiments, a compound of Formula (I) or (I') inhibits SOS1 activity or disrupts interaction or binding between SOS1 and one or more of the following: K-RasG12D mutant and K-RasG12V mutant. [00161] In some embodiments, provided is a method of reducing Ras signaling output in a cell by contacting the cell with a compound of the present disclosure. A reduction in Ras signaling can be evidenced by one or more members of the following: (i) an increase in steady state level of GDP-bound Ras protein; (ii) a reduction of phosphorylated AKTs473, (iii) a reduction of phosphorylated ERKT202/y204, (iv) a reduction of phosphorylated S6S235/236, (v) reduction (e.g., inhibition) of cell growth of Ras-driven tumor cells (e.g., those derived from a tumor cell line disclosed herein), and (vi) an interference or disruption of the interaction or binding between a SOS protein (e.g., SOS1) with a Ras protein such as a wildtype or a mutant Ras. In some cases, the reduction in Ras signaling output can be evidenced by two, three, four, five or all of (i)-(vi) above. In some embodiments, the reduction of any one or more of (i)-(vi) can be 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8- fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800- fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more as compared to a control untreated with a subject compound. A reduction in cell growth can be demonstrated with the use of tumor cells or cell lines. A tumor cell line can be derived from a tumor in one or more tissues, e.g., pancreas, lung, ovary, biliary tract, intestine (e.g., small intestine, large intestine (i.e. colon)), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), etc. Examples of the tumor cell line with a K-Ras mutation may include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), GP2D (e.g., K-Ras G12D), GSU (e.g., K-Ras G12F), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), L3.3 (e.g., K-Ras G12D), LoVo (e.g., K-Ras G13D), LS180 (e.g., K-Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K-Ras G12A), NCI-H1944 (e.g., K-Ras G13D), NCI-H2009 (e.g., K-Ras G12A), NCI-H441 (e.g., K-Ras G12V), NCI-H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), OV7 (e.g., K-Ras G12D), PANC0203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G12D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G12D), PANC1 (e.g., K-Ras G12D), Panc- 10.05 (e.g., K-Ras G12D), PaTu-8902 (e.g., K-Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), PK59 (e.g., K-Ras G12D), SK-CO-1 (e.g., K-Ras G12V), SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras G12D), SNU1033 (e.g., K-Ras G12D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g., K-Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K-Ras G12D), SNU869 (e.g., K-Ras G12D), SNU-C2A (e.g., K-Ras G12D), SU.86.86 (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K-Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), TCC-PAN2 (e.g., K-Ras G12R), TGBC11TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12C)). [00162] In some embodiments is a SOS protein (e.g., SOS1) bound by a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein interaction of SOS1 protein with a Ras protein is reduced as compared to a SOS1 protein unbound to said compound. Pharmaceutical compositions and methods of administration [00163] The compounds of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent diseases, disorders or conditions. Administration of the compounds described herein can be in any pharmacological form including a therapeutically effective amount of a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, alone or in combination with a pharmaceutically acceptable carrier. [00164] In certain embodiments, the compounds described herein are administered as a pure chemical. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00165] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, together with one or more pharmaceutically acceptable excipients. The excipient(s) (or carrier(s)) is acceptable or suitable if the excipient is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition. [00166] In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I) or (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments is a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I'), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. [00167] In some embodiments of the methods described herein, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be affected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ. [00168] In some embodiments of the methods described herein, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste. [00169] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses. [00170] In some embodiments of the methods described herein, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [00171] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [00172] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. EXAMPLES [00173] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. [00174] Unless noted otherwise, all materials, such as reagents, starting materials, and solvents, were purchased from commercial suppliers, such as Sigma-Aldrich, VWR, and the like, and were used without further purification. Reactions were run under nitrogen or argon atmosphere, unless noted otherwise. Progress of reactions was typically monitored by thin layer chromatography (TLC) or liquid chromatography mass spectrometry (LCMS). [00175] Reactions were worked up as described specifically in each preparation; commonly, reaction mixtures were purified by extraction and other purification methods such as temperature- and solvent-dependent crystallization, and precipitation. In addition, reaction mixtures were routinely purified by preparative HPLC, for example, using Microsorb C18 or Microsorb BDS column packings and conventional eluents. Characterization of isomers was typically done by Nuclear Overhauser effect spectroscopy (NOE). Characterization of reaction products was routinely carried out by mass spectrometry and/or ¹H-NMR spectroscopy. For NMR measurement, samples were dissolved in deuterated solvent (CD3OD, CDCl3, or DMSO-d6). [00176] Example 1: Synthesis of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-isopropyl- 1,2,3,6-tetrahydropyridin-4-yl)-2,7-dimethyl-4a,8a-dihydropyrido[3,4-d]pyrimidin-8(7H)-one (113).

[00177] Step A: Preparation of ethyl 2-(4,6-dihydroxy-2-mthylpyrimidin-5-yl)acetate (1-3). To a solution of 1-1 (100 g, 406 mmol, 1.0 eq) in EtOH (600 mL) was added 1-2 (49.9 g, 528 mmol, 1.0 eq, HCl) and NaOEt (276 g, 812 mmol, 20% purity, 2.0 eq) at 20 °C. The mixture was stirred at 75 °C for 12 hrs. LC-MS showed the desired product was detected. The mixture was concentrated to give the crude product and was poured into 0.5 M HCl solution (800 mL) and the resulting mixture was stirred at 25 °C for 0.5 hr. The mixture was filtered to give the filter cake and the filter cake was dried to give compound 1-3 as an off-white solid. ESI (m/z) [M+H]+: 213.1. [00178] Step B: Preparation of ethyl 2-(4-hydroxy-2-methyl-6-(((trifluoromethyl)sulfonyl)oxy)pyrimidin-5- yl)acetate (1-4). To a solution of 1-3 (55.0 g, 259 mmol, 1.0 eq) in Py (330 mL) was added Tf₂O (73.1 g, 259 mol, 1.0 eq) at 0 °C and the mixture was stirred at 25 °C for 12 hrs. LC-MS showed the desired product was detected. The mixture was poured into ice water (300 mL), the pH adjusted to 3-4 with 3 M HCl solution (500 mL), then diluted with EtOAc (500 mL). The mixture was separated and the aqueous phase was extracted with EtOAc (300 mL). The organic layer was combined and concentrated under reduced pressure to give 1-4 (48.0 g, crude) as a brown oil. ESI (m/z) [M+H]+: 345.0. [00179] Step C: Preparation of methyl 5-(2-ethoxy-2-oxoethyl)-6-hydroxy-2-methylpyrimidine-4-carboxylate (1-5). To a solution of 1-4 (48.0 g, 139 mmol, 1.0 eq) in MeOH (300 mL) was added Pd(dppf)Cl₂ (10.2 g, 13.9 mmol, 0.1 eq) and DIPEA (54.0 g, 418 mmol, 3.0 eq). The mixture was stirred at 50 °C for 12 hrs at 50 psi under CO. LC-MS showed the desired product was detected. The mixture was filtered to give the filtrate and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (50:1~0:1) and ethyl acetate/MeOH (50:1~0:1) to give the 1-5 (24.5 g, 96.3 mmol, 69.1% yield) as yellow solid. ESI (m/z) [M+H]+: 255.1. [00180] Step D: Preparation of methyl 6-chloro-5-(2-ethoxy-2-oxoethyl)-2-methylpyrimidine-4-carboxylate (1-6). A mixture of 1-5 (24.5 g, 96.3 mmol, 1.0 eq) in POCl3 (120 mL) was stirred at 100 °C for 3 hrs. LC-MS showed the desired product was detected. The mixture was concentrated to give the residue and the residue was poured into ice water (300 mL) and diluted with EtOAc (300 mL). The mixture was adjusted to pH = 7-8 with saturated NaHCO3 solution (200 mL), then separated and the aqueous phase extracted with EtOAc (150 mL). The organic layer was combined and concentrated under reduced pressure to give 1-6 (15.4 g, crude) as a black oil. ESI (m/z) [M+H]+: 273.0. [00181] Step E: Preparation of methyl 5-(2-ethoxy-2-oxoethyl)-2-methyl-6-(methylthio)pyrimidine-4-carboxylate (1-7). To a solution of 1-6 (15.4 g, 56.4 mmol, 1.0 eq) in THF (90 mL) was added NaSMe (39.5 g, 113 mmol, 36.0 mL, 20% purity solution in water, 2.0 eq) at -20 °C and the mixture was stirred at 0 °C for 2 hrs. LC-MS showed the desired product was detected. The mixture was poured into ice water (200 mL) and diluted with DCM (300 mL). The mixture was separated and the aqueous phase was extracted with DCM (100 mL). The organic layer was combined and concentrated under reduced pressure to give 1-7 (9.50 g, crude) as a brown oil. ESI (m/z) [M+H]+: 285.0. [00182] Step F: Preparation of 2,7-dimethyl-4-(methylthio)pyrido[3,4-d]pyrimidine-6,8(5H,7H)-dione (1-8). To a solution of 1-7 (9.50 g, 33.4 mmol, 1.0 eq) in EtOH (60 mL) was added MeNH2 (17.3 g, 167 mmol, 30% purity, 5.0 eq) at 25 °C and the resulting mixture was stirred at 25 °C for 12 hrs. LC-MS showed the desired product was detected. The mixture was concentrated to give the crude product. The crude product was purified by column chromatography on silica gel with DCM/MeOH (100:1~0:1) to give 1-8 (4.30 g, 18.1 mmol, 54.2% yield) as a light brown solid. ESI (m/z) [M+H]+: 285.0. [00183] Step G: Preparation of 6-bromo-2,7-dimethyl-4-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (1-9). Compound 1-8 (2 gram) was added to POBr₃ (10 mL) and the mixture was heated at 80 °C for 3 hours. It was cooled to room temperature, then POBr₃ was removed under high vacuum. The residue was dissolved in DCM (100 mL) and NaHCO3 (1 M) was added slowly at 0 °C. The organics were separated, washed with brine, and dried over Na2SO4, then filtered and solvent removed to give desired product 1-9, which was used directly in the next step. ESI (m/z) [M+H]+: 299.9. [00184] Step H: Preparation of tert-butyl4-(2,7-dimethyl-4-(methylthio)-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin- 6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-11). To a solution of 1-9 (500 mg, 1.67 mmol) in 1,4-dioxane and water (4:1, 50 mL) were added 1-10 (622 mg, 2.01 mmol), Pd(PPh3)4 (209 mg, 0.167 mmol) and Na2CO3 (533 mg, 5.01 mmol). The resulting mixture was then heated to 100 °C overnight then cooled to room temperature. NaHCO₃ (aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, and dried over Na2SO4. It was filtered and solvent was removed under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel to provide the desired product. ESI-MS m/z[M+H]⁺: 403.1. [00185] Step I: Preparation of tert-butyl 4-(4-hydroxy-2,7-dimethyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-6- yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-12). To a solution of 1-11 (650 mg, 1.61 mmol) in DCM (50 mL) was added 3-chloroperbenzoic acid (830 mg, 4.83 mmol) at 0 °C. The resulting mixture was stirred at room temperature overnight, then NaHCO₃ (aq, 20 mL) was added, and the mixture was extracted with DCM. The extracts were combined, washed with brine, and dried over Na₂SO₄, then filtered and solvent was removed under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel to give 1-12. ESI-MS m/z[M+H]⁺: 373.3. [00186] Step J: Preparation of tert-butyl4-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7- dimethyl-8-oxo-4a,7,8,8a-tetrahydropyrido[3,4-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1-14). To a solution of 1-12 (450 mg, 1.2 mmol) in MeCN (20 ml) were added BOP (880 mg, 1.81 mmol), DMAP (32 mg, 0.24 mmol), DIEA (0.64 ml, 3.6 mmol) and 1-13 (385 mg, 1.57 mmol). The mixture was stirred at 60 °C overnight, then cooled and NaHCO3 (aq, 5 mL) added. The mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, and dried over Na₂SO₄, then filtered and solvent removed under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel to give the desired product. ESI-MS m/z[M+H]⁺: 546.6. [00187] Step K: Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-isopropyl-1,2,3,6- tetrahydropyridin-4-yl)-2,7-dimethyl-4a,8a-dihydropyrido[3,4-d]pyrimidin-8(7H)-one (113). To a solution of 1-14 (150 mg, 0.27 mmol) in DCM (8 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 1h. The volatiles were evaporated to afford the product. Acetone (2 mL) and excess NaBH3CN in methanol (15 mL) were added to the residue. The mixture was stirred at 60 °C overnight. It was cooled to room temperature and NaHCO₃ (aq, 5 mL) was added. The reaction mixture was extracted with ethyl acetate and the extracts were combined, washed with brine, and dried over Na₂SO₄. The dried extracts were then filtered and solvent was removed to give a residue. The residue was purified by flash column chromatography on silica gel to give 113. ESI-MS m/z[M+H]⁺: 488.5. HNMR (400 MHz, CD3OD) 7.56 (t, J = 7.2 Hz, 1H ), 7.40 (t, J = 6.8 Hz, 1H ) , 7.26-7.23 (m, 1H ), 7.18 (t, J = 7.6 Hz, 1H ), 6.90 (t, J = 54.8 Hz, 1H), 6.07-6.05 (m, 1H), 5.77-5.73 (m, 1H), 3.75- 3.76 (brs, 1H), 3.6-3.59 (s , 3H), 3.5-3.46 (m , 2H), 3.3-3.24 (m, 1H), 2.67-2.59 (m, 5 H), 1.62-1.59 (m, 3H), 1.35- 1.18 (m, 6H), 0.81-0.75 (m, 2H). [00188] Example 2: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1,1-dioxido-3,6- dihydro-2H-thiopyran-4-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (126) and (R)-4-((1-(3- (difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2,7-dimethylpyrido[3,4- d]pyrimidin-8(7H)-one (105).

[00189] Step A: Preparation of 6-bromo-2,7-dimethyl-4-(methylsulfinyl)pyrido[3,4-d]pyrimidin-8(7H)-one (2-1). To a stirred solution of 1-9 (300 mg) in DCM (30 mL) were added NaHCO3 (300 mg) and m-CPBA (400 mg) at -30 °C to -10 °C. The mixture was stirred for 1 hour at -30 °C to -10 °C, then extracted by DCM and NaHCO₃ (aq). The organics were separated, washed with brine and dried over Na₂SO₄, then filtered and solvent removed at room temperature to give 2-1. The product was used in the next step without farther purification. ESI-MS m/z[M+H]⁺: 316.1. [00190] Step B: Preparation of 6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7- dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (2-2). To a stirred solution of 2-1 (150 mg) in DMSO (20 mL) was added 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (104 mg) and KF (168 mg). The mixture was stirred for 1 hour at 100 °C, then cooled to room temperature and extracted by ethyl acetate. The combined organic extracts were washed with water and dried over Na₂SO₄, then filtered and the solvent removed to give a residue. The residue was purified by flash chromatography to afford 2-2. ESI-MS m/z[M+H]⁺: 441.2. [00191] Step C: Preparation of (R)-6-(1,1-dioxidothiomorpholino)-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl) ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (2-3). To a stirred solution of 2-2 (90 mg) in dioxane (15 mL) and water (3 mL) were added 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (69 mg), Na₂CO₃ (65 mg) and Pd(PPh₃)₄ (20 mg) under argon. The mixture was stirred overnight at 100 °C, then cooled to room temperature and the solvent removed to give a residue. The residue was purified by flash chromatography to afford the desired product. ESI-MS m/z[M+H]⁺: 461.2. [00192] Step D: Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1,1-dioxido-3,6- dihydro-2H-thiopyran-4-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (126). To a stirred solution of 2-3 (60 mg) in DCM (30 mL) was added NaHCO3 (66 mg) and m-CPBA (66 mg). The mixture was stirred for 1 hour at room temperature, then extracted by DCM and washed NaHCO3 (aq). The organics were dried over Na2SO4, then filtered and the solvent removed under reduced pressure to give a crude residue. The residue was purified by flash chromatography to afford the desired product. ESI-MS m/z[M+H]⁺: 493.1. [00193] Step E: Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (105). To a stirred solution of 126 (30 mg) in MeOH (15 mL) was added Pd(OH)₂/C (6 mg) under hydrogen. The mixture was stirred for 1 hour at 50 °C under hydrogen, then filtered through celite. The solvent was removed and the residue was purified by flash chromatography to afford 105. ESI-MS m/z[M+H]⁺: 495.2, ¹H NMR (400 MHz, MeOD) 7.55 (t, J = 6.8 Hz, 1H), 7.44 (t, J = 6.8 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.96 (t, J = 54.0 Hz, 1H), 5.8-5.7 (m, 1H), 3.68 (s, 3H), 3.5-3.35 (m, 2H), 3.2-3.0 (m, 3H), 2.5-2.3 (m, 7H), 1.64 (d, J=6.8 Hz, 3H). [00194] Example 3: Synthesis of (R)-6-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-4-((1-(2-fluoro-3- (trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (115) and (R)-6-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2,7- dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (132).

[00195] Step A: Preparation of (R)-6-bromo-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2,7- dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (3-1). To a stirred solution of 2-1 (280 mg) in DMSO (20 mL) was added (R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethan-1-amine (230 mg) and KF (400 mg). The mixture was stirred for 1 hour at 100 °C, then cooled to room temperature, extracted with ethyl acetate and washed with water. The combined organic extracts were filtered and the solvent was removed to give a residue. The residue was purified by flash chromatography to afford 3-1. ESI-MS m/z [M+H]⁺: 459.2. [00196] Step B: Preparation of (R)-6-(3,6-dihydro-2H-thiopyran-4-yl)-4-((1-(2-fluoro-3- (trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (3-2). To a stirred solution of 3-1 (100 mg) in dioxane (15 mL) and H₂O (3 mL) were added 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (75 mg), Na₂CO₃ (65 mg) and Pd(PPh₃)₄ (20 mg) under argon. The mixture was stirred overnight at 100 °C and cooled to room temperature, then extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The extract was then filtered and the solvent removed under reduced pressure to give a residue. The residue was purified by flash chromatography to afford 3-2. ESI-MS m/z [M+H]⁺: 479.2. [00197] Step C: Preparation of (R)-6-(1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl)-4-((1-(2-fluoro-3- (trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (115). To a stirred solution of 3-2 (70 mg) in DCM (30 mL) was added NaHCO3 (80 mg) and m-CPBA (80 mg). The mixture was stirred for 1 hour at room temperature then the mixture was extracted by DCM and washed with NaHCO₃ (aq). It was filtered and the solvent was removed under reduced pressure to give a crude residue. The residue was purified by flash chromatography to afford 115. ESI-MS m/z [M+H]⁺: 511.1. [00198] Step D: Preparation of (R)-6-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-((1-(2-fluoro-3- (trifluoromethyl)phenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (132). To a stirred solution of 115 (20 mg) in MeOH (10 mL) was added Pd(OH)₂/C (4 mg) under hydrogen. The mixture was stirred for 1.5 hour at room temperature under hydrogen, then filtered and the solvent removed to give a residue. The residue was purified by flash chromatography to afford 132 (5 mg) ESI-MS m/z [M+H]⁺: 513.3. ¹H NMR (400 MHz, MeOD) 7.72 (t, J=6.8 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.29 (t, J= 8.0 Hz, 1H), 7.09 (brs, 1H), 5.9-5.7 (m, 1H), 3.73 (s, 3H), 3.5-3.35 (m, 3H), 3.25-3.1 (m, 2H), 2.45-2.3 (m, 4H), 1.71 (d, J=7.2 Hz, 3H), 1.27-1.86 (m, 3 H). [00199] Example 4: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethyl-6- (tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8(7H)-one (104).

[00200] Step A: Preparation of 6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7- dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (4-1). To a stirred solution of 2-1 (150 mg) in DMSO (20 mL) was added 1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (104 mg) and KF (168 mg). The resulting mixture was stirred for 1 hour at 100^oC. The mixture was cooled to room temperature, extracted by ethyl acetate, washed with water and dried over sodium sulfate. It was filtered and the solvent was removed to give a residue. The residue was purified by flash chromatography to afford 4-1. ESI-MS m/z[M+H]⁺: 441.2. [00201] Step B: Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(3,6-dihydro-2H- pyran-4-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (4-2). To a stirred solution of 4-1 (70 mg) in dioxane (10 mL) and water (1 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (67 mg), Na2CO3 (51 mg) and Pd(PPh3)4 (14 mg) under argon. The resulting mixture was stirred overnight at 100 °C. The mixture was cooled, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. It was filtered and the solvent was removed under reduced pressure to give a residue. The residue was purified by flash chromatography to afford 4-2. ESI-MS m/z[M+H]⁺: 445.2. [00202] Step C: Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethyl-6- (tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8(7H)-one (104). To a stirred solution of 4-2 (15 mg) in MeOH (10 mL) was added Pd(OH)₂/C (10 mg) under nitrogen. The mixture was stirred for 4 hour at room temperature under H₂, then filtered and the solvent removed under reduced pressure to give a residue. The residue was purified by flash chromatography to afford 104. ESI-MS m/z [M+H]⁺: 447.2¹H NMR (400 MHz, MeOD) 7.64 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.38 (s, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.7-5.7 (m, 1H), 4.15- 4.05 (m, 2H), 3.85 (s, 3H), 3.7-3.6 (m, 2H), 3.3-3.2 (m, 1H), 2.8 (s, 3H), 2.0-1.8 (m, 4H), 1.73 (d, J = 7.2 Hz, 3H). [00203] Example 5: Synthesis of (R)-6-(4,4-difluorocyclohex-1-en-1-yl)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (112) and (R)-6-(4,4- difluorocyclohexyl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin- 8(7H)-one (107).

[00204] Step A: Preparation of (R)-6-(4,4-difluorocyclohex-1-en-1-yl)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (112). A mixture of 4-1 (50 mg, 0.114 mmol), 5-1 (55 mg, 0.228 mmol), Na₂CO₃ (78 mg, 0.741 mmol) and Pd(PPh₃)₄ (14 mg, 0.0114 mmol) in 1,4- dioxane/H2O (5 mL/1 mL) was stirred at 100 °C for 1 h under N2. The mixture was then cooled to room temperature and poured into water. The resultant solution was extracted with ethyl acetate (20 mL x 3) and the combined organic layers were dried over Na₂SO₄. It was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC to give 112 as a white solid. LC-MS: (ESI, m/z): [M+H]⁺=479.2.¹H NMR (400 MHz, DMSO) 7.64 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 6.9 Hz, 1H), 7.39 – 7.06 (m, 2H), 6.88 (s, 1H), 5.88 (brs, 1H), 5.70 (q, J = 6.9 Hz, 1H), 3.39 (s, 3H), 2.78 (t, J = 13.6 Hz, 2H), 2.34 (s, 3H), 2.29 – 2.16 (m, 2H), 1.56 (d, J = 7.1 Hz, 3H). [00205] Step B: Preparation of (R)-6-(4,4-difluorocyclohexyl)-4-((1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (107).112 (29 mg, crude) and Pd(OH)₂/C (6 mg) in MeOH (6 mL) were heated to 60 °C for 18 h under H2 atmosphere. LCMS showed no starting material and the mixture was cooled to room temperature. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (NH₃-H₂O) to give the desired product as a white solid. LC-MS: (ESI, m/z): [M+H]⁺=481.2.¹H NMR (400 MHz, MeOD) δ 7.56 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 6.9 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.15 – 6.85 (m, 2H), 5.76 (q, J = 7.0 Hz, 1H), 3.70 (s, 3H), 3.04 (t, J = 11.4 Hz, 1H), 2.40 (s, 3H), 2.28 – 1.80 (m, 8H), 1.66 (d, J = 7.1 Hz, 3H). [00206] Example 6: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-isopropyl-2,5- dihydro-1H-pyrrol-3-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (127) and 4-(((R)-1-(3-(difluoromethyl)-2- fluorophenyl)ethyl)amino)-6-(1-isopropylpyrrolidin-3-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (119).

[00207] Step A: Preparation of tert-butyl (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7- dimethyl-8-oxo-7,8-dihydropyrido[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (6-2). A mixture of 4-1 (90 mg, 0.205 mmol), 6-1 (121 mg, 0.41 mmol), Na₂CO₃ (142 mg, 1.333 mmol) and Pd(PPh₃)₄ (24 mg, 0.0205mmol) in 1,4-dioxane/H₂O (10 mL/2mL) was stirred at 100 °C for 2h under N₂. The mixture was then cooled to room temperature and poured into water. The resultant solution was extracted with ethyl acetate (20 mL x 3) and the combined organic layers were dried over Na2SO4. It was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by com-flash column (0%~3% MeOH in DCM) to give the desired product as a light yellow oil. LC-MS: (ESI, m/z): [M+H]⁺=530.2. [00208] Step B: Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(2,5-dihydro-1H- pyrrol-3-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (6-3). To a stirred solution of 6-2 (133 mg, crude) in DCM (5 mL) was added drop-wise TFA (1 mL) and the resultant solution was stirred at room temperature for 30 min. LCMS showed the starting material was consumed completely and the mixture was concentrated under reduced pressure to give a crude product as a yellow solid, which was used directly in the next step without further purification. LC-MS: (ESI, m/z): [M+H]⁺=430.2. [00209] Step C: Preparation of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-isopropyl-2,5- dihydro-1H-pyrrol-3-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (127). A mixture of compound 6-3 (133 mg crude, ~0.205 mmol), acetone (1 mL), NaCNBH3 (64 mg, 1.02 mmol) and HOAc (two drops) in MeOH (10 mL) was heated to 60 °C for 4h. The mixture was cooled to room temperature and the solvent was removed. The mixture was diluted with ethyl acetate and water (20 mL/15 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over Na₂SO₄. It was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (NH3-H2O) to give 127 as a white solid. LC-MS: (ESI, m/z): [M+H]⁺=472.2. ¹H NMR (400 MHz, MeOD) δ 7.69 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 6.9 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.24 (s, 1H), 6.98 (t, J = 54.7 Hz, 1H), 6.46 (s, 1H), 5.96 (q, J = 7.1 Hz, 1H), 4.63 – 4.33 (m, 4H), 3.82 – 3.70 (m, 1H), 3.69 (s, 3H), 2.65 (s, 3H), 1.75 (d, J = 7.1 Hz, 3H), 1.46 (d, J = 6.5 Hz, 6H). [00210] Step D: Preparation of 4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1- isopropylpyrrolidin-3-yl)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (119).127 (60 mg) and Pd(OH)₂/C (6 mg) in MeOH (10 mL) were heated to 60 °C for 32 h under H₂ atmosphere. No starting material was detected by LCMS and the mixture was cooled to room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (NH3-H2O) to give 119 as a white solid. LC- MS: (ESI, m/z): [M+H]⁺=474.3.¹H NMR (400 MHz, MeOD) δ 7.63 – 7.54 (m, 1H), 7.47 (t, J = 6.6 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.16 – 6.82 (m, 2H), 5.84 – 5.71 (m, 1H), 3.77 – 3.52 (m, 4H), 3.35 - 3.21 (m, 1H), 3.02 – 2.89 (m, 1H), 2.85 – 2.75 (m, 2H), 2.61 – 2.51 (m, 1H), 2.47 – 2.37 (m, 4H), 2.12 – 1.97 (m, 1H), 1.67 (d, J = 7.1 Hz, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H). [00211] Compounds of the present disclosure provided in Table 1 were synthesized in the same or a similar manner as described in Examples 1-6, one of the general routes outlined in Schemes 1-5, or by methods generally known in the art. Exemplary compounds may include, but are not limited to, a compound selected from Table 1, or a salt or solvate thereof. Table 1

Example 7: Ras sequence [00212] Human K-Ras4b (SEQ ID NO.1): 1 MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET 51 CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI 101 KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ 151 GVDDAFYTLV REIRKHKEKM SKDGKKKKKK SKTKCVIM [00213] Human SOS1 (SEQ ID NO.3): 1 MQAQQLPYEF FSEENAPKWR GLLVPALKKV QGQVHPTLES NDDALQYVEE 51 LILQLLNMLC QAQPRSASDV EERVQKSFPH PIDKWAIADA QSAIEKRKRR 101 NPLSLPVEKI HPLLKEVLGY KIDHQVSVYI VAVLEYISAD ILKLVGNYVR 151 NIRHYEITKQ DIKVAMCADK VLMDMFHQDV EDINILSLTD EEPSTSGEQT 201 YYDLVKAFMA EIRQYIRELN LIIKVFREPF VSNSKLFSAN DVENIFSRIV 251 DIHELSVKLL GHIEDTVEMT DEGSPHPLVG SCFEDLAEEL AFDPYESYAR 301 DILRPGFHDR FLSQLSKPGA ALYLQSIGEG FKEAVQYVLP RLLLAPVYHC 351 LHYFELLKQL EEKSEDQEDK ECLKQAITAL LNVQSGMEKI CSKSLAKRRL 401 SESACRFYSQ QMKGKQLAIK KMNEIQKNID GWEGKDIGQC CNEFIMEGTL 451 TRVGAKHERH IFLFDGLMIC CKSNHGQPRL PGASNAEYRL KEKFFMRKVQ 501 INDKDDTNEY KHAFEIILKD ENSVIFSAKS AEEKNNWMAA LISLQYRSTL 551 ERMLDVTMLQ EEKEEQMRLP SADVYRFAEP DSEENIIFEE NMQPKAGIPI 601 IKAGTVIKLI ERLTYHMYAD PNFVRTFLTT YRSFCKPQEL LSLIIERFEI 651 PEPEPTEADR IAIENGDQPL SAELKRFRKE YIQPVQLRVL NVCRHWVEHH 701 FYDFERDAYL LQRMEEFIGT VRGKAMKKWV ESITKIIQRK KIARDNGPGH 751 NITFQSSPPT VEWHISRPGH IETFDLLTLH PIEIARQLTL LESDLYRAVQ 801 PSELVGSVWT KEDKEINSPN LLKMIRHTTN LTLWFEKCIV ETENLEERVA 851 VVSRIIEILQ VFQELNNFNG VLEVVSAMNS SPVYRLDHTF EQIPSRQKKI 901 LEEAHELSED HYKKYLAKLR SINPPCVPFF GIYLTNILKT EEGNPEVLKR 951 HGKELINFSK RRKVAEITGE IQQYQNQPYC LRVESDIKRF FENLNPMGNS 1001 MEKEFTDYLF NKSLEIEPRN PKPLPRFPKK YSYPLKSPGV RPSNPRPGTM 1051 RHPTPLQQEP RKISYSRIPE SETESTASAP NSPRTPLTPP PASGASSTTD 1101 VCSVFDSDHS SPFHSSNDTV FIQVTLPHGP RSASVSSISL TKGTDEVPVP 1151 PPVPPRRRPE SAPAESSPSK IMSKHLDSPP AIPPRQPTSK AYSPRYSISD 1201 RTSISDPPES PPLLPPREPV RTPDVFSSSP LHLQPPPLGK KSDHGNAFFP 1251 NSPSPFTPPP PQTPSPHGTR RHLPSPPLTQ EVDLHSIAGP PVPPRQSTSQ 1301 HIPKLPPKTY KREHTHPSMH RDGPPLLENA HSS [00214] Human SOS2 (SEQ ID NO.5): 1 MQQAPQPYEF FSEENSPKWR GLLVSALRKV QEQVHPTLSA NEESLYYIEE 51 LIFQLLNKLC MAQPRTVQDV EERVQKTFPH PIDKWAIADA QSAIEKRKRR 101 NPLLLPVDKI HPSLKEVLGY KVDYHVSLYI VAVLEYISAD ILKLAGNYVF 151 NIRHYEISQQ DIKVSMCADK VLMDMFDQDD IGLVSLCEDE PSSSGELNYY 201 DLVRTEIAEE RQYLRELNMI IKVFREAFLS DRKLFKPSDI EKIFSNISDI 251 HELTVKLLGL IEDTVEMTDE SSPHPLAGSC FEDLAEEQAF DPYETLSQDI 301 LSPEFHEHFN KLMARPAVAL HFQSIADGFK EAVRYVLPRL MLVPVYHCWH 351 YFELLKQLKA CSEEQEDREC LNQAITALMN LQGSMDRIYK QYSPRRRPGD 401 PVCPFYSHQL RSKHLAIKKM NEIQKNIDGW EGKDIGQCCN EFIMEGPLTR 451 IGAKHERHIF LFDGLMISCK PNHGQTRLPG YSSAEYRLKE KFVMRKIQIC 501 DKEDTCEHKH AFELVSKDEN SIIFAAKSAE EKNNWMAALI SLHYRSTLDR 551 MLDSVLLKEE NEQPLRLPSP EVYRFVVKDS EENIVFEDNL QSRSGIPIIK 601 GGTVVKLIER LTYHMYADPN FVRTFLTTYR SFCKPQELLS LLIERFEIPE 651 PEPTDADKLA IEKGEQPISA DLKRFRKEYV QPVQLRILNV FRHWVEHHFY 701 DFERDLELLE RLESFISSVR GKAMKKWVES IAKIIRRKKQ AQANGVSHNI 751 TFESPPPPIE WHISKPGQFE TFDLMTLHPI EIARQLTLLE SDLYRKVQPS 801 ELVGSVWTKE DKEINSPNLL KMIRHTTNLT LWFEKCIVEA ENFEERVAVL 851 SRIIEILQVF QDLNNFNGVL EIVSAVNSVS VYRLDHTFEA LQERKRKILD 901 EAVELSQDHF KKYLVKLKSI NPPCVPFFGI YLTNILKTEE GNNDFLKKKG 951 KDLINFSKRR KVAEITGEIQ QYQNQPYCLR IEPDMRRFFE NLNPMGSASE 1001 KEFTDYLFNK SLEIEPRNCK QPPRFPRKST FSLKSPGIRP NTGRHGSTSG 1051 TLRGHPTPLE REPCKISFSR IAETELESTV SAPTSPNTPS TPPVSASSDL 1101 SVFLDVDLNS SCGSNSIFAP VLLPHSKSFF SSCGSLHKLS EEPLIPPPLP 1151 PRKKFDHDAS NSKGNMKSDD DPPAIPPRQP PPPKVKPRVP VPTGAFDGPL 1201 HSPPPPPPRD PLPDTPPPVP LRPPEHFINC PFNLQPPPLG HLHRDSDWLR 1251 DISTCPNSPS TPPSTPSPRV PRRCYVLSSS QNNLAHPPAP PVPPRQNSSP 1301 HLPKLPPKTY KRELSHPPLY RLPLLENAET PQ Example 8: Protein expression [00215] DNA expression constructs encoding one or more protein sequences of interest (e.g., Kras fragments thereof, mutant variants thereof, etc.) and its corresponding DNA sequences are optimized for expression in E. coli and synthesized by, for example, the GeneArt Technology at Life Technologies. In some cases, the protein sequences of interest are fused with a tag (e.g., glutathione S-transferase (GST), histidine (His), or any other affinity tags) to facilitate recombinant expression and purification of the protein of interest. Such tag can be cleaved subsequent to purification. Alternatively, such tag may remain intact to the protein of interest and may not interfere with activities (e.g., target binding and/or phosphorylation) of the protein of interest. [00216] A resulting expression construct is additionally encoded with (i) att-site sequences at the 5' and 3' ends for subcloning into various destination vectors using, for example, the Gateway Technology, as well as (ii) a Tobacco Etch Virus (TEV) protease site for proteolytic cleavage of one or more tag sequences. The applied destination vectors can be a pET vector series from Novagen (e.g., with ampicillin resistance gene), which provides an N- terminal fusion of a GST-tag to the integrated gene of interest and/or a pET vector series (e.g., with ampicillin resistance gene), which provides a N-terminal fusion of a HIS-tag to the integrated gene. To generate the final expression vectors, the expression construct of the protein of interest is cloned into any of the applied destination vectors. The expression vectors are transformed into E. coli strain, e.g., BL21 (DE3). Cultivation of the transformed strains for expression is performed in 10 L and 1 L fermenter. The cultures are grown, for example, in Terrific Broth media (MP Biomedicals, Kat. #113045032) with 200 ug/mL ampicillin at a temperature of 37 ºC to a density of 0.6 (OD600), shifted to a temperature of ~27 ºC (for K-Ras expression vectors) induced for expression with 100 mM IPTG, and further cultivated for 24 hours. After cultivation, the transformed E. coli cells are harvested by centrifugation and the resulting pellet is suspended in a lysis buffer, as provided below, and lysed by passing three- times through a high pressure device. The lysate is centrifuged (49000g, 45 min, 4 ºC) and the supernatant is used for further purification. Example 9: Ras protein Purification [00217] A Ras (e.g., K-Ras wildtype or a mutant such as K-Ras G12D, K-Ras G12V or K-Ras G12C) construct or a variant thereof is tagged with GST. E. coli culture from a 10L fermenter is lysed in lysis buffer (50 mM Tris HCl 7.5, 500 mM NaCl, 1 mM DTT, 0.5% CHAPS, Complete Protease Inhibitor Cocktail-(Roche)). As a first chromatography step, the centrifuged lysate is incubated with 50 mL Glutathione Agarose 4B (Macherey-Nagel; 745500.100) in a spinner flask (16 h, 10Ό). The Glutathione Agarose 4B loaded with protein is transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system. The column is washed with wash buffer (50 mM Tris HCl 7.5, 500 mM NaCl, 1 mM DTT) and the bound protein is eluted with elution buffer (50 mM Tris HCl 7.5, 500 mM NaCl, 1 mM DTT, 15 mM Glutathione). The main fractions of the elution peak (monitored by OD280) are pooled. For further purification by size-exclusion chromatography, the above eluate volume is applied to a column Superdex 200 HR prep grade (GE Healthcare) and the resulting peak fractions of the eluted fusion protein are collected. Native mass spectrometry analyses of the final purified protein construct can be performed to assess its homogeneous load with GDP. Example 10: SOS purification [00218] A SOS construct or a variant thereof is His10-tagged. E. coli cultures is induced in a fermenter, harvested, and lysed in lysis buffer, for example, in 25 mM Tris HCl 7.5, 500 mM NaCl, 20 mM Imidazol, Complete EDTA- free (Roche). For immobilized metal ion affinity chromatography (IMAC), the centrifuged lysate (50,000 x g, 45 min, 40) is incubated with 30 mL Ni-NTA (Macherey-Nagel; #745400.100) in a spinner flask (16 h, 40) and subsequently transferred to a chromatography column connected to a chromatography system, e.g., an Akta chromatography system. The column is rinsed with wash buffer, e.g., in 25 mM Tris HCl 7.5, 500 mM NaCl, 20 mM Imidazol and the bound protein is eluted with a linear gradient (0-100%) of elution buffer (25 mM Tris HCl 7.5, 500 mM NaCl, 300 mM Imidazol). The main fractions of the elution peak (monitored by OD280) containing homogenous His10-hSOS are pooled. Example 11: Ras-SOS interaction assay [00219] The ability of any compound of the present disclosure to reduce a Ras protein signaling output by, e.g., interfering or disrupting interaction (or binding) between SOS1 and a Ras protein can be assessed in vitro. For example, the equilibrium interaction of human SOS1 (hSOS1) with human wildtype Kras or K-Ras mutant (e.g., hK-Ras G12C mutant, or hK-Ras G12C) can be assessed as a proxy or an indication for a subject compound's ability to inhibit SOS. Detection of such interaction is achieved by measuring homogenous time-resolved fluorescence resonance energy transfer (HTRF) from (i) a fluorescence resonance energy transfer (FRET) donor (e.g., antiGST-Europium) that is bound to GST-tagged K-Ras G12C to (ii) a FRET acceptor (e.g., anti-6His-XL665) bound to a His-tagged hSOS1. [00220] The assay buffer can contain 5 mM HEPES pH 7.4, 150 mM NaCl, 10 mM EDTA, 1 mM DTT, 0.05% BSA, 0.0025% (v/v) Igepal and 100 mM KF. A Ras working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., GST-tagged hK-Ras G12C) and 2 nM of the FRET donor (e.g., antiGST-Eu(K) from Cisbio, France). A SOS1 working solution is prepared in assay buffer containing typically 10 nM of the protein construct (e.g., His-hSOS1) and 10 nM of the FRET acceptor (e.g., anti-6His-XL665 from Cisbio, France). An inhibitor control solution is prepared in assay buffer containing 10 nM of the FRET acceptor without the SOS1 protein. [00221] A fixed reaction mixture with or without test compound is transferred into a 384-well plate. Ras working solution is added to all wells of the test plate. SOS1 working solution is added to all wells except for those that are subsequently filled with the inhibitor control solution. After a 60 min incubation, the fluorescence is measured with a M1000Pro plate reader (Tecan) using HTRF detection (excitation 337 nm, emission 1 : 620 nm, emission 2: 665nm). Compounds are tested in duplicate at different concentrations (for example, 10 μΜ, 2.5 μΜ, 0.63 μΜ, 0.16 μΜ, 0.04 μΜ, 0.01 μΜ test compound). The ratiometric data (i.e., emission 2 divided by emission 1) is used to calculate IC50 values against SOS1 using GraphPad Prism (GraphPad software). [00222] Table 2 below shows the resulting IC50 values of the compounds exemplified in Table 1 against SOS1 using the Ras-SOS interaction assay as described above, wherein K-Ras G13D is utilized. The results demonstrate that compounds disclosed herein are capable of reducing Ras protein signaling by inhibiting SOS1-mediated signaling. One or more of the exemplified compounds are potent SOS1 inhibitors, exhibiting an IC50 value against SOS1 less than about 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 80 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, or even less than 10 nM. For example, compounds 101, 103, 105, 106, 109, 110, 111, 114, 116, 121, 123, 124, 125, 126, 127, 128, 131, and 132 exhibit IC50 values less than 50 nM, 40 nM, 30 nM, 20 nM, or 10 nM against SOS1. [00223] Table 2 shows the resulting IC50 values of selected compounds against SOS1 using the Ras-SOS interaction assay described herein. Compound numbers correspond to the numbers and structures provided in Table 1 and Examples 1-6. IC50 values were not determined for compounds of Table 1 that are not listed in Table 2. Table 2

Example 12: ERK phosphorylation assay [00224] An ERK phosphorylation assay is used to examine the potency with which compounds disclosed herein inhibit the SOS1-mediated signaling and hence Ras signaling output in a Kras mutant cancer cell line. MIA PaCa-2 cells (ATCC CRL-1420) expressing K-Ras G12C are grown in DMEM/Ham's F12 medium supplemented with 10% fetal calf serum, glutamine and ~2.5% horse serum. Alternatively, other cell lines with aberrant Ras signaling output can be utilized. Non-limiting exemplary cell lines include NCI-H358 and H1975. Cells are plated in 96-well plates at a concentration of 40,000 cells/well and allowed to attach for at least 8 hours. Following, diluted solutions of test inhibitor compounds are added to the cell culture. After ~2 hours of incubation, the medium is removed and lysis buffer from AlphaLISA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) assay kit (Perkin Elmer ALSU-PERK- A10K) is added to the cells. The plate is agitated for 10 min at room temperature and 10 μL of the lysate is transferred to a 384-well Optiplate™ (Perkin Elmer) for assay. Thereafter ~5 μL of Acceptor Mix from the p-ERK AlphaLISA assay kit is added to wells and the plate is sealed with adhesive film. The samples are incubated for one hour at room temperature. Following, 5 μL of Donor Mix is added to the wells and the plate is re-sealed with adhesive film and incubated for one hour at room temperature. The plate is then read on a multimode microplate reader (e.g., SPARK^®Tecan) equipped with Alpha detection module. The data can be fitted to four-parameter dose- response curve using Prism version 9 (GraphPad) to calculate an IC50 for the inhibition of ERK phosphorylation. Certain compounds disclosed herein when assessed in this ERK phosphorylation assay are expected to exhibit IC50 values less than about 1 µM, about 500 nM, about 200 nM, about 100 nM, or 50 nM. Example 13: Ras-SOS cellular growth inhibition assay [00225] The ability of any compound of the present disclosure to inhibit SOS1-mediated signaling and hence Ras protein signaling can be demonstrated by inhibiting growth of a given Kras mutant cell line. [00226] Growth of cells with K-Ras G12C mutation: MIA PaCa-2 (ATCC CRL-1420) and NCI-H1792 (ATCC CRL-5895) cell lines comprise a G12C mutation and can be used to assess Ras cellular signaling in vitro, e.g., in response to a subject compound of the present disclosure. This cellular assay can also be used to discern selective inhibition of subject compounds against certain types of Kras mutants, e.g., more potent inhibition against Kras G12D relative to Kras G12C mutant, by using MIA PaCa-2 (G12C driven tumor cell line) as a comparison. Cell culture medium (comprising, for example, MIA PaCa-2 cells) is prepared with DMEM/Ham's F12 (e.g., with stable Glutamine, 10% FCS, and 2.5% Horse Serum). NCI-H1792 culture medium is prepared with RPMI 1640 (e.g., with stable Glutamine) and 10% FCS. A CellTiter-Glo (CTG) luminescent based assay (Promega) is used to assess growth of the cells, as a measurement of the ability of the compounds herein to inhibit Ras signaling in the cells. The cells (e.g., 800-1200 per well) are seeded in their respective culture medium in standard tissue culture-treated ultra-low attachment surface 96-well format plates (Corning Costar #3474). The day after plating, cells are treated with a dilution series (e.g., a 9 point 3-fold dilution series) of the compounds herein (e.g., approximately 125 µL final volume per well). Cell viability can be monitored (e.g., approximately 5 days later) according to the manufacturer's recommended instructions, where the CellTiter-Glo reagent is added (e.g., approximately 65 µL), vigorously mixed, covered, and placed on a plate shaker (e.g., approximately for 20 min) to ensure sufficient cell lysis prior to assessment of luminescent signal. The IC50 values are determined using the four-parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce cell growth of Ras-driven cells as representative tumor cells. See Table 3. The results demonstrate that the subject compounds are effective in inhibiting growth of tumor cells including cells comprising one or more Kras mutations, e.g., Ras-driven tumor cells carrying a Kras G12C mutation. One or more of the exemplified compounds are potent SOS1 inhibitors, capable of reducing cell growth with an IC50 value less than about 10 µM, 5 µM, 1 µM, 500 nM, 400 nM, 300 nM, 200 nM, or even less than 150 nM. For example, compounds 101, 109, 111, 115, and 118 exhibit IC50 values less than 500 nM, 400 nM, 300 nM, 200 nM, or even less than 150 nM, in inhibiting MIA PaCa-2 cell growth. Example 14: EGFR-SOS cellular inhibition assay [00227] The ability of any compound of the present disclosure to inhibit SOS1-mediated signaling and hence Ras protein signaling can be demonstrated by inhibiting growth of a given EGFR mutant cell line. [00228] Growth of cells with EGFR T790M L858R double mutation: The NCI-H1975 (ATCC CRL-5908) cell line comprises an EGFR T790M L858R double mutation and can be used to assess EGFR cellular signaling in vitro, e.g., in response to a subject compound of the present disclosure. NCI-H1975 culture medium is prepared with RPMI 1640 (e.g., with stable Glutamine) and 10% FCS. A CellTiter-Glo (CTG) luminescent based assay (Promega) is used to assess growth of the cells, as a measurement of the ability of the compounds herein to inhibit EGFR signaling in the cells. The cells (e.g., 800-1200 per well) are seeded in their respective culture medium in standard tissue culture-treated ultra-low attachment surface 96-well format plates (Corning Costar #3474). The day after plating, cells are treated with a dilution series (e.g., a 9 point 3-fold dilution series) of the compounds herein (e.g., approximately 125 µL final volume per well). Cell viability can be monitored (e.g., approximately 5 days later) according to the manufacturer's recommended instructions, where the CellTiter-Glo reagent is added (e.g., approximately 65 µL), vigorously mixed, covered, and placed on a plate shaker (e.g., approximately for 20 min) to ensure sufficient cell lysis prior to assessment of luminescent signal. The IC50 values are determined using the four- parameter fit. The resulting IC50 value is a measurement of the ability of the compounds herein to reduce growth of EGFR-driven tumor cells. See Table 3. One or more of the exemplified compounds are potent SOS1 inhibitors, capable of reducing cell growth with an IC50 value less than about 10 µM, 5 µM, 1 µM, 500 nM, 400 nM, 300 nM, 200 nM, or even less than 150 nM. For example, compounds 101, 103, 105, 109, 111, 115, 117, 118, 121, 127, 128, and 132 exhibit IC50 values less than 500 nM, 400 nM, 300 nM, 200 nM, or even less than 150 nM, in inhibiting growth of an NCI-H1975 (ATCC CRL-5908) cell line comprising an EGFR T790M L858R double mutation. [00229] Table 3 shows the resulting IC50 values of selected compounds against SOS1 using the cell proliferation assays described herein. Compound numbers correspond to the numbers and structures provided in Table 1 and Examples 1-6. IC50 values were not determined for compounds of Table 1 that are not listed in Table 3. Table 3

Example 15: In vivo Ras inhibition and synergistic reduction of tumor growth in a Ras-driven model [00230] The in vivo reduction in Ras signaling output by a subject compound alone and synergistic reduction of tumor growth in combination with another therapeutic agent are determined in a mouse tumor xenograft model. [00231] Xenograft with K-Ras G12C mutation: In an example, tumor xenografts are established by administration of tumor cells with K-Ras G12C mutation (e.g., MIA PaCa-2 cells) into mice, e.g., injection of the tumor cells into the right flanks of female BomTacNMRI-Foxn1nu mice with an age between 6 to 8 weeks. In case of the subcutaneous (s.c.) MIA PaCa-2 xenograft mouse models, MIA PaCa-2 cells are grown in cell culture flasks in appropriate medium. Cultures are incubated at 37 °C and 5% CO2 in a humidified atmosphere, with medium change or subcultivation performed 2-3 times a week. For injection, the cultured tumor cells are mixed with PBS including 5% FCS and Matrigel in a 1:1 ratio. About 0.5x10E7 cells in a volume of 100 μL is injected s.c. in each mouse to establish tumors. Mice are randomized into treatment groups of 6-10 mice, once tumors reach a desirable size (e.g., between about 88 to about 504 mm³, or between about 103 to about 377 mm³). Treatment with a subject compound of the present disclosure or with a control (e.g., vehicle control) may start on the day of randomization and can be continued until end of the study (e.g., 18 days). The test samples are administered intragastrically using a gavage needle at an application volume of 10 mL/kg in a volume of 10 mL/kg per mouse twice daily with a 6h difference. [00232] Mice are housed under standardized conditions at 21.5 ± 1.5 °C and 55 ± 10% humidity. Standardized irradiated diet and autoclaved tap water is provided ad libitum. In some cases, tags (e.g., ear tags, microchips implanted subcutaneously under isoflurane anesthesia) are used to identify each mouse. The tumor diameter is measured two or three times a week with a caliper. The volume of each tumor (in mm³) is calculated according to the formula “tumor volume = (π * length * width²) / 6.” To monitor side effects of treatment, mice are inspected daily for abnormalities and body weight is determined, e.g., daily. Animals are sacrificed at the end of the study. Animals with necrotic tumors or tumor sizes exceeding 1500 mm³ are sacrificed early during the study for ethical reasons. A compound disclosed herein is expected to inhibit tumor growth alone at an appropriate dose, and further to synergistically inhibit tumor growth when administered in conjunction with a Kras G12C inhibitor. Example 16: In vivo Ras inhibition and synergistic reduction of tumor growth in an EGFR mutation-driven model [00233] The in vivo reduction in Ras signaling output by a subject compound alone and synergistic reduction of tumor growth in combination with another therapeutic agent is determined in a mouse tumor xenograft model. [00234] Xenograft with EGFR mutations: In an example, tumor xenografts are established by administration of NCI-H1975 (ATCC CRL-5908) tumor cells into mice, e.g., injection of the tumor cells into the right flanks of female BomTacNMRI-Foxn1nu mice with an age between 6 to 8 weeks. In case of the subcutaneous (s.c.) NCI- H1975 xenograft mouse models, NCI-H1975 cells are grown in cell culture flasks in appropriate medium. Cultures are incubated at 37 °C and 5% CO2 in a humidified atmosphere, with medium change or subcultivation performed 2- 3 times a week. For injection, the cultured tumor cells are mixed with PBS including 5% FCS and Matrigel in a 1:1 ratio. About 0.5x10E7 cells in a volume of 100 μL is injected s.c. in each mouse to establish tumors. Mice are randomized into treatment groups of 6-10 mice, once tumors reach a desirable size (e.g., between about 88 to about 504 mm³, or between about 103 to about 377 mm³). Treatment with an inhibitor compound of the present disclosure or with a control (e.g., vehicle control) may start on the day of randomization and can be continued until end of the study (e.g., 18 days). The test samples are administered intragastrically using a gavage needle at an application volume of 10 mL/kg in a volume of 10 mL/kg per mouse twice daily with a 6h difference. [00235] Mice are housed under standardized conditions at 21.5 ± 1.5 °C and 55 ± 10% humidity. Standardized irradiated diet and autoclaved tap water is provided ad libitum. In some cases, tags (e.g., ear tags, microchips implanted subcutaneously under isoflurane anesthesia) are used to identify each mouse. The tumor diameter is measured two or three times a week with a caliper. The volume of each tumor (in mm³) is calculated according to the formula “tumor volume = (π * length * width²) / 6.” To monitor side effects of treatment, mice are inspected daily for abnormalities and body weight is determined, e.g., daily. Animals are sacrificed at the end of the study. Animals with necrotic tumors or tumor sizes exceeding 1500 mm³ are sacrificed early during the study for ethical reasons. A compound disclosed herein is expected to inhibit tumor growth alone at an appropriate dose, and further to synergistically inhibit tumor growth when administered in conjunction with an EGFR inhibitor, such as osimertinib. Example 17: Metabolic (Microsomal) Stability Assay [00236] The metabolic stability of a test compound is assayed at 37 °C using pooled liver microsomes (mouse or human liver microsomes). An aliquot of 10 µL of 50 µM test compound is mixed with 490 µL of 0.611 mg/mL liver microsomes, and then, 50 μL of the mixtures are dispensed to the 96 well tubes and warmed at 37 °C for 10 minutes. The reactions are initiated by adding 50 μL of the pre-warmed NADPH regeneration system solution (add 1.2 μL solution, 240 µL solution B, mix with 10.56 mL KPBS) and then incubated at 37 °C. The final incubation solution contains 100 mM potassium phosphate (pH 7.4), 1.3 mM NADP+, 3.3 mM glucose 6-phosphate, 0.4 Unit/mL of glucose 6-phosphate dehydrogenase, 3.3 mM magnesium chloride, 0.3 mg/mL liver microsomes and 0.5 μM test article. After 0, 15, 30 and 60 minutes in a shaking incubator, the reactions are terminated by adding 100 μL of acetonitrile containing 200 nM buspirone as an internal standard. All incubations are conducted in duplicate. Plates are vortexed vigorously by using Fisher Scientific microplate vortex mixer (Henry Troemner, US). Samples are then centrifuged at 3500 rpm for 10 minutes (4 °C) using Sorvall Legend XRT Centrifuge (Thermo Scientific, GE). Supernatants (40 μL) are transferred into clean 96-deep well plates. To each well is added 160 μL of ultrapure water (Milli-Q, Millipore Corporation) with 0.1% (v/v) formic acid (Fisher Chemical) and the resulting solutions mixed thoroughly and subjected to LC/MS/MS analysis in MRM positive ionization mode. [00237] All the samples are measured using a mass spectrometer (QTrap 5500 quadrupole/ion trap) coupled with a Shimadzu HPLC system. The HPLC system consists of a Shimadzu series degasser, binary quaternary gradient pumps, column heater coupled to an autosampler, and a Phenomenex Gemini-NX, C18, 3.0 µm or Phenomenex Lunar, C8, 5.0 µM HPLC column (Phenomenex, Torrance, CA), and eluting with a mobile phase gradient consisting of Solution A (0.1% formic acid water) and Solution B (0.1% formic acid acetonitrile). The column temperature is maintained at 40 °C. All the analytes are detected with positive-mode electrospray ionization (ES+). [00238] The half-life for the metabolic degradation of the test compound is calculated by plotting the time-course disappearance of the test compound during the incubation with liver microsomes. Each plot is fitted to a first-order equation for the elimination of the test compound (% remaining compound) versus time using non-linear regression (Equation 1). Equation 1:

where Ct is the mean relative substrate concentration at time t and C0 is the initial concentration (0.5 ^M) at time 0. Note that the area ratio of the substrate peak to an internal standard peak is proportional to the analyte concentration and is used for regression analysis to derive a value of k. [00239] The half-life t1/2 for metabolic (microsome) stability is derived from the test compound elimination constant k using Equation 2 below. Equation 2:

Example 18: CYP2C19 Inhibition Assay [00240] Some xenobiotics can inhibit cytochrome P450 (CYP) enzyme function, which alters their ability to metabolize drugs. Administration of a CYP inhibitor with a drug whose clearance is dependent on CYP metabolism can result in increased plasma concentrations of this concomitant drug, leading to potential toxicity. The inhibition of CYP2C19 by a test compound is assayed in human liver microsomes using S-Mephenytoin as a CYP2C19 substrate. The stock solution of the test compound or known CYP2C19 inhibitor as a positive control (10 mM) is diluted with KPBS to 40 ^M. In a similar way, the stock solutions of the human liver microsomes and S- Mephenytoin are diluted with KPBS buffer. The pre-incubations are started by incubating a plate containing 25 ^L human liver microsomes (final concentration of 0.2 mg/mL), 25 ^L NADPH-generating system, and a 25 ^L test compound (final concentration 10 ^M) or the positive control for 30 min at 37±1 °C. After the pre-incubation, 25 ^L S-Mephenytoin (final concentration 200 ^M) is added and incubated another 12 minutes at 37±1 °C for substrate metabolism. The reactions are terminated by addition of 100 µL of ice-cold acetonitrile containing an internal standard (buspirone). Precipitated proteins are removed by centrifugation at 3500 rpm for 10 minutes at 4 °C (Allegra 25R, Beckman Co. Fullerton, CA) and then an aliquot of the supernatant is transferred to an assay plate. [00241] All the samples are assessed using a mass spectrometer (QTrap 5500 quadrupole/ion trap) coupled with a Shimadzu HPLC system, following the manufacturer's instructions. The metabolism of S-Mephenytoin in human liver microsomes is monitored by LC/MS/MS as representative of CYP2C19 inhibitory activity. The amount of metabolite formed is assessed by the peak area ratio (metabolite/IS) and % inhibition at 10 ^M is expressed as a percentage of the metabolite signal reduced compared to the control (i.e. an incubation that contained no inhibitor and represented 100% enzyme activity): % inhibition = (1-A/B) × 100%, where A is the metabolite peak area ratio formed in the presence of test compound or inhibitor at 10 ^M and B is the metabolite peak area ratio formed without test compound or inhibitor in the incubation. Example 19: Mouse and Human Protein Binding Assay to Assess Free Drug Concentration [00242] The assay is to determine the plasma protein binding of the test compound in the plasma of human and animal species using a Rapid Equilibrium Dialysis (RED) device for equilibrium dialysis and LC-MS/MS for sample analysis. Test compound is spiked in. The stock solution of the test compound is prepared at 5 mM concentration, then one µL of 5 mM working solution is added to 1000 µL plasma to achieve a final concentration of 5 µM. The spiked plasma is placed on a rocker and gently agitated for approximately 20 minutes. A volume of 300 µL of the plasma sample containing 5 µM test compound from each species is added to designate RED device donor chambers followed by addition of 500 µL of potassium phosphate buffer to the corresponding receiver chambers in duplicate. The RED device is then sealed with sealing tape and shaken at 150 RPM for 4 hours at 37 °C. Post-dialysis donor and receiver compartment samples are prepared for LC-MS/MS analysis, including spiking samples with an internal standard for the bioanalytical analysis. Warfarin and propranolol are purchased from Sigma-Aldrich (St. Louis, MO), and used as positive controls for low and high plasma protein binding, respectively. [00243] All the samples are analyzed using an Agilent Technologies 6430 Triple Quad LC/MS system. The HPLC system consisted of Agilent 1290 Infinity Liquid Chromatograph coupled to an autosampler (Agilent 1290 Infinity LC Injector HTC), and a Phenomenex Gemini-NX, C18, 3.0 µm or Phenomenex Lunar, C8, 5.0 µM HPLC column (Phenomenex, Torrance, CA), and are eluted with a mobile phase gradient consisting of Solution A (0.1% formic acid water) and Solution B (0.1% formic acid acetonitrile). The column temperature is maintained at 40 °C. All the analytes are detected with positive-mode electrospray ionization (ES+). The percentage of the test compound bound to plasma is calculated following Equation 3 and 4. Equation 3

E^{quation 4} % _{plasma protein bound test compound = 100 − % Free test compound} Example 20: hERG (automated patch-clamp) Assay [00244] The human ether-a-go-go related gene (hERG) encodes the voltage gated potassium channel in the heart (IKr) which is involved in cardiac repolarization. Inhibition of the hERG causes QT interval prolongation and can lead to potentially fatal events in humans. It is thus important to assess hERG inhibition early in drug discovery. A hERG automated patch-clamp assay is done using a hERG CHO-K1 cell line using an incubation time of 5 min. The degree of hERG inhibition (%) is obtained by measuring the tail current amplitude, which is induced by a one second test pulse to - 40 mV after a two second pulse to + 20 mV, before and after drug incubation (the difference current is normalized to control and multiplied by 100 to obtain the percent of inhibition). The percent hERG inhibition is measured in the presence of 10 µM test compound. Example 21: Rat Oral Exposure (%F) [00245] A pharmacokinetic profile for a test compound is assessed by single dosing in jugular vein cannulated male Sprague-Dawley rats. Animal weights are typically over 200 grams, and animals are allowed to acclimate to their new environment for at least 3 days prior to the initiation of any studies. One set of animals is dosed intravenous (IV) with test compound, 2 mg/kg in 20% HP-beta-CD or 20% Captisol, pH adjusted to ~4 by citric acid. IV dosing solution concentration is 0.4 mg/mL test compound. Time of blood sampling is 5 minutes, 15 minutes, 30 minutes, 90 minutes, 360 minutes, and 24 hours following IV dosing. Another set of animals is dosed oral (po) with test compound, 10 mg/kg in 20% HP-beta-CD or 20% Captisol, pH adjusted to ~4 by citric acid. Oral dosing solution concentration is 1 mg/mL test compound. Time of blood sampling is 15 minutes, 30 minutes, 90 minutes, 180 minutes, 360 minutes and 24 hours following oral (po) dosing. Blood samples (~0.2 mL/sample) are collected via jugular vein and placed in tubes containing EDTA-K2 and stored on ice until centrifuged. The blood samples are centrifuged at approximately 6800g for 6 minutes at 2-8 °C and the resulting plasma will be separated and stored frozen at approximately -80 °C. [00246] All the plasma samples are analyzed using an Agilent Technologies 6430 Triple Quad LC/MS system, following the manufacturer instructions. All the analytes are detected with positive-mode electrospray ionization (ES+). A standard curve for each test compound is generated and used to measure test compound concentrations in the rat plasma samples. Based on the time course sampling, an area under the curve is calculated for the oral dose group and the intravenous dose group. Percentage rat bioavailability is calculated based on equation 5. Equation 5 where F is bioavailability, AUC_po is area under curve of oral drug, AUC_IV is

area under curve of intravenous drug, Dose_IV is the intravenous dose and Dose_po is the oral dose. Example 22: Kinase selectivity assay [00247] Eurofins DiscoverX (USA) commercially offers measurement on its KINOMEscan scanEDGE™ 97Panel comprising of 97 potential kinase off-targets. The KINOMEscan™ screening platform employs an active site- directed competition binding assay to quantitatively measure interactions between test compounds and kinases. Test compound is screened at 10 µM, and results for primary screen binding interactions are reported as ‘Percent control', where lower numbers indicate stronger binding to a kinase being examined.

, where the negative control = DMSO (100%Ctrl) and the positive control = control compound (0%Ctrl).

Claims

CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

Formula (I); wherein: R¹ is a 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, or 5-10 membered heteroaryl ring, wherein the 3-12 membered cycloalkyl ring, 3-12 membered heterocycloalkyl ring, 6-10 membered aryl ring, and 5-10 membered heteroaryl ring are optionally substituted with one or more R¹⁰; L¹ is a bond or C_1-6alkyl; R² is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(H)(R¹²), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), - CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, and -CH₂S(O)₂N(R¹²)(R¹³), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3- 6cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20a; R³ is selected from halogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, C_1- 9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -N(R¹⁴)S(O)R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, -C(O)N(R¹²)(R¹³), - C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), -S(O)N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), -CH₂S(O)R¹⁵, -CH₂S(O)N(R¹²)(R¹³), -CH₂N(R¹²)S(O)(R¹³) and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C3-14cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b; R⁴ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁵ is selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; R⁶ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C_{2- 9}heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; R⁷ is selected from hydrogen, halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, C₂- 9heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c; each R¹⁰ is independently selected from halogen, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2- 9heterocycloalkyl, C_6-10aryl, C_1-9heteroaryl, -OR¹², -SR¹², -N(R¹²)(R¹³), -C(O)OR¹², -OC(O)N(R¹²)(R¹³), - N(R¹⁴)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)OR¹⁵, -N(R¹⁴)S(O)₂R¹⁵, -C(O)R¹⁵, -S(O)R¹⁵, -OC(O)R¹⁵, - C(O)N(R¹²)(R¹³), -C(O)C(O)N(R¹²)(R¹³), -N(R¹⁴)C(O)R¹⁵, -S(O)₂R¹⁵, -S(O)₂N(R¹²)(R¹³), - S(=O)(=NH)N(R¹²)(R¹³), -CH₂C(O)N(R¹²)(R¹³), -CH₂N(R¹⁴)C(O)R¹⁵, -CH₂S(O)₂R¹⁵, -CH₂S(O)₂N(R¹²)(R¹³), - CH₂N(R¹²)S(O)₂(R¹³), and -P(O)(R¹⁷)(R^17a), wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d; each R¹² is independently selected from hydrogen, C_1-6alkyl, C_1-6 haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20e; each R¹³ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; or R¹² and R¹³, together with the nitrogen to which they are attached, form a C_2-9heterocycloalkyl ring optionally substituted with one, two, or three R^20f; each R¹⁴ is independently selected from hydrogen, C_1-6alkyl, and C_1-6haloalkyl; each R¹⁵ is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C6- 1₀aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_{6- 10}aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20g; each R¹⁷ and each R^17a are independently selected from C_1-6alkyl and C_3-6cycloalkyl, wherein C_1-6alkyl and C3- 6cycloalkyl are optionally substituted with one, two or three of R^20h; or R¹⁷ and R^17a are combined to form a C₂- 9heterocycloalkyl ring; each R^20a, R^20b, R^20c, R^20d, R^20e, R^20f, R^20g, and R^20h is independently selected from halogen, oxo, =NH, -CN, C_1- 6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂-C₂- 9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, C_1-9heteroaryl, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², - C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), -OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, - N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, -S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), -OCH₂C(O)OR²², and -OC(O)R²⁵, wherein C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-10cycloalkyl, -CH₂-C_3-10cycloalkyl, C_2-9heterocycloalkyl, -CH₂- C_2-9heterocycloalkyl, C_6-10aryl, -CH₂-C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, C_{1- 6}haloalkoxy, -OR²¹, -SR²¹, -N(R²²)(R²³), -C(O)OR²², -C(O)N(R²²)(R²³), -C(O)C(O)N(R²²)(R²³), - OC(O)N(R²²)(R²³), -N(R²⁴)C(O)N(R²²)(R²³), -N(R²⁴)C(O)OR²⁵, -N(R²⁴)C(O)R²⁵, -N(R²⁴)S(O)₂R²⁵, -C(O)R²⁵, - S(O)₂R²⁵, -S(O)₂N(R²²)(R²³), and -OC(O)R²⁵; each R²¹ is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_{2- 9}heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1- 9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²² is independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C₂- 9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_{1- 9}heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; each R²³ is independently selected from H and C_1-6alkyl; each R²⁴ is independently selected from H and C_1-6alkyl; and each R²⁵ is selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1- 9heteroaryl, wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C_1-6alkyl, C_1-6haloalkyl, C₁- 6alkoxy, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is selected from hydrogen, C_1-6alkyl, C_3-6cycloalkyl, and C_2-9heterocycloalkyl, wherein C_1-6alkyl, C_3-6cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20a.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_1-6alkyl optionally substituted with one, two, or three R^20a.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_1-6alkyl substituted with one, two, or three R^20a.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_1-6alkyl.

6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is - CH₃.

7. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_3-6cycloalkyl optionally substituted with one, two, or three R^20a.

8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_3-6cycloalkyl.

9. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20a.

10. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is C_2-9heterocycloalkyl substituted with one, two, or three R^20a.

11. The compound of claim 9, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is unsubstituted C_2-9heterocycloalkyl.

12. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R² is hydrogen.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from -N(R¹²)(R¹³), -C(O)R¹⁵, -C(O)N(R¹²)(R¹³), -SO2R¹⁵, -SO2N(R¹²)(R¹³), - P(O)(R¹⁷)(R^17a), C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_{1- 6}alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20b.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is selected from -N(R¹²)(R¹³), C_1-6alkyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl, wherein C_{1- 6}alkyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20b.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_2-9heterocycloalkyl optionally substituted with one, two, or three R^20b.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_3-10cycloalkyl optionally substituted with one, two, or three R^20b.

17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is C_1-6alkyl optionally substituted with one, two, or three R^20b.

18. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R³ is -N(R¹²)(R¹³).

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is selected from hydrogen, halogen, C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, and C₁- 9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is independently selected from hydrogen, halogen, and unsubstituted C_1-6alkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁶ is hydrogen.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is selected from hydrogen, halogen, C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, and C₁- 9heteroaryl, wherein C_1-6alkyl, C_3-10cycloalkyl, C_2-9heterocycloalkyl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20c.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is independently selected from hydrogen, halogen, and unsubstituted C_1-6alkyl.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is unsubstituted C_1-6alkyl.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁷ is hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is selected from C_1-6alkyl and C_1-6haloalkyl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁵ is -CH₃.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R⁴ is hydrogen.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein L¹ is a bond.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 6-10 membered aryl ring substituted with one or more R¹⁰.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one or more R¹⁰.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is phenyl substituted with one, two, or three R¹⁰.

33. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one or more R¹⁰.

34. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein R¹ is a 5-10 membered heteroaryl ring substituted with one, two, or three R¹⁰.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C6- 10aryl, C_1-9heteroaryl, -OR¹², and -N(R¹²)(R¹³), wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C6- 1₀aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three R^20d.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen, C_1-6alkyl, and -N(R¹²)(R¹³), wherein C_1-6alkyl is optionally substituted with one, two, or three R^20d.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is substituted with one, two, or three R^20d, and each R^20d is halogen.

38. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R¹ is phenyl substituted with one, two, or three R¹⁰; L¹ is a bond; R² is -CH₃; R³ is selected from -N(R¹²)(R¹³), C_1-6alkyl, C_3-10cycloalkyl, and C_2-9heterocycloalkyl, wherein C_1-6alkyl, C3- 1₀cycloalkyl, and C_2-9heterocycloalkyl are optionally substituted with one, two, or three R^20b; R⁴ is hydrogen; R⁵ is -CH₃; R⁶ is hydrogen; and R⁷ is independently selected from hydrogen, halogen, and unsubstituted C_1-6alkyl.

39. The compound of claim 38, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R³ is selected from C4-8cycloalkyl and C₂-7heterocycloalkyl, each of which is optionally substituted with one, two, or three R^20b; and R⁷ is -CH₃.

40. The compound of claim 38 or 39, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R¹⁰ is independently selected from halogen and C_1-6alkyl, wherein C_1-6alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C₂-7heterocycloalkyl, and -OH, wherein C₂- 7heterocycloalkyl is optionally substituted with one, two, or three groups independently selected from halogen and C_1-6alkyl; and each R^20b is independently selected from halogen, oxo, and C_1-6alkyl, wherein C_1-6alkyl is optionally substituted with one, two, or three groups selected from halogen.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein each R²⁵ is independently selected from C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl, wherein C_1-6alkyl, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, C_1-6alkyl, C₁- 6haloalkyl, C_1-6alkoxy, C_3-7cycloalkyl, C_2-9heterocycloalkyl, C_6-10aryl, and C_1-9heteroaryl.

42. A compound selected from:

, or a

pharmaceutically acceptable salt, solvate, or prodrug thereof.

43. A compound selected from:

, ,

and or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

44. A pharmaceutical composition comprising a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

45. 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 1-43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

46. The method of claim 45, wherein the cancer is a solid tumor or a hematological cancer.

47. The method of claim 45, wherein the subject is administered an additional agent or therapy.

48. A method of reducing Ras signaling output, comprising contacting a SOS1 protein with an effective amount of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, thereby reducing the Ras signaling output.

49. The method of claim 48, wherein the compound disrupts interaction between a Ras protein and SOS1.

50. The method of claim 49, wherein the Ras protein is a wildtype K-Ras or a mutant K-Ras.

51. A method of inhibiting cell growth, comprising administering to a cell expressing SOS1 an effective amount of a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, thereby inhibiting growth of said cells.

52. The method of claim 51, further comprising administering to the cell an additional agent.

53. The method of claim 47 or claim 52, wherein the additional agent is an inhibitor against one or more targets selected from the group of: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, FGFR4, mitotic kinase, topoisomerase, ALK, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1/2, IGF1-R, CDK9, SHC, GAB, GRB, PI3-kinase, MAPK, SHIP1, SHIP2, SHP1, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, WT Ras, mutant Ras, ROS1, CDK4/6, and a mutant of the one or more target thereof.

54. The method of claim 47 or claim 52, wherein the additional agent is a chemotherapeutic agent, a radioactive agent, or an immune modulator.

55. A SOS1 protein bound by a compound of any one of claims 1-43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein interaction of the SOS1 protein with a Ras protein is reduced as compared to a SOS1 protein unbound to said compound.