Macrocyclic ras inhibitors

Abstract

This disclosure provides compounds of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or pharmaceutically acceptable salts thereof, that inhibit a Ras GTPase (e.g., a KRas, NRas, and / or HRas GTPase). In some embodiments, the Ras protein is a dysregulated Ras protein that has a mutation (referred to herein as a mutant Ras protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) Ras activation, such as Ras activation associated with a mutant Ras protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II- c)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] MACROCYCLIC RAS INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial Nos.63 / 706,569, filed October 11, 2024; 63 / 711,089, filed October 23, 2024; 63 / 725,963, filed November 27, 2024; 63 / 737,117, filed December 20, 2024; 63 / 771,572, filed March 13, 2025; and 63 / 773,308, filed March 17, 2025, each of which is incorporated by reference it its entirety herein. SEQUENCE LISTING This application contains a Sequence Listing that has been submitted electronically as an XML file named “TRLN-022-010WO1SequenceListing.XML.” The XML file, created on September 26, 2025 and is 6 KB in size. The material in the XML file is hereby incorporated by reference in its entirety. TECHNICAL FIELD This disclosure provides compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, that inhibit a Ras GTPase (e.g., a KRas, NRas, and / or HRas GTPase). In some embodiments, the Ras protein is a dysregulated Ras protein that has a mutation (referred to herein as a mutant Ras protein). These compounds are useful, for example, for treating a disease, disorder, or condition in which increased and / or sustained (e.g., excessive) Ras activation, such as Ras activation associated with a mutant Ras protein, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. BACKGROUND Ras proteins, including KRas, NRas, and HRas, belong to a protein family of small GTPases that act as binary molecular switches cycling between active guanosine triphosphate (GTP)-bound (ON) and inactive guanosine diphosphate (GDP)-bound (OFF) states. These switches are normally tightly controlled, but in certain diseases, such as cancer, mutations in the Ras genes or their regulators render Ras proteins persistently active. As Ras mutations are an important factor in the development of cancer, mutant Ras has become an important cancer treatment target. SUMMARY This disclosure provides compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, that inhibit a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein)))). The compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, selectively inhibit the GTP-bound (ON) state of Ras (e.g., selectively inhibit over the GDP-bound (OFF) state of Ras). The compounds form part of a three-component complex that also includes Ras (e.g., KRas, NRas, or HRas) and a cytosolic chaperone in the cell (e.g., cyclophilin A). The compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, are useful, for example, for treating a disease, disorder, or condition in which increased Ras activation, such as Ras activation associated with a mutant Ras protein or Ras activation associated with Ras amplification, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. Provided herein are compounds of Formula (I):

[0002] or pharmaceutically acceptable salts thereof, wherein: R1, R3, R4, and R5are each as defined herein. Also provided herein are compounds of Formula (II): or pharmaceutically acceptable salts thereof, wherein: R1, R3, R4, and R5are each as defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Provided herein are methods for treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising (a) determining that the cancer has a Ras dysregulation (e.g., a Ras mutation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation), aNRas mutation (e.g., aNRas Q61K mutation, aNRas Q61L mutation, or a NRas Q61R mutation), or a HRas mutation (e.g., a HRas Q61H mutation or a HRas Q61L mutation))); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0003] Further provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to a subject identified or diagnosed as having a cancer that has a Ras dysregulation (e.g., a Ras mutation (e.g., a KRas mutation (e.g., a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation), a NRas mutation (e.g., a NRas Q61K mutation, a NRas Q61L mutation, or a NRas Q61R mutation), or a HRas mutation (e.g., a HRas Q61H mutation or a HRas Q61L mutation))) a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0004] To facilitate understanding of the disclosure set forth herein, a number of terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In the case of conflict between the present disclosure and any content incorporated by reference, the present disclosure controls.

[0005] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0006] DETAILED DESCRIPTION

[0007] This disclosure provides compounds of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or pharmaceutically acceptable salts thereof, that inhibit a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein)))). The compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, selectively inhibit the GTP-bound (ON) state of Ras (e.g., selectively inhibit over the GDP-bound (OFF) state of Ras). The compounds form part of a three-component complex that also includes Ras (e.g., KRas, NRas, or HRas) and a cytosolic chaperone in the cell (e.g., cyclophilin A). The compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, are useful, for example, for treating a disease, disorder, or condition in which increased Ras activation, such as Ras activation associated with a mutant Ras protein or Ras activation associated with Ras amplification, contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same. Ras family genes (e.g., KRAS, NRAS, and HRAS) were the first oncogenes identified and are some of the most commonly mutated of all discovered oncogenes. See, e.g., Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15-0203. The Ras family are guanine nucleotide binding proteins generally found at the inner leaflet of the cell membrane. A wild type Ras protein becomes activated when bound to GTP, but it is inactive when bound to GDP. Normally, growth factors bind to extracellular receptors to induce nucleotide exchange with the help of guanine nucleotide exchange factors (GEF) (e.g., Son of sevenless homolog 1 (SOS1)). These GEFs allow GDP to dissociate from a Ras protein and GTP to bind. Ras proteins can interact with effector proteins such as cRAF when bound to GTP. Hydrolysis of GTP to form GDP can deactivate Ras proteins, and the hydrolysis can be achieved through the intrinsic GTPase activity, which may be enhanced by binding to a GTPase activating protein (GAP). Some oncogenic Ras missense mutations can prevent or slow GTP hydrolysis and result in the accumulation of Ras in the active state. For example, mutant KRas proteins often have altered Raf affinity and / or altered intrinsic GTPase activity. See, Table 1 reproduced from Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15-0203. These changes and other factors can contribute to increased KRas signaling in mutant KRas proteins. Table 1 Signaling pathways associated with Ras are persistently activated in many cancers, where they participate in cellular growth and proliferation, differentiation, protein synthesis, glucose metabolism, cell survival, and inflammation. Ras inhibitors are described in, for example, International Publication Nos. WO 2025 / 201453; WO 2025 / 162395; WO 2025 / 171296; WO2025 / 051241; WO2025 / 045233; WO2024 / 208934; WO2024 / 189481; WO2024 / 249299; WO2024 / 222864; WO2024 / 211712; WO2024 / 211663; WO2024 / 169914; WO2024 / 153208; WO2024 / 104364; WO2024 / 067857; WO2024060966; WO2024 / 017859; WO2024 / 008834; WO2024 / 008610; WO2023 / 240263; WO2023 / 232776; WO2023 / 025832; WO2022 / 060836; WO2021 / 091956; CN Application Nos. CN117534687; CN117534685; and CN117534684. Compound Embodiments Provided herein are compounds of Formula (I): or pharmaceutically acceptable salts thereof, wherein: R1is selected from the group consisting of: X1is O or S; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy optionally substituted with 1-3 Rc; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; (i) -ORb1; and (j) halo; n is 1 or 2; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: (iii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond, -C(=O)-, or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; Z1is -N(R8)- or -O-; R8 is -H or C1-3alkyl optionally substituted with 1-3 Rc;m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)O-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; (b) –(C0-3alkylene)-S(O)2(C1-3alkyl); (c) –(C0-3alkylene)-N(Rf)2; (d) C3-8cycloalkyl optionally substituted with 1-3 Ra; (e) 5-6 membered heteroaryl optionally substituted with 1-3 Ra; and (f) –(5-membered heteroarylene)-(C0-3alkylene)-(4-8 membered heterocyclyl), wherein the 4-8 membered heterocyclyl is optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1 is independently selected from the group consisting of: C3-8 cycloalkyl, 4-8membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (I), L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; L3is -C(=O)N(Rf)-C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; (b) –(C0-3alkylene)-S(O)2(C1-3alkyl); and (c) –(C0-3alkylene)-N(Rf)2. In some embodiments of Formula (I): R1is selected from the group consisting of: X1is O or S; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy optionally substituted with 1-3 Rc; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; (i) -ORb1; and (j) halo; n is 1 or 2; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: (iii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; Z1is -N(R8)- or -O-; R8is -H or C1-3alkyl optionally substituted with 1-3 Rc; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (I): R1is each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo; n is 1 or 2; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: (iii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; Z1is -N(R8)- or -O-; R8is -H or C1-3alkyl optionally substituted with 1-3 Rc; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and(k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. Also provided herein are compounds of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of:

[0008] wherein: X1is O or S; n is 1 or 2; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy optionally substituted with 1-3 Rc; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; (i) -ORb1; and (j) halo; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: (ii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond, -C(=O)-, or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)O-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; (b) –(C0-3alkylene)-S(O)2(C1-3alkyl); (c) –(C0-3alkylene)-N(Rf)2; (d) C3-8cycloalkyl optionally substituted with 1-3 Ra; (e) 5-6 membered heteroaryl optionally substituted with 1-3 Ra; and (f) –(5-membered heteroarylene)-(C0-3alkylene)-(4-8 membered heterocyclyl), wherein the 4-8 membered heterocyclyl is optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rh is independently selected from the group consisting of: halo, -CN, -OH, -N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (II), L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; L3is -C(=O)N(Rf)-C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; (b) –(C0-3alkylene)-S(O)2(C1-3alkyl); and (c) –(C0-3alkylene)-N(Rf)2. In some embodiments of Formula (II): R1is selected from the group consisting of:

[0009] wherein: X1is O or S; n is 1 or 2; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy optionally substituted with 1-3 Rc; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; (i) -ORb1; and (j) halo; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3 is C1-6alkyl;R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: (ii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rh is independently selected from the group consisting of: halo, -CN, -OH, -N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (II): R1is selected from the group consisting of: n is 1 or 2; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1;R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: (ii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rg is independently selected from the group consisting of: Rh and C1-6alkyloptionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (I): R1is each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo; n is 1 or 2; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; and (c) phenylene optionally substituted with 1-3 Ra; (d) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; Z1is -N(R8)- or -O-; R8is -H or C1-3alkyl optionally substituted with 1-3 Rc; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (II): R1is selected from the group consisting of: n is 1 or 2; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; and (c) phenylene optionally substituted with 1-3 Ra; (d) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl;(f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. In some embodiments of Formula (II), R1is In some embodiments of Formula (I) or (II), n is 1. In some embodiments of Formula (I) or (II), R1is In some embodiments of Formula (I) or (II), R2is -NH2or -N(Rf)R21. In some embodiments of Formula (I) or (II), R2is -NH2. In some embodiments of Formula (I) or (II), R2is -N(Rf)R21. In some embodiments, R21is C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2. In some embodiments, R21is C1-3alkyl. For example, R2can be -N(C1-3alkyl)2(e.g., -NMe2). In some embodiments, R21is selected from the group consisting of: Rb1and -(C1-3alkylene)-Rb1. In some embodiments, R21is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, -CN, -OH, -N(Rf)2, C1- 6 alkoxy, C1-6haloalkoxy, and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -F and -OH; and (b) -(C1-3alkylene)- (4-8 membered heterocyclyl), wherein the 4-8 membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, C1-6haloalkoxy, and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -F and -OH. In some embodiments of Formula (I) or (II), R2is -N(Rf)C(=O)R21(e.g., - N(H)C(=O)Me). In some embodiments of Formula (I) or (II), R2is C1-3alkoxy. In some embodiments of Formula (I) or (II), R2is Rb1. In some embodiments, R2is a 4-8 membered heterocyclyl (e.g., azetidinyl) optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, -CN, -OH, -N(Rf)2, C1-6alkoxy, C1- 6 haloalkoxy, and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -F and -OH. In some embodiments of Formula (I) or (II), R1is In some embodiments, X1is O. In some embodiments, R2is -NH2or -N(Rf)R21. In some embodiments, R21is C1-3alkyl. In some embodiments of Formula (II), R1is In some embodiments of Formula (I) or (II), RNis C1-3alkyl (e.g., methyl). In some embodiments of Formula (I) or (II), RZis C1-6alkyl optionally substituted with 1-3 Rc. In some embodiments, RZis C1-3alkyl. For example, RZcan be isopropyl. In some embodiments of Formula (I) or (II), RNis methyl; and RZis isopropyl. In some embodiments of Formula (I), R5is In some embodiments, m is 0. In some embodiments of Formula (I) or (II), L1is a phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra. In some embodiments, L1is a phenylene optionally substituted with 1-2 Ra. In some embodiments, L1is a phenylene. In some embodiments, L1is a 6-membered heteroarylene (e.g., pyrimidylene) optionally substituted with 1-2 Ra. In some embodiments, L1is a 6-membered heteroarylene. For example, L1can be pyrimidylene (e.g., In some embodiments of Formula (I) or (II), L1is –S(O)2–. In some embodiments of Formula (I) or (II), L1 is -C(=O)–.In some embodiments of Formula (I) or (II), L2is a straight-chain C1-4alkylene optionally substituted with 1-2 Ra. For example, L2can be -CH2- or -CH2CH2-. In some embodiments of Formula (I) or (II), L2is a bond. In some embodiments of Formula (I) or (II), R5is -L3-L4-R9. In some embodiments of Formula (I) or (II), L3is -C(=O)N(Rf)-* (e.g., -C(=O)N(Me)- *). In some embodiments of Formula (I) or (II), L3is -S(O)2N(Rf)-* (e.g., -S(O)2N(Rf)-). In some embodiments of Formula (I) or (II), L4is C1-3alkylene optionally substituted with 1-3 Rc(e.g., L4is -CH2-). In some embodiments of Formula (I) or (II), L4is a bond. In some embodiments of Formula (I) or (II), R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 -F. For example, R9can be selected from the group consisting of: , , , In some embodiments of Formula (I) or (II), R9is a C3-8cycloalkyl optionally substituted with 1-3 Ra. In some embodiments, R9is a C3-8cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc. For example, R9can be . In some embodiments of Formula (I) or (II), R9is a 5-membered heteroaryl (e.g., pyrazolyl) optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc. For example, R9can be . In some embodiments of Formula (I) or (II), R7is a 4-8 membered heterocyclyl optionally substituted with 1-3 R17. In some embodiments, R7is a 4-8 membered heterocyclyl (e.g., morpholinyl or azetidinyl) optionally substituted with 1-2 Ra. In some embodiments of Formula (I) or (II), R7is a 4-8 membered heterocyclyl (e.g., morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, thiomorpholinyldioxide (e.g., optionally substituted with 1-2 substituents independently selected from the group consisting of: -F; -CN; -OH; -NRdRe; and C1-6alkyl optionally substituted with 1-6 Rc, wherein: Rdand Reare each independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 Rc; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F. In some embodiments of Formula (I) or (II), R7is a 5-6 membered heteroaryl (e.g., pyrazolyl) optionally substituted with 1-2 R17. In some embodiments of Formula (I) or (II), R7is -H. In some embodiments of Formula (I), R5is In some embodiments of Formula (I), Z1is -N(R8)-. For example, Z1can be -N(Me)-. In some embodiments of Formula (I) or (II), m is 0. In some embodiments of Formula (I) or (II), R5is -L3-L4-R9. In some embodiments, L3is -C(=O)N(Rf)-* (e.g., -C(=O)N(Me)-*). In some embodiments, L4is C1-3alkylene optionally substituted with 1-3 Rc(e.g., L4is -CH2-). In some embodiments, R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc. For example, R9is In some embodiments of Formula (I) or (II), R4is C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R4is C1-3alkyl substituted with C1-3alkoxy. For example, R4can be In some embodiments of Formula (I) or (II), R3is C1-3alkyl. For example, R3can be ethyl. In some embodiments, the compounds of Formula (II) are compounds of Formula (II- a): or pharmaceutically acceptable salts thereof, wherein: Rf1is Rf; L4is a bond or -CH2-; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc; (b) C3-8cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc; and (c) 5-membered heteroaryl (e.g., pyrazolyl) optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc; R3is C1-3alkyl; R1is wherein: RZis C1-6alkyl optionally substituted with 1-3 Rc; RNis C1-3alkyl; R2is selected from the group consisting of: (a) -NH2; and (b) -N(Rf)R21; and R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F. In some embodiments of Formula (II-a), L4is -CH2-; and R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments of Formula (II-a), each Rcis independently selected from the group consisting of: halo, -CN, -OH, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F. In some embodiments of Formula (II-a), R9is selected from the group consisting of: 9 , , , For example, R can be In some embodiments of Formula (II-a), R9is a C3-8cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc. For example, R9can be In some embodiments of Formula (II-a), Rf1is methyl. In some embodiments, the compounds of Formula (II) are compounds of Formula (II- b): or pharmaceutically acceptable salts thereof, wherein: L1is –S(O)2– or -C(=O)–; R7is a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from the group consisting of: -F; -CN; -OH; -NRdRe; and C1-6alkyl optionally substituted with 1-6 Rc; R3is C1-3alkyl; R1is wherein: RZis C1-6alkyl optionally substituted with 1-3 Rc; RNis C1-3alkyl; R2is selected from the group consisting of: (a) -NH2; and (b) -N(Rf)R21; R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2; Rdand Reare each independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 Rc; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F. In some embodiments of Formula (II-b), R7is selected from the group consisting of: In some embodiments, the compounds of Formula (II) are compounds of Formula (II- c): or pharmaceutically acceptable salts thereof, wherein: L1is phenylene or 6-membered heteroarylene; R7is a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from the group consisting of: -F; -CN; -OH; -NRdRe; and C1-6alkyl optionally substituted with 1-6 Rc; R3is C1-3alkyl; R1is wherein: RZis C1-6alkyl optionally substituted with 1-3 Rc; RNis C1-3alkyl; R2is selected from the group consisting of: (a) -NH2; and (b) -N(Rf)R21; R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2; Rdand Reare each independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 Rc; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F. In some embodiments of Formula (II-c), L1is a 6-membered heteroarylene. For example, L1can be In some embodiments of Formula (II-c), R7is In some embodiments of Formula (II-a), (II-b), or (II-c), R1is . In some embodiments, R2is -NH2. In some embodiments, R2is -N(Rf)R21; and R21is C1-3alkyl. In some embodiments of Formula (II-a), (II-b), or (II-c), R1is In some embodiments of Formula (II-a), (II-b), or (II-c), RZis isopropyl; and RNis methyl. In some embodiments of Formula (II-a), (II-b), or (II-c), R3is ethyl. In some embodiments, the compounds of Formula (I) or (II) are selected from the group consisting of the compounds depicted in Table C1, or pharmaceutically acceptable salts thereof. Table C1 In certain compounds of Table C1, one or more stereogenic centers are denoted with the “enhanced stereochemical notation” (see: support.collaborativedrug.com / hc / en- us / articles / 360020872171-Advanced-Stereochemistry-Registration-Atropisomers-Mixtures- Unknowns-and-Non-Tetrahedral-Chirality, accessed on November 29, 2023 and Accelrys Chemical Representation Guide, Accelrys Software Inc., 2014, each of which is incorporated by reference herein in its entirety). Using this stereochemical notation, certain stereogenic centers are denoted with “abs”, “&x”, or “orx”, wherein x is an integer (e.g., 1 or 2). For avoidance of doubt, the stereochemical notations in Table C1 have the following meaning: When a structure does not contain any wedged or hashed bonds (i.e., each stereogenic center is undefined), then each stereogenic center can independently adopt a (R) or (S) stereochemical configuration. For avoidance of doubt, such structures also encompass mixtures of stereoisomers. For example, represents , , or a mixture . When a structure contains a stereogenic center or a plurality of stereogenic centers that is depicted with wedges and hashes (i.e., one or more stereogenic center is defined), the following notations are used: (1) When a defined stereogenic center is denoted with “abs” or when the defined stereogenic center is not denoted with an enhanced stereochemical notation (e.g., “abs”, “&x”, or “orx”), the defined stereogenic center has the absolute configuration as depicted by the structural formula. For example, both of the structures and refer to (S)-(1-methylpyrrolidin-2-yl)methanol. (2) When a defined stereogenic center is denoted with “orx” in a structural formula, the defined stereogenic center has been resolved but the configuration at the defined stereogenic center has not been determined. For example, the structure refers to one stereoisomer selected from the group consisting of (S)-(1- methylpyrrolidin-2-yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol. (3) When a defined stereogenic center is denoted with “&x” in a structural formula, a stereoisomeric mixture differing at this stereogenic center is represented. For example, the structure: represents a mixture of (S)-(1-methylpyrrolidin-2- yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol. As another example, the structure: represents a mixture of ((2S,3S)-1,3-dimethylpyrrolidin-2- yl)methanol and ((2R,3S)-1,3-dimethylpyrrolidin-2-yl)methanol. (4) When two or more defined stereogenic centers are denoted with “orx” in a structural formula, each of these defined stereogenic centers has been resolved but the configurations at the defined stereogenic centers have not been determined. Specifically: a. For any pair of defined stereogenic centers denoted with “orx” in a structural formula, when the numerical parts in the notation are different (e.g., two defined stereogenic centers denoted with “or1” and “or2” respectively), each defined stereogenic center should be independently interpreted according to “(2)” supra. For example, the structure refers to one stereoisomer selected from the group consisting of: , . b. For any pair of defined stereogenic centers denoted with “orx” in a structural formula, when the numerical part in the notation is identical (e.g., two defined stereogenic centers are each denoted with “or1”), the structural formula refers to one stereoisomer having the relative stereochemistry at these stereogenic centers as depicted in the structural formula, but the absolute configurations of these stereogenic centers have not been determined. For example, the structure refers to one of the two “syn” stereoisomers: or As another example, the structu re refers to one of the two “anti” stereoisomers: . (5) When two or more defined stereogenic centers are denoted with “&x” in a structural formula, the structural formula refers to a mixture of stereoisomers that differ in the configuration at the defined stereogenic centers. Specifically: a. For any pair of defined stereogenic centers denoted with “&x” in a structural formula, when the numerical parts in the notation are different (e.g., two defined stereogenic centers denoted with “&1” and “&2” respectively), the structural formula refers to a mixture of stereoisomers at these two defined stereogenic centers, wherein the configuration at each of the defined stereogenic centers can vary independently of one another. For example, the structure refers to a mixture of four stereoisomers: , , b. For any pair of defined stereogenic centers denoted with “&x” in a structural formula, when the numerical part in the notation is identical (e.g., two defined stereogenic centers are each denoted with “&1”), the structural formula refers to a mixture of stereoisomers at these two defined stereogenic centers, wherein the relative configurations are as depicted in the structural formula. For example, the structure refers to a mixture of “syn” stereoisomers: As another example, the structure refers to a mixture of “anti” stereoisomers: In some embodiments, the compounds of Formula (I) or (II) are selected from the group consisting of the compounds depicted in Table C1 of U.S. Application Provisional Nos. 63 / 706,569, filed October 11, 2024; 63 / 711,089, filed October 23, 2024; 63 / 725,963, filed November 27, 2024; 63 / 737,117, filed December 20, 2024; 63 / 771,572, filed March 13, 2025; and 63 / 773,308, filed March 17, 2025; each Table C1 is incorporated by reference it its entirety herein. Chemical definitions The term “halo” refers to fluoro (-F), chloro (-Cl), bromo (-Br), or iodo (-I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F). The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3). The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCF3, -OCHF2, or -OCH2F). The term “alkylene” refers to a divalent alkyl (e.g., -CH2-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two radicals can be on the same ring carbon atom (e.g., a geminal diradical such as ) or on different ring atoms (e.g., ring carbon and / or nitrogen atoms (e.g., vicinal ring carbon and / or nitrogen atoms)) (e.g., The term “alkenyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents. The term “alkynyl” refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents. The term “aryl” refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14- carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term “cycloalkyl” as used herein refers to mono-, bi-, tri-, or polycyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. Examples of saturated cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Partially unsaturated cycloalkyl may have any degree of unsaturation provided that one or more double bonds is present in the cycloalkyl, none of the rings in the ring system are aromatic, and the partially unsaturated cycloalkyl group is not fully saturated overall. Examples of partially unsaturated cycloalkyl include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentyl, spiro[2.5]octyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[3.5]nonyl, spiro[4.4]nonyl, spiro[2.6]nonyl, spiro[4.5]decyl, spiro[3.6]decyl, spiro[5.5]undecyl, and the like. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 15 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S (inclusive of oxidized forms such as: and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3- c]pyridinyl, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromanyl, 2,3- dihydrobenzo[b][1,4]dioxinyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzofuranyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[b][1,4]oxathiinyl, isoindolinyl, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridonyl (e.g., , , pyrimidonyl (e.g., pyridazinonyl (e.g., pyrazinonyl (e.g., and imidazolonyl (e.g., wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). The term “heterocyclyl” refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, S (inclusive of oxidized forms such as: and P (inclusive of oxidized forms such as (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, S, or P if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. Examples of saturated heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Partially unsaturated heterocyclyl groups may have any degree of unsaturation provided that one or more double bonds is present in the heterocyclyl, none of the rings in the ring system are aromatic, and the partially unsaturated heterocyclyl group is not fully saturated overall. Examples of partially unsaturated heterocyclyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3- azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7- azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 2- azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 2-oxabicyclo[1.1.0]butyl, 2- oxabicyclo[2.1.0]pentyl, 2-oxabicyclo[1.1.1]pentyl, 3-oxabicyclo[3.1.0]hexyl, 5- oxabicyclo[2.1.1]hexyl, 3-oxabicyclo[3.2.0]heptyl, 3-oxabicyclo[4.1.0]heptyl, 7- oxabicyclo[2.2.1]heptyl, 6-oxabicyclo[3.1.1]heptyl, 7-oxabicyclo[4.2.0]octyl, 2- oxabicyclo[2.2.2]octyl, 3-oxabicyclo[3.2.1]octyl, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentyl, 4- azaspiro[2.5]octyl, 1-azaspiro[3.5]nonyl, 2-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2- azaspiro[4.4]nonyl, 6-azaspiro[2.6]nonyl, 1,7-diazaspiro[4.5]decyl, 7-azaspiro[4.5]decyl 2,5- diazaspiro[3.6]decyl, 3-azaspiro[5.5]undecyl, 2-oxaspiro[2.2]pentyl, 4-oxaspiro[2.5]octyl, 1- oxaspiro[3.5]nonyl, 2-oxaspiro[3.5]nonyl, 7-oxaspiro[3.5]nonyl, 2-oxaspiro[4.4]nonyl, 6- oxaspiro[2.6]nonyl, 1,7-dioxaspiro[4.5]decyl, 2,5-dioxaspiro[3.6]decyl, 1- oxaspiro[5.5]undecyl, 3-oxaspiro[5.5]undecyl, 3-oxa-9-azaspiro[5.5]undecyl and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g., (ii) a single ring atom (spiro-fused ring systems) (e.g., , or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: . Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Methods of Treatment Indications Provided herein are methods for inhibiting a Ras protein (e.g., KRas, NRas, and / or HRas). For example, provided herein are inhibitors of a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) useful for treating or preventing diseases or disorders associated with the Ras protein, such as cancer (e.g., a cancer having a dysregulated Ras (e.g., a mutant Ras protein)).

[0010] The phrase “dysregulation of a RAS gene, a Ras protein, or the expression or activity or level of any of the same” refers to (i) a genetic mutation (e.g., a mutation in a RAS gene that results in the expression of the corresponding Ras protein that includes a deletion of at least one amino acid as compared to the wild type Ras protein, a mutation in a RAS gene that results in the expression of the corresponding Ras protein with one or more point mutations as compared to the wild type Ras protein, a mutation in a RAS gene that results in the expression of the corresponding Ras protein with at least one inserted amino acid as compared to the wild type Ras protein; (ii) a gene duplication that results in an increased level of the Ras protein in a cell; (iii) a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of the Ras protein in a cell); (iv) an alternative spliced version of a Ras mRNA that results in the corresponding Ras protein having a deletion of at least one amino acid in the Ras protein as compared to the wild type Ras protein; or (v) increased expression (e.g., increased levels) of a wild type Ras protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non- cancerous cell). In some embodiments, a dysregulation of a RAS gene, a Ras protein, or expression or activity, or level of any of the same, can be a mutation in a RAS gene that encodes a Ras protein that has low GTPase activity and / or has increased signaling activity as compared to a protein encoded by a RAS gene that does not include the mutation. In some embodiments, a dysregulation of a RAS gene, a Ras protein, or expression or activity, or level of any of the same, can be a Ras amplification. In some embodiments, a Ras amplification is an amplification of the wild type Ras. In some embodiments, a Ras amplification is an amplification of a mutant Ras.

[0011] In some embodiments, the Ras protein is a wild type Ras protein (e.g., a wild type KRas protein, a wild type NRas protein, or a wild type HRas protein). In some embodiments, the Ras protein is a dysregulated Ras protein. For example, the dysregulated Ras protein can be a Ras amplification (e.g., an amplified wildtype KRas protein, an amplified wild type NRas protein, or an amplified wild type HRas protein). In some embodiments, the dysregulated Ras protein is a mutant Ras protein (e.g., a mutant KRas protein, a mutant NRas protein, or a mutant HRas protein).

[0012] For example, a mutation in a KRAS gene that results in the expression of a KRas protein that includes a deletion of at least one amino acid as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with one or more point mutations as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with at least one inserted amino acid as compared to a wild type KRas protein, a gene duplication that results in an increased level of KRas protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of KRas protein in a cell); an alternative spliced version of a KRas mRNA that results in a KRas protein having a deletion of at least one amino acid in the KRas protein as compared to the wild type KRas protein; or increased expression (e.g., increased levels) of a wild type KRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As an example, a dysregulation of a KRAS gene, a KRas protein, or expression or activity, or level of any of the same, can be a mutation in a KRAS gene that encodes a KRas protein that has low GTPase activity and / or has increased signaling activity as compared to a protein encoded by a KRAS gene that does not include the mutation. As another example, a dysregulation of a KRAS gene, a KRas protein, or expression or activity, or level of any of the same, can be a KRas amplification. In some embodiments, a KRas amplification is an amplification of the wild type KRas. In some embodiments, a KRas amplification is an amplification of a mutant KRas.

[0013] As another example, a mutation in a NRAS gene that results in the expression of a NRas protein that includes a deletion of at least one amino acid as compared to a wild type NRas protein, a mutation in a NRas gene that results in the expression of a NRas protein with one or more point mutations as compared to a wild type NRas protein, a mutation in a NRAS gene that results in the expression of a NRas protein with at least one inserted amino acid as compared to a wild type NRas protein, a gene duplication that results in an increased level of NRas protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of NRas protein in a cell); an alternative spliced version of a NRas mRNA that results in a NRas protein having a deletion of at least one amino acid in the NRas protein as compared to the wild type NRas protein; or increased expression (e.g., increased levels) of a wild type NRas protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). As an example, a dysregulation of a NRAS gene, a NRas protein, or expression or activity, or level of any of the same, can be a mutation in a NRAS gene that encodes a NRas protein that has low GTPase activity and / or has increased signaling activity as compared to a protein encoded by a NRAS gene that does not include the mutation. As another example, a dysregulation of a NRAS gene, a NRas protein, or expression or activity, or level of any of the same, can be a NRas amplification. In some embodiments, a NRas amplification is an amplification of the wild type NRas. In some embodiments, a NRas amplification is an amplification of a mutant NRas.

[0014] A “dysregulated Ras protein” as used herein refers to (i) a Ras protein having a mutation (e.g., a deletion of at least one amino acid as compared to a wild type Ras protein, one or more point mutations as compared to a wild type Ras protein, or an insertion of at least one amino acid as compared to a wild type Ras protein); (ii) a Ras protein resulting from a gene duplication event, e.g., of the gene encoding the Ras protein (e.g., the wild type Ras protein), thus resulting in an increased level and / or activity of the Ras protein (e.g., the wild type Ras protein) in a cell; (iii) a Ras protein resulting from a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that can also result in an increased level and / or activity of the Ras protein (e.g., the wild type Ras protein) in a cell); (iv) a Ras protein resulting from an alternative spliced version of a Ras mRNA that results in a Ras protein having a deletion of at least one amino acid in the Ras protein as compared to the wild type Ras protein); or (v) a Ras protein resulting from increased expression (e.g., increased levels) of a wild type Ras protein in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non-cancerous cell). In some embodiments, a dysregulated Ras protein is a dysregulated human Ras protein. A dysregulated Ras protein is selected from one or more of a dysregulated KRas protein, a dysregulated NRas protein, and a dysregulated HRas protein.

[0015] A “mutant Ras protein” as used herein refers to a Ras protein including a substitution, an insertion, a deletion, a truncation, and / or a fusion relative to the wild type human Ras sequence (e.g., a mutant KRas protein includes a substitution, an insertion, a deletion, a truncation, and / or a fusion related to the wild type human KRas sequence as shown in SEQ ID NO: 1; a mutant NRas protein includes a substitution, an insertion, a deletion, a truncation, and / or a fusion related to the wild type human KRas sequence as shown in SEQ ID NO:2; and a mutant HRas protein includes a substitution, an insertion, a deletion, a truncation, and / or a fusion related to the wild type human KRas sequence as shown in SEQ ID NO:3). A mutant Ras protein is selected from one or more of a mutant KRas protein, a mutant NRas protein, and a mutant HRas protein. For example, a mutant human KRas protein includes a substitution at any amino acid position (relative to SEQ ID NO: 1). An exemplary sequence of mature human KRas protein is shown below (UniProtKB entry P01116) (SEQ ID NO: 1) MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM An exemplary sequence of mature human NRas protein is shown below (UniProtKB entry P01111) (SEQ ID NO: 2) MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNSKSF ADINLYREQI KRVKDSDDVP MVLVGNKCDL PTRTVDTKQA HELAKSYGIP FIETSAKTRQ GVEDAFYTLV REIRQYRMKK LNSSDDGTQG CMGLPCVVM An exemplary sequence of mature human HRas protein is shown below (UniProtKB entry P01112) (SEQ ID NO: 3) MTEYKLVVVG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHQYREQI KRVKDSDDVP MVLVGNKCDL AARTVESRQA QDLARSYGIP YIETSAKTRQ GVEDAFYTLV REIRQHKLRK LNPPDESGPG CMSCKCVLS In some embodiments, a mutant Ras protein is a mutant KRas protein selected from the group consisting of a KRas G12X mutant protein (e.g., a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12F mutant protein, a KRas G12L mutant protein, a KRas G12R mutant protein, a KRas G12S mutant protein, or a KRas G12V mutant protein); a KRas G13X mutant protein (e.g., a KRas G13C mutant protein, a KRas G13D mutant protein, a KRas G13R mutant protein, or a KRas G13V mutant protein); a KRas V14X mutant protein (e.g., a KRas V14I mutant protein); a KRas L19X mutant protein (e.g., a KRas L19F mutant protein); a KRas Q22X mutant protein (e.g., a KRas Q22K mutant protein); KRas A59X mutant protein (e.g., a KRas A59T mutant protein); KRas Q61X mutant protein (e.g., a KRas Q61H mutant protein, a KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas or Q61R mutant protein); KRas K117X mutant protein (e.g., a KRas K117N mutant protein); KRas A146X mutant protein (e.g., a KRas A146P mutant protein, a KRas A146T mutant protein, a KRas A146V mutant protein); and combinations thereof. In some embodiments, a mutant KRas protein is selected from the group consisting of a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein. In some embodiments, a mutant Ras protein is a mutant NRas protein selected from the group consisting of a NRas G12X mutant protein (e.g., a NRas G12A mutant protein, a NRas G12C mutant protein, a NRas G12D mutant protein, a NRas G12R mutant protein, a NRas G12S mutant protein, or a NRas G12V mutant protein); a NRas G13X mutant protein (e.g., a NRas G13C mutant protein, a NRas G13D mutant protein, a NRas G13R mutant protein, or a NRas G13 V mutant protein); a NRas E49X mutant protein (e.g., a NRas E49K mutant protein); a NRas T50X mutant protein (e.g., a NRas T50I mutant protein); a NRas A59X mutant protein (e.g., a NRas A59D mutant protein or a NRas A59T mutant protein); a NRas G60X mutant protein (a NRas G60E mutant protein); a NRas Q61X mutant protein (a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, a NRas Q61P mutant protein, or a NRas Q61R mutant protein); a NRas E132X mutant protein (e.g., a NRas E132K mutant protein); a NRas A146X mutant protein (e.g., a NRas A146T mutant protein or a NRas A146V mutant protein); a NRas P185X mutant protein (e.g., a NRas P195S mutant protein); and combinations thereof. In some embodiments, a mutant NRas protein is selected from the group consisting of a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, and a NRas Q61R mutant protein. In some embodiments, a mutant NRas protein is selected from the group consisting of a NRas Q61K mutant protein, a NRas Q61L mutant protein, and a NRas Q61R mutant protein.

[0016] In some embodiments, a mutant Ras protein is a mutant HRas protein selected from the group consisting of a HRas G12X mutant protein (e.g., a HRas G12A mutant protein, a HRas G12C mutant protein, a HRas G12D mutant protein, a HRas G12N mutant protein, a HRas G12R mutant protein, a HRas G12S mutant protein, or a HRas G12V mutant protein); a HRas G13X mutant protein (e.g., a HRas G13C mutant protein, a HRas G13D mutant protein, a HRas G13N mutant protein, a HRas G13R mutant protein, a HRas G13S mutant protein, or a HRas G13V mutant protein); a HRas A18X mutant protein (e.g., a HRas A18V mutant protein); a HRas A59X mutant protein (e.g., a HRas A59T mutant protein); a HRas Q61X mutant protein (a HRas Q61H mutant protein, a HRas Q61K mutant protein, a HRas Q61L mutant protein, or a HRas Q61R mutant protein); a HRas A66X mutant protein (a HRas A66T mutant protein); a HRas K117X mutant protein (e.g., a HRas K117N mutant protein); a HRas D119X mutant protein (e.g., a HRas D119N mutant protein); a HRas A146X mutant protein (e.g., a HRas A146T mutant protein or a HRas A146V mutant protein); and combinations thereof. In some embodiments, a mutant HRas protein is selected from the group consisting of a HRas Q61H mutation or a HRas Q61L mutation. In some embodiments, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit two or more Ras proteins (e.g., wild type Ras proteins and / or mutant Ras proteins) (“pan Ras inhibitors”). For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit two or more KRas proteins (e.g., wild type KRas and / or mutant KRas proteins), NRas proteins (e.g., wild type NRas and / or mutant NRas proteins), HRas proteins (e.g., wild type HRas and / or mutant HRas proteins), or a combination thereof. In some embodiments, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or pharmaceutically acceptable salts thereof, can inhibit two or more KRas proteins (e.g., two or more of a KRas wild type protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein). In some embodiments, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit two or more NRas proteins (e.g., two or more of a NRas wild type protein, a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, and a NRas Q61R mutant protein). In some embodiments, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit two or more HRas proteins (e.g., two or more of a HRas wild type protein, a HRas Q61H mutation, or a HRas Q61L mutation). In some embodiments, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit one or more KRas proteins (e.g., one or more of a KRas wild type protein, a KRas G12D mutant protein, a KRas G12R mutant protein, and a KRas G12V mutant protein) and one or more NRas proteins (e.g., one or more of a NRas wild type protein, a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, and a NRas Q61R mutant protein). For example, such compounds can inhibit one or more KRas proteins (e.g., one or more mutant KRas proteins or two or more mutant KRas proteins) with an IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). As another example, such compounds can inhibit ERK phosphorylation in cell lines each expressing a KRas protein with an independent IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in the cell lines. For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a KRas G12D mutant protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a KRas G12V mutant protein with an IC50of less than 1 µM. As another example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a KRas wild type protein with an IC50of less than 1 µM, can inhibit ERK phosphorylation in a cell line expressing a KRas G12D mutant protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a KRas G12V mutant protein with an IC50of less than 1 µM. For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit one or more NRas proteins (e.g., one or more mutant NRas proteins or two or more mutant NRas proteins) with an IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). As another example, such compounds can inhibit ERK phosphorylation in cell lines each expressing a mutant NRas protein with an independent IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in the cell lines. For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61R mutant protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a NRas Q61H mutant protein with an IC50of less than 1 µM. As another example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas wild type protein with an IC50of less than 1 µM, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61K mutant protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a NRas Q61H mutant protein with an IC50of less than 1 µM. For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit one or more NRas proteins (e.g., one or more mutant NRas proteins or two or more mutant NRas proteins) with an IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). As another example, such compounds can inhibit ERK phosphorylation in cell lines each expressing a mutant NRas protein with an independent IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in the cell lines. For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61R mutant protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a NRas Q61K mutant protein with an IC50of less than 1 µM. As another example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas wild type protein with an IC50of less than 1 µM, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61R mutant protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a NRas Q61K mutant protein with an IC50of less than 1 µM. As another example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit one or more Ras proteins (e.g., one or more KRas proteins and one or more NRas proteins) with an IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, inhibit wild type Ras and one or more mutant Ras proteins. For example, such compounds can inhibit ERK phosphorylation in cell lines each expressing a NRas protein (e.g., a NRas wild type protein, a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein) or a KRas protein (e.g., a KRas wild type protein, a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein) with an independent IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM) in the cell lines. For example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61X mutant protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein) with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a KRas G12X mutant protein (e.g., KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein) with an IC50of less than 1 µM. As another example, compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas wild type protein with an IC50of less than 1 µM, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61R mutant protein with an IC50of less than 1 µM, can inhibit ERK phosphorylation in a cell line expressing a KRas wild type protein with an IC50of less than 1 µM, and can inhibit ERK phosphorylation in a cell line expressing a KRas G12D mutant protein with an IC50of less than 1 µM. The ability of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or a pharmaceutically acceptable salt thereof, to bind to a Ras protein can be measured, for example, by a direct determination method (e.g., surface plasmon resonance or isothermal titration calorimetry); by radio labelling the compound prior to binding, isolating the compound / protein complex, and determining the amount of radio label bound; or by running a competition experiment where new compounds are incubated with the protein bound to known radioligands. As another example, the occupancy of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can be determined using a proximity-based technique, such as time-resolved Fluorescence Resonance Energy Transfer (FRET); for instance, using a labeled probe that binds mutually exclusively with the inhibitor, and using an antibody that binds to a position on the protein separate from where the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, binds (for example, an antibody that binds to an N- terminal tag). It will be understood that the antibody and probe can be tagged with any appropriate FRET pair. See, e.g., International Publication Nos. WO 2021 / 041671, WO 2021 / 120890, and U.S. Publication No. US 2021 / 0179633. In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, with a Ras protein (e.g., a wild type Ras protein or a mutant Ras protein) in the GDP-bound and / or GTP-bound state can be measured using methods known in the art (e.g., using SPR). Binding affinity with the Ras protein in the GDP-bound state can be measured by loading the Ras protein with GDP. Binding affinity with the Ras protein in the GTP-bound state can be measured by loading the Ras protein with GMPPNP. In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof with cyclophilin A (CypA) can be measured using methods known in the art (e.g., using SPR, e.g., using methods as described herein, e.g., Example B3). Binding affinity of the compound bound to CypA with a Ras protein can be measured using methods known in the art (e.g., using SPR, e.g., using methods as described herein, e.g., Example B4). Another exemplary assay for determining the potency of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound of Formula (I) or (II) (e.g., Formula (II-a), (II- b), or (II-c)), or a pharmaceutically acceptable salt thereof, on cell proliferation. Cell proliferation assays can be performed in a number of formats, including 2D and 3D. Similarly, a cell proliferation assay can be performed with any appropriate cell line, including, for example, A375, A427, A549, AGS, ASPC1, CAL62, CALU1, Capan-1, Capan-2, CFPAC-1, DAN-G, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAF-II (HPAFII), HS852T, HS936T, HTK, HUPT3, IPC298, KMS20, KP2, KP4, LS123, MELJUSO, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H2122, NCI-H424, NCI-H526, NCI-H727, Panc 02.03, Panc 04.03, Panc 05.04, Panc 08.13, PATC50, PC9, PK8, PSN1, RKN, SKMEL2, SKMEL30, SW620, and / or TCCPAN2 (TCC-Pan2). In some embodiments, the cell line can be A-375, NCI-H2122, NCI-H358, NCI-H441, Panc 02.03, HPAC, MIA PaCa-2, KP-2, PSN-1, TCC- Pan2, AsPC-1, Panc 04.03, Panc 05.04, Panc 08.13, HPAF-II, Capan-1, Capan-2, CFPAC-1, NCI-H727, RKN, and / or SW620. As an illustrative example, a 3D cell proliferation assay can include growing cells in a 3D medium, contacting the cells with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO® 3D), and then comparing the signal from the experiment with the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c))). As another illustrative example, a 2D cell proliferation assay can include plating cells onto a growth surface, optionally letting the cells grow for a period of time, contacting the cells with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, measuring the cellular proliferation using an appropriate reagent (e.g., CELLTITERGLO®), and then comparing the signal from the experiment with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof). See, e.g., Example B1 and Example B8 herein. In some embodiments, cellular proliferation can be assessed using a platform for live cell imaging (e.g., an INCUCYTE® SX5 Live-Cell Analysis Instrument). See also, e.g., U.S. Publication No. US 2021 / 0179633, US 2021 / 0230142, and US 2019 / 0284144. As another example, the potency and / or efficacy of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a xenograft model (e.g., using an established cancer cell line such as H727, H441, AGS, A427 and / or ASPC1 or a patient-derived xenograft (PDX) model). See, e.g., U.S. Publication No. US 2021 / 0179633. In some embodiments, a PDX can be ME11977, ME12064, ME12079, ME12134, ME14010, ME14017, ME5285, ME9392, ME9395, or ME9396, such as those available from Crown Biosciences. Additional assays can include, for example, assays based on hydrogen exchange (HX) mass spectrometry. Such assays can be useful, for example, to evaluate whether a compound (e.g., a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof) stabilizes the GTP-bound state or GDP-bound state of a Ras protein (e.g., a wild type Ras protein or a dysregulated Ras protein, e.g., an amplified Ras protein or a mutant Ras protein (e.g., a KRas G12C mutant protein, a KRas G12D mutant protein, or a KRas G12V mutant protein)). In such assays, the rate of hydrogen exchange of the backbone amide hydrogens can be measured for a Ras protein (e.g., a wild type Ras protein or a dysregulated Ras protein, e.g., an amplified Ras protein or a mutant Ras protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein)) bound to a non-hydrolyzable GTP mimic (GMPPNP), GDP, or a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof. See, e.g., Lim et al. Angew Chem Int Ed Engl.2014; 53(1): 199–204, doi: 10.1002 / anie.201307387. In some embodiments, potency of a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, as provided herein can be determined by EC50value. A compound with a lower EC50value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50value. In some embodiments, an EC50value can be determined (e.g., using a Ras- dependent phosphorylation level (e.g., a phosphoERK level (sometimes called a “pERK” level)) or using a cell viability assay) in cells (e.g., in tumor cells, (e.g., cell lines such as NCI- H2122, NCI-H358, NCI-H441, Panc 02.03, HPAC, MIA PaCa-2, KP-2, PSN-1, TCC-Pan2, AsPC-1, Panc 04.03, Panc 05.04, Panc 08.13, HPAF-II, Capan-1, Capan-2, CFPAC-1, NCI- H727, RKN, and / or SW620) expressing a Ras protein, such as a dysregulated KRas protein (e.g., a mutant KRas protein or an amplified wild type KRas protein), or a fragment thereof). In some embodiments, potency of a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, as provided herein can also be determined by IC50value. A compound with a lower IC50value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC50value. In some embodiments, an IC50value can be determined (e.g., using a Ras-dependent phosphorylation level (e.g., a phosphoERK level) or using a cell viability assay) in cells (e.g., in tumor cells, (e.g., cell lines such A375, A427, A549, AGS, ASPC1, CAL62, CALU1, Capan- 1, Capan-2, CFPAC-1, DAN-G, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAF- II, HS852T, HS936T, HTK, HUPT3, IPC298, KMS20, KP2, KP4, LS123, MELJUSO, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H2122, NCI-H424, NCI-H526, NCI- H727, Panc 02.03, Panc 04.03, Panc 05.04, Panc 08.13, PATC50, PC9, PK8, PSN1, RKN, SKMEL2, SKMEL30, SW620, and / or TCCPAN2) expressing a Ras protein, such as a dysregulated KRas protein (e.g., a mutant KRas protein or an amplified KRas protein), or a fragment thereof). In some embodiments, measuring the potency of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, includes measuring the phosphorylation of a downstream kinase, such as ERK (e.g., ERK1 and / or ERK2) or MEK. Such assays can be used to measure the inhibition of KRas signaling activity, for instance, in a cell line (e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, Capan-1, Capan-2, CFPAC-1, DAN-G, H358, H441, H460, H727, HCT116, HKA1, HPAC, HPAF-II, HS852T, HS936T, HTK, HUPT3, IPC298, KMS20, KP2, KP4, LS123, MELJUSO, MIAPaCa-2, MKN1, NCI-H1993, NCI-H211, NCI-H2122, NCI-H424, NCI-H526, NCI- H727, Panc 02.03, Panc 04.03, Panc 05.04, Panc 08.13, PATC50, PC9, PK8, PSN1, RKN, SKMEL2, SKMEL30, SW620, and / or TCCPAN2). For example, cells can be contacted with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof for a period of time, then lysed or permeabilized, and total ERK or MEK and phosphoERK or phosphoMEK content can be determined (e.g., using antibodies, or a kit, such as Invitrogen InstantOne ERK1 / ERK2 (Phospho) [pT202 / pY204] / [pT185 / pY187] ELISA, MesoScale Discovery p / t ERK1 / 2, AlphaScreen SUREFIRE® p-ERK1 / 2 (Thr202 / Tyr204), or an HTRF® Phospho-ERK (Thr202 / Tyr204) cellular kit (CisBio)). In some embodiments, multiple concentrations of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof can be used to construct a dose response curve. See, e.g., Example B2 and Example B9 herein. See, e.g., International Publication No. WO 2021 / 041671, U.S. Publication Nos. US 2021 / 0122764, US 2018 / 0334454, US 2021 / 0179633, US 2018 / 0334454, and US 2019 / 0144444. Additional assays for evaluating the potency of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can also include, for example, a RAF kinase interaction assay. Such assays can be used to measure the affinity of Ras:nucleotide complexes for the Ras Binding Domain (RBD) of a RAF protein kinase (e.g., as impacted by a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof). For example, FLAG tagged Ras protein can be preloaded with the GTP analogue GppNHp and then incubated with biotinylated Raf- RBD to form complexes. A competition assay can then be performed by adding untagged Ras protein preloaded with GppNHp, which had been preloaded with various test molecules, over a range of concentrations. The proximity-dependent signal after addition of streptavidin donor and anti-flag acceptor beads (e.g., ALPHASCREEN® beads) can be measured to determine the affinity of the Ras protein for the Raf kinase. See, e.g., Hunter et al. Mol Cancer Res.2015; 13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15-0203; Lim et al. Angew Chem Int Ed Engl. 2014; 53(1): 199–204, doi: 10.1002 / anie.201307387; and Durrant, et al. Molecular Cancer Therapeutics 20.9 (2021): 1743-1754, doi: 10.1158 / 1535-7163.MCT-21-0175. As another example, for compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, that may bind selectively to the GTP-state, His- tagged Ras protein can be preloaded with the GTP analogue GppNHp and then incubated with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to form complexes. A competition assay can then be performed by adding Raf-RBD. The proximity-dependent signal after addition of Alpha detection reagents, compared to the signal from the same experiment using GDP instead of GppNHP, can be used to determine an IC50value. See, e.g., International Publication No. WO 2021 / 085653. It will be understood that in many cases, tagging technologies (e.g., FLAG tag, His tag, biotinylation) may be altered in an assay by one of skill in the art. In some embodiments, a RAF kinase interaction assay can be coupled with a nucleotide exchange assay; for example, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can be incubated with a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) and GDP, then GTP (and optionally, a GEF such as SOS1) can be introduced. Then, RAF (e.g., cRAF) acceptor beads (e.g., GST-tagged acceptor beads) can be incubated with the Ras mixture, followed by introduction of donor beads (e.g., glutathione donor beads) and measurement using ALPHASCREEN® technology. As an alternative to ALPHASCREEN® technology, any appropriate FRET pair can be used to perform homogenous time resolved fluorescence. See, e.g., U.S. Publication Nos. US 2018 / 0334454 and US 2021 / 0230142. Another exemplary assay to measure the affinity of Ras:nucleotide complex for a RBD is to incubate cells with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, lyse the cells, then pull down non-RBD-bound Ras using an immobilized RBD. See, e.g., U.S. Publication No. US 2019 / 0233440. As another example, the effect of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or a pharmaceutically acceptable salt thereof, on the interaction between Ras and Raf-RBD can be evaluated using HiBiT and / or NANOBIT™ technology, wherein two parts of an enzyme are fused to or inserted into two proteins of interest (e.g., Ras and Raf-RBD); when the two proteins of interest are in proximity, the two parts of the enzyme complement each other to complete an enzyme that has signaling activity (e.g., that produces luminescence). In some such assays, the affinity of the two parts of the enzyme can be tuned, for example, to reduce or eliminate signal based on proximity driven by the two parts of the enzyme. See, e.g., Schwinn, et al. ACS Chemical Biology 13.2 (2018): 467-474, doi: 10.1021 / acschembio.7b00549. Similarly, the effect of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or a pharmaceutically acceptable salt thereof, on the interaction between Ras and Raf-RBD can be evaluated using NANOBRET™ technology, wherein two parts of signaling system (e.g., a protein and a ligand) are fused to or inserted into two proteins of interest (e.g., Ras and Raf-RBD); when the two proteins of interest are in proximity, the two parts of the signaling system have signaling activity (e.g., producing fluorescence). See, e.g., Durrant, et al. Molecular Cancer Therapeutics 20.9 (2021): 1743-1754, doi: 10.1158 / 1535-7163.MCT-21- 0175. In some embodiments, a RAF kinase interaction assay can be used to determine if a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is selective for a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) in the GDP-bound state or the GTP-bound state. Inhibition of the interaction between the Ras protein and Raf-RBD by compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, can be measured using methods known in the art. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, modulates the interaction between the Ras protein and one or more Raf proteins. In some embodiments, the compounds inhibit the interaction between the Ras protein and Raf-RBD with an IC50of less than 1 µM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM). In some embodiments, the compounds inhibit the interaction between the Ras protein and Raf-RBD with an IC50of less than 200 nM (e.g., e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, or less than 0.01 nM). For example, the compounds inhibit the interaction between the Ras protein and Raf-RBD with an IC50from 0.001 nM to 500 nM, from 0.005 nM to 100 nM, from 0.025 nM to 100 nM, from 0.1 nM to 50 nM, or from 0.1 nM to 10 nM. As one example, an assay can be used to measure the ability of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to facilitate ternary complex formation between a nucleotide-loaded Ras isoform and cyclophilin A. It is understood that the resulting ternary complex can disrupt binding to a BRAF Ras-binding domain construct, inhibiting Ras signaling through a RAF effector. This assay can be performed with any Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) as described herein. An exemplary protocol for a KRas G12C protein follows. In assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCl, and 5 mM MgCl2, tagless cyclophilin A, His6-K-Ras-GMPPNP, and GST-BRAF Ras-binding domain construct are combined in a 384-well assay plate at final concentrations of 25 µM, 12.5 nM, and 50 nM, respectively. A compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is present in plate wells as a 10-point 3-fold dilution series (e.g., starting at a final concentration of 30 pM). After incubation at 25 ºC for 3 hours, a mixture of Anti-His Eu-W1024 and anti-GST allophycocyanin is added to the assay sample wells at final concentrations of 10 nM and 50 nM, respectively, and the reaction incubated for an additional 1.5 hours. TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665 / 615 nm). Compounds that facilitate disruption of a KRas:RAF complex are identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells. Data is reported as IC50values. See also the assays described in International Publication Nos. WO2025 / 119392; WO2025 / 087431; WO2025 / 051241; WO2025 / 045233; WO2024 / 208934; WO2024 / 189481; WO2024 / 249299; WO2024 / 222864; WO2024 / 211712; WO2024 / 211663; WO2024 / 169914; WO2024 / 104364; WO2024 / 067857; WO2024060966; WO2024 / 017859; WO2024 / 008834; WO2024 / 008610; WO2023 / 240263; WO2023 / 232776; WO2023 / 025832; WO2022 / 060836; WO2021 / 120890; WO2021 / 091956; WO2021 / 041671; CN Application Nos. CN117534687; CN117534685; and CN117534684; and U.S. Publication Nos. US 2021 / 0130369; US 2021 / 0179633; US 2018 / 0334454; and US 2021 / 0122764. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can bind to a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) in the GTP-bound state. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can bind selectively to a Ras protein in the GTP-bound state. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can bind to a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) in the GDP-bound state. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can bind selectively to a Ras protein in the GDP-bound state. As used herein, “selective” or “selectively”, when referring to an assayed compound, indicates at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) superior performance in an assay (e.g., binding affinity and / or potency) for a specified condition with reference to a comparator protein variant in the assay. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is selective for one or more first Ras proteins (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein, a mutant NRas protein, or a mutant HRas protein)) over one or more second Ras proteins (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein, a mutant NRas protein, or a mutant HRas protein)). For example, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can be selective for one or more mutant Ras proteins over other Ras mutant proteins or wild type Ras proteins. Various assays can be used to measure selectivity (e.g., Ras- Raf binding assay, SPR assay, and pERK assay, cell proliferation assays). For example, if compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or a pharmaceutically acceptable salt thereof, binds selectively to a first KRas G12X mutant protein over a second KRas G12X mutant protein as determined by a surface plasmon resonance (SPR) assay, then the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, has at least a 5-fold (e.g., at least a 10- fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller KD value for the first KRas G12X mutant protein than for the second KRas G12X mutant protein when measured by the SPR assay. As a further example, if a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, selectively reduces the viability the KRas G12V mutant protein-expressing cells over the cells expressing KRas G12C protein as determined by a cell proliferation assay, then the compound has at least a 5-fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) EC50value for the KRas G12V mutant protein-expressing cells than for the KRas G12C protein-expressing cells when measured by the cell proliferation assay. In another example, if a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, selectively inhibits a NRas Q61X mutant protein over a HRas G12X mutant protein as determined by a Raf kinase interaction assay, then the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, has at least a 5- fold (e.g., at least a 10-fold, at least a 25-fold, at least a 50-fold, or at least a 100-fold) smaller IC50value for the NRas Q61X mutant protein than for the HRas G12X mutant protein when measured by the Raf kinase interaction assay. Provided herein are methods of treating a cancer in a subject in need of such treatment, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided herein are methods of treating a cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a monotherapy. In some embodiments, the subject is treatment naïve with respect to the cancer. In some embodiments, the subject has received one or more lines of previous therapy for the cancer. Provided herein is use of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II- b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of cancer, for example, any of the cancers provided herein. Provided herein is use of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II- b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, for example, any of the cancers provided herein. Provided herein is use of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II- b), or (II-c)), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, for example, any of the cancers provided herein. Provided herein is a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament. Also provided herein is a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament for the treatment of cancer, for example, any of the cancers provided herein. Provided herein is a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a cancer, for example, any of the cancers provided herein. As used herein, “monotherapy”, when referring to a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, means that the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). As a person of ordinary skill in the art would understand, monotherapy does not exclude the co-administration of medicaments for the treatment of side effects or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritus, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite. These types of medicaments are sometimes referred to as “supportive care” or “supportive therapy”.

[0017] As used herein, “the subject has previously received one or more therapeutic agents or therapies for the cancer” means that the subject has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy) for the cancer other than a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. In some embodiments, the subject cannot tolerate the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1). In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician.

[0018] In some embodiments, a subject with melanoma (e.g., unresectable or metastatic melanoma) has previously received one or more of combination checkpoint blockade (e.g., anti-PD-1 therapy combined with anti-LAG3 therapy or anti-CTLA4 therapy), anti-PDl monotherapy, BRAF-targeted therapy (e.g., for a subject that has a cancer with a BRAF mutation) (e.g., a BRAF inhibitor combined with a MEK inhibitor, optionally also combined with anti-PD-1 therapy), or tumor infiltrating lymphocytes. In some embodiments, a subject with melanoma (e.g., unresectable or metastatic melanoma) has previously received one or more of nivolumab, ipilimumab, relatlimab, pembrolizumab, dabrafenib, vemurafenib, encorafenib, trametinib, cobimetinib, binimetinib, atezolizumab, or lifileucel.

[0019] In some embodiments, a subject with melanoma (e.g., unresectable or metastatic melanoma) has previously received:

[0020] (a) combination checkpoint blockade of nivolumab and ipilimumab; (b) combination checkpoint blockade of nivolumab and relatlimab;

[0021] (c) anti-PDl monotherapy of pembrolizumab;

[0022] (d) anti-PDl monotherapy of nivolumab;

[0023] (e) a combination of pembrolizumab and ipilimumab;

[0024] (f) BRAF-targeted therapy of dabrafenib and trametinib (e.g., for a subject that has a cancer with a BRAF mutation);

[0025] (g) BRAF-targeted therapy of vemurafenib and cobimetinib, optionally also combined with atezolizumab (e.g., for a subject that has a cancer with a BRAF mutation);

[0026] (h) BRAF-targeted therapy of encorafenib and binimetinib (e.g., for a subject that has a cancer with a BRAF mutation); or

[0027] (i) tumor infiltrating lymphocyte therapy of lifileucel.

[0028] In some embodiments, a subject with melanoma (e.g., unresectable or metastatic melanoma) has previously received one of (a)-(h) as a first-line therapy. In some embodiments, a subject with melanoma (e.g., unresectable or metastatic melanoma) has previously received one of (a)-(h) as a first-line therapy and a different one of (a)-(i) as a second-line therapy.

[0029] As used herein, “the subject is treatment naive with respect to the cancer” means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer.

[0030] For any of the solid tumors described herein, the solid tumors can be primary tumors or metastatic (or secondary) tumors. As used herein, “primary” tumors are those located at the site where the tumor began to grow (i.e., where it originated). As used herein, “metastatic” (or “secondary”) tumors are those that have spread to other parts of body from the original tumor site. In some embodiments, the metastatic or secondary tumors are the same type of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumors are not genetically identical to the primary tumor.

[0031] In some embodiments, the subject has been identified or diagnosed as having a cancer with a Ras dysregulation (e.g., a Ras mutation or amplification) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a cancer (e.g., a tumor sample) that has a Ras dysregulation (e.g., a Ras mutation or amplification) (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a cancer (e.g., one or more tumor samples) that is positive for a Ras dysregulation (e.g., a Ras mutation or amplification) (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject is suspected of having a mutant Ras-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a cancer (e.g., a tumor sample) that has a Ras dysregulation (e.g., a Ras mutation or amplification) (and optionally the clinical record indicates that the subject should be treated with any of the compounds and / or compositions provided herein).

[0032] In some embodiments, the cancer comprises a wild type Ras protein (e.g., a wild type KRas protein, a wild type NRas protein, or a wild type HRas protein). In some embodiments, the cancer comprises a Ras dysregulation. For example, the Ras dysregulation is a Ras amplification (e.g., an amplified wildtype KRas protein, an amplified wild type NRas protein, or an amplified wild type HRas protein).

[0033] In some embodiments, the Ras dysregulation is a Ras mutation. For example, a KRas mutation, a NRas mutation, a HRas mutation, or a combination thereof.

[0034] In some embodiments, the Ras dysregulation is a KRas mutation selected from the group consisting of a KRas G12X mutation (e.g., a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRas G12F mutation, a KRas G12L mutation, a KRas G12R mutation, a KRas G12S mutation, or a KRas G12V mutation); a KRas G13X mutation (e.g., a KRas G13C mutation, a KRas G13D mutation, a KRas G13R mutation, or a KRas G13V mutation); a KRas V14X mutation (e.g., a KRas V14I mutation); aKRas L19X mutation (e.g., a KRas L19F mutation); a KRas Q22X mutation (e.g., a KRas Q22K mutation); KRas A59X mutation (e.g., a KRas A59T mutation); KRas Q61X mutation (e.g., a KRas Q61H mutation, a KRas Q61K mutation, a KRas Q61L mutation, a KRas or Q61R mutation); KRas KI 17X mutation (e.g., a KRas KI 17N mutation); KRas A146X mutation (e.g., a KRas A146P mutation, a KRas A146T mutation, a KRas A146V mutation); and combinations thereof. In some embodiments, a mutant KRas protein is selected from the group consisting of a KRas G12D mutation, a KRas G12R mutation, and a KRas G12V mutation.

[0035] In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation, a KRas G12R mutation, or KRas G12V mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12D mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12R mutation. In some embodiments, the cancer (e.g., a tumor sample) has a KRas G12V mutation.

[0036] In some embodiments, the Ras dysregulation is a NRas mutation selected from the group consisting of a NRas G12X mutation (e.g., a NRas G12A mutation, a NRas G12C mutation, a NRas G12D mutation, a NRas G12R mutation, a NRas G12S mutation, or a NRas G12V mutation); a NRas G13X mutation (e.g., a NRas G13C mutation, a NRas G13D mutation, a NRas G13R mutation, or a NRas G13V mutation); a NRas E49X mutation (e.g., a NRas E49K mutation); a NRas T50X mutation (e.g., a NRas T50I mutation); a NRas A59X mutation (e.g., a NRas A59D mutation or a NRas A59T mutation); a NRas G60X mutation (a NRas G60E mutation); a NRas Q61X mutation (a NRas Q61H mutation, a NRas Q61K mutation, a NRas Q61L mutation, a NRas Q61P mutation, or a NRas Q61R mutation); a NRas E132X mutation (e.g., aNRas E132K mutation); a NRas A146X mutation (e.g., a NRas A146T mutation or aNRas A146V mutation); a NRas P185X mutation (e.g., a NRas P195S mutation); and combinations thereof. In some embodiments, a mutant NRas protein is selected from the group consisting of a NRas Q61K mutation, a NRas Q61L mutation, and a NRas Q61R mutation.

[0037] In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61H mutation, a NRas Q61K mutation, aNRas Q61L mutation, or NRas Q61R mutation. In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61K mutation, a NRas Q61L mutation, or NRas Q61R mutation. In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61H mutation. In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61K mutation. In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61L mutation. In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61R mutation.

[0038] In some embodiments, the Ras dysregulation is a HRas mutation selected from the group consisting of a HRas G12X mutation (e.g., a HRas G12A mutation, a HRas G12C mutation, a HRas G12D mutation, a HRas G12N mutation, a HRas G12R mutation, a HRas G12S mutation, or a HRas G12V mutation); a HRas G13X mutation (e.g., a HRas G13C mutation, a HRas G13D mutation, a HRas G13N mutation, a HRas G13R mutation, a HRas G13S mutation, or a HRas G13V mutation); a HRas A18X mutation (e.g., a HRas A18V mutation); a HRas A59X mutation (e.g., a HRas A59T mutation); a HRas Q61X mutation (a HRas Q61H mutation, a HRas Q61K mutation, a HRas Q61L mutation, or a HRas Q61R mutation); a HRas A66X mutation (a HRas A66T mutation); a HRas KI 17X mutation (e.g., a HRas K117N mutation); a HRas D119X mutation (e.g., a HRas D119N mutation); a HRas A146X mutation (e.g., a HRas A146T mutation or a HRas A146V mutation); and combinations thereof. In some embodiments, a mutant HRas protein is selected from the group consisting of a HRas Q61H mutation or a HRas Q61L mutation.

[0039] In some embodiments, the cancer (e.g., a tumor sample) has a HRas Q61H mutation or a HRas Q61L mutation. In some embodiments, the cancer (e.g., a tumor sample) has a HRas Q61H mutation. In some embodiments, the cancer (e.g., a tumor sample) has a HRas Q61L mutation.

[0040] Such mutations can be associated with the development of a variety of cancers. See, e.g., Hunter et al. Mol Cancer Res. 2015;13(9):1325-35, doi: 10.1158 / 1541-7786.MCR-15- 0203. Ras mutations can be detected using a variety of methods. Exemplary methods include next generation sequencing, pyrosequencing, immunohistochemistry, fluorescence microscopy, Southern blotting, Western blotting, FACS analysis, Northern blotting, PCR- based amplification (e.g., RT-PCR and quantitative real-time RT-PCR), and utilization of a high-sensitivity diagnostic assay (with CE-IVD mark), e.g., as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012); DOI: / 10.5114 / pjp.2012.3149 and WO 2020 / 106640. In some embodiments, the assay is performed on a tumor biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the assay is a liquid biopsy. Liquid biopsies can be performed on biological samples obtained from a subject (e.g., via a blood draw) and are generally less invasive than traditional methods used to detect tumor burden and / or Ras dysregulation. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA- approved kit. In some embodiments of any of the methods or uses described herein, the cancer is breast cancer (e.g., breast invasive carcinoma, breast invasive ductal carcinoma), central or peripheral nervous system tissue cancer (e.g., brain cancer (e.g., astrocytoma, glioblastoma, glioma, oligoastrocytoma)), endocrine or neuroendocrine cancer (e.g., adrenal cancer (e.g., adrenocortical carcinoma, pheochromocytoma, paraganglioma), multiple neuroendocrine type I and type II tumors, parathyroid cancer, pituitary tumors, thyroid cancer (e.g., papillary thyroid cancer)), eye cancer (e.g., uveal cancer (e.g., uveal melanoma)), gastrointestinal cancer (e.g., anal cancer, bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma, mucinous adenocarcinoma, mucinous carcinoma), esophageal cancer (e.g., esophageal adenocarcinoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, liver cancer (e.g., hepatocellular carcinoma, intrahepatic bile duct cancer), pancreatic cancer (e.g., pancreatic adenocarcinoma, pancreatic islet cell cancer), small intestine cancer, or stomach cancer (e.g., stomach adenocarcinoma, signet ring cell carcinoma of the stomach)), genitourinary cancer (e.g., bladder cancer (e.g., bladder urothelial carcinoma), kidney cancer (e.g., renal clear cell carcinoma, renal papillary cell carcinoma, kidney chromophobe), prostate cancer (e.g., prostate adenocarcinoma), testicular cancer (e.g., testicular germ cell tumors, seminoma), or ureter cancer), gynecologic cancer (e.g., cervical cancer (e.g., cervical squamous cell carcinoma, endocervical adenocarcinoma, mucinous carcinoma), ovarian cancer (e.g., serous ovarian cancer, ovarian serous cystadenocarcinoma), uterine cancer (e.g., uterine carcinosarcoma, uterine endometrioid carcinoma, uterine serous carcinoma, uterine papillary serous carcinoma, uterine corpus endometrial carcinoma), or vulvar cancer), head and neck cancer (e.g., ear cancer (e.g., middle ear cancer), head and neck squamous cell carcinoma, nasal cavity cancer, oral cancer, pharynx cancer (e.g., hypopharynx cancer, nasopharynx cancer, oropharyngeal cancer), hematological cancer (e.g., leukemia (e.g., chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL) (e.g., Philadelphia chromosome positive ALL), acute myeloid leukemia (AML) (e.g., acute promyelocytic leukemia (APL)), chronic myeloid leukemia (CML)), lymphoma (e.g., Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)), non-Hodgkin lymphoma (e.g., Burkitt lymphoma (BL), diffuse large B- cell lymphoma (DLBCL), diffuse histiocytic lymphoma (DHL), follicular lymphoma (FL), intravascular large B-cell lymphoma (IVLBCL), mantle cell lymphoma (MCL), small lymphocytic lymphoma (SLL))), or myeloma (e.g., multiple myeloma)), Li-Fraumeni tumors, mesentery cancer (e.g., omentum cancer, peritoneal cancer), pleural cancer, respiratory cancer (e.g., larynx cancer, lung cancer (e.g., lung squamous cell carcinoma, lung adenocarcinoma, mesothelioma, non-small cell lung cancer (NSCLC)), tracheal cancer), sarcoma (e.g., bone cancer (e.g., osteosarcoma, chondrosarcoma) or soft tissue sarcoma (Ewing sarcoma, leiomyosarcoma, myxofibrosarcoma, rhabdomyosarcoma)), skin cancer (e.g., melanoma), thymus cancer (e.g., thymoma), or a combination thereof. In some embodiments, the cancer is a hematological cancer, a soft tissue cancer, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, rectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, or uterine cancer. In some embodiments, the cancer is a hematological cancer, bile duct cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, testicular cancer (e.g., seminoma), skin cancer, stomach cancer, thymus cancer, thyroid cancer, urothelial cancer, or uterine cancer. In some embodiments, the cancer is a pancreatic cancer (e.g., pancreatic ductal adenocarcinoma). In some embodiments, the cancer is a skin cancer (e.g., a melanoma (e.g., cutaneous melanoma)). In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is unresectable or metastatic melanoma. In some cases, the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response can be determined following administration of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof. For example, following administration of one or more doses (e.g., one dose, two doses, three doses, four doses, five doses, or more) of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to a subject, a tumor sample (e.g., a biopsy) or a blood sample (e.g., a sample containing circulating tumor DNA (ctDNA), circulating cell-free tumor RNA (cfRNA), and / or circulating tumor cells (CTCs)) can be obtained from the subject, and an assay can be performed to determine the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response. Any appropriate biomarker of response can be used, for instance, a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))), ERK1 and / or ERK2 (e.g., phosphoERK1 and / or phosphoERK2), DUSP6 (dual specificity protein phosphatase 6), and / or SPRY4 (protein sprouty homolog 4). See, e.g., Riely, Gregory J., et al. Journal of Thoracic Oncology 16.4 (2021): S751-S752, doi: 10.1016 / S1556- 0864(21)01941-9; and Hallin, Jill, et al. Molecular Cancer Research 21.5_Supplement (2023): B012-B012, doi: 10.1158 / 1557-3125.RAS23-B012. Determining the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response can be performed using any appropriate method, including consulting the subject’s medical record (i.e., if a level (e.g., a baseline level) of the biomarker of response was previously determined), and / or performing an assay, such as an immunohistochemical (IHC) assay, an immunofluorescence assay, a PCR assay (e.g., RT-qPCR assay or a digital droplet PCR assay), and / or a sequencing assay (e.g., a next-generation sequencing (NGS) assay). In some embodiments, the biomarker of response is a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))), and the assay is an IHC assay, a PCR assay (e.g., RT-qPCR assay or a digital droplet PCR assay), or a sequencing assay (e.g., a next-generation sequencing assay). In some embodiments, the biomarker of response is ERK1 and / or ERK2 (e.g., phosphoERK1 and / or phosphoERK2), and the assay is an IHC assay or an immunofluorescence assay. In some embodiments, the biomarker of response is DUSP6, and the assay is a PCR assay (e.g., RT- qPCR assay or a digital droplet PCR assay). In some embodiments, the biomarker of response is SPRY4, and the assay is a PCR assay (e.g., RT-qPCR assay or a digital droplet PCR assay). See, e.g., Holm, Matilda, et al. PLoS One 15.11 (2020): e0239819, doi: 10.1371 / journal.pone.0239819; Li, Jun, et al. Oncotarget 7.3 (2016): 2646, doi: 10.18632 / oncotarget.6104; Van Herpen, Carla ML, et al. Oncotarget 10.19 (2019): 1850, doi: 10.18632 / oncotarget.26753; Raez, L., et al. Journal of Thoracic Oncology 13.9 (2018): S153- S154, doi: 10.1016 / j.jtho.2018.07.024; and Thatikonda, Venu, et al. bioRxiv (2023), doi: 10.1101 / 2023.01.23.525210. Accordingly, in some embodiments of the methods provided herein, the method includes (a) administering a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to a subject; and (b) determining the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response (e.g., a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein)))), ERK1 and / or ERK2 (e.g., phosphoERK1 and / or phosphoERK2), DUSP6, and / or SPRY4). In some embodiments, determining the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response includes performing an assay on a sample (e.g., a tumor sample or a blood sample) obtained from the subject. In some embodiments, prior to administering a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to a subject, the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response is determined (e.g., by performing an assay or by consulting the subject’s medical record); in some cases, this can be referred to as a baseline level. Thus, in some embodiments of the methods provided herein, the method includes (a) administering a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to a subject; (b) after (a) determining the level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response; and (c) comparing the level of the biomarker(s) of response to a baseline level of the biomarker(s) of response. In some embodiments of the methods provided herein, the method includes (a) determining a first (e.g., baseline) level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of a biomarker of response; (b) after (a), administering a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to a subject; (c) after (b), determining a second level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of the biomarker of response; and (d) comparing the second level of the biomarker(s) of response to the first level of the biomarker(s) of response. In some such embodiments, step (a) is performed before the subject has received any doses of the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes (e) after (c), administering a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or a pharmaceutically acceptable salt thereof, to the subject; (f) after (e), determining a third level (e.g., the protein expression level, the mRNA expression level, and / or the ctDNA level) of the biomarker of response; and (g) comparing the third level of the biomarker(s) of response to a previous level of the biomarker(s) of response (e.g., the first level of the biomarker(s) of response and / or the second level of the biomarker(s) of response). In some embodiments, steps (e) through (g) are repeated one or more times (e.g., two or more times, three or more times, four or more times, five or more times, or more). In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II- c)), or a pharmaceutically acceptable salt thereof, to a subject comprises administration of one or more doses (e.g., one dose, two doses, three doses, four doses, five doses, or more) of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof to the subject. Also provided is a method for modulating (e.g., decreasing) Ras protein activity (e.g., dysregulated Ras protein activity (e.g., dysregulated KRas protein activity (e.g., mutant KRas protein activity (e.g., KRas G12R mutant protein activity or G12V mutant protein activity)))) in a cell, comprising contacting the cell with a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is ex vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to a subject having a cell having a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein)))). In some embodiments, the contacting is ex vivo, wherein the method comprises contacting a cell from a subject having a Ras protein (e.g., a wild type Ras protein (e.g., wild type KRas protein, wild type NRas protein, or wild type HRas protein) or a dysregulated Ras protein (e.g., an amplified Ras protein (e.g., amplified wild type KRas protein, amplified wild type NRas protein, or amplified wild type HRas protein) or a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein))) with a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a cancer cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a mammalian cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a pancreatic cancer cell or is a skin cancer cell. In some embodiments, the cancer cell has a dysregulated Ras protein (e.g., a mutant Ras protein (e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein), a mutant NRas protein (e.g., a NRas Q61H mutant protein, a NRas Q61K mutant protein, a NRas Q61L mutant protein, or a NRas Q61R mutant protein), or a mutant HRas protein (e.g., a HRas Q61H mutant protein or a HRas Q61L mutant protein)).

[0041] As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system. For example, “contacting” a Ras protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a Ras protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the Ras protein.

[0042] Also provided herein is a method of inhibiting cell proliferation, in vitro, in vivo, or ex vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. In some embodiments, the cell has a Ras dysregulation. In some embodiments, the cell has a KRas dysregulation. In some embodiments, the cell has a KRas mutation. In some embodiments, the cell has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the cell has a KRas G12D mutation. In some embodiments, the cell has a KRas G12R mutation. In some embodiments, the cell has a KRas G12V mutation. In some embodiments, the cell has a KRas amplification. In some embodiments, the cell has a NRas dysregulation. In some embodiments, the cell has a NRas mutation. In some embodiments, the cell has a NRas Q61H mutation, a NRas Q61K mutation, a NRas Q61L mutation, or a NRas Q61R mutation. In some embodiments, the cell has a NRas Q61H mutation In some embodiments, the cell has a NRas Q61K mutation, aNRas Q61L mutation, or aNRas Q61R mutation. In some embodiments, the cell has a NRas Q61K mutation. In some embodiments, the cell has a NRas Q61L mutation. In some embodiments, the cell has a NRas Q61R mutation. In some embodiments, the cell has a NRas amplification. In some embodiments, the cell has a HRas dysregulation. In some embodiments, the cell has a HRas mutation. In some embodiments, the cell has a HRas Q61H mutation or a HRas Q61L mutation. In some embodiments, the cell has a HRas Q61H mutation. In some embodiments, the cell has a HRas Q61L mutation. In some embodiments, the cell has a HRas amplification.

[0043] Further provided herein is a method of increasing cell death, in vitro, in vivo, or ex vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. In some embodiments, the cell has a Ras dysregulation. In some embodiments, the cell has a KRas dysregulation. In some embodiments, the cell has a KRas mutation. In some embodiments, the cell has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation. In some embodiments, the cell has a KRas G12D mutation. In some embodiments, the cell has a KRas G12R mutation. In some embodiments, the cell has a KRas G12V mutation. In some embodiments, the cell has a KRas amplification. In some embodiments, the cell has a NRas dysregulation. In some embodiments, the cell has a NRas mutation. In some embodiments, the cell has a NRas Q61H mutation, a NRas Q61K mutation, a NRas Q61L mutation, or a NRas Q61R mutation. In some embodiments, the cell has a NRas Q61H mutation. In some embodiments, the cell has a NRas Q61K mutation, a NRas Q61L mutation, or aNRas Q61R mutation. In some embodiments, the cell has aNRas Q61K mutation. In some embodiments, the cell has a NRas Q61L mutation. In some embodiments, the cell has a NRas Q61R mutation. In some embodiments, the cell has a NRas amplification. In some embodiments, the cell has a HRas dysregulation. In some embodiments, the cell has a HRas mutation. In some embodiments, the cell has a HRas Q61H mutation or a HRas Q61L mutation. In some embodiments, the cell has a HRas Q61H mutation. In some embodiments, the cell has a HRas Q61L mutation. In some embodiments, the cell has a HRas amplification.

[0044] The term “wild type” or “wild-type” describes a nucleic acid (e.g., a RAS gene or a Ras mRNA) or protein (e.g., a Ras protein) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein. Although a wild type nucleic acid or protein sequence is the sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein, it is not necessarily the case that a subject that has a disease or disorder related to the reference nucleic acid or protein lacks the wild type sequence. For example, a subject with a gene duplication of the reference gene may have the wild type sequence but could still have a disease or disorder related to the reference nucleic acid or protein due to the duplication event. As another example, a subject with a disease or disorder related to the reference nucleic acid or protein may have one allele that encodes wild type protein, and another allele that encodes a mutant protein.

[0045] The term “inhibitor” , as used herein, means a compound or agent (e.g., a peptide or an antibody) that prevents a biomolecule, (e.g., a protein) from completing or initiating a reaction. An inhibitor can inhibit a reaction by competitive, uncompetitive, or non-competitive means.

[0046] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0047] As used herein, the terms “subject,” “individual,” or “patient,” are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.

[0048] In some embodiments, the subject is a pediatric subject.

[0049] The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph ’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.

[0050] The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0051] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0052] The phrase “therapeutically effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a cancer as provided herein, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of the particular disease, disorder, or condition described herein. The amount of a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[0053] As used herein, an “effective amount” refers to an amount of the compound sufficient to effect a beneficial or desired result. For example, an “effective amount” as used herein can refer to an amount of the compound sufficient to modulate (e.g., increase or decrease) (1) activity or amount of a protein; (2) proliferation of a cell (e.g., a cancer cell); and / or (3) one or more cellular signaling pathways associated with a protein’s activity. Combinations In any of the indications described herein, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I) or (II) (e.g., Formula (II- a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a kinase inhibitor, immunotherapy, or radiation). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a kinase inhibitor, immunotherapy, or radiation). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is Ras inhibitor naïve. In some embodiments, a subject is not Ras inhibitor naïve. In some embodiments, a subject has undergone prior therapy. For example, treatment with surgery, radiation, a chemotherapeutic agent, an immunotherapy, a multi-kinase inhibitor (MKI), a Ras inhibitor (e.g., a KRas inhibitor), a RAF / MEK / PI3K pathway inhibitor, a MEK inhibitor, a Raf inhibitor, a YAP inhibitor, a proteasome inhibitor, a PI3K-AKT-mTOR pathway inhibitor, an ERK inhibitor, a pan-ErbB inhibitor, a MET inhibitor, a farnesyl transferase inhibitor, a FAK inhibitor, a HSP90 inhibitor, or a combination thereof. In some embodiments of any the methods described herein, the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents. Non-limiting examples of additional therapeutic agents include: RAS pathway targeted therapeutic agents (e.g., Ras / RAF / MEK / PI3K pathway inhibitors or degraders, (e.g., Ras inhibitors or degraders, KRas-targeted therapeutic agents, SOS1 inhibitors or degraders, SOS1 / Ras protein-protein interaction inhibitors, SHP2 inhibitors or degraders, PI3K-AKT- mTOR pathway inhibitors or degraders)), kinase-targeted therapeutics (e.g., MEK inhibitors or degraders, ERK inhibitors or degraders, Raf inhibitors or degraders (e.g., BRaf inhibitors or degraders), PI3K inhibitors or degraders, AKT inhibitors or degraders, mTOR inhibitors or degraders, CDK4 / 5 inhibitors or degraders, CDK4 / 6 inhibitors or degraders, MET inhibitors or degraders, FAK inhibitors or degraders, ErbB family inhibitors or degraders (e.g., EGFR inhibitors or degraders, Her2 inhibitors or degraders), Src inhibitors or degraders), mTORC1 inhibitors or degraders, YAP inhibitors or degraders, proteasome inhibitors or degraders, farnesyl transferase inhibitors or degraders, HSP90 inhibitors or degraders, PTEN inhibitors or degraders, signal transduction pathway inhibitors or degraders, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., venetoclax, navitoclax, obataclax), chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents including immunomodulatory imide drugs (sometimes called “IMiDs” or “CELMoDs”), immunotherapy (e.g., anti-PD1, anti-PD-L1, anti-CTLA4, anti-LAG3, anti-TIM3, anti-B7-H3, anti-VISTA therapies, including antibodies (e.g., single-targeted antibodies targeting one or more of PD1, PD-L1, CTLA4, LAG3, TIM3, B7-H3, or VISTA; bispecific antibodies (including bispecific T cell engagers (BiTEs)) targeting one or more of PD1, PD-L1, CTLA4, LAG3, TIM3, B7- H3, or VISTA; and antibody-drug conjugates (ADCs) incorporating one or more of PD1, PD- L1, CTLA4, LAG3, TIM3, B7-H3, or VISTA) or antigen-binding fragments thereof, a PD-1 inhibitor, a PD-L1 inhibitor, or an ADOR2A inhibitor), cell-based therapeutics (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), and radiotherapy. See also, e.g., the therapeutic agents listed in U.S. Publication No. US 2021 / 0130303. A “degrader” as used herein is a heterobifunctional molecule that induces degradation of a target protein, the degrader including a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply an E3), these two moieties being optionally separated by a linker. Such degraders are sometimes known as “PROTACs”. A “Ras pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a Ras pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and / or induction of degradation). Non-limiting examples of a protein in a Ras pathway include any one of the proteins in the Ras-RAF-MAPK pathway or PI3K / AKT pathway such as Ras (e.g., KRas, HRas, and NRas), RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a Ras pathway modulator can be selective for a protein in a Ras pathway, e.g., the Ras pathway modulator can be selective for Ras (also referred to as a Ras modulator). In some embodiments, a Ras modulator is a covalent inhibitor. In some embodiments, a Ras pathway targeted therapeutic agent is a “KRas pathway modulator.” A KRas pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRas pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and / or induction of degradation). Non-limiting examples of a protein in a KRas pathway include any one of the proteins in the KRas-RAF-MAPK pathway or PI3K / AKT pathway such as KRas, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRas pathway modulator is a KRas-targeted therapeutic agent. In some embodiments, the Ras pathway targeted therapeutic agent is a SOS1 inhibitor or a SHP2 inhibitor. Non-limiting examples of SOS1 inhibitors include MRTX-0902, and RMC-5845. Non-limiting examples of SHP2 inhibitors include batoprotafib (TNO-155), vociprotafib (RMC-4630), ARRY-558, BBP-398, ENT-03, ERAS-601, ET-0038, GDC-1971 (RLY-1971), GH-21, HS-10381, ICP-189, JAB-3068, JAB-3312, and SH-3809. Non-limiting examples of KRas-targeted therapeutic agents include a KRas-selective inhibitor, a Ras inhibitor, and an anti-KRas antibody. In some embodiments, the KRas inhibitor is a covalent inhibitor. In some embodiments, the KRas-targeted therapeutic agent is adagrasib, divarasib (GDC-6036), sotorasib, ARS-1620, ARS-3248, ARS-853, ASP-3082, ATG-012, BI- 1701963, BI-1823911, BPI-421286, D-1553, ERAS-3490, GFH-925, JAB-21822, JDQ-443, LY-3537982, MRTX-1133, MRTX-1257, RMC-6236, RMC-6291, RSC-1255, or a combination thereof. In some embodiments, the KRas-targeted therapeutic agent is an agent that inhibits the interaction between KRas and SOS1 or SHP2. Non-limiting examples of an agent that inhibits the interaction between SOS1 and KRas include BI-3406, BI-1701963, and BAY 293. Additional Ras-targeted therapeutic agents include those disclosed in International Publication Nos. WO 2021 / 104431; WO WO2021 / 119343; WO2021 / 113595; WO 2021 / 107160; WO 2016 / 161361; WO 2016 / 17262; WO 2020 / 035031; WO 2021 / 041671; WO 2016 / 077793; WO 2020 / 180768; WO 2021 / 092115; WO 2020 / 180770; U.S. Patent Nos. US 10,898,487; US 10,829,487; US 10,858,359; US 10,561,655; US 10,532,042; U.S. Publication Nos. US 2021 / 0101870; US 2019 / 0231805; US 2020 / 0017517; US 2020 / 0017511; US 2020 / 0147058; US 2021 / 0009577; and Hillig et al. PNAS. 2019; 116(7): 2551-2560, doi: 10.1073 / pnas.1812963116. Further non-limiting examples of Ras pathway-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is avutometinib, dabrafenib (e.g., dabrafenib mesylate, TAFINLAR®), encorafenib (BRAFTOVI™), naporafenib, sorafenib (e.g., sorafenib tosylate), vemurafenib (ZELBORAF®), ARQ 736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265, FORE-8394, GDC-0879, GSK2118436, HLX-208, HM95573, LGX818, LXH254, PLX-3603, PLX-4720, PLX-8394, RAF265, RO5126766, RO5185426, or a combination thereof. In some embodiments, the BRAF inhibitor is avutometinib, dabrafenib (e.g., dabrafenib mesylate), encorafenib, naporafenib, sorafenib (e.g., sorafenib tosylate), vemurafenib, C17071479-F, CHIR-265, FORE-8394, HLX-208, or a combination thereof. In some embodiments, the MEK inhibitor is avutometinib, binimetinib (MEKTOVI®, MEK162), cobimetinib (e.g., cobimetinib fumarate, COTELLIC®), mirdametinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate, AZD6244), trametinib (e.g., trametinib dimethyl sulfoxide, GSK-1120212 MEKINIST®), zapnometinib, hypothemycin, CI1040 (PD184352), CS3006, FCN-159, MSC1936369B, NFX-179, PD0325901, PD98059,RO5126766, SHR7390, TAK-733, WX-554, or a combination thereof. In some embodiments, the MEK inhibitor is avutometinib, binimetinib, cobimetinib (e.g., cobimetinib fumarate), mirdametinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate), trametinib (e.g., trametinib dimethyl sulfoxide, GSK-1120212), zapnometinib, FCN-159, NFX-179, TAK-733, or a combination thereof. In some embodiments, the ERK inhibitor is 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), 5-7-Oxozeaenol, 5-iodotubercidin, AEZ-131 (AEZS-131), AEZS- 136, ASN007, AZ-13767370, BL-EI-001, CC-90003, FR148083, FR-180204, FRI-20 (ON- 01060), GDC0994, GDC-0994 (RG-7482), KO-947, KO-947, LTT-462, LY-3214996, MK- 8353 (SCH900353), ONC201SCH772984, ulixertinib (BVD-523), VTX-11e, or a combination thereof. In some embodiments, the ERK inhibitor is rineterkib, ulixertinib, or a combination thereof. In some embodiments, PI3K inhibitor is alpelisib (BYL719), apitolisib (GDC-0980), buparlisib (BKM120), copanlisib (ALIQOPA™, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), gedatolisib (PF-05212384, PKI-587), omipalisib (GSK2126458, GSK458), pictilisib (GDC-0941), pilaralisib (XL147, SAR245408), rigosertib, serabelisib (TAK-117, MLN1117, INK 1117), sonolisib (PX-866), taselisib (GDC-0032, RG7604), voxtalisib (XL756, SAR245409), wortmannin, AMG 511, AMG319, ASN003, AZD8835, BGT-226 (NVP-BGT226), CH5132799, CUDC-907, GDC-0077, GDC-0084 (RG7666), GS-9820, GSK1059615, GSK2636771, KIN-193 (AZD-6428), LY2023414, LY294002, PF-04691502, PI-103, PKI-402, PQR309, SAR260301, SF1126, VS-5584 (SB2343), WX-037, XL-765, ZSTK474, or a combination thereof. In some embodiments, the PI3K inhibitor is alpelisib, amdizalisib, apitolisib, bimiralisib, buparlisib, copanlisib (e.g., copanlisib dihydrochloride or a hydrate of copanlisib dihydrochloride), dactolisib, dezapelisib, dordaviprone, duvelisib (e.g., a hydrate of duvelisib), eganelisib, fimepinostat, gedatolisib, idelalisib, inavolisib, leniolisib (e.g., leniolisib phosphate), linperlisib, parsaclisib, paxalisib, risovalisib, seletalisib, serabelisib, sonolisib, tenalisib, umbralisib (e.g., umbralisib tosylate), zandelisib, PF- 04691502, SHC-014748-M, TQ-B-3525, or a combination thereof. In some embodiments, the AKT inhibitor is 2-[4-(2-aminoprop-2-yl)phenyl]-3- phenylquinoxaline, 3-oxo-tirucallic acid, A-443654, A-674563, afuresertib, API-1, ARQ092, AT13148, AT7867, AZD5363, BAY 1125976, boc-Phe-vinyl ketone, CCT128930, DC120, DM-PIT-1, edelfosine, erucylphophocholine, erufosine, GSK2141795, GSK690693, H-89, ipatasertib (GDC-0068, RG7440), lactoquinomycin, miltefosine (IMPADIVO®), MK-2206, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin-3- yl)benzyl)-3-fluorobenzamide, NL-71-101, ONC201, OSU-A9, Perifosine (D-21266), PH- 316, PHT-427, PIT-1, SR13668, TCN, TCN-P, triciribine (Triciribine Phosphate Monohydrate), uprosertib, wortmannin, or a combination thereof. In some embodiments, the AKT inhibitor is capivasertib (AZD-5363), miransertib (e.g., miransertib mesylate), pifusertib, uprosertib, BXT-10, or a combination thereof. In some embodiments, the mTOR inhibitor is MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP- 23573), sirolimus (rapamycin), or a combination thereof. In some embodiments, the mTOR inhibitor is apitolisib, bimiralisib, dactolisib, everolimus, fosciclopirox (e.g., fosciclopirox sodium), gedatolisib, onatasertib, paxalisib, sapanisertib, sirolimus, sodium 2- hydroxylinoleate, temsirolimus, umirolimus, zandelisib, zotarolimus, BI-860585, CC-115, PF- 04691502, or a combination thereof. In some embodiments, the farnesyl transferase inhibitor is lonafarnib, tipifarnib, BMS- 214662, L778123, L744832, and FTI-277. In some embodiments, the farnesyl transferase inhibitor is lonafarnib, tipifarnib, BMS-214662, or a combination thereof. In some embodiments, a chemotherapeutic agent includes a DNA replication inhibitor (e.g., a DNA intercalator (e.g., an anthracycline)), a DNA crosslinker (e.g., cyclophosphamide, a mitomycin (e.g., mitomycin C), a platinum complex), a ribonucleotide-diphosphate reductase inhibitor (e.g., gemcitabine), or a topoisomerase inhibitor), an anti-microtubule agent (e.g., a taxane a vinca alkaloid, or eribulin), or a combination thereof. Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof. In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof. In some embodiments, the chemotherapy is a platinum complex, a microtubule inhibitor (e.g., a microtubule destabilizer or a microtubule stabilizer), a topoisomerase inhibitor, or an antibody-drug conjugate including any thereof. In some embodiments, the platinum complex is carboplatin, cisplatin, lobaplatin, miriplatin, oxaliplatin, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, colchicine, desoxyepothilone B, docetaxel, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, plinabulin, sabizabulin, tirbanibulin, vinblastine, vinflunine, vinorelbine, or a combination thereof. In some embodiments, the microtubule inhibitor is cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, or a combination thereof. In some embodiments, the topoisomerase inhibitor is aclarubicin, amsacrine, belotecan, camptothecin, daunorubicin, dexrazoxane, elliptinium, epirubicin, etoposide, gepotidacin, idarubicin, mitoxantrone, nemonoxacin, pirarubicin, pixantrone, razoxane, rubitecan, sobuzoxane, temozolomide, teniposide, topotecan, SN-38, or a combination thereof. In some embodiments, the hypomethylating agent is azacitidine, decitabine, or a combination thereof. In some embodiments, the chemotherapy is a platinum complex and a topoisomerase inhibitor (e.g., cisplatin and etoposide). In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is belantamab mafodotin, brentuximab vedotin, cofetuzumab pelidotin, disitamab vedotin, enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof), mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof), polatuzumab vedotin, telisotuzumab vedotin, tisotumab vedotin, trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof), tusamitamab ravtansine, upifitamab rilsodotin, zilovertamab vedotin, Alpha-Her2-pAF1-AS-269, BAT-8001, TAA-013, biosimilars thereof, or a combination thereof. In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the microtubule inhibitor is trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the topoisomerase inhibitor is datopotamab deruxtecan, patritumab deruxtecan, sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof), trastuzumab deruxtecan (fam-trastuzumab deruxtecan- nxki, or a biosimilar thereof), or a combination thereof. In some embodiments, the antibody- drug conjugate including the topoisomerase inhibitor is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof). In some embodiments, the antibody-drug conjugate including the topoisomerase inhibitor is trastuzumab deruxtecan (e.g., fam- trastuzumab deruxtecan-nxki, or a biosimilar thereof). In some embodiments, the EGFR inhibitor is abivertinib, afatinib, alflutinib, almonertinib, amivantamab, befotertinib, bleomycetin, brigatinib, canertinib, cetuximab, dacomitinib, delphinidin, depatuxizumab, dovitinib, duligotumab, erlotinib, furmonertinib, futuximab, gefitinib, icotinib, imgatuzumab, lapatinib, lazertinib, lisocabtagene, mereletinib, mobocertinib, modotuximab, nazartinib, necitumumab, neratinib, nimotuzumab, olmutinib, osimertinib, panitumumab, pelitinib, pingyangmycin, poziotinib, pyrotinib, quercetin, sapitinib, tarloxotinib, tesevatinib, tomuzotuximab, vandetanib, varlitinib, zalutumumab, and zorifertinib. In some embodiments, the EGFR inhibitor is abivertinib, afatinib (e.g., afatinib dimaleate), alflutinib (e.g., alflutinib mesylate), almonertinib (e.g., almonertinib mesylate), befotertinib, brigatinib, canertinib, dacomitinib (e.g., dacomitinib monohydrate), dovitinib, erlotinib (e.g., erlotinib hydrochloride), gefitinib, icotinib, lapatinib (e.g., lapatinib ditosylate monohydrate), larotinib, lazertinib, limertinib, mobocertinib (e.g., mobocertinib succinate), nazartinib, neratinib (e.g., neratinib maleate), olmutinib, osimertinib (e.g., osimertinib mesylate), pelitinib, poziotinib, pyrotinib (e.g., pyrotinib maleate), ruserontinib (SKLB-1028), sapitinib, sunvozertinib, tesevatinib, vandetanib, varlitinib, zorifertinib, BIBW-2948, BPI- 7711, HA-121-28, SH-1028, or a combination thereof In some embodiments, the PARP inhibitor is iniparib, niraparib, olaparib (LYNPARZA®), pamiparib (BGB-290), rucaparib, talazoparib, veliparib, 2X-121, ABT-767, BMN 673, BSI-201, CEP 9722, E7016, IMP4297, INO-1001, JPI-289, KU-0059436 (AZD2281), NOV1401, PF-01367338, and RBN-2397. In some embodiments, the PARP inhibitor is fuzuloparib (fluzoparib), niraparib (e.g., niraparib tosylate monohydrate), olaparib, pamiparib, rucaparib (e.g., rucaparib camsylate), saruparib (AZD5305), senaparib, stenoparib, talazoparib (e.g., talazoparib tosylate), veliparib, CEP-9722, JPI-289, NMS-03305293, or a combination thereof. In some embodiments, the PARP inhibitor is a PARP1 inhibitor. In some embodiments, the PARP1 inhibitor is saruparib (AZD5305), NMS-03305293, or a combination thereof. Non-limiting examples of immunotherapy include immune checkpoint therapies. Non- limiting examples of immune checkpoint therapies include antibodies and / or inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, ADORA2A, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodiments, the anti-CTLA4 therapy is abatacept (e.g., ORENCIA® (abatacept), or a biosimilar thereof), botensilimab, cadonilimab, erfonrilimab, gotistobart, ipilimumab (e.g., YERVOY® (ipilimumab), or a biosimilar thereof), nurulimab, quavonlimab, tremelimumab (ticilimumab) (e.g., IMIUDO® (tremelimumab), or a biosimilar thereof), volrustomig, vudalimab, zalifrelimab, BMS-986218, PSB-205, biosimilars thereof, or a combination thereof. In some embodiments, the anti-PD1 therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab (e.g., cemiplimab-rwlc, or a biosimilar thereof), cetrelimab, dostarlimab (e.g., dostarlimab-gxly, or a biosimilar thereof), ezabenlimab, geptanolimab, ivonescimab, nivolumab (e.g., OPDIVO® (nivolumab), or a biosimilar thereof), nofazinlimab, pembrolizumab (e.g., KEYTRUDA® (pembrolizumab), or a biosimilar thereof), penpulimab, pidilizumab, pimivalimab, prolgolimab, pucotenlimab, retifanlimab (e.g., retifanlimab-dlwr, or a biosimilar thereof), rilvegostomig, rosnilimab, rulonilimab, sasanlimab, serplulimab, sintilimab (e.g., TYVYT® (sintilimab), or a biosimilar thereof), spartalizumab, tebotelimab, tislelizumab, toripalimab, volrustomig, vudalimab, zimberelimab, QL-1604, HX-009, INCB- 086550, RG-6139, BAT-1306, SG-001, biosimilars thereof, or a combination thereof. In some embodiments, the anti-PD-L1 therapy is adebrelimab, atezolizumab (e.g., TECENTRIQ® (atezolizumab), or a biosimilar thereof), avelumab (e.g., BAVENCIO® (avelumab), or a biosimilar thereof), bintrafusp alfa, cosibelimab, danburstotug, durvalumab (e.g., IMFINZI® (durvalumab), or a biosimilar thereof), envafolimab (e.g., ENWEIDA® (envafolimab), or a biosimilar thereof), erfonrilimab, pacmilimab, socazolimab, sugemalimab (e.g., CEJEMLY® (sugemalimab), or a biosimilar thereof), A-167, APL-502, AUPM-170, BNT-311, SHR-1701, biosimilars thereof, or a combination thereof. In some embodiments, the PD-L1 inhibitor is INCB-086550. In some embodiments, the anti-LAG3 therapy is eftilagimod alfa, favezelimab, fianlimab, ieramilimab, INCAGN-02385, miptenalimab, relatlimab (e.g., relatlimab-rmbw, or a biosimilar thereof), tebotelimab, IBI-110, LBL-007, RG-6139, biosimilars thereof, or a combination thereof. In some embodiments, the ADOR2A inhibitor is etrumadenant, inupadenant, istradefylline, mefloquine (e.g., mefloquine), taminadenant, CPI-444, PBF-999, or a combination thereof. In some embodiments, the ADOR2A inhibitor is etrumadenant, inupadenant, istradefylline, mefloquine (e.g., mefloquine), taminadenant, PBF-999, or a combination thereof. In some embodiments, the anti-TIM3 therapy is cobolimab, sabatolimab (MBG-453), AZD-7789, INCAGN-02390, TQB-2618, or a combination thereof. In some embodiments, the anti-B7-H3 therapy is omburtamab, enoblituzumab, or a combination thereof. In some embodiments, the anti-VISTA therapy is onvatilimab (JNJ-61610588), HMBD-002, K01401-020, KVA-12.1, SNS-101, or a combination thereof. In some embodiments, the IDO inhibitor (e.g., IDO1 and / or IDO2 inhibitor) is 3- deazaguanine, beta-lapachone, diindolylmethane, epacadostat, indole-3-carbinol, indoximod, sertaconazole (e.g., sertaconazole nitrate), or a combination thereof. See, for example, Marin-Acevedo, et al., J Hematol Oncol. 11: 39 (2018), doi: 10.1186 / s13045-018-0582-8. In some embodiments, the additional therapy or therapeutic agent is a combination of atezolizumab and nab-paclitaxel. Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof (a) a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. These additional therapeutic agents may be administered with one or more doses of the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art. Pharmaceutical Compositions and Administration General In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. In some embodiments, the compounds of Formula (I) or (II) (e.g., Formula (II-a), (II- b), or (II-c)), or pharmaceutically acceptable salts thereof, can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium- chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK.2012). Routes of Administration and Composition Components In some embodiments, the compounds of Formula (I) or (II) (e.g., Formula (II-a), (II- b), or (II-c)), or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salts thereof , can be administered to a subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). In some embodiments, a compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered orally to a subject in need thereof. Without being bound by any particular theory, it is believed that oral dosing (e.g., versus IV dosing) can be preferred by patients for convenience, perception of efficacy, and / or past experience. Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[0054] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0055] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0056] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0057] Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795, doi: 10.1593 / neo.06436.

[0058] Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl capryl ocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[0059] In certain embodiments, suppositories can be prepared by mixing a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[0060] In other embodiments, the compounds described herein, or a pharmaceutical composition thereof, are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[0061] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound of Formula (I) or (II) (e.g., Formula (II- a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0062] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a compound of Formula (I) or (II) (e.g., Formula (II-a), (Il-b), or (II-c)), or a pharmaceutically acceptable salt thereof, provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEGs, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or pharmaceutically acceptable salts thereof, provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0063] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0064] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, sterility is not required. The USP / NF standard is usually sufficient.

[0065] In certain embodiments, solid oral dosage forms can further include one or more components that chemically and / or structurally predispose the composition for delivery of the compound of Formula (I) or (II) (e.g., Formula (II-a), (II-b), or (II-c)), or a pharmaceutically acceptable salt thereof, to the stomach or the lower GI; e.g., the ascending colon and / or transverse colon and / or distal colon and / or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776- 802, doi: 10.2174 / 1568026611313070002.

[0066] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric / pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

[0067] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0068] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic, or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating, and non-sensitizing.

[0069] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. Dosages

[0070] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treated, and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

[0071] In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0.1 mg / kg to about 200 mg / kg; from about 0.1 mg / kg to about 150 mg / kg; from about 0.1 mg / kg to about 100 mg / kg; from about 0.1 mg / kg to about 50 mg / kg; from about 0.1 mg / kg to about 10 mg / kg; from about 0.1 mg / kg to about 5 mg / kg; from about 0.1 mg / kg to about 1 mg / kg; from about 0.1 mg / kg to about 0.5 mg / kg).

[0072] Regimens

[0073] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[0074] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. “API” refers to an active pharmaceutical ingredient. The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The term “pharmacologically acceptable salts” is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine, and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. Compound Preparation The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. EXAMPLES General Analytical Methods Method A: Column: Welch Boltimate® Core-Shell 2.7 µm, 3.0 x 30 mm; Flow rate: 1.7 mL / min; Mobile phase: 0.04% TFA in a mixture of water (solvent A) and 0.02% TFA in acetonitrile (solvent B), using the elution gradient 10%-95% (solvent B) over 0.9 minutes and holding at 95% for 0.1 minutes Method B: Pre-column: VanGuard Pre-Column CSH C18, 1.7 μm, 2.1 x 5 mm; Pre- run: 1mL / min for 0.7 min; Column: Acuity UPLC, CSH C18, 1.7 μm, 2.1 x 30 mm; Flow rate: 0.9 mL / min; Mobile phase: 50 to 100% MeCN / water (+ 10 mM ammonium bicarbonate) for 3 minutes. Method C: Pre-column: VanGuard Pre-Column CSH C18, 1.7 μm, 2.1 x 5 mm; Pre- run: 1 mL / min for 0.7 min; Column: Acuity UPLC, CSH C18, 1.7 μm, 2.1 x 30 mm; Flow rate: 0.9 mL / min; Mobile phase: 5 to 100% MeCN / water (+ 10 mM ammonium bicarbonate) for 3 minutes. Method D: Pre-column: VanGuard Pre-Column CSH C18, 1.7 μm, 3.0 x 50 mm; Pre- run: 0.65 mL / min for 2.5 min; Column: Acquity UPLC, CSH C18, 1.7 μm, 2.1 x 75 mm; Flow rate: 0.6 mL / min; Mobile phase: 5 to 100% MeCN / water (+ 10 mM ammonium bicarbonate) for 7.5 minutes. Method E: Pre-column: VanGuard Pre-Column CSH C18, 1.7 μm, 2.1 x 5 mm; Pre- run: 1 mL / min for 0.7 min; Column: Acquity UPLC, CSH C18, 1.7 μm, 2.1 x 30 mm; Flow rate: 0.9 mL / min; Mobile phase: 5 to 100% MeCN / water (+ 10 mM formic acid) for 3 minutes. Method F: Pre-column: VanGuard Pre-Column CSH C18, 1.7 μm, 2.1 x 5 mm; Pre- run: 1 mL / min for 0.7 min; Column: Acuity UPLC, CSH C18, 1.7 μm, 2.1 x 30 mm; Flow rate: 0.9 mL / min; Mobile phase: 5 to 100% MeCN / water (+ 10 mM ammonium bicarbonate) for 2 minutes. Synthesis of INT-2 and INT-6 Step 1. To a solution of benzyl 4-(5-((63S,4S)-4-((tert-butoxycarbonyl)amino)-11- ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro- 11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)- 1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate (INT-1, prepared using methods similar to those described in International Application Publication No. WO 2021 / 091956) (25.0 g, 22.4 mmol) in MeOH (250 mL) was added Pd(OH)2on carbon (6.00 g, 42.7 mmol) under a N2atmosphere. The suspension was degassed and purged with H2gas (x 3). The mixture was stirred under H2pressure (30 psi) at room temperature for 12 hours. The reaction mixture was filtered to collect tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(piperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66- hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4- yl)carbamate (INT-2) (22.0 g, crude) as a yellow solid, which was used directly in the next step without further purification. Step 2. To a solution of tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5- (piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (INT-2) (22.0 g, 22.4 mmol) in MeOH (250 mL) was added AcOH (3.85 mL, 67.3 mmol) and HCHO (4.01 g, 49.4 mmol, 3.68 mL, 37% purity) followed by NaBH3CN (1.69 g, 26.9 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude residue, which was purified by silica gel chromatography using 0-50% EtOAc / petroleum ether to give tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin- 3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro- 11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (INT-3) (17.0 g, 17.1 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+995.4, tR= 0.838 minutes (Method A) Step 3. To a solution of tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5- (4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (INT-3) (17.0 g, 17.1 mmol) in CH2Cl2(170 mL) was added TFA (85 mL) at 0 °C. The mixture was warmed to room temperature and was stirred for an additional 0.5 hours. The reaction mixture was concentrated under reduced pressure to give (63S,4S)-4-amino-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro- 11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-5,7-dione (INT-4) as a crude residue (15.3 g), which was used without further purification. LCMS: m / z (ESI) [M+H]+894.4, tR= 0.625 minutes (Method A) Step 4. To a stirred solution of (63S,4S)-4-amino-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-5,7-dione (INT-4) (15.3 g, 17.1 mmol) in DMF (151 mL) at 0 °C was added DIPEA (44.2 g, 342 mmol, 59.6 mL), N-(tert-butoxycarbonyl)- N-methyl-L-valine (7.91 g, 34.2 mmol) and COMU (7.32 g, 17.1 mmol). The mixture was stirred at 0 °C for 0.5 hours. The residue was diluted with H2O (500 mL) and was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (3 x 1000 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by SFC (column: Daicel Chiralpak IBN 250 mm x 50 mm x 10 mm; mobile phase: [CO2-EtOH (0.1%NH4OH)]; B%: 30%, isocratic elution mode) to provide tert-butyl ((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (INT- 5) (16.0 g, 14.5 mmol) was obtained as a yellow solid. LCMS: m / z (ESI) [M+H]+1108.5, tR= 0.882 minutes (Method A) Step 5. To a stirred solution of tert-butyl ((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2- yl)(methyl)carbamate (INT-5) (16.0 g, 14.5 mmol) in CH2Cl2(160 mL) was added TFA (80 mL) at 0 °C. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give (2S)-N-((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide (INT-6) as a crude residue (14.6 g), which was used without further purification. LCMS: m / z (ESI) [M+H]+1007.5, tR= 0.648 minutes (Method A) Synthesis of INT-19 and INT-20: Step 1. To a solution of (S)-3-bromo-2-(1-methoxyethyl)pyridine (INT-15) (25.0 g, 116 mmol) and B2pin2(88.1 g, 347 mmol) in 1,4-dioxane (150 mL) was added KOAc (34.1 g, 347 mmol) and PdCl2(dppf) •CH2Cl2(2.84 g, 3.47 mmol) under N2. The mixture was stirred at 90 °C for 12 hours under N2. The reaction was cooled to room temperature and a separate batch ran using the same conditions (25 g of (S)-3-bromo-2-(1-methoxyethyl)pyridine) (INT-15) was combined with this batch to work up together. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude mixture was diluted with water (300 mL) and an aqueous solution of HCl (6M, 500 mL) followed by EtOAc (200 mL). The mixture was then stirred at room temperature for 20 hours. The mixture was separated and extracted with EtOAc (6 x 700 mL). The pH of the water phase was adjusted to pH = 7~8 with NaHCO3solid. The mixture was filtered, extracted with a 3 / 1 mixture of DCM / iPrOH (6 x 500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-(2-(1- methoxyethyl)pyridin-3-yl)boronic acid (INT-16) (36 g, 200 mmol) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, 1H), 7.88 (s, 2H), 7.72 (dd, 1H), 7.20 (dd, 1H), 4.50 (q, 1H), 3.19 (s, 3H), 1.42 (d, 3H) Step 2. To a solution of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-2-iodo-1H-indole (INT-24) (25.0 g, 38.7 mmol) and (S)-(2-(1- methoxyethyl)pyridin-3-yl)boronic acid (INT-16) (9.10 g, 50.3 mmol) in toluene (210 mL), 1,4-dioxane (70.0 mL) and H2O (35.0 mL), was added K3PO4 (24.6 g, 116 mmol) and PdCl2(dppf) • CH2Cl2(1.58 g, 1.93 mmol). The mixture was stirred at 80 °C for 4 hours under N2. The reaction was cooled to room temperature and separate batches ran using the same conditions (45 g of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo- 1H-indole) (INT-24) were combined with this batch to work up together. The mixture was diluted with EtOAc (500 mL) and filtered. Water (500 mL) was added to the filtrate, and the organic layer was separated. The aqueous phase was extracted with additional EtOAc (3 x 500 mL) and the combined organic layers were washed with brine (3 x 500 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by flash silica gel chromatography eluting with 0– 20% EtOAc / petroleum ether gradient to give (S)-5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)- 2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (INT-17) (60 g, 91 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (dd, 1H), 7.77 (d, 1H), 7.72 (dd, 1H), 7.56-7.49 (m, 4H), 7.44-7.30 (m, 8H), 7.21 (dd, 1H), 4.18 (q, 1H), 3.32-3.22 (m, 2H), 2.90 (s, 3H), 2.69 (d, 1H), 2.61-2.52 (m, 1H), 1.36-1.29 (m, 3H), 0.96 (s, 9H), 0.67-0.57 (m, 6H) Step 3. To a solution of (S)-5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (INT-17) (20.0 g, 30.5 mmol) in DMF (150 mL) was added NaH (2.440 g, 60% purity, 61.0 mmol) at 0 °C for 30 minutes under N2followed by the addition of ethyl iodide (6.18 g, 39.7 mmol). The mixture was stirred at room temperature for 2 hours under N2. Two separate batches ran using the same conditions (total 40 g of (S)-5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-(2-(1- methoxyethyl)pyridin-3-yl)-1H-indole) (INT-17) were combined with this batch to work up together. The mixture was quenched with saturated aqueous ammonium chloride (60 mL), diluted with EtOAc (150 mL) and water (150 ml), and extracted with additional EtOAc (3 x 150 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by flash silica gel chromatography eluting with 0–15% EtOAc / petroleum ether to give compound (S)-5-bromo-3-(3-((tert- butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H- indole (INT-18) (61.5 g, 89.9 mmol) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (dd, 1H), 7.81 (dd, 1H), 7.76-7.66 (m, 1H), 7.55-7.47 (m, 5H), 7.46-7.34 (m, 7H), 7.31-7.25 (m, 1H), 4.10-3.87 (m, 2H), 3.82-3.61 (m, 1H), 3.38 (dd, 1H), 3.15 (t, 1H), 3.02-2.79 (m, 3H), 2.78-2.68 (m, 1H), 2.48-2.29 (m, 1H), 1.36-1.16 (m, 3H), 1.14-1.02 (m, 3H), 0.94 (d, 9H), 0.75-0.57 (m, 6H) Step 4. To a solution of (S)-5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (INT-18) (21.5 g, 31.4 mmol) in THF (40 mL) was added TBAF (126 mL, 1 M in THF, 126 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction was cooled to room temperature and two separate batches ran using the same conditions (total 40 g of (S)-5-bromo-3-(3-((tert- butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H- indole) (INT-18) were combined with this batch to work up together. The reaction mixture was diluted with EtOAc (500 mL) and water (500 mL), and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude product. The crude material was purified by flash silica gel chromatography eluting with 0–30% EtOAc / petroleum ether to give INT-19 (18.3 g, 39.7 mmol) and INT-20 (17.2 g, 38.6 mmol). INT-19:1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, 1H), 7.89 (d, 1H), 7.84 (dd, 1H), 7.53-7.46 (m, 2H), 7.28 (dd, 1H), 4.52 (t, 1H), 4.11-3.99 (m, 2H), 3.84-3.75 (m, 1H), 3.07-3.02 (m, 1H), 2.98-2.93 (m, 1H), 2.85 (s, 3H), 2.65 (d, 1H), 2.12 (d, 1H), 1.38 (d, 3H), 1.10 (t, 3H), 0.58 (d, 6H) INT-20:1H NMR (400 MHz, DMSO-d6) δ 8.75 (dd, 1H), 7.92 (d, 1H), 7.86 (dd, 1H), 7.51-7.45 (m, 2H), 7.28 (dd, 1H), 4.53 (t, 1H), 4.02-3.92 (m, 2H), 3.68-3.58 (m, 1H), 3.12-3.07 (m, 1H), 3.05 (s, 3H), 2.99-2.94 (m, 1H), 2.73 (d, 1H), 2.26 (d, 1H), 1.21 (d, 3H), 1.07 (t, 3H), 0.63 (d, 6H) Synthesis of INT-23: Step 1. To a stirred solution of INT-19 (14.7 g, 33.0 mmol) at 0 °C in CH2Cl2(150 mL) was added Et3N (13.8 mL 99.0 mmol), Ac2O (3.74mL, 39.6 mmol) and DMAP (403 mg, 3.30 mmol). The mixture was warmed to room temperature and stirred for 1 hour. At this time, the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude residue was purified by flash silica gel chromatography eluting with 0–35% ethyl acetate / petroleum ether gradient to give (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)- 2,2-dimethylpropyl acetate (INT-21) (15.1 g, 31.0 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (t, 1H), 7.87 (d, 1H), 7.79 (d, 1H), 7.52-7.49 (m, 2H), 7.30 (d, 1H), 4.15-4.04 (m, 2H), 4.02-4.00 (m, 1H), 3.70 (dd, 2H), 2.84 (s, 3H), 2.72 (d, 1H), 2.26 (d, 1H), 1.87 (s, 3H), 1.41 (d, 3H), 1.11 (t, 3H), 0.71 (d, 6H) Step 2. A mixture of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H- indol-3-yl)-2,2-dimethylpropyl acetate (INT-21) (5.40 g, 11.1 mmol), B2pin2(4.22 g, 16.6 mmol), bis(1,5-cyclooctadiene)diiridium(I) dichloride (744 mg, 1.11 mmol) and dtbpy (892 mg, 3.32 mmol) in THF (50 mL) was degassed and purged with N2(x 3). The resulting mixture was stirred at 75 °C for 12 hours under N2atmosphere. The reaction was cooled to room temperature and was concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography eluting with 0–5% MeOH / DCM to give compound (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1- methoxyethyl)pyridin-3-yl)boronic acid (INT-22) (7 g, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 9.02 (d, 1H), 8.45 (s, 2H), 8.12 (d, 1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.28 (d, 1H), 4.10-4.03 (m, 2H), 3.81-3.80 (m, 1H), 3.54 (dd, 2H), 2.84 (s, 3H), 2.70 (d, 1H), 2.25 (d, 1H), 1.84 (s, 3H), 1.40 (d, 3H), 1.11 (t, 3H), 0.67 (d, 6H) Step 3. To a solution of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl- 1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (INT-22) (7.00 g, 13.2 mmol) and chloramine-T trihydrate (26.0 g, 92.2 mmol) in THF (70 mL) at 0 °C under an N2atmosphere was added a solution of NaI (13.8 g, 92.2 mmol) in H2O (20 mL). The mixture was then stirred at 65 °C for 12 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (3 x 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. This residue was triturated with petroleum ether / EtOAc = 1 / 1 at room temperature for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography eluting with 0–15% EtOAc / petroleum ether to give compound INT-23 (2.8 g) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.29 (s, 1H), 7.81 (s, 1H), 7.51 (d, 1H), 7.30 (d, 1H), 4.04-4.01 (m, 2H), 3.86-3.82 (m, 1H), 3.60 (dd, 2H), 2.83 (s, 3H), 2.70 (d, 1H), 2.23 (d, 1H), 1.87 (s, 3H), 1.37 (d, 3H), 1.11 (t, 3H), 0.70 (d, 6H) Synthesis of INT-26: Step 1. To a solution of INT-23 (5.0 g, 8.2 mmol) in MeOH (100 mL) was added Et3N (5.7 mL, 41 mmol) and Pd(dppf)Cl2(1.2 g, 1.6 mmol) under an argon atmosphere. The mixture was stirred at 70 °C for 3 hours under a CO atmosphere (50 psi). The reaction mixture was cooled to room temperature and filtered through a pad of celite which was rinsed thoroughly with MeOH. The filtrate was then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0–30% EtOAc / petroleum ether to give methyl (S)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-indol-2-yl)-6-(1- methoxyethyl)nicotinate (INT-25) (3.9 g, 7.1 mmol) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.38 (d, 1H), 8.28 (d, 1H), 7.80 (d, 1H), 7.36 (dd, 1H), 7.27-7.24 (m, 1H), 4.21-4.16 (m, 1H), 4.06-3.94 (m, 4H), 3.92-3.79 (m, 1H), 3.71-3.60 (m, 2H), 3.07 (s, 3H), 2.73 (d, 1H), 2.29 (d, 1H), 1.98 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H), 1.20 (t, 3H), 0.87-0.71 (m, 6H) Step 2. To a solution of methyl (S)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1- ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)nicotinate (INT-25) (3.9 g, 7.1 mmol) in MeOH (45 mL) was added LiOH•H2O (3.0 g, 71 mmol) in H2O (15 mL). After addition, the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give the crude residue, which was adjusted to pH ~6-7 with 1 N HCl and then extracted with CH2Cl2(3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated to yield (R)-5-(5-bromo-1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)nicotinic acid (INT-26) (3.5 g, 7.2 mmol) as a white solid, which was used directly for the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 9.44 (d, 1H), 8.36 (d, 1H), 7.90 (d, 1H), 7.37 (dd, 1H), 7.25 (s, 1H), 4.20-4.09 (m, 1H), 4.08-3.95 (m, 1H), 3.91-3.78 (m, 1H), 3.30-3.24 (m, 2H), 3.10 (s, 3H), 2.74 (d, 1H), 2.24 (d, 1H), 1.48 (d, 3H), 1.20 (t, 3H), 0.80 (d, 6H)

[0075] Synthesis of INT-40 Step 1: To a solution of 3-bromofuran-2-carboxylic acid (INT-42) (10.3 g, 53.9 mmol, 1 equiv.) and potassium carbonate (18.6 g, 135 mmol, 2.5 equiv.) in DMF (100 mL) was added MeI (6.74 mL, 108 mmol, 2 equiv.) at 0 °C. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was then added to water (300 mL) and extracted with EtOAc (600 mL). The combined organic layers were washed with brine (600 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (EtOAc / petroleum ether) to give methyl 3-bromofuran-2- carboxylate (INT-43) (10.5 g, 51.2 mmol) as a white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.51 (d, 1H), 6.61 (d, 1H), 3.94 (s, 3H) Step 2: To a solution of methyl 3-bromofuran-2-carboxylate (INT-43) (8.00 g, 39.0 mmol, 1 equiv.), (4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (INT-44) (11.1 g, 46.8 mmol, 1.2 equiv.), and potassium carbonate (13.5 g, 97.6 mmol, 2.5 equiv.) in 1,4-dioxane (80 mL) and water (16 mL) was added Pd(dppf)Cl2(3.19 g, 3.90 mmol, 0.1 equiv.). The resulting mixture was stirred at 80 °C for 12 hours. The reaction mixture was added to water (300 mL) and extracted with EtOAc (600 mL). The combined organic layers were washed with brine (600 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (EtOAc / petroleum ether) to give methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)furan-2-carboxylate (INT-45) (14 g, 38 mmol) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.56 (d, 2H), 7.54 (s, 1H), 7.42 (d, 2H), 6.62 (d, 1H), 6.57 (s, 1H), 3.86 (s, 3H), 1.54 (s, 9H) Step 3: A solution of methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)furan-2- carboxylate (INT-45) (0.5 g, 1 equiv.) in THF (10 mL) and MeOH (10 mL) was passed through a fixed bed (5 mL) packed with 5% Pd(OH)2 / Al2O3(100 mg) at 80 °C under H2atmosphere (1.5 MPa) with a flow rate of 30 mL / min. The solution was pumped at 0.3 mL / min through the reactor. The collected reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (EtOAc / petroleum ether) to give methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)tetrahydrofuran-2-carboxylate (INT- 46) (13 g obtained from 15.5 g of INT-45, 40 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.28 (s, 1H), 7.35 (d, 2H), 7.06 (d, 2H), 4.58 (d, 1H), 4.27-4.17 (m, 1H), 3.89 (q, 1H), 3.72-3.58 (m, 1H), 3.23 (s, 3H), 2.32-2.17 (m, 2H), 1.46 (s, 9H) Step 4: Isomers of methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)tetrahydrofuran- 2-carboxylate (INT-46) (13.0 g, 1 equiv., 40.5 mmol) was separated by SFC (column: Daicel Chiralpak AD (250 mm x 50 mm, 10 µm); mobile phase: [A: CO2; B: MeOH (0.1% NH4OH)]; B%: 50.00%-50.00%, 100.00 min; flow rate: 200.00 g / min) to give methyl (2R,3R)-3-(4-((tert- butoxycarbonyl)amino)phenyl)tetrahydrofuran-2-carboxylate (INT-47a) (5.28 g, 16.4 mmol, enantiomeric excess (e.e.) = 100.0 %) as a yellow solid and methyl (2S,3S)-3-(4-((tert- butoxycarbonyl)amino)phenyl)tetrahydrofuran-2-carboxylate (INT-47b) (5.17 g, 16.1 mmol, e.e. = 100.0 %) as a yellow solid. INT-47a:1H NMR (400 MHz, DMSO-d6): δ ppm 9.28 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 4.58 (d, J = 8.0 Hz, 1H), 4.25-4.18 (m, 1H), 3.93-3.85 (m, 1H), 3.70-3.61 (m, 1H), 3.23 (s, 3H), 2.30-2.17 (m, 2H), 1.46 (s, 9H) Step 5. methyl (2R,3R)-3-(4-((tert-butoxycarbonyl)amino)phenyl)tetrahydrofuran-2- carboxylate (INT-47a) (1.0 g, 3.11 mmol, 1 equiv.) in THF (15 mL) and water (7.5 mL) was added LiOH (745 mg, 31.1 mmol, 10 equiv.). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then cooled to 0 °C, diluted with EtOAc (20 mL), and the pH was adjusted to pH ~ 4–5 with aqueous 1 M HCl. The aqueous layer was then extracted with EtOAc (90 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (2R,3R)-3-(4-((tert- butoxycarbonyl)amino)phenyl)tetrahydrofuran-2-carboxylic acid (INT-40) (970 mg) as a white solid, which was used in the next step without further purification. LCMS: m / z (ESI) [M-H]+306.1, tR= 1.23 minutes (Method B) Synthesis of INT-41 Step 1: To a solution of (R)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide (INT- 48) (5.00 g, 20.6 mmol, 1 equiv.) and 1-iodo-4-nitrobenzene (20.6 g, 82.5 mmol, 4 equiv.) in toluene (40 mL) was added Pd(OAc)2(463 mg, 2.06 mmol, 0.1 equiv.) and AgOAc (7.58 g, 2.33 mL, 45.4 mmol, 2.2 equiv.). The mixture was stirred at 110°C for 16 hours under a N2atmosphere. The mixture was diluted with EtOAc (100 mL) and the suspension was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0–35% ethyl acetate / petroleum ether) to give (2R,3R)-3-(4- nitrophenyl)-N-(quinolin-8-yl)tetrahydrofuran-2-carboxamide (INT-49) (4.9 g) as a brown solid. LCMS: m / z (ESI) [M-H]+364.0 1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H), 8.94 (dd, J = 1.6, 4.4 Hz, 1H), 8.38 (dd, J = 1.6, 8.4 Hz, 1H), 8.27 (dd, J = 1.2, 7.6 Hz, 1H), 8.02-7.93 (m, 2H), 7.67-7.59 (m, 2H), 7.53-7.42 (m, 3H), 4.82 (d, J = 6.8 Hz, 1H), 4.57-4.45 (m, 1H), 4.15-3.99 (m, 2H), 2.63- 2.55 (m, 1H), 2.25-2.14 (m, 1H) Step 2: To a solution of (2R,3R)-3-(4-nitrophenyl)-N-(quinolin-8-yl)tetrahydrofuran- 2-carboxamide (INT-49) (3.6 g, 9.9 mmol, 1 equiv.) in MeOH (20 mL) and THF (20 mL) was added Pd / C (1.1 g, 0.99 mmol, 10% purity, 0.1 equiv.) at 25°C under an Ar atmosphere. The mixture was then stirred at 25°C for 2 hours under a H2atmosphere (15 psi). The mixture was filtered, and the filter cake was washed with MeOH (300 mL). The filtrate was concentrated under reduced pressure to give (2R,3R)-3-(4-aminophenyl)-N-(quinolin-8-yl)tetrahydrofuran- 2-carboxamide (INT-50) (3.0 g) as a yellow solid. LCMS: m / z (ESI) [M-H]+334.1 1H NMR (400 MHz, DMSO-d6) δ ppm 10.43 (s, 1H), 8.94 (dd, J = 1.6, 4.0 Hz, 1H), 8.42-8.30 (m, 2H), 7.67-7.59 (m, 2H), 7.51-7.44 (m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.28 (d, J = 8.4 Hz, 2H), 4.72 (s, 2H), 4.60 (d, J = 6.8 Hz, 1H), 4.45-4.37 (m, 1H), 4.08-3.98 (m, 1H), 3.68-3.59 (m, 1H), 2.48-2.38 (m, 1H), 2.12-2.00 (m, 1H) Step 3: To a solution of (2R,3R)-3-(4-aminophenyl)-N-(quinolin-8-yl)tetrahydrofuran- 2-carboxamide (INT-50) (1.0 g, 3.0 mmol, 1 equiv.) and HCHO (0.45 g, 0.45 mL, 15 mmol, 5 equiv.) in MeOH (13 mL) was added NaBH3CN (0.94 g, 0.87 mL, 15 mmol, 5 equiv.). The mixture was stirred at 70°C for 1 hour. The mixture was diluted with ethyl acetate (40 mL) and water (40 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (120 mL). The combined organic layers were washed with brine (120 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0–20% ethyl acetate / petroleum ether) to give (2R,3R)-3-(4-(dimethylamino)phenyl)-N-(quinolin-8-yl)tetrahydrofuran-2- carboxamide (INT-51) (1.1 g) as a pale yellow oil. LCMS: m / z (ESI) [M-H]+362.21H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (s, 1H), 8.93 (dd, J = 1.6, 4.4 Hz, 1H), 8.42-8.30 (m, 2H), 7.66-7.58 (m, 2H), 7.51-7.40 (m, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.46-6.36 (m, 2H), 4.64 (d, J = 6.8 Hz, 1H), 4.47-4.38 (m, 1H), 4.11-4.04 (m, 1H), 3.74-3.66 (m, 1H), 2.63 (s, 6H), 2.48-2.41 (m, 1H), 2.13-2.03 (m, 1H) Step 4: To a solution of (2R,3R)-3-(4-(dimethylamino)phenyl)-N-(quinolin-8- yl)tetrahydrofuran-2-carboxamide (INT-51) (400 mg, 1.11 mmol, 1 equiv.) in toluene (12 mL) and H2O (2.0 mL) was added CF3SO3H (3 g, 2 mL). The mixture was stirred at 110°C for 12 hours. The reaction mixture was neutralized to pH 9–10 with saturated sodium carbonate solution and extracted with EtOAc (100 mL). The aqueous phase was lyophilized to give a residue, which was purified by flash reversed-phase C18 column chromatography (2–20% MeOH / H₂O) to give a residue, which was purified by prep-HPLC to give (2R,3R)-3-(4- (dimethylamino)phenyl)tetrahydrofuran-2-carboxylic acid (INT-41) (50 mg, 0.21 mmol) as a white solid. The residue was purified again by prep-HPLC to give (2R,3R)-3-(4- (dimethylamino)phenyl)tetrahydrofuran-2-carboxylic acid (INT-41) (22.70 mg) as a white solid. LCMS: m / z (ESI) [M-H]+236.1 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (s, 1H), 7.07-7.02 (m, 2H), 6.66-6.59 (m, 2H), 4.43 (d, J = 8.0 Hz, 1H), 4.20-4.12 (m, 1H), 3.85 (q, J = 7.6 Hz, 1H), 3.56 (q, J = 8.0 Hz, 1H), 2.84 (s, 6H), 2.28-2.12 (m, 2H) Example 1. Synthesis of Compound 113a:

[0076] Step 1. To a stirred solution of (2S)-N-((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)- 5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide (INT-6) (30 mg, 0.030 mmol) and (2R,3R)-3-(4-((tert- butoxycarbonyl)amino)phenyl)tetrahydrofuran-2-carboxylic acid (INT-40) (14 mg, 0.045 mmol) in DMF (0.5 mL) at 0 °C was added a solution of DIPEA (0.052 mL, 0.30 mmol) and HATU (23 mg, 0.060 mmol) in DMF (0.5 mL) dropwise. The mixture was stirred at 0 °C for 2 hours. The mixture was warmed to room temperature and stirred for 16 hours. The residue was diluted with H2O (5 mL) and was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by silica gel chromatography using 0-8% MeOH in CH2Cl2 / CH2Cl2to give tert-butyl (4-((2R,3R)-2- (((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin- 3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro- 11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3- methyl-1-oxobutan-2-yl)(methyl)carbamoyl)tetrahydrofuran-3-yl)phenyl)carbamate (INT-7) (35 mg, 0.027 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+ / 2649.3, tR= 2.13 minutes (Method C) Step 2. To a stirred solution of tert-butyl (4-((2R,3R)-2-(((2S)-1-(((63S,4S)-11-ethyl- 12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2- yl)(methyl)carbamoyl)tetrahydrofuran-3-yl)phenyl)carbamate (INT-7) (33 mg, 0.025 mmol) in CH2Cl2(0.5 mL) at 0 °C was added TFA (0.12 mL, 1.5 mmol). The mixture was stirred at 0 °C for 0.5 hours then warmed to room temperature. The resulting mixture was stirred for an additional 0.5 hours. The reaction mixture was concentrated under reduced pressure to give (2R,3R)-3-(4-aminophenyl)-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N-methyltetrahydrofuran- 2-carboxamide (INT-8) as crude residue (33 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1197.7, tR= 2.28 minutes (Method C) Step 3. To a stirred solution of (2R,3R)-3-(4-aminophenyl)-N-((2S)-1-(((63S,4S)-11- ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl- 5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)- N-methyltetrahydrofuran-2-carboxamide (INT-8) (30 mg, 0.025 mmol) in DMF (0.3 mL) at room temperature was added solid CsF (23 mg, 0.15 mmol). The reaction was stirred at room temperature for 1 hour. At this time, an additional aliquot of CsF (46 mg, 0.3 mmol) was added in one portion. After stirring for an additional 1 hour at room temperature, the reaction was diluted with water (5 mL) and was extracted with EtOAc (2 × 5 mL) followed by a mixture of 1:3 iPrOH / CHCl3(1 × 10 mL). The combined organic extracts were washed with brine (1 × 5 mL) and water (1 × 5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give a crude solid. The crude material was purified by reverse phase chromatography on C-18 column using MeCN / 0.1 M ammonium carbonate to give Compound 113a (12 mg) as a white solid. An additional purification by prep HPLC using MeCN / 0.1 M ammonium carbonate was completed to isolated Compound 113a (5 mg, 5.1 mmol) as a white solid. LCMS: m / z (ESI) [M+2H]+1041.1, tR= 1.59 minutes (Method C) 1H NMR (400 MHz, DMSO-d6): δ 8.51 – 8.42 (m, 1H), 7.89 (s, 1H), 7.78 – 7.69 (m, 1H), 7.64 – 7.48 (m, 2H), 7.31 – 7.20 (m, 2H), 6.99 (s, 1H), 6.96 – 6.89 (m, 2H), 6.58 (s, 1H), 6.45 – 6.38 (m, 2H), 5.38 – 5.30 (m, 1H), 5.25 – 5.16 (m, 1H), 5.04 – 4.97 (m, 1H), 4.84 (s, 2H), 4.36 – 4.29 (m, 1H), 4.28 – 4.19 (m, 3H), 4.14 – 4.04 (m, 2H), 3.88 – 3.73 (m, 2H), 3.68 – 3.59 (m, 1H), 3.59 – 3.51 (m, 1H), 3.28 – 3.22 (m, 3H), 3.09 (s, 3H), 2.82 – 2.59 (m, 10H), 2.48 – 2.41 (m, 4H), 2.28 – 2.18 (m, 5H), 2.05 – 1.43 (m, 4H), 1.40 – 1.29 (m, 3H), 1.23 (s, 1H), 1.03 – 0.94 (m, 3H), 0.79 (s, 3H), 0.73 – 0.69 (m, 4H), 0.51 (s, 3H), 0.19 – 0.07 (m, 3H) Example 2. Synthesis of Compound 109a: Step 1. To a stirred solution of (2S)-N-((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)- 5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide (INT-6) (50 mg, 0.050 mmol) in DMF (0.5 mL) at 0 °C was added a solution of (2R,3R)-3-(4- (dimethylamino)phenyl)tetrahydrofuran-2-carboxylic acid (INT-41) (14 mg, 0,060 mmol), HATU (28 mg, 0.074 mmol), and DIPEA (0.086 mL, 0.50 mmol). The mixture was stirred at 0 °C for 2 hours and warmed to room temperature. The resulting mixture was stirred for 16 hours. The reaction mixture was quenched with ice water, which resulted in the precipitation of a solid. The solid was isolated by filtration and was washed with hexane and dried in vacuo to provide (2R,3R)-3-(4-(dimethylamino)phenyl)-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)-N- methyltetrahydrofuran-2-carboxamide (INT-9) (48 mg, 0.039 mmol) as an off white solid. LCMS: m / z (ESI) [M+H]+ / 2613.3, tR= 2.22 minutes (Method B) Step 2. To a stirred solution of (2R,3R)-3-(4-(dimethylamino)phenyl)-N-((2S)-1- (((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-methylpiperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl- 1-oxobutan-2-yl)-N-methyltetrahydrofuran-2-carboxamide (INT-9) (48 mg, 0.039 mmol) in THF (0.5 mL) at 0 °C was added a 1 M solution of TBAF in THF (0.047 mL, 0.039 mmol). The reaction mixture was stirred at 0 °C for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride (aq) causing a solid precipitate to form. The solid was filtered and the filtrate was concentrated and purified by reverse phase chromatography on a C-18 column using MeOH / 0.1 M ammonium carbonate to give Compound 109a (12 mg) as a white solid, which was purified again by prep HPLC using MeOH / 0.1 M ammonium carbonate to give Compound 109a (6 mg, 5.6 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1068.9, tR= 1.78 minutes (Method C) 1H NMR (400 MHz, CDCl3): δ 8.48 (d, 1H), 8.16 (s, 1H), 8.08 – 8.01 (m, 1H), 7.72 – 7.61 (m, 1H), 7.43 – 7.35 (m, 1H), 7.23 – 7.12 (m, 4H), 7.10 – 7.01 (m, 1H), 6.67 – 6.63 (m, 2H), 6.62 – 6.55 (m, 2H), 5.62 – 5.52 (m, 1H), 5.20 – 5.12 (m, 1H), 4.70 – 4.62 (m, 1H), 4.63 – 4.52 (m, 1H), 4.40 – 4.33 (m, 1H), 4.31 – 4.23 (m, 2H), 4.21 – 4.14 (m, 2H), 4.08 – 4.01 (m, 2H), 3.97 – 3.89 (m, 1H), 3.80 – 3.70 (m, 2H), 3.47 – 3.33 (m, 7H), 3.07 – 2.95 (m, 2H), 2.88 (s, 7H), 2.83 – 2.78 (m, 2H), 2.77 – 2.72 (m, 2H), 2.65 (s, 1H), 2.60 (s, 3H), 2.50 (s, 2H), 2.38 – 2.32 (m, 1H), 2.20 – 2.11 (m, 1H), 1.99 – 1.90 (m, 2H), 1.44 – 1.41 (m, 3H), 1.25 (s, 3H), 1.10 – 1.05 (m, 1H), 1.00 – 0.93 (m, 3H), 0.92 – 0.87 (m, 3H), 0.80 – 0.76 (m, 3H), 0.46 (s, 3H), 0.08 – 0.03 (m, 4H) Example 3. Synthesis of Compound 110a: Step 1. A suspension of tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5- (piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (INT-2) (200 mg, 0.204 mmol), 4-((5- bromopyrimidin-2-yl)methyl)morpholine (63 mg, 0.245 mmol), Pd2dba3 (19 mg, 0.0204 mmol), BINAP (25 mg, 0.0408 mmol), and cesium carbonate (100 mg, 0.306 mmol) in toluene (2.6 mL) was degassed and refilled with argon (× 3). The sealed reaction mixture was stirred and heated to 80 °C for 26 hours. The reaction mixture was cooled to room temperature, poured into water (5 mL) and extracted with CH2Cl2(3 × 15 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated to give a crude residue. The crude material was purified by silica gel column chromatography using 10% MeOH in CH2Cl2 / CH2Cl2to give tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5- (4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (INT-10) (108 mg, 0.084 mmol) as an off-white solid. LCMS: m / z (ESI) [M+H]+1158.8, tR= 2.31 minutes (Method D) Step 2. To a stirred solution of tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (INT-10) (103 mg, 0.080 mmol) in CH2Cl2 (6.2 mL) at 0 °C was added TFA (0.43 mL, 5.6 mmol).The reaction mixture was warmed to room temperature and stirred for an additional 1.5 hours. The reaction mixture was concentrated under reduced pressure to give (63S,4S)-4-amino-11- ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro- 11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-5,7-dione (INT-11) as crude material (93 mg) as a yellow solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1057.8, tR= 1.54 minutes (Method C) Step 3. To a stirred solution of (63S,4S)-4-amino-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-5,7-dione (INT-11) (93 mg, 0.080 mmol) and N-(tert-butoxycarbonyl)-N-methyl-L-valine (INT-35) (39 mg, 0.17 mmol) in DMF (2.8 mL) at 0 °C was added DIPEA (0.14 mL, 0.80 mmol) and COMU (41 mg, 0.097 mmol). The reaction mixture was stirred at 0 °C for 0.5 hours. At this time, an additional aliquot of N- (tert-butoxycarbonyl)-N-methyl-L-valine (7.4 mg, 0.032 mmol), DIPEA (0.028 mL, 0.16 mmol), and COMU (9 mg, 0.020 mmol) was added. The mixture was stirred at 0 °C for an additional 0.5 hours. The residue was diluted with H2O and was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by silica gel chromatography using 10% MeOH in CH2Cl2 / CH2Cl2to provide tert- butyl ((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-(2- (morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2- yl)(methyl)carbamate (INT-12) (88 mg, 0.066 mmol) as a yellow solid. LCMS: m / z (ESI) [M+H]+ / 2636.5, tR= 2.19 minutes (Method B) Step 4. To a stirred solution of tert-butyl ((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl- 1-oxobutan-2-yl)(methyl)carbamate (INT-12) (70 mg, 0.055 mmol) in CH2Cl2(4.2 mL) at 0 °C was added TFA (0.29 mL, 3.9 mmol). The reaction mixture was warmed to room temperature and stirred for an additional 2 hours. The reaction mixture was concentrated under reduced pressure to give (2S)-N-((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-(2- (morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide (INT-13) as crude material (70 mg) as a yellow solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1171.8, tR= 1.75 minutes (Method B) Step 5. To a stirred solution of (2S)-N-((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)- 5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)-3-methyl-2- (methylamino)butanamide (INT-13) (50 mg, 0.050 mmol) and (2R,3R)-3- phenyltetrahydrofuran-2-carboxylic acid (INT-38) (13 mg, 0.066 mmol) in DMF (0.8 mL) at 0 °C was added HATU (31 mg, 0.083 mmol) and DIPEA (0.096 mL, 0.55 mmol). The mixture was stirred at 0 °C for 2 hours, warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water (5 mL) and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with saturated aqueous NaHCO3(10 mL), brine (10 mL), dried over sodium sulfate, filtered, and concentrated to give the crude reaction residue. This residue was combined with another of the same reactions using (2S)-N- ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(4-(2-(morpholinomethyl)pyrimidin-5- yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide (INT-13) (15 mg, 0.012 mmol) and (2R,3R)-3-phenyltetrahydrofuran-2-carboxylic acid (2.7 mg, 0.014 mmol) and the mixture was purified by silica gel chromatography using 10% MeOH in CH2Cl2 / CH2Cl2to give (2R,3R)-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)- 5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)- N-methyl-3-phenyltetrahydrofuran-2-carboxamide (INT-14) (60 mg, 0.043 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+ / 2673.5, tR= 1.98 minutes (Method B) Step 6. To a stirred solution of (2R,3R)-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(4-(2-(morpholinomethyl)pyrimidin-5-yl)piperazin-1-yl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl- 1-oxobutan-2-yl)-N-methyl-3-phenyltetrahydrofuran-2-carboxamide (INT-14) (55 mg, 0.039 mmol) in DMF (1.5 mL) at room temperature was added solid CsF (36 mg, 0.24 mmol). The reaction was stirred at room temperature for 2 hours. At this time, the reaction was diluted with water (5 mL) and was extracted with EtOAc (2 x 5 mL). The combined organic extracts were washed with brine (1 x 5 mL) and water (1 x 5 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give a crude solid. The crude material was purified by prep HPLC using MeOH / 0.1 M ammonium carbonate to give Compound 110a (27 mg, 0.022 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1186.9, tR= 1.71 minutes (Method C) 1H NMR (400 MHz, CDCl3): δ 8.59 – 8.51 (m, 1H), 8.41 (s, 2H), 8.09 – 8.02 (m, 2H), 7.72 – 7.65 (m, 1H), 7.44 – 7.39 (m, 1H), 7.32 – 7.29 (m, 3H), 7.22 – 7.20 (m, 1H), 7.16 (s, 1H), 7.12 – 7.09 (m, 1H), 6.63 – 6.58 (m, 1H), 6.56 – 6.50 (m, 1H), 5.62 – 5.55 (m, 1H), 5.27 – 5.17 (m, 1H), 4.75 – 4.65 (m, 1H), 4.63 – 4.53 (m, 1H), 4.36 – 4.27 (m, 2H), 4.25 – 4.13 (m, 2H), 4.10 – 3.98 (m, 3H), 3.96 – 3.89 (m, 1H), 3.85 – 3.79 (m, 1H), 3.78 – 3.74 (m, 6H), 3.43 (s, 8H), 3.36 (s, 3H), 3.07 – 2.99 (m, 1H), 2.94 – 2.87 (m, 1H), 2.85 – 2.76 (m, 2H), 2.74 – 2.66 (m, 1H), 2.62 (s, 3H), 2.58 – 2.55 (m, 4H), 2.53 – 2.47 (m, 1H), 2.46 – 2.39 (m, 1H), 2.21 – 2.12 (m, 1H), 2.02 – 1.73 (m, 4H), 1.51 – 1.43 (m, 4H), 1.35 – 1.23 (m, 1H), 1.04 – 0.93 (m, 4H), 0.90 (s, 3H), 0.81 – 0.74 (m, 3H), 0.48 (s, 3H), 0.09 – -0.05 (m, 3H) Example 4. Synthesis of Compound 131a: Step 1. To a solution of (R)-5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)- 1H-indol-2-yl)-6-((S)-1-methoxyethyl)nicotinic acid (INT-26) (1.00 g, 2.04 mmol), benzyl (R)-2-((methylamino)methyl)morpholine-4-carboxylate (INT-27) (648 mg, 2.45 mmol) and HATU (2.33 g, 6.13 mmol) in DMF (12 mL) was added DIPEA (1.78 mL, 10.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was added to H2O (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude residue. The residue was purified with flash chromatography on silica gel eluting with 0–98% EtOAc / petroleum ether to give benzyl (R)-2-((5-(5-bromo-1- ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)-N- methylnicotinamido)methyl)morpholine-4-carboxylate (INT-28) (695 mg, 0.945 mmol) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.75 (d, 1H), 7.96-7.81 (m, 2H), 7.54-7.45 (m, 1H), 7.38-7.23 (m, 6H), 5.12-5.05 (m, 2H), 4.52 (t, 1H), 4.16-4.01 (m, 2H), 3.92-3.58 (m, 6H), 3.49- 3.36 (m, 2H), 3.12-2.92 (m, 6H), 2.89-2.79 (m, 4H), 2.66 (d, 1H), 2.23-2.11 (m, 1H), 1.41 (d, J = 5.6 Hz, 3H), 1.12-1.02 (m, 3H), 0.63-0.53 (m, 6H) Step 2. To a solution of benzyl (R)-2-((5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-1H-indol-2-yl)-6-((S)-1-methoxyethyl)-N- methylnicotinamido)methyl)morpholine-4-carboxylate (INT-28) (125 mg, 0.170 mmol) and methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3- carboxylate (INT-29) (146 mg, 0.212 mmol) in dioxane (1.6 mL), and H2O (0.4 mL) was added sodium carbonate (54 mg, 0.510 mmol) and Pd(dtbpf)Cl2(33 mg, 0.051 mmol). The mixture was stirred at 85 °C for 2 hours under Ar. The reaction was cooled to room temperature and was partitioned between EtOAc and water. The organic layer was removed, and aqueous layer was extracted with additional EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified with silicagel chromatography eluting with 0-20% MeOH / CH2Cl2 to provide benzyl (R)-2-((5-(5-(3-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-(methoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-3- oxopropyl)-5-((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H- indol-2-yl)-6-((S)-1-methoxyethyl)-N-methylnicotinamido)methyl)morpholine-4-carboxylate (INT-30) (130 mg, 0.107 mmol) as a solid. LCMS: m / z (ESI) [M – Boc + H]+1119.7, tR= 2.36 minutes (Method C) Step 3. To a stirred solution of benzyl (R)-2-((5-(5-(3-((S)-2-((tert- butoxycarbonyl)amino)-3-((S)-3-(methoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-3- oxopropyl)-5-((triisopropylsilyl)oxy)phenyl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H- indol-2-yl)-6-((S)-1-methoxyethyl)-N-methylnicotinamido)methyl)morpholine-4-carboxylate (INT-30) (240 mg, 0.197 mmol) in DCE (15 mL) was added solid Me3SnOH (267 mg, 1.48 mmol). The resulting mixture was stirred at 65 °C for 20 hours. The reaction mixture was cooled to room temperature and was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude material was dissolved in water and the pH was adjusted to pH = ~4 using 1 M HCl (aq). The aqueous layer was extracted with CH2Cl2(3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to provide (S)-1-((S)-3-(3-(2-(5-((((R)-4- ((benzyloxy)carbonyl)morpholin-2-yl)methyl)(methyl)carbamoyl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (INT-31) (323 mg) as a light brown solid that was used without further purification. LCMS: m / z (ESI) [M – Boc + H]+1105.9, tR= 1.82 minutes (Method C) Step 4. To a stirred solution of crude (S)-1-((S)-3-(3-(2-(5-((((R)-4- ((benzyloxy)carbonyl)morpholin-2-yl)methyl)(methyl)carbamoyl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (INT-31) (323 mg) in CH2Cl2(13 mL) at 0 °C was added EDC•Cl (1.62 g, 8.47 mmol), HOBt (201 mg, 1.31 mmol), and DIPEA (1.87 mL, 10.7 mmol). The reaction mixture was gradually warmed to room temperature and was stirred for 16 hours. The reaction mixture was partitioned between CH2Cl2and water, followed by removal of the organic layer. The aqueous layer was extracted with additional CH2Cl2. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to provide the crude material. The crude residue was purified by silica gel chromatography eluting with 0-20% MeOH / CH2Cl2to give benzyl (2R)- 2-((5-((63S,4S)-4-((tert-butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)-N- methylnicotinamido)methyl)morpholine-4-carboxylate (INT-32) (145 mg, 0.122 mmol) as a solid. LCMS: m / z (ESI) [M+H]+1187.9, tR= 2.43 minutes (Method C) Step 5. To a stirred solution of benzyl (2R)-2-((5-((63S,4S)-4-((tert- butoxycarbonyl)amino)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)-N- methylnicotinamido)methyl)morpholine-4-carboxylate (INT-32) (145 mg, 0.122 mmol) and paraformaldehyde (37 mg, 1.22 mmol) in MeOH (5 mL) under an Ar atmosphere was added 20 wt% Pd(OH)2on carbon (86 mg, 0.122 mmol). The resulting suspension was bubbled with Ar gas for 10 minutes, followed by H2for an additional 10 minutes. The sealed reaction mixturewas stirred under H2 at room temperature for 20 hours. The reaction suspension was filteredand washed with additional MeOH (3 x 20 mL). The filtrate was concentrated and was purified with silica gel chromatography eluting with 0–20% MeOH / CH2Cl2to give tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(methyl(((S)-4-methylmorpholin-2- yl)methyl)carbamoyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)carbamate (INT-33) (95 mg, 0.089 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1067.9, tR= 2.37 minutes (Method C) Step 6. To a stirred solution of tert-butyl ((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(methyl(((S)-4-methylmorpholin-2-yl)methyl)carbamoyl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (INT- 33) (95 mg) in CH2Cl2(5.7 mL) at 0 °C was added TFA (0.480 mL, 6.20 mmol). The stirred reaction mixture was gradually warmed to room temperature over 1 hour. At this time, the reaction mixture was concentrated under reduced pressure to provide 5-((63S,4S)-4-amino-11- ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro- 11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)- 1-methoxyethyl)-N-methyl-N-(((S)-4-methylmorpholin-2-yl)methyl)nicotinamide (INT-34) (120 mg) as a pale yellow oil that was used without further purification. LCMS: m / z (ESI) [M+H]+967.8, tR= 2.13 minutes (Method C) Step 7. To a stirred solution of crude 5-((63S,4S)-4-amino-11-ethyl-10,10-dimethyl- 5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)-N- methyl-N-(((S)-4-methylmorpholin-2-yl)methyl)nicotinamide (INT-34) (120 mg) and N-(tert- butoxycarbonyl)-N-methyl-L-valine (INT-35) (58 mg, 0.250 mmol) in DMF (3.6 mL) at 0 °C was added DIPEA (0.208 mL, 1.19 mmol), and COMU (61 mg, 0.143 mmol). The mixture was stirred at 0 °C for 1 hour. The residue was diluted with H2O (50 mL) and was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. The residue was purified by flash silica gel chromatography eluting with 0-20% MeOH / CH2Cl2to give tert-butyl ((2S)-1- (((63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(methyl(((S)-4-methylmorpholin-2- yl)methyl)carbamoyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)- benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamate (INT- 36) (115 mg, 0.098 mmol) as a solid. LCMS: m / z (ESI) [M+H]+1180.1, tR= 2.47 minutes (Method C) Step 8. To a stirred solution of tert-butyl ((2S)-1-(((63S,4S)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(methyl(((S)-4-methylmorpholin-2-yl)methyl)carbamoyl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl- 1-oxobutan-2-yl)(methyl)carbamate (INT-36) (90 mg, 0.076 mmol) in CH2Cl2(5.4 mL) at 0°C was added TFA (0.41 mL, 5.30 mmol). The stirred reaction mixture was gradually warmed to room temperature over 2 hours. At this time, the reaction mixture was concentrated under reduced pressure to provide 5-((63S,4S)-11-ethyl-10,10-dimethyl-4-((S)-3-methyl-2- (methylamino)butanamido)-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66- hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-12- yl)-6-((S)-1-methoxyethyl)-N-methyl-N-(((S)-4-methylmorpholin-2-yl)methyl)nicotinamide (INT-37) (115 mg) as a pale yellow oil that was used without further purification. LCMS: m / z (ESI) [M+2H]+1081.7, tR = 2.27 minutes (Method C) Step 9. To a stirred solution of 5-((63S,4S)-11-ethyl-10,10-dimethyl-4-((S)-3-methyl- 2-(methylamino)butanamido)-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66- hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-12- yl)-6-((S)-1-methoxyethyl)-N-methyl-N-(((S)-4-methylmorpholin-2-yl)methyl)nicotinamide (INT-37) (115 mg) and (2R,3R)-3-phenyltetrahydrofuran-2-carboxylic acid (INT-38) (29 mg, 0.149 mmol) in DMF (3.5 mL) at 0 °C was added HATU (65 mg, 0.170 mmol) and DIPEA (0.186 mL, 1.07 mmol). The stirred reaction mixture was gradually warmed to room temperature and was left to stir for an additional 20 hours. The reaction mixture was diluted with diluted with EtOAc and washed with saturated aqueous NaHCO3. After removal of the organic extracts, the aqueous layer was extracted with additional EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and evaporated to give the crude residue. The crude material was purified by silica gel chromatography eluting with 0-15% MeOH in CH2Cl2to provide 5-((63S,4S)-11-ethyl-10,10- dimethyl-4-((S)-3-methyl-2-((2R,3R)-N-methyl-3-phenyltetrahydrofuran-2- carboxamido)butanamido)-5,7-dioxo-25-((triisopropylsilyl)oxy)-61,62,63,64,65,66- hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-12- yl)-6-((S)-1-methoxyethyl)-N-methyl-N-(((S)-4-methylmorpholin-2-yl)methyl)nicotinamide (INT-39) (93 mg, 0.074 mmol) as a solid. LCMS: m / z (ESI) [M / 2+H]+627.6, tR= 2.37 minutes (Method C) Step 10. To a stirred solution of 5-((63S,4S)-11-ethyl-10,10-dimethyl-4-((S)-3-methyl- 2-((2R,3R)-N-methyl-3-phenyltetrahydrofuran-2-carboxamido)butanamido)-5,7-dioxo-25- ((triisopropylsilyl)oxy)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-12-yl)-6-((S)-1-methoxyethyl)-N-methyl-N- (((S)-4-methylmorpholin-2-yl)methyl)nicotinamide (INT-39) (70 mg, 0.056 mmol) in DMF (2.1 mL) at room temperature was added solid CsF (51 mg, 0.34 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was partitioned between EtOAc and saturated aqueous NaHCO3. Following removal of the organic layer, the aqueous layer was extracted with additional EtOAc (3 x 5 mL). The combined organic extracts were washed with brine and evaporated under reduced pressure. The crude material was purified by prep reverse- phase column chromatography using MeOH / 10 mM ammonium carbonate to give Compound 131a (35 mg, 0.032 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1097.5, tR= 1.65 minutes (Method C) 1H NMR (400 MHz, CDCl3): δ 8.90 – 8.82 (m, 1H), 8.07 – 8.01 (m, 2H), 7.76 – 7.63 (m, 2H), 7.48 – 7.36 (m, 1H), 7.32 – 7.27 (m, 4H), 7.23 – 7.17 (m, 2H), 7.16 – 7.13 (m, 1H), 6.61 – 6.58 (m, 1H), 6.56 – 6.51 (m, 1H), 5.60 – 5.54 (m, 1H), 5.23 – 5.17 (m, 1H), 4.71 – 4.65 (m, 1H), 4.61 – 4.53 (m, 1H), 4.44 – 4.36 (m, 1H), 4.34 – 4.27 (m, 1H), 4.26 – 4.15 (m, 3H), 4.09 – 3.96 (m, 2H), 3.94 – 3.69 (m, 5H), 3.69 – 3.47 (m, 1H), 3.39 (s, 3H), 3.21 – 2.95 (m, 4H), 2.92 – 2.56 (m, 8H), 2.55 – 2.36 (m, 2H), 2.31 – 1.99 (m, 4H), 1.97 – 1.84 (m, 3H), 1.82 – 1.75 (m, 1H), 1.54 – 1.42 (m, 3H), 1.32 – 1.22 (m, 1H), 1.06 – 0.85 (m, 7H), 0.79 – 0.73 (m, 3H), 0.53 – 0.42 (m, 3H), 0.06 – -0.05 (m, 3H) The following examples were synthesized in a similar manner as described above:

[0077] Example B1. In Vitro Proliferation Assay Cell lines (see Table B1) are purchased from ATCC or JCRB and cultured in the manufacturer’s recommended cell culture conditions. All cells are maintained in a cell culture incubator at 37°C with 5% CO2. Cells are maintained at recommended subculturing conditions for optimal cell growth prior to in vitro testing. Cells are harvested with 0.05% Trypsin-EDTA. The cell count and viability is assessed with a Vi-CELL BLU cell counter and cell viability analyzer. Cells are plated in 384-well TC- treated microplates (Corning®, 3765) at 1,000 cells per well in 45 μL of subculturing media. Plates are incubated overnight at 37°C with 5% CO2to allow for cell attachment. The following day, serial dilutions of drug treatments are prepared and added to the cell assay plates at a final concentration range of 0.003 – 250 nM and a final volume of 50 μL per well. Each compound and dosing concentration is tested in quadruplicates. Plates are incubated for 120 hours at 37°C with 5% CO2. At the time of dosing, an untreated assay plate is measured to record an initial value of cell viability. The CellTiter-Glo® Luminescent Cell Viability Assay (Promega, G7571) is used to lyse the cells and record the luminescent signal that is proportional to the total amount of ATP present, therefore measuring metabolic activity. For this measurement, 25 μL of CellTiter- Glo® Reagent is added to each well and plates are incubated at room temperature for 10 minutes. The luminescent signal is measured with the PHERAstar FSX Microplate Reader and the average RLU (Relative Light Unit) is recorded for day 0 in order to calculate growth inhibition. After the plates are incubated for 120 hours, cell viability is assessed with the CellTiter- Glo® Luminescent Cell Viability Assay. At this time, 25 μL of CellTiter-Glo® Reagent is added to each well and plates are incubated at room temperature for 10 minutes. The luminescent signal is measured with the PHERAstar FSX Microplate Reader and the Relative Light Units (RLUs) for the treated conditions are recorded. To evaluate growth inhibition, RLUs from wells containing treated cells are normalized to the RLUs of the wells containing untreated cells at 120 hours and also to the RLUs of the wells at the day of dosing. The data is analyzed using GraphPad PRISM version 10.1.2 or Genedata Screener software. Graphs are generated and a four-parameter dose-response curvemodel is applied to the data. GIC50s are extrapolated from the generated curves.Table B1. Example B2. In Vitro p-ERK HTRF Assay Cell lines (see Table B2) are purchased from ATCC or JCRB and cultured in the manufacturer’s recommended cell culture conditions. All cells are cultured in an incubator at 37°C with 5% CO2. Cells are maintained at recommended subculturing conditions for optimal cell growth prior to in vitro testing. Cells are harvested with 0.05% Trypsin-EDTA. The cell count and viability are assessed with a Vi-CELL BLU cell counter and cell viability analyzer. Cells are then plated in 384-well TC-treated microplates (Corning®, 3765) at 15,000 cells per well in 45 μL of subculturing media. Plates are then incubated overnight at 37°C with 5% CO2to allow for cell attachment. The following day, serial dilutions of drug treatments are prepared and added to the cell assay plates at a final concentration range of 0.003 – 250 nM. and a final volume of 30 μL per well. Each compound and dosing concentration is tested in quadruplicates. Plates are incubated for a minimum of 4 hours at 37°C with 5% CO2. After incubation times, the levels of phosphorylated ERK are determined using the Revvity HTRF Human and Mouse Advanced phospho-ERK (Thr202 / Tyr204) Detection Kit (64AERPEG). Cell supernatant for treated and control wells is removed carefully by either aspirating or by flicking the plate. Supplemented 1X lysis buffer is prepared by diluting 4X lysis buffer, provided by the kit, 4-fold in distilled water and then diluting the blocking reagent stock, provided by the kit, 100-fold with the 1X lysis buffer. Immediately, 30 μL of 1X supplemented lysis buffer is added to the assay plate. Plates are incubated for at least 30 minutes at room temperature with shaking. After homogenization, 16 μL of cell lysates from the assay plates are transferred to a small volume 384-shallow well ProxiPlate (Revvity, 6008230). Next, working antibody solutions are prepared by diluting the Eu Cryptate-antibody and the d2-antibody 1:20 each with detection buffer, provided by the kit. Finally, 1 volume of Eu Cryptate-antibody solution and 1 volume of d2-antibody solution are combined to generate the working antibody mix. Next, 4 μL of working antibody mix is added to each well of the ProxiPlate containing cell lysates. Plates are then incubated for a duration of 4 – 24 hours at room temperature. The HTRF signal generated at emission 620 nm and 655 nm are measured on the PHERAstar FSX Microplate Reader. The HTRF ratio is calculated for each well following the manufacturer’s protocol. Treated cell replicates are normalized to untreated cell control wells and the resultant data is analyzed using GraphPad PRISM version 10.1.2 software. Graphs are generated and a four-parameter dose-response curve model is applied to the data and p-ERK EC50s are extrapolated from the generated curves. Table B2. Example B3. SPR Affinity Determination to CypA (“Binary Direct Binding Assay”): The binding affinity of compounds for cyclophilin A (CypA) is assessed by surface plasmon resonance (SPR) on a Biacore 8K instrument. AviTag-CypA (prepared internally at Treeline) is immobilized on a streptavidin sensor chip (Cytiva 29104992), and varying compound concentrations are flowed over the chip in assay buffer (20 mmol / L HEPES-NaOH pH 7.5, 150 mmol / L NaCl, 5 mmol / L MgCl2, 0.005% v / v Surfactant P20, 1 mM TCEP, 1 µM supplemented nucleotide, 2% v / v DMSO). The SPR sensograms are fit using either a steady- state affinity model or a 1:1binding (kinetic) model to assess the KD for CypA binding. Example B4. SPR Affinity Determination of Compound-Bound CypA to RAS proteins (“Ternary Direct Binding Assay”) The binding affinity of compound-bound CypA for the mutant oncogenic RAS proteins is assessed by SPR on a Biacore 8K instrument. AviTag-RAS [1–169] (prepared internally at Treeline) is immobilized on a streptavidin sensor chip (Cytiva 29104992), and varying compound concentrations are flowed over the chip in assay buffer (20 mmol / L HEPES-NaOH pH 7.5, 150 mmol / L NaCl, 5 mmol / L MgCl2, 0.005% v / v Surfactant P20, 1 mM TCEP, 1 µM supplemented nucleotide, 2% v / v DMSO, 25 μmol / L CypA). The SPR sensorgrams are fit using either a steady-state affinity model or a 1:1 binding (kinetic) model to assess the KD for RAS binding. Orthogonally, the binding affinity of compound-bound CypA for the mutant oncogenic RAS proteins is assessed by SPR on a Biacore 8K instrument. AviTag-CypA (prepared internally at Treeline) is immobilized on a streptavidin sensor chip (Cytiva 29104992), and A- B-A mode is utilized to first saturate AviTag-CypA with compound, and varying RAS protein concentrations are flowed over the chip in assay buffer (20 mmol / L HEPES-NaOH pH 7.5, 150 mmol / L NaCl, 5 mmol / L MgCl2, 0.005% v / v Surfactant P20, 1 mM TCEP, 1 µM supplemented nucleotide, 2% v / v DMSO). The SPR sensorgrams are fit using either a steady-state affinity model or a 1:1 binding (kinetic) model to assess the KD for RAS binding. Example B5. KRas-cRAF Protein-Protein Interaction (PPI) Assay Compounds are pre-dispensed using acoustic transfer technology into a black, low volume 384-well assay plate. A 10-point dose response of each compound is performed with a 30µM top dose. Biotinylated KRas protein (e.g., KRas G12R(1-169)) is loaded with GppNHp (i.e., GMPPNP) nucleotide and GST-cRAF(1-149) are diluted to 90 nM and 30 nM, respectively, in assay buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, and 0.005% CA680).5 µL of KRas protein is added to wells of a black, low-volume 384-well assay plate. The KRas-compound mixture is incubated for 30 minutes at room temperature.5 µL of GST- cRAF protein is added to the KRas-compound mixture and incubated for 30 minutes at room temperature. 100x stocks of Tb cryptate-labeled anti-GST antibody (Anti-GST-Tb) (Cisbio) and Streptavidin-XL655 (Cisbio) are used to make a 3x detection mixture in a total volume of 5 µL of assay buffer. The detection mixture is added to the assay wells and incubated an additional 1 hour at room temperature. Time resolved fluorescence is read on a PHERAstar plate reader equipped with a filter module with excitation = 337 nm and emission 1 = 620 nm, emission 2 = 665 nm. The TR-FRET signal is calculated as the ratio of fluorescence intensity [emission 665 nm] / [excitation 337 nm]. IC50values are calculated using a four-parameter, variable response sigmoidal dose response curve fit in PerkinElmer Signals VitroVivo. Example B6. KRas-cRAF Protein-Protein Interaction (PPI) Assay Compounds are pre-dispensed via Echo liquid handling (acoustic, touch-free) to generate assay ready plates (ARP). A 10-point dose response of each compound is performed with a 30µM top dose. Biotinylated KRas G12V (aa 1-169) loaded with GMPPNP nucleotide and Streptavidin-Europium (SA-EU, Columbia Biosciences) are preincubated in assay buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 mM DTT, 0.01% Brij-35, 0.3 mg / ml BSA) on ice for 30 min. Separately GST-tagged cRAF(1-149) and anti-GST-APC antibody (Columbia Biosciences) are preincubated in assay buffer on ice for 30 min. After incubation, 5 µL buffer and 5 µL of KRas G12V-SA-Eu are added to each well of the ARP. After a 30- minute equilibration phase at room temperature, 5 uL of GST-cRAF-anti-GST-APC is added to each well. The final concentrations in the assay are 10 nM KRas G12V, 10 nM cRAF. The reaction is allowed to proceed for 60-90 minutes after which the plate is read on a PHERAstar FSX plate reader (exc: 337 nm, em 1: 665 nm, em 2: 620 nm). After normalization of the raw data (ratio of Signal665nm / Signal620nm) the data is fit to a four-parameter logistic curve in GraphPad Prism (v9.4.1). Example B7. Computational Assessment of Compounds Binding affinity of compounds described herein was assessed with Free Energy Perturbation (FEP) computational methods. Principles and methods of conducting FEP have been described in e.g., Schindler et al. J. Chem. Inf. Model. 2020, 60, 11, 5457–5474; doi: 10.1021 / acs.jcim.0c00900. The crystal structure of a ternary complex of a ligand (selected from Table BC1) bound to cyclophilin A and KRas G12R was solved (see SEQ ID NO: 4). The crystal was obtained using the following method: purified human CypA and KRas G12R bound to GMPPNP were combined in a 2:1 CypA:KRas molar ratio in a buffer solution of HEPES (15mM, pH = 7.5), NaCl (75mM), and MgCl2(5 mM). Ligand was added for a final concentration of 100 µM KRas, 200 µM CypA, and 300 µM ligand in a total volume of 1 mL. The mixture was incubated for 1 hour on ice and then purified using a Superdex 7516 / 600 column. Fractions containing the complex were pooled and concentrated to 15 mg / mL, and then 150 nL was combined with 150 nL of reservoir solution [lithium sulfate (0.2 M); Tris HCl (0.1 M, pH = 7); and ammonium sulfate (2 M)] in a 96-well sitting drop plate and incubated at 20 °C. Crystals appeared after 2 days and were cryo-protected using the reservoir solution supplemented with 20% ethylene glycol prior to flash freezing in liquid nitrogen. Crystals were diffracted to high resolution (1.38Å), and data was processed using Global Phasing AutoPROC in the primitive monoclinic space group (p21) with a unit cell: 76.889 / 59.822 / 83.624Å 90.00 / 99.00 / 90.00°. Two copies of the CypA / KRas / ligand complex were present in the asymmetric unit. Refinement using the CCP4 program REFMAC5 produced a final R / Rfree of 0.177 / 0.199. The R12 residue of the crystal structure was subsequently computationally mutated to a cysteine and used as input for the model. The model was validated using 16 representative compounds and their associated activity (ability to disrupt B-Raf Ras-binding domain (BRAFrbd) interaction with K-Ras G12C (hereinafter FRET G12C)) from WO 2021 / 091956. Ligands were prepared with Ligprep and molecular docking was performed with Glide. Schrodinger Maestro release 2023-4 was used for this study (Table BC1). An in-house FEP implementation based on openMM (see Wade et al. J. Chem. Theory Comput. 2022, 18, 6, 3972–3987; DOI: 10.1021 / acs.jctc.2c00114) was used to assess the relative free energy of binding of all compounds. This training set was used to determine the accuracy of FEP predictions for compounds that bind to the cyclophilin A / KRas-G12C complex. As highlighted in Table BC1, our FEP model predicted IC50s for the representative compounds correlate with experimentally determined FRET G12C IC50 activity. Subsequently, the FRET G12C IC50 activity of the compounds described herein were predicted using the validated model (Table BC2). SEQ ID NO: 4 MTEYKLVVVG ARGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET CLLDILDTAG QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM Table BC1 Note: A: IC50≤ 0.01µM; B: 0.01 µM < IC50≤ 0.1 µM; C: 0.1 µM <IC50≤ 1 µM; D: 1 µM < IC50≤ 10 µM Table BC2

[0078] Note: A: IC50≤ 0.01µM; B: 0.01 µM < IC50≤ 0.1 µM; C: 0.1 µM <IC50≤ 1 µM; D: 1 µM < IC50≤ 10 µM Example B8. In Vitro Proliferation Assay Cell lines (see Table B8) were purchased from ATCC or JCRB and cultured in the manufacturer’s recommended cell culture conditions. All cells were maintained in a cell culture incubator at 37 °C with 5% CO2. Cells were maintained at recommended subculturing conditions for optimal cell growth prior to in vitro testing. Cells were harvested with 0.05% Trypsin-EDTA. The cell count and viability were assessed with a Vi-CELL BLU cell counter and cell viability analyzer. Cells were plated in 384-well TC-treated microplates (CORNING®, 3765) at 1,000 cells per well in 50 μL of subculturing media. Plates were incubated overnight at 37°C with 5% CO2to allow for cell attachment. The following day, serial dilutions of drug treatments were prepared and added to the cell assay plates at a final concentration range of 0.003 – 250 nM and a final volume of 50 μL per well. Each compound and dosing concentration was tested in quadruplicate. Plates were incubated for 120 hours at 37 °C with 5% CO2. At the time of dosing, an untreated assay plate was measured to record an initial value of cell viability. The CELLTITER-GLO® Luminescent Cell Viability Assay (Promega, G7571) was used to lyse the cells and record the luminescent signal that was proportional to the total amount of ATP present, therefore measuring metabolic activity. For this measurement, 25 μL of CELLTITER-GLO® Reagent was added to each well and plates were incubated at room temperature for 10 minutes. The luminescent signal was measured with the PHERAstar FSX Microplate Reader and the average RLU (Relative Light Unit) was recorded for day 0 in order to calculate growth inhibition. After the plates were incubated for 120 hours, cell viability was assessed with the CELLTITER-GLO® Luminescent Cell Viability Assay. At this time, 25 μL of CELLTITER- GLO® Reagent was added to each well and plates were incubated at room temperature for 10 minutes. The luminescent signal was measured with the PHERAstar FSX Microplate Reader and the Relative Light Units (RLUs) for the treated conditions and untreated control wells were recorded. To evaluate growth inhibition, RLUs from wells containing treated cells were normalized to the RLUs of the wells containing untreated cells at 120 hours and also to the RLUs of the wells at the day of dosing. The data was analyzed using GraphPad PRISM version 10.1.2 or Genedata Screener software. Graphs were generated and a four-parameter dose- response curve model was applied to the data. GI50values were determined from the generated curves. Data is presented in Table B8 as geometric means of multiple runs, if applicable.

[0079] Table B8. Notes: (1) "A": GI50< 1 nM; "B": 1 nM ≤ GI50< 10 nM; "C": 10 nM ≤ GI50< 100 nM; "D": 100 nM ≤ GI50< 1000 nM; "E": GI50≥ 1000 nM (2) ND = not determined (3) *: a GI50value could not be determined under the conditions of the assay Example B9. In Vitro p-ERK HTRF Assay Cell lines (see Table B9) were purchased from ATCC or JCRB and cultured in the manufacturer’s recommended cell culture conditions. All cells were cultured in an incubator at 37 °C with 5% CO2. Cells were maintained at recommended subculturing conditions for optimal cell growth prior to in vitro testing. Cells were harvested with 0.05% Trypsin-EDTA. The cell count and viability were assessed with a Vi-CELL BLU cell counter and cell viability analyzer. Cells were then plated in 384-well TC-treated microplates (CORNING®, 3765) at 15,000 cells per well in 50 μL of subculturing media. Plates were then incubated overnight at 37 °C with 5% CO2to allow for cell attachment. The following day, serial dilutions of drug treatments were prepared and added to the cell assay plates at a final concentration range of 0.003 – 250 nM. and a final volume of 50 μL per well. Each compound and dosing concentration was tested in quadruplicates. Plates were incubated for a minimum of 4 hours at 37 °C with 5% CO2. After incubation times, the levels of phosphorylated ERK were determined using the Revvity HTRF Human and Mouse Advanced phospho-ERK (Thr202 / Tyr204) Detection Kit (64AERPEG). Cell supernatant for treated and control wells was removed carefully by either aspirating or by flicking the plate. Supplemented 1X lysis buffer was prepared by diluting 4X lysis buffer, provided by the kit, 4-fold in distilled water and then diluting the blocking reagent stock, provided by the kit, 100-fold with the 1X lysis buffer. Immediately, 30 μL of 1X supplemented lysis buffer was added to the assay plate. Plates were incubated for at least 30 minutes at room temperature with shaking. After homogenization, 16 μL of cell lysates from the assay plates were transferred to a small volume 384-shallow well ProxiPlate (Revvity, 6008230). Next, working antibody solutions were prepared by diluting the Eu Cryptate- antibody and the d2-antibody 1:20 each with detection buffer, provided by the kit. Finally, 1 volume of Eu Cryptate-antibody solution and 1 volume of d2-antibody solution were combined to generate the working antibody mix. Next, 4 μL of working antibody mix was added to each well of the ProxiPlate containing cell lysates. Plates were then incubated for a duration of 4 – 24 hours at room temperature. The HTRF signal generated at emission 620 nm and 655 nm were measured on the PHERAstar FSX Microplate Reader. The HTRF ratio was calculated for each well following the manufacturer’s protocol. Treated cell replicates were normalized to untreated cell control wells and the resultant data was analyzed using GraphPad PRISM version 10.1.2 or Genedata Screener software. Graphs were generated and a four-parameter dose- response curve model was applied to the data and p-ERK IC50values were determined from the generated curves. Data is presented in Table B9 as geometric means of multiple runs, if applicable. Table B9.

[0080] Notes: "A": IC50< 10 nM; "B": 10 nM ≤ IC50< 100 nM; "C": 100 nM ≤ IC50< 1000 nM EXEMPLARY EMBODIMENTS P01 Embodiments Embodiment 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1is each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo; n is 1 or 2; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of: L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; and (c) phenylene optionally substituted with 1-3 Ra; (d) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; Z1is -N(R8)- or -O-; R8is -H or C1-3alkyl optionally substituted with 1-3 Rc; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and(k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy. Embodiment 2. A compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of: n is 1 or 2; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo; RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3 is C1-6alkyl;R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; and (c) phenylene optionally substituted with 1-3 Ra; (d) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl;(g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl); (i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of whi...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of:n is 1 or 2; each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy optionally substituted with 1-3 Rc; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; (i) -ORb1; and (j) halo;RNis -H or C1-3alkyl; each R21is independently selected from the group consisting of: (a) C1-3alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; RZis selected from the group consisting of: (a) C1-6alkyl optionally substituted with 1-3 Rc; (b) Rb1; and (c) -(C1-3alkylene)-Rb1; R3is C1-6alkyl; R4is selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 Rc; R5is selected from the group consisting of:and (ii) -L3-L4-R9; L1is selected from the group consisting of: (a) -C(=O)-; (b) -S(O)1-2-; (c) –C(=O)N(Rf)-*, wherein the * represents the point of attachment to L2; (d) phenylene optionally substituted with 1-3 Ra; and (e) 5-6 membered heteroarylene optionally substituted with 1-3 Ra; L2is a bond, -C(=O)-, or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra;R7is selected from the group consisting of: (a) -H; (b) -F; (c) C3-8cycloalkyl optionally substituted with 1-3 R17; (d) 4-8 membered heterocyclyl optionally substituted with 1-3 R17; (e) phenyl optionally substituted with 1-3 R17; and (f) 5-6 membered heteroaryl optionally substituted with 1-3 R17; each R17is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R6is an independently selected C1-3alkyl optionally substituted with 1-3 -F; L3is -C(=O)N(Rf)-*, -C(=O)O-*, -C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; L4is a bond or C1-3alkylene optionally substituted with 1-3 Rc; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; (b) –(C0-3alkylene)-S(O)2(C1-3alkyl); (c) –(C0-3 alkylene)-N(Rf)2;(d) C3-8cycloalkyl optionally substituted with 1-3 Ra; (e) 5-6 membered heteroaryl optionally substituted with 1-3 Ra; and (f) –(5-membered heteroarylene)-(C0-3alkylene)-(4-8 membered heterocyclyl), wherein the 4-8 membered heterocyclyl is optionally substituted with 1-3 Ra; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) -NRdRe; (e) -C(=O)C1-6alkyl; (f) -C(=O)OC1-6alkyl; (g) -C(=O)N(Rf)2; (h) -S(O)0-2(C1-6alkyl);(i) -S(O)1-2N(Rf)2; (j) C1-6alkyl optionally substituted with 1-6 Rc; and (k) C1-6alkoxy optionally substituted with 1-3 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and Rb1, wherein: b is 1 or 2; each Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(C1-3alkyl)-, -S(O)0-2-, -C(=O)-, and C1-3alkylene; and each Rb1is independently selected from the group consisting of: C3-8cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; each Rdand Reis independently selected from the group consisting of: -H, -C(=O)C1-6alkyl, -C(=O)OC1-6alkyl, -C(=O)N(Rf)2, -S(O)1-2(C1-6alkyl), -S(O)1-2(C1-6haloalkyl), -S(O)1-2N(Rf)2, and C1-6alkyl optionally substituted with 1-3 Rc; each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F; each Rgis independently selected from the group consisting of: Rhand C1-6alkyl optionally substituted with 1-3 Rc; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, - N(Rf)2, C1-6alkoxy, and C1-6haloalkoxy.

2. The compound of claim 1, wherein: L2is a bond or a straight-chain C1-4alkylene optionally substituted with 1-2 Ra; L3is -C(=O)N(Rf)-C(=O)-, -S(O)2N(Rf)-*, or -S(O)2-, wherein the * represents point of attachment to L4; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; (b) –(C0-3alkylene)-S(O)2(C1-3alkyl); and (c) –(C0-3alkylene)-N(Rf)2.

3. The compound of claim 1 or 2, wherein R1isand each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc; (h) Rb1; and (i) halo.

4. The compound of any one of claims 1-3, wherein n is 1.

5. The compound of any one of claims 1-4, wherein R1isand each R2is independently selected from the group consisting of: (a) -NH2; (b) -N(Rf)R21; (c) -N(Rf)C(=O)R21; (d) -OH; (e) C1-3alkoxy; (f) -CN; (g) C1-3alkyl optionally substituted with 1-3 Rc;(h) Rb1; and (i) halo.

6. The compound of any one of claims 1-5, wherein R2is -NH2or -N(Rf)R21.

7. The compound of any one of claims 1-6, wherein R2is -NH2.

8. The compound of claim 1 or 2, wherein R1is9. The compound of any one of claims 1-8, wherein RNis C1-3alkyl (e.g., methyl).

10. The compound of any one of claims 1-9, wherein RZis C1-6alkyl optionally substituted with 1-3 Rc.

11. The compound of any one of claims 1-10, wherein RZis C1-3alkyl.

12. The compound of any one of claims 1-11, wherein RZis isopropyl.

13. The compound of any one of claims 1-8, wherein RNis methyl; and RZis isopropyl.

14. The compound of any one of claims 1-13, wherein R5is15. The compound of claim 14, wherein L1is phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra.

16. The compound of claim 14 or 15, wherein L1is a phenylene optionally substituted with 1-2 Ra(e.g., L1is a phenylene).

17. The compound of claim 14 or 15, wherein L1is a 6-membered heteroarylene (e.g., pyrimidylene) optionally substituted with 1-2 Ra(e.g., L1is a 6-membered heteroarylene (e.g., pyrimidylene (e.g.,18. The compound of claim 14, wherein L1is –S(O)2–.

19. The compound of claim 14, wherein L1is -C(=O)–.

20. The compound of any one of claims 14-19, wherein L2is a straight-chain C1-4alkylene optionally substituted with 1-2 Ra.

21. The compound of any one of claims 14-20, wherein L2is -CH2- or -CH2CH2-.

22. The compound of any one of claims 14-19, wherein L2is a bond.

23. The compound of any one of claims 14-22, wherein R7is a 4-8 membered heterocyclyl optionally substituted with 1-3 R17.

24. The compound of any one of claims 14-23, wherein R7is a 4-8 membered heterocyclyl optionally substituted with 1-2 Ra.

25. The compound of any one of claims 14-24, wherein R7is a 4-8 membered heterocyclyl (e.g., morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, azetidinyl, thiomorpholinyldioxide (e.g.,optionally substituted with 1-2 substituents independently selected from the group consisting of: -F; -CN; -OH; -NRdRe; and C1-6alkyl optionally substituted with 1-6 Rc, wherein:Rdand Reare each independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 Rc; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F.

26. The compound of any one of claims 14-25, wherein R7is selected from the group consisting of:

27. The compound of any one of claims 14-26, wherein m is 0.

28. The compound of any one of claims 1-13, wherein R5is -L3-L4-R9.

29. The compound of any one of claims 1-13 or 28, wherein L3is -C(=O)N(Rf)-* (e.g., -C(=O)N(Me)-*).

30. The compound of any one of claims 1-13 or 28, wherein L3is -S(O)2N(Rf)-* (e.g., -S(O)2N(Rf)-).

31. The compound of any one of claims 1-13 or 29-30, wherein L4is C1-3alkylene optionally substituted with 1-3 Rc(e.g., L4is -CH2-).

32. The compound of any one of claims 1-13 or 29-30, wherein L4is a bond.

33. The compound of any one of claims 1-13 or 29-32, wherein R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substitutedwith 1-3 Rc.

34. The compound of any one of claims 1-13 or 29-33, R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 -F.

35. The compound of any one of claims 1-13 or 29-34, wherein R9is selected from the group consisting of:.

36. The compound of any one of claims 1-13 or 29-32, wherein R9is a C3-8cycloalkyl optionally substituted with 1-3 Ra.

37. The compound of any one of claims 1-13, 29-32, or 36, wherein R9is a C3-8cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc(e.g., R9is38. The compound of any one of claims 1-13 or 29-32, wherein R9is a 5-6 membered heteroaryl optionally substituted with 1-3 Ra.

39. The compound of any one of claims 1-13, 29-32, or 38, wherein R9is a 5- membered heteroaryl (e.g., pyrazolyl) optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc(e.g., R9is40. The compound of any one of claims 1-39, wherein R4is a C1-3alkyl optionally substituted with 1-3 Rc(e.g., C1-3alkyl substituted with C1-3alkoxy).

41. The compound of any one of claims 1-40, wherein R4is.

42. The compound of any one of claims 1-41, wherein R3is a C1-3alkyl.

43. The compound of any one of claims 1-42, wherein R3is ethyl.

44. The compound of claim 1, wherein the compound is a compound of Formula (II-a):or a pharmaceutically acceptable salt thereof, wherein: Rf1is Rf; L4is a bond or -CH2-; R9is selected from the group consisting of: (a) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc; (b) C3-8cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc; and (c) 5-membered heteroaryl (e.g., pyrazolyl) optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1- 3 alkyl optionally substituted with 1-3 Rc; R3is C1-3alkyl;R1iswherein: RZis C1-6alkyl optionally substituted with 1-3 Rc; RNis C1-3alkyl; R2is selected from the group consisting of: (a) -NH2; and (b) -N(Rf)R21; R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F.

45. The compound of claim 44, wherein L4is -CH2-; and R9is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: halo, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc.

46. The compound of claim 44 or 45, wherein each Rcis independently selected from the group consisting of: halo, -CN, -OH, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-3alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F.

47. The compound of any one of claims 44-46, wherein R9is selected from the group consisting of:

48. The compound of claim 44 or 46, wherein R9is a C3-8cycloalkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -OH, and C1-3alkyl optionally substituted with 1-3 Rc(e.g., R9is49. The compound of any one of claims 44-48, wherein Rf1is methyl.

50. The compound of claim 1, wherein the compound is a compound of Formula (II-b):or a pharmaceutically acceptable salt thereof, wherein: L1is –S(O)2– or -C(=O)–; R7is a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from the group consisting of: -F; -CN; -OH; -NRdRe; and C1-6alkyl optionally substituted with 1-6 Rc; R3is C1-3alkyl; R1iswherein: RZis C1-6alkyl optionally substituted with 1-3 Rc; RNis C1-3alkyl; R2is selected from the group consisting of: (a) -NH2; and(b) -N(Rf)R21; R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2; Rdand Reare each independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 Rc; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F.

51. The compound of claim 50, wherein R7is selected from the group consisting of:

52. The compound of claim 1, wherein the compound is a compound of Formula (II-c):or a pharmaceutically acceptable salt thereof, wherein: L1is phenylene or 6-membered heteroarylene;R7is a 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from the group consisting of: -F; -CN; -OH; -NRdRe; and C1-6alkyl optionally substituted with 1-6 Rc; R3is C1-3alkyl; R1is, wherein: RZis C1-6alkyl optionally substituted with 1-3 Rc; RNis C1-3alkyl; R2is selected from the group consisting of: (a) -NH2; and (b) -N(Rf)R21; R21is C1-3alkyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -OH, and -N(Rf)2; Rdand Reare each independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 Rc; each Rcis independently selected from the group consisting of: halo, -CN, -OH, C1-6alkoxy, C1-6haloalkoxy, and -N(Rf)2; and each Rfis independently selected from the group consisting of: -H and C1-6alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of -OH and -F.

53. The compound of claim 52, wherein L1is a 6-membered heteroarylene.

54. The compound of claim 52 or 53, wherein L1is.

55. The compound of any one of claims 52-54, wherein R7is56. The compound of any one of claims 44-55, wherein R1is.

57. The compound of claim 56, wherein R2is -NH2.

58. The compound of claim 56, wherein R2is -N(Rf)R21; and R21is C1-3alkyl.

59. The compound of any one of claims 44-55, wherein R1is.

60. The compound of any one of claims 44-59, wherein RZis isopropyl; and RNis methyl.

61. The compound of any one of claims 44-60, wherein R3is ethyl.

62. A compound selected from the group consisting of the compounds depicted in Table C1, or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition comprising a compound of any one of claims 1- 62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

64. A method for treating cancer in a subj ect in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-62, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63.

65. A method of treating cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a cancer having a Ras dysregulation a therapeutically effective amount of a compound of any one of claims 1-63 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 64.

66. A method of treating cancer in a subject, the method comprising:(a) determining that the cancer in the subject has a Ras dysregulation; and(b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63.

67. The method of any one of claims 65 or 66, wherein the Ras dysregulation is selected from a KRas dysregulation, a NRas dysregulation, and a HRas dysregulation.

68. The method of claim 67, wherein the KRas dysregulation is a KRas mutation.

69. The method of claim 68, wherein the KRas mutation is selected from the group consisting of: a KRas G12D mutation, a KRas G12R mutation, and a KRas G12V mutation.

70. The method of claim 67, wherein the NRas dysregulation is a NRas mutation.

71. The method of claim 70, wherein the NRas mutation is selected from the group consisting of: a NRas Q61K mutation, a NRas Q61L mutation, and a NRas Q61R mutation.

72. The method of claim 67, wherein the HRas dysregulation is a HRas mutation.

73. The method of claim 72, wherein the HRas mutation is selected from the group consisting of: a HRas Q61H mutation and a HRas Q61L mutation.

74. The method of claim 66, wherein the step of determining that the cancer in the subject has a Ras dysregulation includes performing an assay to detect the Ras dysregulation (e.g., a Ras mutation) in a tumor sample from the subject.

75. The method of any one of claims 64-74, wherein the cancer is selected from the group consisting of: a hematological cancer, a soft tissue cancer, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, urothelial cancer, uterine cancer, and a combination thereof.

76. The method of claim 75, wherein the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).

77. The method of claim 75, wherein the cancer is a skin cancer (e.g., cutaneous melanoma).

78. The method of claim 77, wherein the cutaneous melanoma is an unresectable or metastatic melanoma.

79. The method of any one of claims 77-78, wherein the subject has previously received one or more of combination checkpoint blockade (e.g., anti-PD-1 therapy combined with anti-LAG3 therapy or anti-CTLA4 therapy), anti-PD1 monotherapy, BRAF-targeted therapy (e.g., for a subject that has a cancer with a BRAF mutation) (e.g., a BRAF inhibitor combined with a MEK inhibitor, optionally also combined with anti-PD-1 therapy), or tumor infiltrating lymphocytes.

80. The method of any one of claims 64-79, comprising administering an additional therapy or therapeutic agent to the subject.

81. The method of claim 80, wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway targeted therapeutic agents, kinase-targetedtherapeutics, mTORCl inhibitors or degraders, YAP inhibitors or degraders, proteasome inhibitors or degraders, HSP90 inhibitors or degraders, famesyl transferase inhibitors or degraders, PTEN inhibitors or degraders, signal transduction pathway inhibitors or degraders, checkpoint inhibitors, modulators of the apoptosis pathway, chemotherapeutics, angiogenesis- targeted therapies, immune-targeted agents, radiotherapy, and combinations thereof.

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