Macrocyclic ras inhibitors

Abstract

This disclosure provides compounds of Formula ( I ) (e.g., Formula ( I-a )), ( II ), ( III ), or ( IV ), 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 ) (e.g., Formula ( I-a )), ( II ), ( III ), or ( IV ), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

Description

[0001] MACROCYCLIC RAS INHIBITORS

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application Serial Nos. 63 / 669,884, filed July 11, 2024; 63 / 669,911, filed July 11, 2024; 63 / 706,518, filed October 11, 2024; 63 / 737,086, filed December 20, 2024; 63 / 771,563, filed March 13, 2025; 63 / 773,307, filed March 17, 2025; 63 / 807,193, filed May 16, 2025; and 63 / 830,245, filed June 25, 2025, each of which is incorporated by reference it its entirety herein.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “TRLN-022-005W01 Sequence Listing. XML.” The XML file, created on June 30, 2025 and is 5 KB in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] This disclosure provides compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV) 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) (e.g., Formula (La)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0008] BACKGROUND

[0009] 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.

[0010] SUMMARY

[0011] This disclosure provides compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0012] Provided herein are compounds of Formula (I) or Formula (II): or pharmaceutically acceptable salts thereof, wherein: L1and L2are independently selected from the group consisting of: a bond, -O-, -N(Rf)- , and C1-3alkylene optionally substituted with 1-3 Rc; Ring E is selected from the group consisting of: phenylene and 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra; R5is a 4-10 membered heterocyclyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R15; Ring E2 is selected from the group consisting of: bicyclic or tricyclic 8-12 membered heterocyclyl and bicyclic or tricyclic 8-12 membered heteroaryl, each of which is optionally substituted with 1-3 R15; each R15is independently selected from the group consisting of Raand Rb; Ring D is selected from the group consisting of: , , wherein xx and yy represent the points of attachment to Ring D; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, and wherein aa represents the point of attachment to Z2, and Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc; Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc; R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; and -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc; each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl optionally substituted with 1-3 Rc; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)- Ri, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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), a NRas mutation (e.g., a NRas Q61H mutation, 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))); and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0013] 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 Q61H mutation, 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0014] 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.

[0015] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and from the claims.

[0016] DETAILED DESCRIPTION

[0017] This disclosure provides compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, selectively inhibit the GTP -bound (ON) state ofRas (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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.

[0018] 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 (SOS 1)). 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).

[0019] 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. WO2025 / 119392; WO2025 / 087431; 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 Formula (I) or Formula (II):

[0020] or pharmaceutically acceptable salts thereof, wherein: L1and L2are independently selected from the group consisting of: a bond, -O-, -N(Rf)- , and C1-3alkylene optionally substituted with 1-3 Rc; Ring E is selected from the group consisting of: phenylene and 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra; R5is a 4-10 membered heterocyclyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R15; Ring E2 is selected from the group consisting of: bicyclic or tricyclic 8-12 membered heterocyclyl and bicyclic or tricyclic 8-12 membered heteroaryl, each of which is optionally substituted with 1-3 R15; each R15is independently selected from the group consisting of Raand Rb; Ring D is selected from the group consisting of: , , wherein xx and yy represent the points of attachment to Ring D; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, and wherein aa represents the point of attachment to Z2, and Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc; Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc; R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; and -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc; each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl optionally substituted with 1-3 Rc; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc;each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6 alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)- Ri, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments of Formula (I) or Formula (II), each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)-Ri, C1-3alkyl, and C1-3haloalkyl.. In some embodiments, the compounds are compounds of Formula (I), or pharmaceutically acceptable salts thereof. In some embodiments of Formula (I), L1is a bond. In some embodiments of Formula (I), L1is O. In some embodiments of Formula (I), L2is a bond. In some embodiments of Formula (I), L2is C1-3alkylene (e.g., L2is CH2). In some embodiments of Formula (I), is selected from the group consisting of: , , , In some embodiments, In some embodiments of Formula (I), Ring E is a phenylene (e.g., 1,4-phenylene) optionally substituted with 1-2 Ra. For example, Ring E can be . In some embodiments of Formula (I), Ring E is a 5-6 membered heteroarylene (e.g., pyrazolylene, isooxazolylene, or pyrimidinylene) optionally substituted with 1-2 Ra. In some embodiments, Ring E is selected from the group consisting of: , , and , wherein aa represents the point of attachment to -L2-R5. In some embodiments of Formula (I), Ring E is a 5-6 membered heteroarylene optionally substituted with 1-2 Ra. In some embodiments, Ring E is oxazolylene, oxadiazolylene, pyrazolylene, isooxazolylene, pyridinylene, or pyrimidinylene (e.g., oxazolylene, oxadiazolylene, pyrazolylene, isooxazolylene, or pyrimidinylene), each of which is optionally substituted with 1-2 Ra. In some embodiments of Formula (I), Ring E is selected from the group consisting of: , , wherein aa represents the point of attachment to -L2-R5. In some embodiments of Formula (I), Ring E is selected from the group consisting of: , , , , , and , wherein aa represents the point of attachment to -L2-R5. In some embodiments of Formula (I), R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 Ra. In some embodiments, R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R5is selected from the group consisting of: . For example, R5can be In some embodiments of Formula (I), R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), andC1-3alkyl optionally substituted with -NH2or -OH. For example, R5can be . In some embodiments of Formula (I), is selected from the group consisting of: , , ,

[0021] In some embodiments of Formula (I), is selected from the group consisting of: In some embodiments of Formula (I), is selected from the group consisting of: In some embodiments of Formula (I), ; Ring E is selected from the group consisting of phenylene and 5-6 membered heteroarylene, each of which optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; and R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with -NH2or -OH. For example, R5can be In some embodiments, R5is a 6-8 membered heterocyclyl having one ring nitrogen atom and one ring S(O)2, wherein the 6-8 membered heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 -F. For example, R5can be In some embodiments, Ring E is selected from the group consisting of: wherein aa represents the point of attachment to -CH2R5. In some embodiments, Ring E is 1,4-phenylene. In some embodiments of Formula (I), Ring E is a 5-membered heteroarylene optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; and R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc. In some embodiments, R5is a 6-8 membered heterocyclyl having one ring nitrogen atom and one ring S(O)2, wherein the 6-8 membered heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 -F. For example, R5can be In some embodiments, Ring E is selected from the group consisting of: and5 wherein aa represents the point of attachment to -CH2R . In some embodiments, Ring E is 1,4-phenylene. In some embodiments, the compounds are compounds of Formula (II), or pharmaceutically acceptable salts thereof. In some embodiments of Formula (II), L1is a bond. In some embodiments of Formula (II), Ring E2 is a bicyclic 8-10 membered heteroaryl optionally substituted with 1-3 R15(e.g., Ring E2 is In some embodiments of Formula (II), Ring E2 is a bicyclic spirocyclic 8-12 membered heterocyclyl optionally substituted with 1-2 R15. In some embodiments, Ring E2 is selected from the group consisting of: In some embodiments of Formula (I) or (II), Ring D is (e.g., In some embodiments of Formula (I) or (II), Ring D is (e.g., In some embodiments of Formula (I) or (II), Ring D is (e.g., In some embodiments of Formula (I) or (II), m is 0. In some embodiments of Formula (I) or (II), m is 1 or 2. In some embodiments of Formula (I) or (II), m is 1; and the moiety is In some embodiments, R2is -F. In some embodiments of Formula (I) or (II), m is 1; and the moiety is In some embod2 iments, R is -F. In some embodiments of Formula (I) or (II), R3is -C1-6alkyl optionally substituted with 1-6 Rc. In some embodiments, R3is -C1-3alkyl optionally substituted with 1-3 -F (e.g., R3is ethyl). In some embodiments of Formula (I) or (II), R4is C1-6alkyl optionally substituted with 1-6 Rc. In some embodiments, R4is C1-3alkyl substituted with C1-3alkoxy. For example, R4can be In some embodiments of Formula (I) or (II), each R6is methyl. In some embodiments of Formula (I) or (II), Z1is In some embodiments, Rzis C1-6alkyl optionally substituted with 1-6 Rc. For example, Rzcan be an isopropyl. In some embodiments, Rzis Rb1, wherein the Rb1is a C3-5cycloalkyl. For example, Rzcan be a cyclopentyl. In some embodiments of Formula (I) or (II), Z1is C(=O). In some embodiments of Formula (I) or (II), Z2is -N(Rf)C(=O)-*. In some embodiments, Z2is -N(Me)C(=O)-*. In some embodiments of Formula (I) or (II), Z2is a bond. In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is: In some embodiments of Formula (I) or (II), NH-Z1-Z2-R1is: In some embodiments of Formula (I) or (II), R1is selected from the group consisting of C3-6cycloalkyl and 4-6 membered heterocyclyl, each of which is optionally substituted with 1-2 R11. In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is selected from the group consisting of: and In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is selected from the group consisting of: , In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is wherein the Rgis -N(Rf)2(e.g., -NH2or -NMe2); and Rzis C1-6alkyl or C3-5cycloalkyl. In some embodiments, -NH-Z1-Z2-R1isg f wherein the R is -N(R)2(e.g., -NH2 or -NMe2). For example, -NH-Z1-Z2-R1can be In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is selected from the group consisting of: , , , , and In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is wherein the Rgis -N(Rf)2(e.g., -NH2or -NMe2). In some embodiments of Formula (I) or (II), -NH-Z1-Z2-R1is selected from the group consisting of: In some embodiments, the compounds of Formula (I) are compounds of Formula (I-a): or pharmaceutically acceptable salts thereof, wherein: Ring E is selected from the group consisting of phenylene and 5-6 membered heteroarylene, each of which optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with 1-3 Rc; R4is a C1-3alkyl substituted with C1-3alkoxy; R3is a C1-6alkyl optionally substituted with 1-6 Rc; and Rzis selected from the group consisting of: (a) C3-5cycloalkyl; and (b) C1-6alkyl optionally substituted with 1-6 Rc. In some embodiments, the compounds of Formula (I) are compounds of Formula (I-a): or pharmaceutically acceptable salts thereof, wherein: Ring E is a 5-membered heteroarylene optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; R4is a C1-3alkyl substituted with C1-3alkoxy; R3is a C1-6alkyl optionally substituted with 1-6 Rc; and Rzis a C1-6alkyl optionally substituted with 1-6 Rc. In some embodiments of Formula (I-a): each Rcis independently selected from the group consisting of: halo, -CN, -OH, -NH2, -C1-6alkoxy, and -C1-6haloalkoxy; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 -F; each Rgis independently selected from the group consisting of: Rh, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy. In some embodiments of Formula (I-a): each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 -F; each Rgis independently selected from the group consisting of: Rh, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy. In some embodiments of Formula (I-a), the moiety is selected from the group consisting of: In some embodiments of Formula (I-a), the moiety is selected from the group consisting of: . In some embodiments of Formula (I-a): Rgis -N(Rf)2. For example, Rgcan be -NH2. In some embodiments of Formula (I-a), the moiety is For example, the moiety can be In some embodiments of Formula (I-a), R5is a 6-8 membered heterocyclyl having one ring nitrogen atom and one ring S(O)2, wherein the 6-8 membered heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 -F. For example, R5can be In some embodiments of Formula (I-a), R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with -NH2or -OH. For example, R5can be In some embodiments of Formula (I-a), Ring E is selected from the group consisting of: wherein aa represents the point of attachment to -CH2R5. 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

[0022]

[0023] In some embodiments, the compounds of Formula (I) or (II) are selected from the group consisting of the compounds depicted in Table C1s of U.S. Provisional Application Serial Nos. 63 / 669,884, filed July 11, 2024; 63 / 706,518, filed October 11, 2024; 63 / 771,563, filed March 13, 2025; 63 / 773,307, filed March 17, 2025; 63 / 807,193, filed May 16, 2025; and 63 / 830,245, filed June 25, 2025, each Table C1 is incorporated by reference it its entirety herein. Provided herein are compounds of Formula (III): or pharmaceutically acceptable salts thereof, wherein: Ring D is selected from the group consisting of: , wherein xx and yy represent the points of attachment to Ring D; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, and wherein aa represents the point of attachment to Z2; Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc; Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc; R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; and -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered monocyclic heterocyclyl optionally substituted with 1-3 R15, wherein each R15is independently selected from the group consisting of Ra, phenyl, and C3-6cycloalkyl; and each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl optionally substituted with 1-3 Rc; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)-Ri, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl;each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl. Also provided herein are compounds of Formula (III): or pharmaceutically acceptable salts thereof, wherein: Ring D is selected from the group consisting of: , , wherein xx and yy represent the points of attachment to Ring D; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, and wherein aa represents the point of attachment to Z2; Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc; Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc; R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; and -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered monocyclic heterocyclyl optionally substituted with 1-3 R15, wherein each R15is independently selected from the group consisting of Ra, phenyl, and C3-6cycloalkyl; and each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl optionally substituted with 1-3 Rc; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)- Ri, C1-3alkyl, and C1-3haloalkyl; each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments of Formula (III), Ring D is selected from the group consisting of: , wherein xx and yy represent the points of attachment to Ring D. In some embodiments of Formula (III), when Ring D is then one or more of the following applies: (i) R5is a 4-5 membered monocyclic heterocyclyl optionally substituted with 1-3 R15; (ii) R5is a 7-8 membered monocyclic heterocyclyl optionally substituted with 1-3 R15; (iii) R5is a morpholinyl optionally substituted with 1-3 R15; (iv) R5is ; (v) R5is , wherein R15is other than methyl (e.g., R15is C(=O)C1-6alkyl optionally substituted with 1-3 Rc; or R15is C(=O)OC1-6alkyl optionally substituted with 1-3 Rc; or R15is C2-6alkyl optionally substituted with 1-6 Rc); (vi) R1is other than (vii) Z1isZ , wherein R is other than isopropyl; or (viii) m is 1 or 2. In some embodiments of Formula (III), Ring D is In some embodiments of Formula (III), Ring D is In some embodiments of Formula (III), m is 0. In some embodiments of Formula (III), m is 1 or 2. Also provided herein are compounds of Formula (IV): or pharmaceutically acceptable salts thereof, wherein: m is 1 or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc; R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, and , wherein aa represents the point of attachment to Z2, and Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc; Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered monocyclic heterocyclyl optionally substituted with 1-3 R15, wherein each R15is independently selected from the group consisting of Ra, phenyl, and C3-6cycloalkyl; and each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)- Ri, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments of Formula (IV): m is 1 or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc;R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, and wherein aa represents the point of attachment to Z2, and Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc; Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered monocyclic heterocyclyl optionally substituted with 1-3 R15, wherein each R15is independently selected from the group consisting of Ra, phenyl, and C3-6cycloalkyl; and each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2; each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)- Ri, C1-3alkyl, and C1-3haloalkyl; each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl. In some embodiments of Formula (III) or (IV), m is 1; and the moiety is In some embodiments2 2 , R is -F. In some embodiments, R is C1-3alkyl optionally substituted with 1-3 Rc(e.g., R2is methyl). In some embodiments, R2is C1-3alkoxy optionally substituted with 1-3 Rc(e.g., R2is methoxy). In some embodiments, R2is CN. In some embodiments of Formula (III) or (IV), m is 1; and the moiety is In some embodiments, R2is -F. In some embodiments, R2is C1-3alkyl optionally substituted with 1-3 Rc(e.g., R2is methyl). In some embodiments, R2is C1-3alkoxy optionally substituted with 1-3 Rc(e.g., R2is methoxy). In some embodiments, R2is CN. In some embodiments of Formula (III) or (IV), R3is C1-6alkyl optionally substituted with 1-6 Rc. In some embodiments of Formula (III) or (IV), R3is C1-3alkyl optionally substituted with 1-3 -F (e.g., R3is ethyl). In some embodiments of Formula (III) or (IV), R4is C1-6alkyl optionally substituted with 1-6 Rc. In some embodiments of Formula (III) or (IV), R4is C1-3alkyl substituted with C1-3alkoxy. For example, R4can be In some embodiments of Formula (III) or (IV), R5is a 4-8 membered monocyclic nitrogen containing heterocyclyl optionally substituted with 1-3 Ra. In some embodiments of Formula (III) or (IV), R5is a 4-8 membered monocyclic nitrogen containing heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 -F. In some embodiments of Formula (III) or (IV), R5is selected from the group consisting of: , , , In some embodiments of Formula (III) or (IV), each R6is methyl. In some embodiments of Formula (III) or (IV), Z1is In some embodiments, Rzis C1-6alkyl optionally substituted with 1-6 Rc. For example, Rzcan be isopropyl. In some embodiments of Formula (III) or (IV), Z1is C(=O). In some embodiments of Formula (III) or (IV), Z2is -N(Rf)C(=O)-*. For example, Z2can be -N(Me)C(=O)-*. In some embodiments of Formula (III) or (IV), Z2is a bond. In some embodiments of Formula (III) or (IV), R1is selected from the group consisting of C3-6cycloalkyl and 4-6 membered heterocyclyl, each of which is optionally substituted with 1-2 R11. In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is: In some embodiments, Rzis C1-6alkyl optionally substituted with 1-6 Rc. For example, Rzcan be isopropyl. In some embodiments, R1is selected from the group consisting of C3-6cycloalkyl and 4-6 membered heterocyclyl, each of which is optionally substituted with 1-2 R11. In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is: . In some embodiments, R1is selected from the group consisting of C3-6cycloalkyl and 4-6 membered heterocyclyl, each of which is optionally substituted with 1-2 R11. In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is selected from the group consisting of: . In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is selected from the group consisting of: , In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is selected from the group consisting of: and In some embodiments of Formula (III) or (IV), -NH-Z1-Z2-R1is selected from the group consisting of: In some embodiments, the compounds of Formula (III) or (IV) are selected from the group consisting of the compounds depicted in Table C2, or pharmaceutically acceptable salts thereof. Table C2

[0024] In certain compounds of Table C1 or Table C2, 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 or Table C2 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 structure 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 (III) or (IV) are selected from the group consisting of the compounds depicted in Table C1 of U.S. Provisional Application Serial Nos.63 / 669,911, filed July 11, 2024; and 63 / 737,086, filed December 20, 2024, each Table C1 is incorporated by reference in 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, C1-10indicates 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)).

[0025] 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.

[0026] 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).

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a) or Formula (I-b)), 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) (e.g., Formula (I-a) or Formula (I-b)), 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) (e.g., Formula (I-a) or Formula (I-b)), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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 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) (e.g., Formula (I-a)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, can inhibit ERK phosphorylation in a cell line expressing a NRas Q61X mutant protein (e.g., 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0033] In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0034] In some cases, binding affinities (e.g., as measured by dissociation constant KD) of the compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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).

[0035] Another exemplary assay for determining the potency of a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, includes measuring the effect of the compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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, HP AC, HPAF-II (HPAFII), HS852T, HS936T, HTK, HUPT3, IPC298, KMS20, KP2, KP4, LS123, MELJUSO, MIAPaCa-2, MKN1, NCI-H1993, NCI- 11211, NCI-H2122, NCI-H424, NCI-H526, NCI-H727, Pane 02.03, Pane 04.03, Pane 05.04, Pane 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, Pane 02.03, HP AC, MIA PaCa-2, KP-2, PSN-1, TCC-Pan2, AsPC-1, Pane 04.03, Pane 05.04, Pane 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) (e.g., Formula (I- a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV)). 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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 F Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, to the signal from a control experiment (e.g., lacking a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof). See, e.g., Example Bl 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.

[0036] As another example, the potency and / or efficacy of a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I- a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, can be measured using methods known in the art. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I- a)), (II), (III), or (IV), 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 / 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; 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, can bind selectively to a Ras protein in the GDP -bound state.

[0037] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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).

[0038] For example, if compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0039] Provided herein is a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0040] As used herein, “monotherapy”, when referring to a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, means that the compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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”.

[0041] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0042] 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.

[0043] 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.

[0044] 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).

[0045] 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). 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] In some embodiments, the cancer (e.g., a tumor sample) has a NRas Q61H mutation, 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 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA- approved kit.

[0055] 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.

[0056] 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.

[0057] 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., cutaneous melanoma).

[0058] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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., phosphoERKl 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., phosphoERKl 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.

[0059] Accordingly, in some embodiments of the methods provided herein, the method includes (a) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (HI), or (IV), 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., phosphoERKl 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (La)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (HI), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof to the subject.

[0060] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I- a)), (II), (III), or (IV), 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) (e.g., Formula (I- a)), (II), (III), or (IV), 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)).

[0061] 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.

[0062] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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. 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.

[0063] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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. 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] In some embodiments, the subject is a pediatric subject.

[0069] 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.

[0070] 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.

[0071] 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).

[0072] 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 disease, disorder, or condition 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0073] 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.

[0074] Combinations

[0075] In any of the indications described herein, a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0076] In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0077] 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 naive. In some embodiments, a subject is not Ras inhibitor naive. 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-mT0R 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.

[0078] In some embodiments of any the methods described herein, the compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0079] 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, SOSl / 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), mTORCl 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-PDl, anti-PD-Ll, 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- Ll, CTLA4, LAG3, TIM3, B7-H3, or VISTA) or antigen-binding fragments thereof, a PD-1 inhibitor, a PD-L1 inhibitor, or an AD0R2A 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.

[0080] 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 moi eties 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.

[0081] 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.

[0082] In some embodiments, the KRas-targeted therapeutic agent is an agent that inhibits the interaction between KRas and S0S1 or SHP2. Non-limiting examples of an agent that inhibits the interaction between S0S1 and KRas include BI-3406, BI-1701963, and BAY 293.

[0083] 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.

[0084] Further non-limiting examples of Ras pathway-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.

[0085] 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.

[0086] 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, CH040 (PD184352), CS3006, FCN-159, MSC1936369B, NFX-179, PD0325901,

[0087] 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.

[0088] 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-1 le, 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.

[0089] 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, 0SU-A9, Perifosine (D-21266), PH- 316, PHT-427, PIT-1, SRI 3668, 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.

[0090] 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.

[0091] In some embodiments, the farnesyl transferase inhibitor is lonafamib, tipifarnib, BMS- 214662, L778123, L744832, and FTI-277. In some embodiments, the farnesyl transferase inhibitor is lonafamib, tipifarnib, BMS-214662, or a combination thereof.

[0092] 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.

[0093] Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.

[0094] In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.

[0095] In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof.

[0096] 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 antibodydrug 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., famtrastuzumab deruxtecan-nxki, or a biosimilar thereof).

[0097] 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

[0098] 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.

[0099] Non-limiting examples of immunotherapy include immune checkpoint therapies. Nonlimiting examples of immune checkpoint therapies include antibodies and / or inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, AD0RA2A, TIM-3, B7-H3, VISTA, IDO, and combinations thereof.

[0100] 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.

[0101] In some embodiments, the anti-PDl 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-Ll 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.

[0102] In some embodiments, the PD-L1 inhibitor is INCB-086550.

[0103] 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.

[0104] In some embodiments, the AD0R2A inhibitor is etrumadenant, inupadenant, istradefylline, mefloquine (e.g., mefloquine), taminadenant, CPI-444, PBF-999, or a combination thereof. In some embodiments, the AD0R2A inhibitor is etrumadenant, inupadenant, istradefylline, mefloquine (e.g., mefloquine), taminadenant, PBF-999, or a combination thereof.

[0105] In some embodiments, the anti-TIM3 therapy is cobolimab, sabatolimab (MBG-453), AZD-7789, INCAGN-02390, TQB-2618, or a combination thereof.

[0106] In some embodiments, the anti-B7-H3 therapy is omburtamab, enoblituzumab, or a combination thereof.

[0107] In some embodiments, the anti-VISTA therapy is onvatilimab (JNJ-61610588), HMBD-002, K01401-020, KVA-12.1, SNS-101, or a combination thereof.

[0108] 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.

[0109] See, for example, Marin-Acevedo, et al., J Hematol Oncol. 11 : 39 (2018), doi: 10.1186 / S13045-018-0582-8.

[0110] In some embodiments, the additional therapy or therapeutic agent is a combination of atezolizumab and nab-paclitaxel.

[0111] Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof (a) a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer.

[0112] These additional therapeutic agents may be administered with one or more doses of the compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0113] Pharmaceutical Compositions and Administration

[0114] General

[0115] In some embodiments, a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0116] In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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, selfemulsifying drug delivery systems (SEDDS) such as d-a-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, sodiumchloride, 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 y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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).

[0117] Routes of Administration and Composition Components

[0118] In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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).

[0119] In some embodiments, a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0120] 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.

[0121] 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.

[0122] 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. 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.

[0123] 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.

[0124] In certain embodiments, suppositories can be prepared by mixing a compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0125] 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.).

[0126] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound of Formula (I) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0127] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0128] 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.

[0129] 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.

[0130] 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) (e.g., Formula (I-a)), (II), (III), or (IV), 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.

[0131] Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

[0132] 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.

[0133] 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.)).

[0134] 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.

[0135] 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.

[0136] Dosages

[0137] 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.

[0138] 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).

[0139] Regimens

[0140] 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).

[0141] 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.

[0142] 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.

[0143] “API” refers to an active pharmaceutical ingredient.

[0144] 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.

[0145] 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.

[0146] 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

[0147] 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.

[0148] 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.

[0149] 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.

[0150] Compounds of Formula (I), (III), or (IV) can be prepared e.g., using methods similar to those described in WO 2021 / 091956; WO 2022 / 060836; WO 2024 / 067857; WO 2024 / 017859; WO 2024 / 008834; WO 2024 / 060966; WO 2024 / 104364; CN 117534684; CN 118047796; CN 118047797; CN 118047798; CN 118047799; CN 117534685; or CN 117534687.

[0151] Scheme 1 provides exemplary methods for preparing Compound 103a: Scheme 1

[0152]

[0153] Scheme 2 provides exemplary methods for preparing Compound 107a:

[0154] Scheme 2

[0155]

[0156] Scheme 3 provides exemplary methods for preparing Compound 201a, a compound of Formula (III): Scheme 3

[0157]

[0158]

[0159] Scheme 4 provides exemplary methods for preparing Compound 203a, a compound of Formula (IV):

[0160] Scheme 4

[0161] EXAMPLES In some of the examples disclosed herein, one or more compounds in a described chemical reaction sequence (e.g., starting materials, intermediates, or products) is structurally depicted with enhanced stereochemical notation(s) at one or more defined stereogenic center(s). Examples of such notations include or1, or2, &1, &2, and the like. In some such examples, in the chemical name of the same compound, each of such defined stereogenic center(s) is assigned a tentative configuration (e.g., (R)- or (S)-) shown by the wedge / hash representation of its structural formula. However, the defined stereogenic center(s) should be understood to have configurations consistent with the enhanced stereochemical notation(s), as described herein, based e.g., on the conventions explained below. For avoidance of doubt, the chemical names of these compounds, having one or more enhanced stereochemical notation(s), adopt the following conventions: When the chemical name of a compound having only one stereogenic center contains the prefix “rel,” the stereogenic center is resolved, but its absolute configuration is either (R) or (S), thereby corresponding to an or1 enhanced stereochemical notation at the corresponding stereogenic center in its structural formula. For example, the chemical name rel-(R)-(1- methylpyrrolidin-2-yl)methanol represents one stereoisomer selected from the group consisting of: . When one stereogenic center is labelled with an asterisk (“*”) in the chemical name of a compound having more than one stereogenic centers (e.g., when a stereogenic center is denoted as (R*)), the stereogenic center labeled with the asterisk is resolved, but its absolute configuration is either (R) or (S), thereby corresponding to an or1 enhanced stereochemical notation at the corresponding stereogenic center in its structural formula. For example, the chemical name ((2R*,4R)-1,4-dimethylpyrrolidin-2-yl)methanol represents one stereoisomer selected from the group consisting of: . When the chemical name of a compound contains two stereogenic centers labelled with asterisks, these two stereogenic centers may have (R) or (S) configurations, either concertedly or independently, in conformity with the orx (e.g., or1 or or2) notations in its structural formula in Table C1 or Table C2. When two stereogenic centers are labelled or1 and or1 in a compound structure, and they are labelled with asterisks in the chemical name, then the relative stereochemistry between the two stereogenic centers (e.g., syn or anti relationship) is as represented by the name, but the absolute configurations of the two stereogenic centers can vary concertedly (e.g., a compound designated (R*,R*) is one stereoisomer selected from (R,R) and (S,S); for avoidance of doubt, the compound designated (R*,R*) does not have (S,R) or (R,S) configurations across these stereogenic centers). For example, the chemical name of is ((2R*,3S,4R*)-3-cyclopropyl-1,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents one stereoisomer selected from the group consisting of: . When two stereogenic centers are labelled or1 and or2 in a compound structure, and they are labelled with asterisks in the chemical name, then the configuration of the two stereogenic centers can vary independently (e.g., a compound designated (R*,R*) is one stereoisomer selected from (R,R), (S,S), (R,S), and (S,R)). For example, the chemical name of is ((2R*,3S,4R*)-3-cyclopropyl-1,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents one stereoisomer selected from the group consisting of: When the chemical name of a compound contains two stereogenic centers designated “RS” and / or “SR,” a mixture of stereoisomers is provided wherein among the constituent stereoisomers these two stereogenic centers differ either concertedly or independently, in conformity with the &x (e.g., &1 or &2) notations in Table C1 or Table C2 for the corresponding compound. When two defined stereogenic centers are labelled &1 and &1 in a chemical structure, and they are designated “RS” and / or “SR” in the corresponding chemical name, then a mixture of two stereoisomers is provided, wherein each constituent stereoisomer has the relative stereochemistry between these two stereogenic centers (e.g., syn or anti relationship) as depicted by the structural formula and by the name. As an example, a chemical name designated (RS,SR) represents a mixture of (R,S) and (S,R) stereoisomers, and this mixture does not include (R,R) or (S,S) stereoisomers. As a second example, a chemical name designated (SR,SR) represents a mixture of (S,S) and (R,R) stereoisomers, and this mixture does not include (R,S) or (S,R) stereoisomers. For example, the chemical name of is ((2RS,3S,4RS)-3-cyclopropyl-1,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents a mixture of two stereoisomers: . When two defined stereogenic centers are labelled &1 and &2 in a chemical structure, and they are designated “RS” and / or “SR” in the corresponding chemical name, then a mixture of four stereoisomers is provided each differing in configuration at one or both of these two stereogenic centers (e.g., a chemical name designated (RS,SR) represents a mixture of (R,S), (S,R), (R,R), and (S,S) stereoisomers). For example, the chemical name of is ((2RS,3S,4RS)-3-cyclopropyl-1,4-dimethylpyrrolidin-2-yl)methanol. This name, taken together with the structural formula, represents a mixture of four stereoisomers: General Analytical Methods Method A: Pre-column: VanGuard CSH C18, 1.7 μm, 2.1 x 5 mm; Pre-run: 1mL / 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: 50 to 100% MeCN / water (+ 10 mM ammonium bicarbonate) for 3 min. Method B: Pre-column: VanGuard 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: 5 to 100% MeCN / water (+ 10 mM ammonium bicarbonate) for 3 min. Method C: Pre-Column: VanGuard CSH C18, 1.7 μm, 3 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 min. Method D: Waters Acquity CSH C18, 2.1 x 30 mm, 1.7 µm and Vanguard Precolumn 2.1 x 5 mm, 1.7 µm. Flow rate: 0.9 mL / min. Total analysis time: 2.7 minutes. Column temperature: 40°C. Mobile phase A: 10mM Ammonium Bicarbonate, Mobile phase B: ACN. Conditions: 95% A 5% B, linear gradient to 0% A 100% B for 2 min, hold at 0% A 100% B for 0.7 min. Method E: Acquity UPLC, CSH C18, 1.7 μm, 2.1 x 50 mm, Mobile phase A: 0.1% TFA in water (v / v); Mobile phase B: 0.1% TFA in acetonitrile (v / v); Gradient: 95% H2O / 5% MeCN hold to 0.5 min, 95% H2O / 5% MeCN linear to 5% H2O / 95% MeCN to 4.0 min, hold at 5% H2O / 95% MeCN to 0.50 min. Then 5% H2O / 95% MeCN linear to 95% H2O / 5% MeCN hold for 0.5 min. Flow: 0.6 mL / min. Method F: Acquity UPLC, CSH C18, 1.7 μm, 2.1 x 50 mm, Mobile phase A: 0.1% formic acid in water (v / v); Mobile phase B: 0.1% formic acid in acetonitrile (v / v); Gradient: 95% H2O / 5% MeCN hold to 0.5 min, 95% H2O / 5% MeCN linear to 5% H2O / 95% MeCN to 4.0 min, hold at 5% H2O / 95% MeCN to 4.50 min. Then 5% H2O / 95% MeCN linear to 95% H2O / 5% MeCN, hold for 0.5 min. Flow: 0.6 mL / min. Synthesis of INT-34 Step 1: To a solution of INT-25 (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 INT-26 (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 INT-26 (8.00 g, 39.0 mmol, 1 equiv.), INT-27 (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 INT-28 (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 INT-28 (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 INT-29 (13 g obtained from 15.5 g of INT-28, 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 INT-29 (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 INT-30a (5.28 g, 16.4 mmol, enantiomeric excess (e.e.) = 100.0 %) as a yellow solid and INT-30b (5.17 g, 16.1 mmol, e.e. = 100.0 %) as a yellow solid. INT-30a: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. To a solution of INT-30a (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 INT-31 (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) Step 6. To a solution of INT-31 (883 mg, 2.87 mmol, 1.2 equiv.) and INT-32 (530 mg, 2.39 mmol, 1 equiv.) in DMF (16 mL) at 0 °C was added HATU (1.46 g, 3.83 mmol, 1.6 equiv.) and DIPEA (3.30 mL, 19.2 mmol, 8 equiv.). The mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (hexane / EtOAc, twice) to give INT-33 (1.09 g, 2.13 mmol), which was used in the next step without further purification. Step 7. A N2-purged flask containing INT-33 (1.10 g, 2.15 mmol, 1 equiv.) and Pd(OH)2(1.51 g, 20 wt%, 2.15 mmol, 1 equiv.) in MeOH (27.5 mL) was further purged with N2using evacuation / N2cycles. The mixture was stirred at room temperature for 1 hour under a H2atmosphere with a balloon attached. The reaction flask was purged with N2, and the solids were removed by filtration through a Celite®pad with additional MeOH washes (150 mL). The filtrate was concentrated under reduced pressure, and the residue was dissolved in MeOH, filtered through a PTFE filter, and washed with additional MeOH (30 mL). All volatiles were removed under reduced pressure to give INT-34 (880 mg, 2.09 mmol) as a white solid. LCMS: m / z (ESI) [M-H]+421.3, tR= 0.98 minutes (Method B) Synthesis of INT-40 Step 1: To a tube containing INT-35 (470 mg, 0.852 mmol, 1 equiv.), INT-9 (705 mg, 1.02 mmol, 1.2 equiv.), cesium carbonate (694 mg, 2.13 mmol, 2.5 equiv.), and Pd(dtbpf)Cl2(139 mg, 0.213 mmol, 0.25 equiv.) under an Ar atmosphere was added dioxane (4.7 mL) and water (0.940 mL). The mixture was degassed with Ar and stirred at 60 °C for 2 hours. The reaction mixture was then diluted with EtOAc and water, and the organic layer was separated. The aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (DCM / MeOH) to give INT-36 (970 mg, 0.790 mmol) as a brown solid. LCMS: m / z (ESI) [M+H]+1034.8, tR= 2.48 minutes (Method B) Step 2: To a solution of INT-36 (970 mg, 0.938 mmol, 1 equiv.) in THF (27 mL) at 0 °C was added aqueous 0.1 M LiOH (18.8 mL, 1.88 mmol, 2 equiv.). The mixture was stirred at 0 °C for 2 hours. The reaction mixture was diluted with water (2 mL) and EtOAc (5 mL) and the pH was adjusted to pH ~ 2–3 with aqueous 1 M HCl. The mixture was then extracted with EtOAc (30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give INT-37 (963 mg, 0.941 mmol), which was used in the next step without further purification. LCMS: m / z (ESI) [M+H]+1020.7, tR= 1.92 minutes (Method B) Step 3: To a solution of INT-37 (960 mg, 0.941 mmol, 1 equiv.) in DCM (38 mL) at 0 °C was added HOBt (792 mg, 5.17 mmol, 5.5 equiv.) and DIPEA (7.37 mL, 42.3 mmol, 45 equiv.) followed by EDC·HCl (6.40 g, 33.4 mmol, 35.5 equiv.). The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM and water, and the organic layer was separated. The aqueous phase was then extracted with additional DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (DCM / MeOH) to give INT-38 (580 mg, 0.579 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1002.8, tR= 2.40 minutes (Method B) Step 4: A solution of INT-38 (575 mg, 0.574 mmol, 1 equiv.) in MeOH (10 mL) was degassed with Ar. To this was added Pd(OH)2on carbon (20 wt%, 403 mg, 0.574 mmol, 1 equiv.). The flask was evacuated and backfilled with Ar, then H2(balloon). The mixture was stirred at room temperature for 2 hours. The H2balloon was removed, and the system was purged with Ar. The mixture was filtered through a Celite®pad and washed sequentially with DCM (20 mL), MeOH (10 mL), and EtOAc (15 mL). The combined organic layers were concentrated under reduced pressure to give INT-39 (515 mg, 0.565 mmol), which was used in the next step without further purification. LCMS: m / z (ESI) [M+H]+912.7, tR= 2.36 minutes (Method B) Step 5: To a solution of INT-39 (460 mg, 0.504 mmol, 1 equiv.) and DIPEA (0.264 mL, 1.51 mmol, 3 equiv.) in DCM (10 mL) was added phenyl triflimide (216 mg, 0.605 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with DCM and washed with water (10 mL) followed by brine (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give INT-40 (740 mg), which was used without further purification. Synthesis of INT-46 Step 1. To a solution of INT-41 (6.0 g, 95 wt%, 23.7 mmol) and imidazole (3.23 g, 47.4 mmol) in DCM (120 mL) at room temperature was added TBDPS-Cl (7.31 mL, 28.5 mmol) by syringe over 10 minutes. The resulting white suspension was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM (150 mL), washed with water (150 mL) and brine (150 mL), and the organic phase was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / hexanes) to give INT-42 (10.2 g, 21.3 mmol) as a colorless oil. LCMS: m / z (ESI) [M-Boc+H]+379.4, tR= 2.33 minutes (Method B) Step 2. To a solution of INT-42 (10.2 g, 21.3 mmol) in DCM (100 mL) was added TFA (32.8 mL, 426 mmol) at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with DCM (200 mL), cooled to 0°C, and basified with saturated aqueous sodium bicarbonate (100 mL). The layers were separated, and the aqueous phase was extracted with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give INT-43 (8.08 g, 21.3 mmol) as a colorless oil and used in the next step without further purification. LCMS: m / z (ESI) [M+H]+379.5, tR= 1.89 minutes (Method B) Step 3. To a solution of INT-43 (4.00 g, 10.1 mmol) in DCM (100 mL) was added INT-44 (1.97 g, 20.3 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (4.30 g, 20.3 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 16 hours, diluted with DCM (100 mL), cooled to 0°C, and basified with saturated aqueous sodium bicarbonate (100 mL). The layers were separated, and the aqueous phase was extracted with DCM (100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / hexanes) to give INT-45 (4.02 g, 8.75 mmol) as a pale-yellow oil. LCMS: m / z (ESI) [M+H]+460.5, tR= 1.96 minutes (Method B) Step 4. To a solution of INT-45 (2.0 g, 4.4 mmol) in THF (30 mL) at −78°C was added LiHMDS (8.7 mL, 1.0 M, 8.7 mmol) under an argon atmosphere. The mixture was stirred at −78°C for 1 hour. ZnCl2(14 mL, 0.5 M in THF, 7.0 mmol) was then added at −78°C under an argon atmosphere. The mixture was stirred at room temperature for 30 minutes, cooled to −78°C, and a solution of iodine (2.2 g, 8.7 mmol) in THF (30 mL) was added. The reaction mixture was warmed to room temperature, stirred for 10 minutes, cooled to 0°C, and quenched by the addition of saturated aqueous ammonium chloride (100 mL) and saturated aqueous sodium thiosulfate (10 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (450 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / hexanes) to give INT-46 (2.1 g, 3.6 mmol). LCMS: m / z (ESI) [M+H]+586.3, tR= 2.11 minutes (Method B) 1H NMR (400 MHz, CDCl3): δ ppm 7.69 – 7.63 (m, 4H), 7.49 – 7.37 (m, 6H), 6.93 – 6.90 (m, 1H), 3.63 (s, 2H), 3.60 (s, 2H), 2.93 – 2.84 (m, 2H), 2.39 (m, 2H), 2.04 – 1.96 (m, 2H), 1.62 – 1.52 (m, 2H), 1.08 (s, 9H). Synthesis of INT-52

[0162] Step 1. To a solution of INT-47 (4.75 g, 19.9 mmol) and triethylamine (16.6 mL, 119 mmol, 6.0 equiv.) in DCM (119 mL) and THF (48 mL) was added 2,5-dioxopyrrolidin-1-yl [2- (trimethylsilyl)ethyl] carbonate (7.72 g, 29.8 mmol). The mixture was stirred at room temperature for 16 hours under an argon atmosphere. The reaction was quenched by the addition of water. Additional DCM was added, and the layers were separated. The aqueous phase was extracted with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ethyl acetate / hexanes) to give INT-48 (8.5 g) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.05 – 4.94 (m, 1H), 4.25 – 4.06 (m, 4H), 3.47 – 3.32 (m, 2H), 3.10 – 2.92 (m, 2H), 1.93 – 1.84 (m, 2H), 1.55 – 1.47 (m, 2H), 1.45 (s, 9H), 1.03 – 0.95 (m, 2H), 0.04 (s, 9H). Step 2. To a solution of INT-48 (4.00 g, 80 wt%, 8.34 mmol) and 2,6-dimethylpyridine (8.94 g, 83.4 mmol) in DMF (120 mL) at 0°C under an argon atmosphere was added TMSOTf (9.27 g, 41.7 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0°C, and quenched by the addition of a 1:1 mixture of MeOH and water (3.0 mL). DCM (10 mL) and water (10 mL) were added, and the layers were separated. The aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (DCM / MeOH) to give INT-49 (1.95 g, 6.88 mmol) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ ppm 5.26 – 5.19 (m, 1H), 4.21 – 4.11 (m, 2H), 3.72 – 3.60 (m, 2H), 3.51 – 3.45 (m, 2H), 3.26 – 3.13 (m, 2H), 2.13 – 2.05 (m, 2H), 1.64 – 1.49 (m, 2H), 1.04 – 0.92 (m, 2H), 0.04 (s, 9H) Step 3. To a solution of INT-49 (950 mg, 90 wt%, 3.02 mmol) and INT-50 (586 mg, 3.62 mmol) in DMF (24 mL) at room temperature was added cesium carbonate (4.03 g, 12.4 mmol) portion wise. The mixture was stirred at room temperature for 1.5 hours. The reaction was quenched by the addition of water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (45 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was resuspended in toluene and concentrated (30 mL) to remove residual DMF. The residue was purified by flash silica gel chromatography (DCM / MeOH) to give INT-51 (580 mg, 1.59 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 6.97 (s, 1H), 4.99 (t, 1H), 4.21 – 4.10 (m, 2H), 3.64 (s, 2H), 3.38 (d, 2H), 2.95 – 2.85 (m, 2H), 2.37 (m, 2H), 1.96 – 1.87 (m, 2H), 1.68 (m, 2H), 1.03 – 0.92 (m, 2H), 0.03 (s, 9H). Step 4. To a solution of INT-51 (1.54 g, 4.22 mmol) in THF (22 mL) at −78°C was added LiHMDS (8.45 mL, 1.0 M, 8.45 mmol) under an argon atmosphere. The mixture was stirred at −78°C for 1 hour. ZnCl2(13.5 mL, 0.5 M in THF, 6.76 mmol) was then added. The mixture was stirred at −78°C for 5 minutes, then at room temperature for 30 minutes, cooled to −78°C, and a solution of iodine (2.14 g, 8.45 mmol) in THF (17 mL) was added. The mixture was stirred at −78°C for 10 minutes, warmed to room temperature, and stirred for 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (150 mL). The combined organic layers were washed with saturated aqueous sodium thiosulfate (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (DCM / MeOH) to give INT-52 (1.63 g, 3.30 mmol). LCMS: m / z (ESI) [M+H]+491.1, tR= 1.55 minutes (Method B) 1H NMR (400 MHz, CDCl3): δ ppm 6.91 (s, 1H), 4.98 (t, 1H), 4.21 – 4.11 (m, 2H), 3.68 – 3.60 (m, 2H), 3.38 (d, 2H), 2.97 – 2.83 (m, 2H), 2.36 (m, 2H), 1.97 – 1.87 (m, 2H), 1.68 (m, 2H), 1.03 – 0.92 (m, 2H), 0.04 (s, 9H). Synthesis of INT-14 Step 1. A mixture of INT-88 (1.07 g, 5.55 mmol, 1 equiv.) and INT-89 (800 mg, 4.27 mmol, 1 equiv.) in DMF (24.0 mL) at 0°C was treated with HATU (2.60 g, 6.83 mmol, 1.23 equiv.) and DIPEA (5.88 mL, 34.2 mmol, 6 equiv.). The mixture was gradually warmed to 25°C and stirred for 16 hours. The reaction mixture was then diluted with EtOAc and quenched with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (hexane / EtOAc) to give INT-90 (1.24 g, 3.42 mmol). LCMS: m / z (ESI) [M+H]+362.2, tR= 0.64 minutes (Method B) Step 2. To a solution of INT-90 (1.22 g, 3.38 mmol, 1 equiv.) in DCM (73.2 mL) at 0°C was added TFA (18.0 mL, 236 mmol, 70 equiv.). The mixture was gradually warmed to 25°C and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with chloroform, and concentrated again under reduced pressure to give INT-14 (1.4 g). LCMS: m / z (ESI) [M+H]+306.4, tR= 0.86 minutes (Method B) Example 1: Compound 114a

[0163] Step 1. To a solution of INT-1 (4.50 g, 45.4 mmol) and PPh3 (13.1 g, 50.0 mmol) in DCM (200 mL) at 0 °C was added N-bromo succinimide (8.89 g, 50.0 mmol) in portions. The mixture was stirred at 0 °C for 2 hours under N2. The mixture was then warmed to room temperature and was concentrated under reduced pressure to give a residue, which was triturated with petroleum ether / EtOAc = 1 / 1 (200 mL) followed by filtration. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by flash silica gel chromatography eluting with 0-30% ethyl acetate / petroleum ether to give INT-2 (4.9 g, 30 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (s, 1H), 7.12 (s, 1H), 4.51 (s, 2H). Step 2. To a solution of INT-2 (4.9 g, 30 mmol) in MeCN (80 mL) was added INT-3 (4.9 g, 36 mmol) and potassium carbonate (13 g, 91 mmol). The mixture was stirred at 60 °C for 12 hours. The mixture was diluted with DCM (150 mL) and filtered over Celite®. The filtrate was concentrated under reduced pressure to give the crude residue, which was purified by flash silica gel chromatography eluting with 0-3% MeOH / DCM to give INT-4 (5.5 g, 25 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (1H), 7.11 (s, 1H), 3.81 (s, 2H), 3.14-3.08 (m, 4H), 2.92-2.86 (m, 4H). Step 3. To a solution of INT-4 (3.20 g, 14.8 mmol) in THF (50 mL) at -78 °C was added LiHMDS (22.2 mL, 1 M, 22.2 mmol) dropwise under N2. The mixture was stirred at - 78 °C for 1 hour followed by the addition of ICH2CH2I (2.36 mL, 16.3 mmol). The mixture was stirred for an additional 5 hours at -78 °C. At this time, the mixture was then quenched with saturated ammonium chloride solution (100 mL) dropwise -78 °C, warmed to room temperature, and was extracted with DCM (3 x 80 mL). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was purified by flash silica gel chromatography eluting with 0-2% MeOH / DCM to give INT-5 (2.2 g, 6.4 mmol) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 6.95 (s, 1H), 3.78 (s, 2H), 3.12-3.05 (m, 8H). Step 4. To a solution of INT-5 (2.42 g, 7.06 mmol) and INT-6 (3.00 g, 5.65 mmol) in 1,4-dioxane (50 mL) and H2O (10 mL) was added Pd(dtbpf)Cl2(368 mg, 0.565 mmol) and cesium carbonate (5.52 g, 16.9 mmol). The mixture was stirred at 80 °C for 3 hours under N2. At this time, the reaction was cooled to room temperature followed by dilution with DCM (100 mL) and poured into ice-water (80 mL) slowly. The resulting mixture was extracted with additional DCM (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was purified by flash silica gel chromatography eluting with 0- 100% ethyl acetate / petroleum ether to give INT-7 (1.5 g) as a yellow oil that was used without further purification. Step 5. To a solution of INT-7 (1.90 g, 2.71 mmol) in MeOH (20 mL) and H2O (4 mL) at 15 °C was added LiOH·H2O (222 mg, 5.42 mmol). The resulting mixture was stirred for 1 hour at this temperature. The mixture was poured into ice-water (50 mL) slowly and was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was purified by SFC (Column: Daicel Chiralcel OD, 250 mm x 50 mm, 10 mm; Mobile phase: A for CO2and B for EtOH (0.1% NH3H2O); Flow rate: 200 g / min; Monitor wavelength: 220 & 254 nm; Column temperature: 40 °C; System back pressure: 100 bar) to give INT-8 (1.04 g, 1.56 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.28 (d, 1H), 8.24 (d, 1H), 7.92 (d, 1H), 7.52 (d, 1H), 7.38-7.25 (m, 2H), 4.52 (s, 1H), 4.16-4.05 (m, 2H), 3.92 (s, 2H), 3.89-3.78 (m, 1H), 3.13-3.10 (m, 4H), 3.07-3.01 (m, 1H), 3.00-2.93 (m, 5H), 2.89 (s, 3H), 2.67 (d, 1H), 2.16 (d, 1H), 1.41 (d, 3H), 1.11 (t, 3H), 0.60 (d, 6H). Step 6. A suspension of INT-8 (200 mg, 0.303 mmol), INT-9 (251 mg, 0.364 mmol), sodium carbonate (80 mg, 0.758 mmol) and Pd(dtbpf)Cl2(40 mg, 0.0606 mmol) in degassed dioxane (4.00 mL), and degassed H2O (0.800 mL) was stirred at 85 °C for 1.5 hours under nitrogen. The reaction was cooled to room temperature and was diluted with water (10 mL) followed by EtOAc washes (3 x 20 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was purified by flash silica gel chromatography eluting with 0-5% MeOH in DCM to give INT-10 (126 mg, 0.110 mmol) as a light brown solid. LCMS: m / z (ESI) [M+H]+1043.6, tR= 1.74 minutes (Method A)

[0164] Step 7. To a stirred solution of INT-10 (120 mg, 0.105 mmol) in DCE (4.2 mL) was added solid Me3SnOH (142 mg, 0.788 mmol). The resulting mixture was stirred at 65 °C for 16 hours. The reaction mixture was cooled to room temperature and was filtered through a pad of Celite®with additional DCM washes (50 mL). All solvents were removed under reduced pressure to give the crude reaction residue. The residue was partitioned between water (10 ml, adjusted to pH ~ 4 with 1 M aqueous HCl solution) and DCM (20 ml). The organic phase was separated, and the aqueous phase was extracted with additional DCM (2 x 20 ml). The combined organic phases were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide INT-11 (180 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1129.8, tR= 1.71 minutes (Method B) Step 8. To a stirred solution of INT-11 (100 mg, 0.0886 mmol) in DCM (4 mL) at 0 °C was added EDC·Cl (603 mg, 3.15 mmol), HOBt (75 mg, 0.487 mmol), and DIPEA (0.650 mL, 3.72 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction was diluted with water (10 mL) and DCM (20 mL). The organic phase was separated, and the aqueous phase was extracted with additional DCM (2 x 20 mL). The combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified using flash column chromatography eluting with MeOH in DCM 0-10% to give impure product. The recovered material was re-subjected to purification using reverse phase chromatography eluting with a gradient of MeCN in aqueous 10 mM ammonium bicarbonate buffer 50-100% to give INT-12 (57 mg, 0.051 mmol) as an off-white solid. LCMS: m / z (ESI) [M+H]+1111.8, tR= 2.34 minutes (Method B) Step 9. To a stirred solution of INT-12 (83 mg, 0.75 mmol) in DCM (5 mL) at 0 °C was added TFA (0.40 mL, 5.20 mmol). The reaction mixture was stirred at 0 °C for 2 hours. All volatiles were removed under reduced pressure, CHCl3(2 ml) was added, and the volatiles were removed again (process repeated 5 times). The resulting material was dried in vacuo to provide INT-13 (83 mg) as a light-yellow solid that was used without further purification. LCMS: m / z (ESI) [M+H]+1011.8, tR= 2.15 minutes (Method B) Step 10. To a stirred solution of INT-13 (76 mg, 0.075 mmol) and DIPEA (0.130 mL, 0.75 mmol) in DMF (1.9 mL) at -20 °C was added INT-14 (38 mg, 0.12 mmol) and HATU (43 mg, 0.11 mmol). The mixture was stirred at -20 °C for 1 hour. Solid CsF (80 mg, 0.53 mmol) was added, and the reaction mixture was gradually warmed to 0 °C and stirred for an additional 3 hours. At this time, the reaction was quenched with saturated aqueous sodium bicarbonate solution (20 ml) and was extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with brine (20 ml), dried over sodium sulfate and was concentrated under reduced pressure. The crude material was purified by reverse phase chromatography using C18 silica with a gradient of MeCN in aqueous 10 mM ammonium bicarbonate buffer 5-100%. The resulting material was further purified using prep-HPLC to give Compound 114a (18 mg, 0.016 mmol) as a white solid. LCMS: m / z (ESI) [M-H]+1141.8, tR= 4.62 minutes (Method C) 1H NMR (400 MHz, CDCl3) δ 9.45 – 9.36 (m, 1H), 8.29 – 8.24 (m, 1H), 8.11 – 8.04 (m, 1H), 7.78 – 7.67 (m, 1H), 7.45 – 7.39 (m, 1H), 7.33 – 7.27 (m, 4H), 7.24 – 7.20 (m, 3H), 7.18 – 7.15 (m, 1H), 6.63 – 6.60 (m, 1H), 6.55 – 6.51 (m, 1H), 5.64 – 5.53 (m, 1H), 5.25 – 5.20 (m, 1H), 4.73 - 4.65 (m, 1H), 4.64 - 4.54 (m, 1H), 4.51 - 4.39 (m, 1H), 4.37 - 4.27 (m, 1H), 4.27 - 4.15 (m, 3H), 4.07 - 3.89 (m, 5H), 3.87 - 3.73 (m, 2H), 3.42 (s, 2H), 3.26 - 3.18 (m, 8H), 3.12 - 3.01 (m, 1H), 2.95 - 2.74 (m, 2H), 2.74 - 2.64 (m, 1H), 2.63 (s, 3H), 2.56 - 2.49 (m, 1H), 2.48 - 2.37 (m, 1H), 2.22 - 2.12 (m, 1H), 1.99 - 1.73 (m, 4H), 1.63 (s, 1H), 1.54 - 1.48 (m, 3H), 1.36 - 1.23 (m, 2H), 0.97 (t, 3H), 0.90 (s, 3H), 0.79 - 0.73 (m, 3H), 0.55 - 0.44

[0165] (m, 3H), 0.01 - -0.08 (m, 3H).

[0166] Example 8: Synthesis of Compound 116a

[0167] Step 1. To a mixture of INT-61 (500 mg, 5.05 mmol) and triphenylphosphine (1.46 g, 5.55 mmol) in DCM (25 mL) at 0°C was added NBS (988 mg, 5.55 mmol) under a N2atmosphere. The mixture was stirred at 0°C for 1 hour. The mixture was added to H2O (30 mL) and extracted with DCM (90 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with EtOAc / hexane to give INT-62 (350 mg, 2.16 mmol) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.40 (s, 1H), 8.22-8.13 (m, 1H), 4.59 (s, 2H). Step 2. To a mixture of INT-62 (350 mg, 2.16 mmol) and INT-3 (350 mg, 2.59 mmol) in MeCN (5 mL) was added potassium carbonate (896 mg, 6.48 mmol). The mixture was stirred at 50°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM to give INT-64 (450 mg, 2.08 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.33 (s, 1H), 8.02 (s, 1H), 3.62 (s, 2H), 3.15- 3.02 (m, 4H), 2.91 (dd, J = 4.0, 6.4 Hz, 4H) Step 3. To a mixture of INT-64 (3.0 g, 14 mmol) in THF (50 mL) at −78°C was added LiHMDS (19 mL, 1 M in THF, 19 mmol) under a N2atmosphere. The mixture was stirred at −78°C for 1 hour. A solution of 1,2-diiodoethane (2.4 mL, 17 mmol) in THF (20 mL) was then added. The mixture was warmed to −20°C and stirred at this temperature for 2 hours. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (50 mL) at a temperature below −30°C and extracted with EtOAc (200 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM to give INT-65 (3.1 g, 9.1 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.13 (s, 1H), 3.59 (s, 2H), 3.14-3.04 (m, 4H), 2.89 (dd, 4H). Step 4. To a mixture of INT-6 (2.0 g, 3.76 mmol) and INT-65 (1.55 g, 4.52 mmol) in 1,4-dioxane (30 mL) and H2O (3.0 mL) was added Pd(dtbpf)Cl2(245 mg, 0.376 mmol) and cesium carbonate (3.68 g, 11.3 mmol). The mixture was stirred at 80°C for 2 hours under a N2atmosphere. Water (30 mL) was added, and the resulting mixture was extracted with EtOAc (90 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM to give INT-66 (2.0 g, 2.9 mmol) as a yellow oil. Step 5. To a solution of INT-66 (3.30 g, 4.70 mmol) in THF (20 mL), MeOH (5.0 mL), and H2O (10 mL) was added LiOH·H2O (592 mg, 14.1 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (150 mL). The combined organic layers were washed with brine (90 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM followed by prep-HPLC to give INT-67 (793 mg, 1.1924 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.30 (d, 1H), 8.30-8.18 (m, 2H), 7.92 (d, 1H), 7.52 (d, 1H), 7.31 (dd, 1H), 4.50 (t, 1H), 4.17-4.01 (m, 2H), 3.92-3.80 (m, 1H), 3.70 (s, 2H), 3.12 (d, 4H), 3.07-2.92 (m, 6H), 2.89 (s, 3H), 2.67 (d, 1H), 2.16 (d, 1H), 1.41 (d, 3H), 1.11 (t, 3H), 0.60 (d, 6H). Step 6. To a degassed suspension of INT-67 (235 mg, 0.356 mmol), INT-9 (344 mg, 0.499 mmol), and sodium carbonate (132 mg, 1.25 mmol) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Pd(dtbpf)Cl2(58 mg, 0.089 mmol). The mixture was stirred at 50°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc (10 mL) and H2O (5 mL), and extracted with EtOAc (150 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM to afford INT-68 (360 mg, 0.315 mmol). LCMS: m / z (ESI) [M+H]+1142.5 tR= 2.23 minutes (Method B)

[0168] Step 7. A suspension of INT-68 (160 mg, 0.140 mmol) and Me3SnOH (190 mg, 1.05 mmol) in DCE (6.5 mL) was stirred at 65°C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc (5 mL) and H2O (1 mL), then acidified to pH ~2 with aqueous 1 M HCl. The organic layer was removed, and the aqueous layer was extracted with EtOAc (60 mL). The combined organic layers were washed with brine (3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give INT-69 (200 mg) as a brown solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1128.7 tR= 1.67 minutes (Method B) Step 8. To a solution of INT-69 (260 mg, 0.182 mmol) in DCM (10.4 mL) at 0°C was added EDC·HCl (1.24 g, 6.46 mmol), HOBt (153 mg, 1.00 mmol), and DIPEA (1.33 mL, 7.64 mmol). The reaction mixture was stirred at 0°C, then gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with DCM (50 mL) and H2O (5 mL). The organic layer was removed, and the aqueous layer was extracted with additional DCM. The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM to give INT-70 (125 mg, 0.113 mmol). LCMS: m / z (ESI) [M+H]+1110.7 tR= 2.34 minutes (Method B) Step 9. To a solution of INT-70 (145 mg, 0.131 mmol) in DCM (7 mL) at 0°C was added TFA (0.70 mL, 9.14 mmol) dropwise. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure and co-evaporated with CHCl3(15 mL) to give INT-71, trifluoroacetic acid (180 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1010.8 tR= 2.18 minutes (Method B) Step 10. To a solution of INT-71, trifluoroacetic acid (160 mg, 0.144 mmol) and N- (tert-butoxycarbonyl)-N-methyl-L-valine (70 mg, 0.303 mmol) in DMF (4.8 mL) at 0°C was added COMU®((1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate) (74 mg, 0.173 mmol) and DIPEA (0.252 mL, 1.44 mmol). The reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was diluted with EtOAc and H2O, and the organic layer was removed. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM to give INT-72 (80 mg, 0.144 mmol). LCMS: m / z (ESI) [M-tBu+H]+1167.7 tR= 2.45 minutes (Method B) Step 11. To a solution of INT-72 (20 mg, 0.016 mmol) in DCM (1 mL) at 0°C was added TFA (0.087 mL, 1.1 mmol) dropwise. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was concentrated under reduced pressure and co-evaporated with CHCl3(15 mL) to give INT-73, trifluoroacetic acid (25 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1123.7 tR= 2.25 minutes (Method B)

[0169] Step 12. To a solution of INT-73, trifluoroacetic acid (60 mg, 0.037 mmol) and INT- 31 (19 mg, 0.063 mmol) in DMF (1.8 mL) at 0°C was added HATU (24 mg, 0.063 mmol) and DIPEA (0.064 mL, 0.37 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (45 mL). The combined organic layers were washed with brine (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography eluting with MeOH / DCM to give INT-74 (65 mg), which was used without further purification. LCMS: m / z (ESI) [M-dipeptide+H]+1010.7 tR= 2.35 minutes (Method B) Step 13. To a solution of INT-74 (55 mg, 0.039 mmol) in DCM (2.5 mL) at 0°C was added TFA (0.21 mL, 2.7 mmol) dropwise. The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was then concentrated under reduced pressure and co-evaporated with CHCl3(15 mL) to afford INT-75 (55 mg), which was used without further purification. LCMS: m / z (ESI) [M-dipeptide+H]+1010.6 tR= 2.18 minutes (Method B) Step 14. To a solution of INT-75 (65 mg, 0.050 mmol) in DMF (2 mL) was added CsF (75 mg, 0.50 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by reverse-phase chromatography on a C-18 column with MeCN / 10 mM ammonium bicarbonate to afford Compound 116a (8.0 mg, 0.070 mmol). LCMS: m / z (ESI) [M+H]+1156.9 tR= 1.55 minutes (Method B) 1H NMR (400 MHz, CDCl3) δ ppm 9.41 (d, 1H), 8.25 (d, 1H), 8.14 (s, 1H), 8.07 (d, 1H), 7.71 – 7.67 (m, 2H), 7.42 (d, 1H), 7.23 – 7.13 (m, 2H), 7.12 – 7.04 (m, 2H), 6.63 – 6.51 (m, 4H), 5.62 – 5.53 (m, 1H), 5.14 (d, 2H), 4.69 – 4.61 (m, 1H), 4.61 – 4.54 (m, 1H), 4.45 – 4.38 (m, 1H), 4.36 (d, 1H), 4.27 – 4.13 (m, 3H), 4.07 – 3.99 (m, 2H), 3.93 (d, 1H), 3.76 (d, 1H), 3.73 – 3.66 (m, 3H), 3.65 – 3.55 (m, 2H), 3.40 (s, 3H), 3.14 – 3.00 (m, 9H), 2.82 (d, 1H), 2.76 – 2.64 (m, 3H), 2.61 (s, 3H), 2.50 (d, 1H), 2.39 – 2.28 (m, 1H), 2.19 – 2.12 (m, 1H), 1.98 – 1.70 (m, 3H), 1.47 (d, 3H), 1.00 – 0.92 (m, 3H), 0.89 (s, 3H), 0.79 (d, 3H), 0.46 (s, 3H), 0.14 (d, 3H). Example 9: Synthesis of Compound 115a

[0170] Step 1. To a solution of INT-13 (89 mg, 0.088 mmol, 1 equiv.) and N-(tert- butoxycarbonyl)-N-methyl-L-valine (43 mg, 0.18 mmol, 2 equiv.) in DMF (2.7 mL) at 0 °C was added DIPEA (114.01 mg, 150.03 μL, 0.88 mmol, 10 equiv.) followed by COMU®(45 mg, 0.11 mmol, 1.25 equiv.). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a C-18 column using MeCN / 10 mM ammonium carbonate to give INT-53 (78 mg, 0.064 mmol) as a white solid. LCMS: m / z (ESI) [M-Boc]+1123.6, tR= 2.43 minutes (Method B) Step 2. To a solution of INT-53 (76 mg, 0.062 mmol, 1 equiv.) in DCM (4.6 mL) at 0 °C was added TFA (501.73 mg, 330.61 μL, 4.3 mmol, 69.35 equiv.) dropwise. The mixture was allowed to warm to 25 °C over 2 hours. The volatiles were removed under reduced pressure, followed by repeated solvent removal after addition of CHCl3to give INT-54 (76 mg), which was used without purification. LCMS: m / z (ESI) [M+H]+1123.9, tR= 2.24 minutes (Method B) Step 3. A mixture of INT-54 (70 mg, 0.062 mmol, 1 equiv.) and INT-31 (29 mg, 0.093 mmol, 1.5 equiv.) in DMF (2.1 mL) was cooled to 0 °C. To this mixture, DIPEA (84.78 mg, 110.88 μL, 0.62 mmol, 10 equiv.) was added, followed by HATU (40 mg, 0.11 mmol, 1.77 equiv.). The mixture was stirred at 0 °C for 20 minutes, then gradually warmed to 25 °C and stirred for 17 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with EtOAc (60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a C-18 column using MeCN / 10 mM ammonium bicarbonate to give INT-55 (89 mg, 0.063 mmol) as an off-white solid. Step 4. To a solution of INT-55 (92 mg, 0.065 mmol, 1 equiv.) in DCM (5.5 mL) at 0 °C was added TFA (532.11 mg, 350.58 μL, 4.6 mmol, 70.77 equiv.) dropwise. The mixture was stirred at 0 °C for 10 minutes, then gradually warmed to 25 °C over 2.5 hours. The volatiles were removed under reduced pressure, followed by repeated solvent removal after addition of CHCl3to give a crude product. The crude residue was dissolved in DMF (2.8 mL), followed by the addition of CsF (69 mg, 0.46 mmol, 7.08 equiv.). The mixture was stirred at 25 °C for 1.5 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with EtOAc (60 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a C-18 column using MeCN / 10 mM ammonium bicarbonate to give Compound 115a (20 mg, 0.017 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1156.7, tR= 1.52 minutes (Method B)1H NMR (400 MHz, CDCl3): δ ppm 9.39 (d, 1H), 8.23 (d, 1H), 8.09 – 8.03 (m, 1H), 7.72 – 7.64 (m, 1H), 7.42 (d, 1H), 7.23 – 7.08 (m, 5H), 6.66 – 6.54 (m, 1H), 5.63 – 5.52 (m, 1H), 5.20 - 5.07 (m, 1H), 4.72 - 4.47 (m, 2H), 4.46 - 4.38 (m, 1H), 4.38 - 4.28 (m, 1H), 4.26 - 4.10 (m, 3H), 4.10 - 3.93 (m, 2H), 3.93 - 3.80 (m, 3H), 3.80 - 3.65 (m, 2H), 3.40 (s, 3H), 3.19 - 2.97 (m, 11H), 2.86 - 2.47 (m, 8H), 2.45 - 2.29 (m, 1H), 2.23 - 2.09 (m, 1H), 2.00 - 1.51 (m, 8H), 1.48 (d, 3H), 1.01 - 0.92, (m, 3H), 0.89 (s, 3H), 0.82 - 0.71 (m, 3H), 0.47 (s, 3H), 0.19 - 0.04 (m, 3H)

[0171] Example 13: Synthesis of Compound 117a

[0172] Step 1. A mixture of INT-76 (2.00 g, 3.26 mmol), zinc cyanide (230 mg, 1.96 mmol), and Pd(PPh3)4(754 mg, 0.652 mmol) in DMF (20 mL) was degassed and purged with N2three times. The mixture was stirred at 80°C for 1 hour under a N2atmosphere. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (90 mL). The combined organic layers were washed with brine (90 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography eluting with EtOAc / hexane to give INT-77 (1.4 g, 2.7 mmol) as a yellow oil. Step 2. To a solution of INT-77 (500 mg, 0.976 mmol) in EtOH (4 mL) and H2O (4 mL) was added hydroxylammonium chloride (102 mg, 1.46 mmol) and sodium carbonate (124 mg, 1.17 mmol). The mixture was stirred at 80°C for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with H2O (10 mL) and extracted with EtOAc (60 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give INT-78 (600 mg) as a yellow oil, which was used without further purification. Step 3. To a solution of INT-78 (600 mg, 1.10 mmol) in DCM (6 mL) at 0°C was added 2-chloroacetyl chloride (149.07 mg, 1.32 mmol) and DIPEA (0.383 mL, 2.20 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in toluene (6 mL) and stirred at 140°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with EtOAc / hexane to give INT-79 (450 mg) as a yellow oil, which was used without further purification. Step 4. To a solution of INT-79 (500 mg, 0.828 mmol) and INT-3 (134 mg, 0.993 mmol) in DMF (5 mL) at 0°C was added DIPEA (0.433 mL, 2.48 mmol). The reaction mixture was stirred at 60°C for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (45 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with EtOAc / hexane to give INT-80 (300 mg, 0.427 mmol) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.34 (d, 1H), 8.34 (d, 1H), 7.83 (s, 1H), 7.54 (d, 1H), 7.37-7.25 (m, 1H), 4.28 (s, 2H), 4.21-4.05 (m, 2H), 3.94-3.83 (m, 1H), 3.63-3.46 (m, 2H), 3.22-3.06 (m, 9H), 2.88 (s, 3H), 2.75 (d, 1H), 2.28 (d, 1H), 1.82 (s, 3H), 1.44 (d, 3H), 1.16-1.09 (m, 3H), 0.77-0.62 (m, 6H). Step 5. To a solution of INT-80 (860 mg, 1.22 mmol) in MeOH (9 mL) and H2O (3 mL) was added LiOH·H2O (257 mg, 6.12 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (90 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with EtOAc / hexane to give INT-81 (520 mg, 0.744 mmol) as a white solid.1H NMR (400 MHz, DMSO-d6): δ ppm 9.34 (d, 1H), 8.31 (d, 1H), 7.93 (d, 1H), 7.52 (d, 1H), 7.31 (dd, 1H), 4.50 (t, 1H), 4.28 (s, 2H), 4.19-4.05 (m, 2H), 3.92-3.79 (m, 1H), 3.14 (m, 8H), 3.04 (dd, 1H), 2.96 (dd, 1H), 2.91 (s, 3H), 2.68 (d, 1H), 2.16 (d, 1H), 1.42 (d, 3H), 1.11 (t, 3H), 0.60 (d, 6H). Step 6. To a solution of INT-81 (400 mg, 0.605 mmol), INT-9 (543 mg, 0.787 mmol), Pd(dtbpf)Cl2(99 mg, 0.151 mmol), and sodium carbonate (225 mg, 2.12 mmol) in a flask purged with Ar was added degassed 1,4-dioxane (8 mL) and degassed H2O (1.6 mL). The mixture was purged with Ar by bubbling through the suspension and stirred at 85°C for 1.5 hours. The reaction mixture was cooled to room temperature and filtered over Celite®, followed by washing with EtOAc (700 mL). The solvent was evaporated to approximately half the volume, and EtOAc (150 mL) and water (150 mL) were added. The organic layer was removed, and the aqueous phase was extracted with additional EtOAc (300 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM followed by prep-HPLC to afford INT-82 (321 mg, 0.281 mmol). LCMS: m / z (ESI) [M-Boc+H]+1043.7 tR= 1.78 minutes (Method A) Step 7. A suspension of INT-82 (320 mg, 0.280 mmol) and Me3SnOH (329 mg, 1.82 mmol) in DCE (9.33 mL) was sealed and stirred at 65°C for 16 hours. The reaction mixture was cooled to room temperature and adjusted to pH ~2–3 by dropwise addition of aqueous 1 M HCl. The organic layer was removed, and the aqueous layer was extracted with DCM (120 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was washed with hexane, sonicated, and evaporated to provide INT-83 (316 mg) as a yellow solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1129.7 tR= 0.76 minutes (Method A)

[0173] Step 8. To a solution of INT-83 (316 mg, 0.280 mmol) in DCM (17.5 mL) at 0°C was added EDC·HCl (1.90 g, 9.93 mmol), HOBt (236 mg, 1.54 mmol), and DIPEA (2.19 mL, 12.6 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was then cooled to 0°C, quenched with H2O (40 mL), and extracted with DCM (120 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography with MeOH / DCM followed by prep-HPLC to afford INT-84 (150 mg, 0.11 mmol). LCMS: m / z (ESI) [M+H]+1111.8 tR= 2.00 minutes (Method A) Step 9. To a solution of INT-84 (60 mg, 0.054 mmol) in DCM (2.7 mL) cooled to 0°C was added TFA (0.29 mL, 3.8 mmol) dropwise. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (45 mL) to afford INT-85, trifluoroacetic acid (61 mg) as a yellow solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1011.7 tR= 1.61 minutes (Method A) Step 10. To a solution of INT-85, trifluoroacetic acid (50 mg, 0.044 mmol) and INT- 34 (33 mg, 0.080 mmol) in DMF (1.1 mL) cooled to −40°C was added HATU (30 mg, 0.080 mmol) and DIPEA (0.077 mL, 0.444 mmol). The mixture was stirred at −40°C for 1 hour. The reaction was warmed to room temperature and diluted with EtOAc (10 mL), followed by the addition of saturated aqueous sodium bicarbonate (10 mL). The organic layer was removed, and the aqueous layer was extracted with additional EtOAc (30 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a C-18 column with MeCN / 0.01 M ammonium bicarbonate to provide INT-86 (35 mg, 0.022 mmol). Step 11. To a solution of INT-86 (35 mg, 0.025 mmol) in DCM (1.2 mL) cooled to 0°C was added TFA (0.13 mL, 1.7 mmol) dropwise. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and co-evaporated with toluene (45 mL) to afford INT-87 (35 mg) as a yellow solid, which was used without further purification. Step 12. To a solution of INT-87, trifluoroacetic acid (35 mg) in DMF (1.3 mL) cooled to 0°C was added CsF (85 mg, 0.56 mmol). The mixture was stirred at 0°C for 3 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (40 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a C-18 column with MeCN / 0.01 M ammonium bicarbonate followed by prep-HPLC to afford Compound 117a (12 mg, 0.010 mmol) as a white solid. LCMS: m / z (ESI) [M+H]+1157.6 tR= 1.56 minutes (Method B) 1H NMR (400 MHz, CDCl3): δ ppm 9.47 (s, 1H), 8.33 – 8.27 (m, 1H), 8.14 (d, 1H), 8.09 (d, 1H), 7.74 – 7.65 (m, 1H), 7.44 – 7.39 (m, 1H), 7.23 – 7.14 (m, 2H) 7.13 – 7.03 (m, 2H), 6.65 – 6.50 (m, 4H), 5.65 – 5.23 (m, 1H), 5.19 – 5.11 (m, 1H), 4.71 – 4.52 (m, 2H), 4.49 – 4.40 (m, 1H), 4.40 – 4.30 (m, 1H), 4.25 – 4.00 (m, 7H), 3.96 – 3.87 (m, 1H), 3.80 – 3.50 (m, 4H), 3.43 – 3.38 (m, 3H), 3.28 – 3.18 (m, 4H), 3.19 – 3.01 (m, 6H), 2.94 – 2.59 (m, 7H), 2.55 – 2.47 (m, 1H), 2.42 – 2.30 (m, 1H), 2.21 – 2.12 (m, 1H), 2.03 – 1.86 (m, 2H), 1.86 – 1.73 (m, 1H), 1.52 – 1.44 (m, 3H), 1.02 – 0.94 (m, 3H), 0.93 – 0.85 (m, 3H), 0.85 – 0.75 (m, 3H), 0.50 – 0.43 (m, 3H), 0.18 – 0.09 (m, 3H) Example 22: Synthesis of Compound 124a

[0174] Step 1. To a solution of INT-40 (67 mg, 0.064 mmol) and INT-56 (27 mg, 0.077 mmol) in degassed 1,4-dioxane (1.3 mL) and degassed H2O (0.27 mL) was added Pd(dtbpf)Cl2(10 mg, 0.016 mmol) and cesium carbonate (52 mg, 0.16 mmol) under an Ar atmosphere. The mixture was purged with Ar and stirred at 65°C for 1 hour. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by reverse-phase chromatography on a C-18 column with MeOH / 0.01 M ammonium bicarbonate to afford INT-57 (37 mg, 0.033 mmol). LCMS: m / z (ESI) [M+H]+1119.9 tR= 2.15 minutes (Method A) Step 2. To a solution of INT-57 (32 mg, 0.028 mmol) in DCM (1.4 mL) cooled to 0°C was added TFA (0.15 mL, 2.0 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure, and co-evaporated with toluene (45 mL) to give INT-58, trifluoroacetic acid (32 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1019.9 tR= 1.81 minutes (Method A) Step 3. To a solution of INT-58, trifluoroacetic acid (32 mg, 0.028 mmol) in DMF (0.7 mL) cooled to −40°C was added INT-34 (21 mg, 0.051 mmol), HATU (19 mg, 0.28 mmol), and DIPEA (0.049 mL, 0.28 mmol). The mixture was stirred at −40°C for 1 hour, then warmed to room temperature. The reaction mixture was directly purified by reverse-phase chromatography on a C-18 column with MeOH / 0.01 M ammonium bicarbonate to afford INT- 59 (32 mg, 0.023 mmol). LCMS: m / z (ESI) [M / 2+H]+711.7 tR= 2.08 minutes (Method A) Step 4. To a solution of INT-59 (32 mg, 0.023 mmol) in DCM (1.1 mL) cooled to 0°C was added TFA (0.12 mL, 1.57 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and co- evaporated with toluene (45 mL) to give INT-60, trifluoroacetic acid (32 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1321.7 tR= 1.84 minutes (Method A) Step 5. To a solution of INT-60, trifluoroacetic acid (32 mg) in DMF (1.1 mL) cooled to 0°C was added CsF (71 mg, 0.47 mmol). The mixture was stirred at 0°C for 4 hours, then warmed to room temperature. The reaction mixture was directly purified by reverse-phase chromatography on a C-18 column with MeCN / 10 mM ammonium bicarbonate to afford Compound 124 (8.1 mg, 0.069 mmol). LCMS: m / z (ESI) [M+H]+1165.9 tR= 1.69 minutes (Method B) 1H NMR (400 MHz, CDCl3) δ ppm 9.02 (d, 1H), 8.14 (s, 1H), 8.07 (d, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.62-7.54 (m, 2H), 7.46-7.40 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 – 7.05 (m, 2H), 6.66 – 6.57 (m, 3H), 6.56 – 6.50 (m, 1H), 5.63 – 5.53 (m, 1H), 5.15 (d, 1H), 4.69 – 4.62 (m, 1H), 4.62 – 4.55 (m, 1H), 4.46 – 4.38 (m, 1H), 4.35 (d, 1H), 4.31 – 4.13 (m, 3H), 4.07 – 3.97 (m, 2H), 3.93 (d, 1H), 3.77 (d, 1H), 3.75 – 3.54 (m, 5H), 3.40 (s, 3H), 3.12 – 2.97 (m, 10H), 2.94 – 2.63 (m, 4H), 2.61 (s, 3H), 2.53 (d, 1H), 2.40 – 2.26 (m, 1H), 2.19 – 2.10 (m, 1H), 2.01 – 1.86 (m, 2H), 1.86 – 1.70 (m, 1H), 1.55 – 1.46 (m, 3H), 1.01 – 0.94 (m, 3H), 0.88 (s, 3H), 0.79 (d, 3H), 0.49 (s, 3H), 0.14 (d, 3H) Example 26: Synthesis of Compound 201a

[0175] Step 1. INT-16 (2.88 g, 4.99 mmol), Pd(dppf)Cl2(521 mg, 0.712 mmol), INT-15 (2.36 g, 3.56 mmol), and sodium carbonate (1.51 g, 14.3 mmol) were charged to a 250 mL round- bottom flask. The reaction vessel was purged with N2three times. Sequentially, 1,4-dioxane (57 mL) and water (11 mL) were added. The reaction mixture was stirred and heated to 80 °C for 4 hours. The reaction was cooled to room temperature, diluted with water and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude residue. This material was purified by silica gel column chromatography (0- 50% ethyl acetate / heptane) and then repurified by reverse-phase chromatography (10-90% MeCN / water with 0.1% TFA). Fractions containing the product were combined and concentrated. The resulting aqueous layer was neutralized with solid sodium bicarbonate, and the product was extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered, and concentrated to afford INT-17 (852 mg, 0.824 mmol). LCMS: m / z (ESI) [M+H]+1035.9, tR= 3.78 min (Method E) Step 2. Trimethyltinhydroxide (968 mg, 5.35 mmol) was added to a 250 mL round- bottom flask containing INT-17 (852 mg, 0.824 mmol) in DCE (52 mL). The reaction vessel was sealed and heated to 65 °C for 48 hours. The mixture was cooled to room temperature, filtered over Celite®, and washed with DCM (50 mL). The filtrate was concentrated to afford INT-18 (927 mg) as a yellow solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1022.0, tR= 3.63 min (Method E) Step 3. To a solution of INT-18 (300 mg, 0.294 mmol), methyl (S)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate trifluoroacetate (103 mg, 0.382 mmol), and HATU (145 mg, 0.382 mmol) in DMF (5.9 mL) under an argon atmosphere at 0 °C was added DIPEA (0.253 mL, 1.47 mmol). The mixture was stirred at 0 °C for 1 hour. The reaction was diluted with water (1 mL) and EtOAc (1 mL), and the organic extracts were removed. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with 10% aqueous LiCl, dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford INT-19 (354 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1158.8, tR= 4.41 min (Method F) Step 4. A solution of INT-19 (341 mg, 0.294 mmol) and trimethyltinhydroxide (319 mg, 1.77 mmol) in DCE (5.9 mL) was heated to 65 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite®, and rinsed with additional DCM. The filtrate was concentrated to afford INT-20 (474 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1145.5, tR= 4.27 min (Method F)

[0176]

[0177] Step 5. To a solution of INT-20 (337 mg, 0.294 mmol) and TCFH (248 mg, 0.883 mmol) in MeCN (15 mL) under an argon atmosphere at 0 °C was added 1 -methylimidazole (145 mg, 1.77 mmol). The reaction mixture was stirred for 2 hours at 0 °C. The mixture was diluted with water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc.

[0178] The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by reverse-phase chromatography (10-90% MeCN / water with 0.1% TFA). The product fractions were combined and concentrated to remove MeCN. The remaining aqueous mixture was neutralized with solid sodium bicarbonate and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to yield INT-21 (61 mg, 0.054 mmol). LCMS: m / z (ESI) [M+Na]+1126.7, tR= 3.87 min (Method E) Step 6. A vial containing INT-21 (60 mg, 0.053 mmol), paraformaldehyde (8.0 mg, 0.27 mmol), and palladium hydroxide on carbon (37 mg, 20% wt, 0.053 mmol) was evacuated and backfilled with N₂ three times. MeOH (1.3 mL) was added, and a hydrogen balloon was attached. Hydrogen was bubbled through the mixture for 10 minutes while stirring at room temperature, and the reaction was then stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was purged with N₂, filtered through a Celite®plug, and the solids were washed with additional MeOH. The combined filtrate was concentrated to yield INT-22 (45 mg) as a white solid, which was used without further purification. LCMS: m / z (ESI) [M+H]+1007.6, tR= 3.22 min (Method E) Step 7. To a solution of INT-22 (60 mg, 0.060 mmol) in DCM (0.4 mL) at room temperature was added TFA (0.14 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated via azeotrope under a stream of nitrogen with DCM three times to provide INT-23 (45 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+906.6 tR= 2.44 min (Method E) Step 8. To a solution of INT-14 (24 mg, 0.079 mmol) and INT-23 (55 mg, 0.061 mmol) in DMF (1.2 mL) at -35 °C (MeCN in a dry ice bath) was added solid HATU (37 mg, 0.097 mmol) followed by DIPEA (85 μL, 0.49 mmol). The reaction mixture was stirred for 1 hour at -35 °C. The reaction was diluted with water and EtOAc, and the organic layer was removed. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide INT-24 (80 mg), which was used without further purification. LCMS: m / z (ESI) [M+H]+1194.4 tR= 3.17 min (Method E) Step 9. To a solution of INT-24 (72 mg, 0.060 mmol) in DMF (0.60 mL) at room temperature was added solid CsF (23 mg, 0.15 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The mixture was diluted with water and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by prep- HPLC to afford Compound 201a (13 mg, 0.013 mmol). LCMS: m / z (ESI) [M+H]+1038.0, tR= 2.31 min (Method E) 1H NMR (400 MHz, CDCl3): δ 8.48 (d, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.65 (d, 1H), 7.40 (d, 1H), 7.34 – 7.26 (m, 5H), 7.24-7.19 (m, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 6.64 (s, 1H), 6.61 – 6.53 (s, 1H), 5.44 – 5.34 (m, 2H), 5.21 (d, 1H), 4.77 – 4.63 (m, 2H), 4.47 (d, 1H), 4.35 – 4.10 (m, 5H), 3.87 – 3.76 (m, 2H), 3.66 (d, 1H), 3.37 (s, 3H), 3.26 (s, 4H), 3.06 – 2.95 (m, 1H), 2.86 – 2.71 (m, 2H), 2.68 – 2.62 (m, 5H), 2.62 – 2.49 (m, 6H) 2.48 – 2.33 (m, 5H), 2.25 – 2.17 (m, 1H), 1.99 – 1.87 (m, 1H), 1.63 – 1.56 (m, 1H), 1.44 (d, 3H), 1.00 – 0.94 (m, 3H), 0.89 (s, 3H), 0.77 (d, 3H), 0.44 (s, 3H), 0.00 (d, 3H) The following examples were synthesized using methods similar to those described above:

[0179] 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 curve model is applied to the data. GIC50s are extrapolated from the generated curves. Table B1.

[0180] 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 or Genedata Screener 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 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 1:1 binding (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] 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 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 that correlate with experimentally determined FRET G12C IC50activity. Subsequently, the FRET G12C IC50activity 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 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 45 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 and untreated conditions 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 doseresponse 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.

[0181] Table B8. Notes: "A": GI50< 0.1 nM; "B": 0.1 nM ≤ GI50< 1 nM; "C": 1 nM ≤ GI50< 10 nM; "D": 10 nM ≤ GI50< 100 nM; "E": 100 nM ≤ GI50< 1000 nM; "F": GI50≥ 1000 nM † : A GI50value could not be determined under the conditions of the experiment N.D. : Not determined 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 45 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 add...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: L1and L2are independently selected from the group consisting of: a bond, -O-, - N(Rf)-, and C1-3alkylene optionally substituted with 1-3 Rc; Ring E is selected from the group consisting of: phenylene and 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra; R5is a 4-10 membered heterocyclyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 R15; each R15is independently selected from the group consisting of Raand Rb; Ring D is selected from the group consisting of:, ,wherein xx and yy represent the points of attachment to Ring D; Z1is selected from the group consisting of -C(=O)-, -S(O)1-2-, andwherein aa represents the point of attachment to Z2, and Rzis selected from the group consisting of: C1-6alkyl optionally substituted with 1-6 Rc;Rb1; and -(C1-3alkylene)-Rb1, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; Z2is selected from the group consisting of: a bond; -N(Rf)-; -O-; -N(Rf)C(=O)-*; - OC(=O)-*; -N(Rf)S(O)1-2-*; -N(Rf)C(=O)O-*; -N(Rf)C(=O)N(Rf)-; and -N(Rf)S(O)1-2N(Rf)-, wherein the * represents point of attachment to R1; R1is selected from the group consisting of: H; C1-6alkyl optionally substituted with 1-6 Rc; and -L10-R10, wherein: L10is a bond or C1-3alkylene optionally substituted with 1-3 Rc, and R10is selected from the group consisting of C3-8cycloalkyl and 4-10 membered heterocyclyl, each of which is optionally substituted with 1-4 R11, wherein each R11is independently selected from the group consisting of: Raand Rb; m is 0, 1, or 2; each R2is independently selected from the group consisting of: halo; CN; C1-3alkyl optionally substituted with 1-3 Rc; and C1-3alkoxy optionally substituted with 1-3 Rc; R3is selected from the group consisting of: -C1-6alkyl optionally substituted with 1-6 Rc; Rb2; and -(C1-3alkylene)-Rb2, wherein the C1-3alkylene portion is optionally substituted with 1- 3 Rc; R4is selected from the group consisting of: H; and C1-3alkyl optionally substituted with 1-3 Rc;each R6is independently selected C1-3alkyl optionally substituted with 1-3 Rc; each Rais independently selected from the group consisting of: (a) halo; (b) -CN; (c) -OH; (d) oxo; (e) -C1-6alkoxy optionally substituted with 1-3 Rc; (f) -NRdRe; (g) C(=O)C1-6alkyl optionally substituted with 1-3 Rc; (h) C(=O)OH; (i) C(=O)OC1-6alkyl optionally substituted with 1-3 Rc; (j) C(=O)N(Rf)2; (k) S(O)0-2(C1-6alkyl) optionally substituted with 1-3 Rc; (l) S(O)1-2N(Rf)2; and (m) C1-6alkyl optionally substituted with 1-6 Rc; each Rbis independently selected from the group consisting of: -(Lb)b-Rb1and -Rb1, wherein: b is 1, 2, or 3; 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, 4-10 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 Rg; each Rb2is independently selected from the group consisting of C3-6cycloalkyl and 4- 6 membered heterocyclyl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: Rh, C1-3alkyl, and C1-3haloalkyl; each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, -C1-6haloalkoxy, -NRdRe, C(=O)OH, C(=O)O(C1-3alkyl), C(=O)N(Rf)2, S(O)0-2(C1-6alkyl), S(O)0-2(C1-6haloalkyl), and S(O)1-2N(Rf)2;each Rdand Reis independently selected from the group consisting of: H, C(=O)C1-6alkyl, C(=O)C1-6haloalkyl, C(=O)OC1-6alkyl, C(=O)OC1-6haloalkyl, 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 Rh; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 Rh; each Rgis independently selected from the group consisting of: Rh, Ri, -(C1-3alkylene)- Ri, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy; and each Riis independently selected from the group consisting of: C3-6cycloalkyl, 4-8 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, - CN, C1-3alkyl, and C1-3haloalkyl.

2. The compound of claim 1, wherein L1is a bond.

3. The compound of claim 1, wherein L1 is O.

4. The compound of any one of claims 1-3, wherein L2is a bond.

5. The compound of any one of claims 1-3, wherein L2is C1-3alkylene (e.g., L2is CH2).

6. The compound of claim 1, whereinis selected from the group consisting of:optionally wherein.

7. The compound of any one of claims 1-6, wherein Ring E is a phenylene (e.g., 1,4-phenylene) optionally substituted with 1-2 Ra.

8. The compound of any one of claims 1-6, wherein Ring E is a 5-6 membered heteroarylene (e.g., oxazolylene, oxadiazolylene, pyrazolylene, isooxazolylene, pyridinylene, or pyrimidinylene) optionally substituted with 1-2 Ra; optionally wherein Ring E is selected from the group consisting of:,wherein aa represents the point of attachment to -L2-R5.

9. The compound of any one of claims 1-8, wherein R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 Ra; optionally wherein R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with 1-3 Rc(e.g., R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with -NH2or -OH); or wherein R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; or wherein R5is selected from the group consisting of:, , , ,10. The compound of claim 1, whereinis selected from the group consisting of:

11. The compound of claim 1, whereinRing E is selected from the group consisting of phenylene and 5-6 membered heteroarylene, each of which optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; andR5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with 1-3 Rc; optionally whereinRing E is a 5-membered heteroarylene optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; and R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc.

12. The compound of claim 11, wherein R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with -NH2or - OH; optionally wherein R5is13. The compound of claim 11, wherein R5is a 6-8 membered heterocyclyl having one ring nitrogen atom and one ring S(O)2, wherein the 6-8 membered heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 -F; optionally wherein R5is14. The compound of any one of claims 11-13, wherein Ring E is selected from the group consisting of:, wherein aa represents the point of attachment to -CH2R5.

15. The compound of any one of claims 11-13, wherein Ring E is 1,4-phenylene.

16. The compound of any one of claims 1-15, wherein Ring D is(e.g.,17. The compound of any one of claims 1-15, wherein Ring D is(e.g.,18. The compound of any one of claims 1-17, wherein m is 0.

19. The compound of any one of claims 1-18, wherein R3is -C1-6alkyl optionally substituted with 1-6 Rc; optionally wherein R3is -C1-3alkyl optionally substituted with 1-3 -F (e.g., R3is ethyl).

20. The compound of any one of claims 1-19, wherein R4is C1-3alkyl optionally substituted with 1-3 Rc; optionally wherein R4is C1-3alkyl substituted with C1-3alkoxy; orwherein R4is21. The compound of any one of claims 1-20, wherein each R6is methyl.

22. The compound of any one of claims 1-21, wherein Z1is23. The compound of any one of claims 1-22, wherein Rzis C1-6alkyl optionally substituted with 1-6 Rc; optionally wherein Rzis an isopropyl.

24. The compound of any one of claims 1-22, wherein Rzis Rb1, wherein the Rb1is a C3-5cycloalkyl; optionally wherein Rzis a cyclopentyl.

25. The compound of any one of claims 1-24, wherein Z2is -N(Rf)C(=O)-*; optionally wherein Z2is -N(Me)C(=O)-*.

26. The compound of any one of claims 1-22, wherein -NH-Z1-Z2-R1is:.

27. The compound of any one of claims 1-26, wherein R1is selected from the group consisting of C3-6cycloalkyl and 4-6 membered heterocyclyl, each of which is optionally substituted with 1-2 R11.

28. The compound of any one of claims 1-22, wherein -NH-Z1-Z2-R1is selectedfrom the group consisting of:(e.g.,and; optionally wherein -NH-Z1-Z2-R1is selected from the group consisting of:, ; wherein -NH-Z1-Z2-R1is whereg fin the R is -N(R)2(e.g., -NH2or -NMe2); and Rzis C1-6alkyl or C3-5cycloalkyl; or wherein -NH-Z1-Z2-R1is whereing fthe R is -N(R)2(e.g., -NH2or -NMe2); orwherein -NH-Z1-Z2-R1is29. The compound of claim 1, wherein the compound is a compound of Formula (I-a):or a pharmaceutically acceptable salt thereof, wherein: Ring E is selected from the group consisting of phenylene and 5-6 membered heteroarylene, each of which optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with 1-3 Rc; R4is a C1-3alkyl substituted with C1-3alkoxy; R3is a C1-6alkyl optionally substituted with 1-6 Rc; and Rzis selected from the group consisting of: (a) C3-5cycloalkyl; and (b) C1-6alkyl optionally substituted with 1-6 Rc.

30. The compound of claim 29, wherein:Ring E is a 5-membered heteroarylene optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 Rc; and Rzis a C1-6alkyl optionally substituted with 1-6 Rc.

31. The compound of claim 29 or 30, wherein: each Rcis independently selected from the group consisting of: halo, -CN, -OH, -NH2, -C1-6alkoxy, and -C1-6haloalkoxy; each Rfis independently selected from the group consisting of: H and C1-6alkyl optionally substituted with 1-3 -F; each Rgis independently selected from the group consisting of: Rh, -N(Rf)2, C1-3alkyl, and C1-3haloalkyl; and each Rhis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy.

32. The compound of any one of claims 29-31, wherein each Rcis independently selected from the group consisting of: halo, -CN, -OH, -C1-6alkoxy, and -C1-6haloalkoxy.

33. The compound of any one of claims 29-32, wherein themoiety is selected from the group consisting of:optionallywherein themoiety is selected from the group consisting of:

34. The compound of any one of claims 29-33, wherein Rgis -N(Rf)2.

35. The compound of any one of claims 29-32, wherein themoiety is(e.g.,36. The compound of any one of claims 29-35, wherein R5is a 6-8 membered heterocyclyl having one ring nitrogen atom and one ring S(O)2, wherein the 6-8 membered heterocyclyl is optionally substituted with 1-3 substituents each independently selected from the group consisting of: -F and C1-3alkyl optionally substituted with 1-3 -F; optionally wherein R5is37. The compound of any one of claims 29, 31, or 33-36, wherein R5is a 4-8 membered heterocyclyl optionally substituted with 1-3 substituents each independentlyselected from the group consisting of: -F, -CN, -S(O)2(C1-6alkyl), and C1-3alkyl optionally substituted with -NH2or -OH; optionally wherein R5is38. The compound of any one of claims 29-37, wherein Ring E is selected from the group consisting of:, wherein aa represents the point of attachment to -CH2R5.

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

40. A pharmaceutical composition comprising a compound of any one of claims 1- 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

41. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

42. 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 1-39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

43. 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 compoundof any one of claims 1-39 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

44. The method of any one of claims 42 or 43, wherein the Ras dysregulation is selected from a KRas dysregulation, a NRas dysregulation, and a HRas dysregulation.

45. The method of any one of claims 41-44, 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.

46. The method of claim 45, wherein the cancer is pancreatic cancer (e.g., pancreatic ductal adenocarcinoma).

47. The method of claim 45, wherein the cancer is a skin cancer (e.g., cutaneous melanoma).

48. The method of any one of claims 41-47, comprising administering an additional therapy or therapeutic agent to the subject.

49. The method of claim 48, wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway targeted therapeutic agents, kinase-targeted therapeutics, 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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