IL327005A

IL327005A - Spirocyclic dihydropyranopyridine kras inhibitors

Info

Publication number: IL327005A
Application number: IL327005A
Authority: IL
Original assignee: Treeline Biosciences Inc
Priority date: 2023-09-21
Filing date: 2024-09-20
Publication date: 2026-05-01
Also published as: EP4780823A1; KR20260074662A; AU2024344161A1; WO2025064848A1; CN121889400A; TW202528315A; MX2026003472A

Description

WO 2025/064848 PCT / US2024 / 0477 Spirocyclic Dihydropyranopyridine KRas Inhibitors LO CROSS - REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial Nos . 63 / 685,160 , filed August 20 , 2024 ; 63 / 675,512 , filed July 25 , 2024 ; 63 / 653,043 , filed May 29 , 2024 ; / 650,239 , filed May 21 , 2024 ; 63 / 567,238 , filed March 19 , 2024 ; 63 / 559,588 , filed February , 2024 ; 63 / 614,278 , filed December 22 , 2023 ; and 63 / 539,749 , filed September 21 , 2023 , each of which is incorporated by reference it its entirety herein .

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY This application contains a Sequence Listing which has been submitted electronically in XML format . The Sequence Listing XML is incorporated herein by reference . The XML file , created on September 9 , 2024 , is named TRLN - 008-017WO1_ST26_SL.xml and is 2,0bytes in size .

TECHNICAL FIELD This disclosure provides compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or pharmaceutically acceptable salts thereof , that inhibit a KRas GTPase ( e.g. , a KRas GTPase that has a dysregulation ( referred to herein as a dysregulated KRas protein ) ) . In some embodiments , the KRas protein is a dysregulated KRas protein that has a mutation ( referred to herein as a mutant KRas protein ) . These compounds are useful , for example , for treating a disease , disorder , or condition in which increased and / or sustained ( e.g. , excessive ) KRas activation , such as KRas activation associated with a mutant KRas 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 ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or pharmaceutically acceptable salts thereof , as well as methods of using and making the same .

BACKGROUND The KRAS gene is frequently dysregulated ( e.g. , mutated or amplified ) in various WO 2025/064848 PCT / US2024 / 0477 LO human cancers . Oncogenic mutations in KRas typically occur at hotspots in the protein such as at amino acids positions 12 , 13 , and 61. In some cases , a mutation can lead to maintenance of KRas activation ( GTP - bound state ) , e.g. , due to a deficiency of intrinsic GTPase activity and / or insensitivity for GTPase - activating proteins ( GAPs ) and consequent increased KRas signaling . Specifically , some of the most common protein mutations include those at position ( referred to herein as G12X ) such as G12A , G12C , G12D , G12R , G12S , and G12V ; position ( referred to herein as G13X ) such as G13C , G13D , and G13V ; and Q61 ( referred to herein as Q61X ) , such as Q61E , Q61H , Q61K , Q61L , Q61P , and Q61R . KRas is widely recognized as a target for the design and development of therapies that can specifically bind and inhibit KRas signaling in cancer cells but had long been considered to be undruggable . Currently , there are few approved KRas - targeted therapies . In some embodiments , the KRas protein is a dysregulated KRas protein that has a mutation ( referred to herein as a mutant KRas protein ) . These compounds are useful , for example , for treating a disease , disorder , or condition in which increased and / or sustained ( e.g. , excessive ) KRas activation , such as KRas activation associated with a mutant KRas 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 the same as well as methods of using and making the same .

SUMMARY This disclosure provides compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or pharmaceutically acceptable salts thereof , that inhibit a KRas protein ( e.g. , a dysregulated KRas protein , such as a mutant KRas protein ) . These compounds are useful , for example , for treating a disease , disorder , or condition in which increased KRas activation , such as KRas activation associated with a mutant KRas protein or KRas activation associated with KRas 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 ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I- b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or pharmaceutically acceptable salts thereof , as well as methods of using and making the same .

Provided herein are compounds of Formula ( A ) 2 R E B ' N ' R Formula ( A ) PCT / US2024 / 0477 or pharmaceutically acceptable salts thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : -CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; A²A b2 ( R7 ) . ( ii ) ﻭ wherein b2 is 0 , 1 , 2 , or 3 ; and A1 and A2 are independently selected from the group consisting of : N , CH , and CR7 ; ( iii ) -N ( ²R ) 2 , wherein each ²R is independently selected from the group consisting of : - H and C1-6 alkyl optionally substituted with 1-3 Rc ; and ( iv ) -H ; each R7 is independently selected from the group consisting of Ra and Rb ; ⁹R Ring B is : b1 ( R10 ) * 3- * E , wherein the marks the ring carbon atom common to both Ring B and 1✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , CHRL , C ( RL ) 2 , and : 3 WO 2025/064848 PCT / US2024 / 0477 ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 ; b1 is 0 , 1 , or 2 ; ⁹R is selected from the group consisting of : -H , -OH , -NRdRe , and halo ; each R10 is independently selected from the group consisting of Ra and ³R ; each R is independently selected from the group consisting of C1-3 alkoxy , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe ; each Ra is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) C1-6 alkoxy ; ( f ) C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) -C ( = O ) C1-6 alkyl ; ( i ) -C ( = O ) C1-6 haloalkyl ; 4 WO 2025/064848 PCT / US2024 / 0477 ( j ) -C ( = O ) OH ; ( k ) -C ( = O ) OC1-6 alkyl ; ( 1 ) -C ( = O ) OC1-6 haloalkyl ; ( m ) -C ( = O ) N ( R ) 2 ; ( n ) -S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) -S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) -S ( O ) 1-2N ( R ) 2 ; and wherein : ( q ) C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 Rc ; each Rb is independently selected from the group consisting of : - ( Lb ) b - ¹bR and ¹bR , b is 1 , 2 , or 3 ; each Lb is independently selected from the group consisting of : O , N ( H ) , N ( C1-3 alkyl ) , S ( O ) 0-2 , C ( = O ) , and C1-3 alkylene ; and each ¹¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; ﺶﻣا each R is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , -NRdRe , -C ( = O ) C1-6 alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) OH , -C ( = O ) N ( ³R ) 2 , -S ( O ) 0-2 ( C1-6 alkyl ) , -S ( O ) 0-2 ( C1-haloalkyl ) , and -S ( O ) 1-2N ( ³R ) 2 ; each Rd and Re is independently selected from the group consisting of : H , -C ( = O ) C1-alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) N ( ³R ) 2 , S ( O ) 1-2 ( C1-6 alkyl ) , -S ( O ) 1-2 ( C1-6 haloalkyl ) , -S ( O ) 1-2N ( R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : -H and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2 .

LO WO 2025/064848 PCT / US2024 / 0477 Also provided herein are pharmaceutical compositions comprising a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I- d ) , or ( I - e ) ) ) or Formula ( B ) , 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 ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I- d ) , or ( I - e ) ) ) or Formula ( B ) , 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 KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ) ) ; and ( b ) administering to the subject a therapeutically effective amount of a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as provided herein . Provided herein are methods of treating a KRas - associated disease or disorder ( e.g. , a mutant KRas - associated disease or disorder ( e.g. , a mutant KRas - associated disease or disorder ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D- associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ) ) in a subject , the methods comprising administering to a subject identified or diagnosed as having a KRas - associated disease or disorder a therapeutically effective amount of a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as provided herein . This disclosure also provides methods of treating a KRas - associated disease or disorder ( e.g. , a mutant KRas - associated disease or disorder ( e.g. , a KRas G12A - associated disease or disorder , a KRas G12C - associated disease or disorder , a KRas G12D - associated disease or disorder , a KRas G12R - associated disease or disorder , a KRas G12S - associated disease or disorder , or a KRas G12V - associated disease or disorder ) ) in a subject , the methods comprising : determining that the disease or disorder in the subject is a KRas - associated disease or disorder ( e.g. , a mutant KRas - associated disease or disorder ( e.g. , a KRas G12A - associated 6 WO 2025/064848 PCT / US2024 / 0477 LO disease or disorder , a KRas G12C - associated disease or disorder , a KRas G12D - associated disease or disorder , a KRas G12R - associated disease or disorder , a KRas G12S - associated disease or disorder , or a KRas G12V - associated disease or disorder ) ) ; and administering to the subject a therapeutically effective amount of a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as provided herein .

Further provided herein are methods of treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ) ) in a subject , the methods comprising administering to a subject identified or diagnosed as having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V- associated cancer ) ) a therapeutically effective amount of a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as provided herein . This disclosure also provides methods of treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ) ) in a subject , the methods comprising : determining that the cancer in the subject has a KRas dysregulation ( e.g. , a KRas G12A mutation , a KRas G12C- mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ) ) ; and administering to the subject a therapeutically effective amount of a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as provided herein . 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 7 WO 2025/064848 PCT / US2024 / 0477 LO 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 . The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below . Other features and advantages of the invention will be apparent from the description and drawings , and from the claims .

DETAILED DESCRIPTION This disclosure provides compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or pharmaceutically acceptable salts thereof , that inhibit a KRas protein ( e.g. , a dysregulated KRas protein , such as a mutant KRas protein ) . These compounds are useful , e.g. , for treating a disease , disorder , or condition associated with a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in which increased and / or sustained ( e.g. , excessive ) KRas activation 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 ) . These compounds can also be useful , e.g. , for treating a disease , disorder , or condition in which a mutant KRas protein ( e.g. , a resistance mutation ) confers intrinsic resistance to one or more KRas inhibitors ( e.g. , a KRas inhibitor selective for a KRas G12C mutant protein ) , or to a non - KRas - targeted therapeutic agent . See , e.g. , Misale , et al . , Nature 486.7404 ( 2012 ) : 532-536 and Awad , et al . , New England Journal of Medicine 384.25 ( 2021 ) : 2382-2393 . This disclosure also provides compositions containing the compounds provided herein as well as methods of using and making the same . Ras family genes ( e.g. , KRAS , NRAS , and HRAS ) were the first oncogenes identified and are some of the most commonly mutated of all discovered oncogenes . See , e.g. , Hunter et al . Mol Cancer Res . 2015 ; 13 ( 9 ) : 1325-35 . The Ras family are guanine nucleotide binding proteins generally found at the inner leaflet of the cell membrane . A wild type Ras protein becomes activated when bound to GTP , but it is inactive when bound to GDP . Normally , growth factors bind to extracellular receptors to induce nucleotide exchange with the help of guanine nucleotide exchange factors ( GEF ) ( e.g. , Son of sevenless homolog 1 ( SOS1 ) ) . These GEFs allow GDP to dissociate from a Ras protein and GTP to bind . Ras proteins can interact with effector proteins such as cRAF when bound to GTP . Hydrolysis of GTP to form GDP can WO 2025/064848 PCT / US2024 / 0477 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 ) . There are major RAS proteins in humans : KRas , HRas , and NRas . Some oncogenic KRas missense mutations can prevent or slow GTP hydrolysis and result in the accumulation of KRas in the active state . Signaling pathways associated with KRas are persistently activated in many cancers , where they participate in cellular growth and proliferation , differentiation , protein synthesis , glucose metabolism , cell survival , and inflammation .

Mutant KRas proteins often have altered Raf affinity and / or altered intrinsic GTPase activity . See , for example , Table 1 reproduced from Hunter et al . Mol Cancer Res . 2015 ; 13 ( 9 ) : 1325-35 . These changes and other factors can contribute to increased KRas signaling in mutant KRas proteins .

Table Raf Affinity High Low G12A G12R Low Intrinsic Q61L G12V GTPase Wild type activity High G12C G12D G13D KRas inhibitors are described in , for example , International Publication Nos . WO 2024/112654 ; WO 2023/154766 ; WO 2023/143623 ; WO 2022/240971 ; WO 2020/236940 ; WO 2022/115439 ; WO 2023/086383 ; WO 2021/093758 ; WO 2022/135546 ; WO 2021/139748 ; WO 2022/251576 ; and WO 2023/025116 . Additional examples of KRas inhibitors are described in , for example , International Publication Nos . WO 2022/132200 ; WO 2022/133038 ; WO 2023/150284 ; WO 2022/261154 ; WO 2023/183585 ; WO 2023/099592 ; WO 2023/099623 ; WO 2023/099624 ; WO 2023/099608 ; WO 2022/250170 ; WO 2022/173870 ; WO 2022/236578 ; WO 2022/237649 ; WO 2022/248885 ; WO 2022/256459 ; WO 2022/258974 ; WO 2022/266015 ; WO 2023/018809 ; WO 2023/018810 ; WO 2023/018812 ; WO 2023/020518 ; WO 2023/020519 ; WO 2023/020521 ; WO 2023/020523 ; WO 2023/046135 ; WO 2023/061294 ; WO 9 WO 2025/064848 PCT / US2024 / 0477 2023/097227 ; WO 2023/114733 ; WO 2023/137223 ; WO 2023/141300 ; WO 2023/138583 ; WO 2023/159086 ; WO 2023/159087 ; WO 2023/173016 ; WO 2023/173017 ; WO 2023/179703 ; WO 2023/125627 ; WO 2022/216762 ; WO 2024/030633 ; WO 2023/230190 ; and CN 116143806 .

Compound Embodiments Provided herein are compounds of Formula ( A ) : R B Formula ( A ) or pharmaceutically acceptable salts thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : -CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; ( ii ) b2 ( R7 ) ' N ' SA²A ﻭ wherein b2 is 0 , 1 , 2 , or 3 ; and A1 and A2 are independently selected from the group consisting of : N , CH , and ²RC ; ( iii ) -N ( ²R ) 2 , wherein each ²R is independently selected from the group consisting of : - H and C1-6 alkyl optionally substituted with 1-3 ºR ; and ( iv ) -H ; each R7 is independently selected from the group consisting of Ra and Rb ; ⁹R X Ring B is : b1 ( º¹R ) + 3-ﻭ PCT / US2024 / 0477 wherein the * marks the ring carbon atom common to both Ring B and 0 ' ; H * ' N ' 1✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and ²X and ³X are independently selected from the group consisting of : ₂HC , ¹RHC , C ( ¹R ) 2 , O , and S ( O ) 0-2 , provided that no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 ; b1 is 0 , 1 , or 2 ; ⁹R is selected from the group consisting of : -H , -OH , ªRªRN- , and halo ; each R10 is independently selected from the group consisting of Ra and ³R ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe : each Ra is independently selected from the group consisting of : 11 PCT / US2024 / 0477 ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) C1-6 alkoxy ; ( f ) C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) -C ( = O ) C1-6 alkyl ; ( i ) -C ( = O ) C1-6 haloalkyl ; ( j ) -C ( = O ) OH ; ( k ) -C ( = O ) OC1-6 alkyl ; ( 1 ) -C ( = O ) OC1-6 haloalkyl ; ( m ) -C ( = O ) N ( R ) 2 ; ( n ) -S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) -S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) -S ( O ) 1-2N ( R ) 2 ; and ( q ) C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 ºR ; each ³R is independently selected from the group consisting of : - ( Lb ) b - ¹bR and ¹bR , wherein : b is 1 , 2 , or 3 ; each Lb is independently selected from the group consisting of : O , N ( H ) , N ( C1-3 alkyl ) , S ( O ) 0-2 , C ( = O ) , and C1-3 alkylene ; and each ¹¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each R is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , eRªRN- , -C ( = O ) C1-6 alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) OH , -C ( = O ) N ( ³R ) 2 , -S ( O ) 0-2 ( C1-6 alkyl ) , -S ( O ) 0-2 ( C1-haloalkyl ) , and -S ( O ) 1-2N ( R ) 2 ; each Rd and Re is independently selected from the group consisting of : H , -C ( = O ) C1-alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) N ( ³R ) 2 , - - 12 WO 2025/064848 PCT / US2024 / 0477 LO S ( O ) 1-2 ( C1-6 alkyl ) , -S ( O ) 1-2 ( C1-6 haloalkyl ) , -S ( O ) 1-2N ( R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : -H and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : ¹R , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2 .

In some embodiments of Formula ( A ) , ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : -CN , halo , C1-3 alkyl , C1-haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; and ( ii ) b2 ( R7 ) . ' N ' -N = A²A , wherein b2 is 0 , 1 , 2 , or 3 ; and A1 and A2 are independently selected from the group consisting of : N , CH , and CR7 ; each R7 is independently selected from the group consisting of ªR and Rb ; ⁹R Ring B is : b1 ( R10 ) EH * , wherein the * marks the ring carbon atom common to both Ring B and 0 : ¹✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and ²X and ³X are independently selected from the group consisting of : ₂HC , ¹RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 ; b1 is 0 , 1 , or 2 ; PCT / US2024 / 0477 R ' is selected from the group consisting of : -H , -OH , ªRªRN- , and halo ; each º¹R is independently selected from the group consisting of Ra and Rb ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe : each ªR is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) C1-6 alkoxy ; ( f ) C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) C ( = O ) C1-6 alkyl ; ( i ) C ( = O ) C1-6 haloalkyl ; ( j ) C ( = O ) OH ; ( k ) C ( = O ) OC1-6 alkyl ; ( 1 ) C ( = O ) OC1-6 haloalkyl ; 14 ( m ) C ( = O ) N ( ¹R ) 2 ; ( n ) S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) S ( O ) 1-2N ( ³R ) 2 ; and ( q ) PCT / US2024 / 0477 C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 Rc ; each Rb is independently selected from the group consisting of : - ( Lb ) b - ¹bR and ¹bR , wherein : b is 1 , 2 , or 3 ; , ﻭ each -L is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , C ( = O ) , and C1-3 alkylene ; and each ¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each R is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , RªRN- , C ( = O ) C1-6 alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) OH , C ( = O ) N ( ³R ) 2 , S ( O ) 0-2 ( C1-6 alkyl ) , S ( O ) 0-2 ( C1-6 haloalkyl ) , and S ( O ) 1-2N ( R ) 2 ; each Rd and Re is independently selected from the group consisting of : H , C ( = O ) C1-alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) N ( ³R ) 2 , S ( O ) 1- ( C1-6 alkyl ) , S ( O ) 1-2 ( C1-6 haloalkyl ) , S ( O ) 1-2N ( ³R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh each R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2 .

In some embodiments , the compounds of Formula ( A ) are compounds of Formula ( I ) : b1 ( R10 ) - ⁹R R Spa X* E ³R PCT / US2024 / 0477 or pharmaceutically acceptable salts thereof . Formula ( I ) In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ) , ⁹R is selected from the group consisting of : -OH and -NRdRe . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ) , R ' is -NRdRe . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ) , R ' is -NH2 .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ) , b1 is 1 or 2 . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ) , each R10 is independently selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

In some embodiments , the compounds of Formula ( A ) ( e.g. , Formula ( I ) ) are compounds of Formula ( I - a ) : NHR b1 ( R10 ) .

-Spa + 2- E Formula ( I - a ) or pharmaceutically acceptable salts thereof , wherein : b1 is 1 or 2 . ﺶﻣا In some embodiments of Formula ( I - a ) , each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-alkyl optionally substituted with 1-3 -F ) . In some embodiments of Formula ( I - a ) , b1 is 1 .

In some embodiments , the compounds of Formula ( A ) ( e.g. , Formula ( I ) ) are 16 compounds of Formula ( I - b ) : ⁹R RCN b4 ( R10 ) . E + - + ' N ' ³R Formula ( I - b ) PCT / US2024 / 0477 or pharmaceutically acceptable salts thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

In some embodiments of Formula ( I - b ) , ⁹R is -NRdRe ( e.g. , -NH2 ) . In some embodiments of Formula ( I - b ) , b4 is 0 . In some embodiments of Formula ( I - b ) , ³R is ºRªRN- ( e.g. , -NH2 ) ; and b4 is 0 .

In some embodiments , the compounds of Formula ( A ) ( e.g. , Formula ( I ) ) are compounds of Formula ( I - c ) : NHR.CN b4 ( R10 ) . E ³R Formula ( I - c ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) . In some embodiments of Formula ( I - c ) , b4 is 0 .

In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , ¹X is -CH2- . 17 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , ²X and ³X are independently selected from the group consisting of : -CH2- , -¹RHC- , -C ( ¹R ) 2- , and -O- . In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , ¹X is -CH2- ; and ²X and ³X are both -CH2- . In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , ¹X is -CH2- ; ²X is -CH2- ; and ³X is -¹RHC- . In some embodiments , ¹R is selected from the group consisting of : -CH3 , -CF3 , -CHF2 , and -CH2F ( e.g. , -CH3 ) . In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , ¹X is -CH2- ; ²X is -O- ; and ³X is selected from the group consisting of : -CH2- , -¹RHC- , and -C ( ¹R ) 2- ( e.g. , ³X is -CH2- or -¹RHC- ) . In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , each RL is independently selected from the group consisting of : -CH3 , -CF3 , -CHF2 , and -CH2F ( e.g. , -CH3 ) . In some embodiments of the compounds of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , or ( I - c ) ) ) , ¹X is -¹RHC- ; ²X is -O- or -CH2- ; and ³X is -¹RHC- , wherein the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) ⁹R ⁹R b1 ( R10 ) b1 ( R10 ) . * cycloalkyl ring . For example , the Xmoiety can be In some embodiments , the compounds of Formula ( A ) ( e.g. , Formula ( I ) ) are compounds of Formula ( I - d ) : ⁹R R b1 ( R10 ) . E X-Y³R Formula ( I - d ) or pharmaceutically acceptable salts thereof , wherein : ¹X is selected from the group consisting of a bond , -S ( O ) 0-2- , -CH2- , -CHRL- , -C ( RL ) 2- and -O- ; and LO WO 2025/064848 PCT / US2024 / 0477 ²X and ³X are independently selected from the group consisting of : -CH2- , -¹RHC- , - C ( RL ) 2- , -O- , and -S ( O ) 0-2- , provided that : at least one of X1 , X2 , and ³X is -¹RHC- or -C ( RL ) 2- , and no more than one of X1 , ²X , and ³X is selected from the group consisting of : -0- and -S ( O ) 0-2- .

In some embodiments of Formula ( I - d ) , ¹X is -CH2- ; ²X is -CH2- ; and ³X is -¹RHC- . In some embodiments of Formula ( I - d ) , RL is selected from the group consisting of : - CH3 , -CF3 , -CHF2 , and -CH2F ( e.g. , CH3 ) . In some embodiments of Formula ( I - d ) , ¹X is -CH2- ; ²X is -CH2- ; and ³X is ¹RHC- wherein ¹R is selected from the group consisting of : -CH3 , -CF3 , -CHF2 , and -CH2F ( e.g. , CH3 ) . ﻭ - In some embodiments , the compounds of Formula ( A ) ( e.g. , Formula ( I ) ) are compounds of Formula ( I - e ) : b1 ( R10 ) - ⁹R R αpS- X+ a- .

E ³R Formula ( I - e ) ﻭ or pharmaceutically acceptable salts thereof , wherein : ¹X is selected from the group consisting of a bond , -S ( O ) 0-2- , -CH2- , -CHRL- , -C ( ¹R ) 2- and -O- ; X2 and ³X are independently selected from the group consisting of : -CH2- , -¹RHC- , - C ( R ) 2- , -O- , and -S ( O ) 0-2- , provided that 2-3 of X1 , ²X , and ³X are independently -¹RHC- or -C ( RL ) 2- , wherein : one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; and each additional RL is independently selected from the group consisting of : C1-3 alkoxy , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

In some embodiments of Formula ( I - e ) , ²X is -CH2- or -O- ( e.g. , -CH2- ) . 19 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( I - e ) , ¹X is -¹RHC- ; ³X is -¹RHC- ; and the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

In some embodiments of Formula ( I - d ) or ( I - e ) , ³R is -NRdRe ( e.g. , -NH2 ) . In some embodiments of Formula ( I - d ) or ( I - e ) , b1 is 1 or 2 ; and each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

In some embodiments of Formula ( I - d ) or ( I - e ) , the NHCN b4 ( R10 ) .

⁹R b1 ( R10 ) . moiety is wherein b4 is 0 or 1 ; and R10 is selected from the group consisting of : - Cl , -F , CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) . In some embodiments , b4 is 0 .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹E is CH . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹E is CR4 . For example , ¹E can be CF.

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ²Y is -CH2- ; and ³R is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-1 additional ring heteroatom selected from the group consisting of oxygen and nitrogen , wherein the heterocyclyl is optionally substituted with 1-6 ªR .

WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ²Y is -CH2- ; and ³R is optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , C1-3 alkoxy , and C1-3 haloalkoxy . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ²Y is -CH2- ; and ³R is .F 1.8is ﻭ , or -N optionally substituted with 1-2 -F ( e.g. , ³R In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- F F c ) , ( I - d ) , or ( I - e ) ) ) , ³R is -N -N ( e.g. , In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- -N N = A²A b2 ( R7 ) ' N ' c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ﻭ wherein b2 is 0 , 1 , or 2 , and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- R7 R c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is or R7 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is R7a or R7a R7b ﻭ wherein : LO R7a is selected from the group consisting of : -C ( = O ) N ( ³R ) 2 , -C ( = O ) N ( C1-3 alkyl ) ¹³R , - C ( = O ) N ( H ) ¹bR , ¹bR , and -C ( = O ) ¹³R ; and R7b is selected from the group consisting of : halo , cyano , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) . In some embodiments , R7a is selected from the group consisting of : ( a ) -C ( = O ) N ( ³R ) 2 , wherein each R is independently -H or C1-3 alkyl optionally substituted with 1-3 Rh ; ( b ) ﻭ -C ( = O ) N ( C1-3 alkyl ) ¹R or -C ( = O ) N ( H ) ¹¹R , wherein : R1 is C3-6 cycloalkyl or 4-6 membered heterocyclyl , each of which is optionally substituted with 1-3 Rg ; and ( c ) -C ( = O ) ¹¹R , wherein R1 is a 4-10 membered heterocyclyl optionally substituted with 1-3 ²R , wherein R1 is attached to the C ( = O ) via a ring nitrogen atom . In some embodiments , R7b is halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) . 7a In some embodiments , ª7R is -C ( = O ) N ( ³R ) 2 , wherein each R is independently -H or C1-3 alkyl optionally substituted with 1-3 Rh . In some embodiments , R7b is halo ( e.g. , -Cl ) .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- Rf -N ' N ' Rf c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is , wherein each R is independently C1-3 alkyl optionally substituted with 1-3 Rh . For example , ¹R can be ' N ' ' N ' -N WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is a 7-10 ( e.g. , 7 ) membered heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R7 . In some embodiments , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein : each RC present on R7 is independently selected from the group consisting of : -F , -OH , and -CN . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is a 7-10 ( e.g. , 7 ) membered monocyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-membered monocyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . In some embodiments , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 RC , wherein each R present on R7 is independently selected from the group consisting of : -F , -OH , and -CN .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is optionally substituted with 1-4 R7 at one or more ring carbon atoms . In some embodiments , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein : each Re present on R7 is independently selected from the group consisting of : -F , -OH , and -CN . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ' N ' In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein : each R © present on R7 is independently selected from the group consisting of : -F , -OH , and -CN . 23 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- ﺱﺮﻣ ﺱﺮﻣ c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ( e.g. , ) , wherein R7 is a 5 - membered heteroaryl optionally substituted with 1-3 Rg . In some embodiments , R7 is pyrazolyl optionally substituted with 1-2 Rg ( e.g. , R7 is optionally substituted with one ºR ) ; or wherein R is oxazolyl optionally substituted with one Rg ( e.g. , R7 is optionally substituted with one R ) . In some embodiments , R7 is or In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is a 7-10 ( e.g. , 7 ) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ( R7 ) n( R7 ) n ☑ A ﻭ wherein : Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms ; n4 is 0 , 1 , or 2 ; and nis 0 , 1 , or 2 , provided that n4 + n5 is 0 , 1 , or 2. In some embodiments , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein : each RC present on R7 is independently selected from the group consisting of : -F , -OH , and -CN .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is , which is optionally substituted with 1-2 R7 . For example , ¹R can be 224 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is or ﻡا each of which is optionally substituted with 1-2 R7 . For example , ¹R can be ( e.g. , or ﺢﻣﺎﻣ ﺢﻣﺎﻣ ) or ( e.g. , or ☑ In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is a 4-7 ( e.g. , 4 or 7 ) membered heterocyclyl having one ring nitrogen atom or having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . In some embodiments , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 R ° , wherein : each Rc present on R7 is independently selected from the group consisting of : -F , -OH , and -CN . In some embodiments , ¹R is a monocyclic heterocyclyl . In some embodiments , ¹R is a spirocyclic bicyclic heterocyclyl . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . In some embodiments , each R7 is independently selected from the group consisting of : -F ; -CN ; -OH ; C1-3 alkyl optionally substituted with 1-3 Rc ; -C ( = O ) N ( ³R ) 2 ; and ¹¹R , wherein the Rb1 is a 5-membered heteroaryl optionally substituted with 1-2 Rg . In some embodiments , each R7 is independently selected from the group consisting of : -F ; -CN ; -OH ; Rb1 , wherein the R1 is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg ; C1-3 alkyl optionally substituted with 1-3 -F ; C1-3 alkyl substituted with -OH or C1-3 alkoxy ; and -C ( = O ) N ( ³R ) 2 .

In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is R-RRR( e.g. , ) or In some embodiments , each R7 is independently selected from the group consisting of : -F ; -CN ; -OH ; C1-3 alkyl optionally substituted with 1-3 R ¢ ; -C ( = O ) N ( R ) 2 ; and Rb1 , wherein the Rb1 is a 5-6 membered heteroaryl WO 2025/064848 PCT / US2024 / 0477 optionally substituted with 1-2 Rg . In some embodiments , each R7 is independently selected from the group consisting of : -F ; -CN ; -OH ; ¹bR , wherein the ¹³R is a 5-6 membered heteroaryl optionally substituted with 1-2 Rg ; C1-3 alkyl optionally substituted with 1-3 -F ; C1-3 alkyl substituted with -OH or C1-3 alkoxy ; and -C ( = O ) N ( ³R ) 2 . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is -R' R ( e.g. , ) , wherein R7 is C1-3 alkyl substituted with - OH or C1-3 alkoxy ( e.g. , C1-3 alkyl substituted with -OH ) . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- OH c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ( e.g. , OH ) . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is R-R ﻭ wherein each R7 is independently selected from the group consisting of : C1-3 alkyl optionally substituted with 1-3 -F ; and C1-3 alkyl substituted with -OH or C1-3 alkoxy . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- R7b -R7a R7b R7a c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ( e.g. , 7a ) , wherein Ra is C1-3 alkyl substituted with -OH ( e.g. , HO₂HC- ) ; and R7b is selected from the group consisting of : ( a ) C1-3 alkyl optionally substituted with 1-3 -F ( e.g. , methyl ) , and ( b ) C1-3 alkyl substituted with -OH or C1-3 alkoxy . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- ☑ OH c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is _ ( e.g. , OH KOH OH ) or In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is a 4-10 membered heterocyclyl substituted with -CN , - ( C1-3 alkylene ) - CN , or - ( C3-6 cycloalkylene ) -CN on a ring carbon atom , wherein the heterocyclyl is further optionally substituted with 1-3 R7 . In some embodiments , each R7 is independently selected 26 WO 2025/064848 PCT / US2024 / 0477 LO from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is a 6-8 membered heterocyclyl substituted with -CN or - ( C1-3 alkylene ) - CN on a ring carbon atom , wherein : the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom ; and the heterocyclyl is further optionally substituted with 1-3 R7 . In some embodiments , each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1- -F ) . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- N N c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is ( e.g. , In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , ¹R is -N ( ²R ) 2 . In some embodiments , each ²R is independently methyl or ethyl , each optionally substituted with 1-3 Rc , wherein each Re present on ²R is independently selected from the group consisting of : -F , cyano , -OH , C1-6 alkoxy , and C1-6 haloalkoxy . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- c ) , ( I - d ) , or ( I - e ) ) ) , the ring carbon atom labelled with * has ( S ) -stereochemistry . In some embodiments of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I- EE' N ' moiety is c ) , ( I - d ) , or ( I - e ) ) ) , the In some embodiments , the compounds of Formula ( I - c ) are compounds of Formula ( I- c1 ) or ( I - c2 ) : N R7a -N NHCN ' N ' b4 ( R10 ) . E* Y³R 27 Formula ( I - c1 ) b4 ( R10 ) - NH R7a -N R7b CN E' N ' -Y PCT / US2024 / 0477 LO Formula ( I - c2 ) or pharmaceutically acceptable salts thereof , wherein : ¹E is CH ; b4 is 0 or 1 ; R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Re : ﻭ ¹X is -CH2- ; and ²X and ³X are independently selected from the group consisting of : -O- , -CH2- , -CHRL- and -C ( RL ) 2- ; R7a is selected from the group consisting of : ( a ) -C ( = O ) N ( R ) 2 , wherein each R is independently -H or C1-3 alkyl optionally substituted with 1-3 Rh : ( b ) -C ( = O ) N ( C1-3 alkyl ) Rb1 or -C ( = O ) N ( H ) ¹ыR , wherein : Rb1 is C3-6 cycloalkyl or 4-6 membered heterocyclyl , each of which is optionally substituted with 1-3 Rg ; and ( c ) -C ( = O ) ¹¹R , wherein Rb1 is a 4-10 membered heterocyclyl optionally substituted with 1-3 RB , wherein R1 is attached to the C ( = O ) via a ring nitrogen atom ; and R7b is halo or C1-3 alkyl ( e.g. , -F , -C1 , or methyl ) .

CHRL- In some embodiments of Formula ( I - c1 ) or ( I - c2 ) , b4 is 0 . In some embodiments of Formula ( I - c1 ) or ( I - c2 ) , ²X is -CH2- ; and ³X is -CH2- or - In some embodiments of Formula ( I - c1 ) or ( I - c2 ) , ²X is -CH2- ; and ³X is -CH2- . In some embodiments of Formula ( I - c1 ) or ( I - c2 ) , ²X is -CH2- ; and ³X is -¹RHC- . In some embodiments of Formula ( I - c1 ) or ( I - c2 ) , ²X is -CH2- ; and ³X is -CHMe- . In some embodiments of Formula ( I - c1 ) or ( I - c2 ) , ª7R is -C ( = O ) N ( R ) 2 , wherein each Rf is an independently selected C1-3 alkyl ; and R7b is -F , -Cl , or methyl . For example , R7a WO 2025/064848 PCT / US2024 / 0477 be -C ( = O ) N ( Me ) 2 ; and R7 can be -F , -Cl , or methyl .

In some embodiments , the compounds of Formula ( I - c ) are compounds of Formula ( I- c3 ) or ( I - c4 ) : b4 ( R10 ) . b4 ( R10 ) - NHCN Formula ( I - c3 ) NH-R ³R CN E³R Formula ( I - c4 ) or pharmaceutically acceptable salts thereof , wherein : , ¹E is CH ; R7 is C1-3 alkyl substituted with -OH ; b4 is 0 or 1 ( e.g. , 0 ) ; R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Re : si¹X -CH2- ; and ²X and ³X are independently selected from the group consisting of : -O- , -CH2- , -CHRL- and -C ( RL ) 2- .

CHRL- In some embodiments of Formula ( I - c3 ) or ( I - c4 ) , ²X is -CH2- ; and ³X is -CH2- or - In some embodiments of Formula ( I - c3 ) or ( I - c4 ) , ²X is -CH2- ; and ³X is -CH2- . In some embodiments of Formula ( I - c3 ) or ( I - c4 ) , ²X is -CH2- ; and ³X is -¹RHC- . In some embodiments of Formula ( I - c3 ) or ( I - c4 ) , ²X is -CH2- ; and ³X is -CHMe- . 29 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( I - c4 ) , the -R7 ' R moiety is In some embodiments of Formula ( I - c4 ) , R7 is HO₂HC- . In some embodiments of Formula ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , or ( I - c4 ) , ²Y is -CH2- ; and ³R is optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , C1-3 alkoxy , and C1-3 haloalkoxy . In some embodiments of Formula ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , or ( I - c4 ) , ²Y is -CH2- ; and ³R is optionally substituted with 1-2 -F .

-N In some embodiments of Formula ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , or ( I - c4 ) , ³R is In some embodiments of Formula ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , or ( I - c4 ) , the E ﻩﺩ ( e.g. , E' N ' moiety is In some embodiments , the compounds of Formula ( A ) or Formula ( I ) are selected from the group consisting of compounds depicted in Table C1 , or pharmaceutically acceptable salts thereof .

Table CNo. 101a Compound Structure NHCN ' N ' F Sams ' N ' NH' N ' CN F ' N ' ' N ' -N NH102 ' N ' CN F ' N ' N ' N ' -N NH102a CN F PCT / US2024 / 047734 N ﻼﻠﻫ -N NH102b .N ' N ' F 103a NHCN NH & ' N ' N CN NH1CN NH104a CN ' N ' N. ' N ' -N -N N N ﻢﻃﺭﺓ PCT / US2024 / 047734 104b ﻼﻠﻫ NH' N ' Espuns orF NH ﻢﺸﻋﺭﺓ NH' N ' 105a 1NH -N N. ' N ' goog NH106a PCT / US2024 / 047734 106b 107a 107b ' N ' ﻼﻬﻣ NH' N ' ﻞﻤﺤﻜﻣﺓ & NHCN ' N ' NH NH & ' N ' CN NH108 ' N ' CN ' N ' ' N ' -N N PCT / US2024 / 047734 NH108a NO ' N ' -N ' N ' ' N ' N NH' N ' 108b & N FL ' N ' PCT / US2024 / 0477 ₂HN 108c ' N ' F NH1CN ' N ' -N CI ' N ' CI NH109a ' N ' CN ' N ' ' N ' N CI ₂HN 109b ' N ' CN & -N CI NH109d ' N ' .CN -N CI NH1CN F NH110a ₂HN 110b CN ' N ' ' N ' ﮧﻳں F & F CI F PCT / US2024 / 047734 NH' N ' CN 111 F 111a NH ' N ' ' N ' ' N ' CN F N ' N ' -N NH' N ' 1CN F NH112a ' N ' CN NH1 N -N CN N CCI N PCT / US2024 / 047734 NH113a CN CCI ₂HN 113b ' N ' CN -N NH1CN F NH114a ' N ' CN F 1NH F ' N ' N ' ⋅N F PCT / US2024 / 047734 NH' N ' 115a N -N NH116 ' N ' F NH116a F 1₂HN NH117a ' N ' N ' N ' ﻞﻣ CI N CI PCT / US2024 / 047734 -N NH1N ' F NH118a -N ₂HN ' N ' 1 NH119a F CI CI ' N ' CI ' N ' ' N ' N ' N ' ' N ' CI F Song NH & D DD KN to ' N ' and PCT / US2024 / 047734 120a DDD NH' N ' 1NH 121a NH -N N ' N ' NH' N ' 122a NH ﻢﻣ NHDD N F F F PCT / US2024 / 047734 123a 124a 125a 126a NHDD ' N ' to F NHN ' N ' Spand NHN ' N ' Song ₂HN N ₂HN N Long NHN F NHN F PCT / US2024 / 047734 127a NH NH ' N ' NH128 ' N ' F NH128a ' N ' NH1 N ' N ' F ' N ' PCT / US2024 / 047734 F NH' N ' 129a F ₂HN ' N ' 1 ' N ' -N F NH130a ' N ' NH131 ' N ' NH131a ' N ' ' N ' N N ' N ' PCT / US2024 / 047734 ' N ' N CI NH132 ' N ' CI ₂HN N 132a CI 1NH' N ' ' N ' ' N ' CI 133a NH' N ' NH1 ' N ' -N CI ' N ' PCT / US2024 / 047734 N CI NH134a ' N ' CI NH' N ' 1 CI NH135a ' N ' N ןוו ' N ' ' N ' 136a NH Eng NHF Expand PCT / US2024 / 047734 NH1.N 137a 138a 139a 139b NH NH.N Spand NH.N Boond NH F ₂HN or N NH Spend or' N ' PCT / US2024 / 047734 140a 141a 142a NH ﻢﺤﻣﻭﺩﺓ ₂HN NH ₂HN sahned F NH NH NH F F PCT / US2024 / 047734 143a 144a NH Ex & NH NHN F F CI NH' N ' 1 ' N ' NH' N ' 145a NHOH ort N ' N ' ' N ' or PCT / US2024 / 047734 146a 146b NHN OH OH NH N -N CI NHN 1 CI NH147a 148 NH ' N ' N N.

-N CI ' N ' ' N ' CN PCT / US2024 / 047734 NH148a ' N ' CI ' N ' CI NH1 N CI NH149a ' N ' ' N ' ' N ' ' N ' ' N ' & 1 N ' N ' CI NH149b CI NH149c ' N ' & oror ' N ' ' N ' ' N ' or PCT / US2024 / 047734 NHﻡا 150a NHCN & 150b 151a 151b 151c NH.CN & NH.CN NH NH NH CN or orCN & CN ' N ' ' N ' F F PCT / US2024 / 047734 152a 152b 153a 153b NHCN NHCN NHCN or NH ' N ' ' N ' F F F NHor Bong NHor ' N ' ₂HN N Song PCT / US2024 / 047734 WO 2025/064848 PCT / US2024 / 0477 154a NH S NH.CN N OH ' N ' Sung NHCN OH 155a 155b NHOH F 156a NHCN S NH OH CN .CN OH .OH OH .OH n ' N ' Song ' N ' F ...... 157a 157b OH CN or OH CN or PCT / US2024 / 0477 LO In certain compounds of Table C1 , one or more stereogenic centers are denoted with the " V3000 enhanced stereochemical notation " ( see : support.collaborativedrug.com/hc/en- us / articles / 360020872171 - Advanced - Stereochemistry - Registration - Atropisomers - Mixtures- Unknowns - and - Non - Tetrahedral - Chirality , accessed on November 29 , 2023 and Accelrys Chemical Representation Guide , Accelrys Software Inc. , 2014 , each of which is incorporated by reference herein in its entirety ) . Using this stereochemical notation , certain stereogenic centers are denoted with " abs " , " & x " , or " orx " , wherein x is an integer ( e.g. , 1 or 2 ) . For avoidance of doubt , the stereochemical notations in Table C1 have the following meaning : When a structure does not contain any wedged or hashed bonds ( i.e. , each stereogenic center is undefined ) , then each stereogenic center can independently adopt a ( R ) or ( S ) stereochemical configuration . For avoidance of doubt , such structures also encompass mixtures of stereoisomers . For example , HO HO N N of and HO HO N- N- 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 55 WO 2025/064848 PCT / US2024 / 0477 depicted by the structural formula . For example , both of the structures abs H 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 or 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 ( ( 2 $ , 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 " orl " and " or2 " respectively ) , each defined stereogenic center should be independently interpreted according to " ( 2 ) " supra .

For example , the structure orOH or NH ' N ' refers to one stereoisomer selected from the group ** abs OH abs ' N ' ﻭ PCT / US2024 / 0477 OH abs OH Di pl pt abs abs ' N ' abs ' N ' consisting of : OH abs abs ' N ' and , , 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 or or1 or' N ' ZI abs abs ZH refers to one of the two " syn " stereoisomers : abs abs or1 or . As another example , the structure ' N ' 100 *** abs abs N abs abs refers to one of the " anti " stereoisomers : or ( 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 : ﻭﻭ 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 57 WO 2025/064848 PCT / US2024 / 0477 vary independently of one another . For example , the structure refers to a mixture of four stereoisomers : abs abs OH ' N ' and , OH abs abs & 1 & N OH abs OH abs abs abs OH ' N ' N , ﻭ LO 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 stereoisomers : abs abs ' N ' & 1 & and refers to a mixture of " syn " abs abs NH ' N ' As another example , the structure & 1 & zi abs abs ' N ' H ' N ' and refers to a mixture of " anti " stereoisomers : abs abs Certain examples of Formula ( A ) or Formula ( I ) were synthesized using methods involving resolution of stereoisomeric mixture ( s ) ( e.g. , SFC separation of stereoisomers ) . In Table C1 , the resolved stereogenic centers in these compounds are labelled with the " orl " and / or " or2 " enhanced stereochemical notations . In some instances , the stereoisomeric WO 2025/064848 PCT / US2024 / 0477 LO resolutions were performed during the last step of the synthesis , thereby providing the individual stereoisomers of the compounds . Alternatively , in some other instances , the resolutions were performed on an intermediate or starting material , wherein each of the constituent stereoisomers of the intermediate or starting material could be separately subjected to the subsequent steps of the synthesis to provide the respective compounds as separate stereoisomers . A person of ordinary skill in the art would understand that , under either approach for stereoisomeric resolution , stereoisomers having both ( R ) - and ( S ) -configurations at a resolved stereogenic center are provided . See Table C2 , wherein Table C1 compounds whose stereoisomers contain the orl and / or or2 stereochemical notations are provided in non- stereogenic form , followed by the respective stereoisomers having the ( R ) - and ( S ) - configurations . Table CNo. 1NH Compound Structure Spand ' N ' ' N ' F NH NHF NHN ' N ' F NH ₂HN NH NH ' N ' ' N ' -N CI PCT / US2024 / 0477 ' N ' N ' N ' -N CI N ' N ' -N CI NH' N ' 60 1NHCN NHCN NHCN 1NHCN ' N ' F ☑ F ' N ' ' N ' F NHCN ☑ Song NHCN Song ' N ' F PCT / US2024 / 047734 1NH NH NH Sound F 1OH CN F OH CN OH CN ' N ' PCT / US2024 / 0477 In some embodiments , the compounds of Formula ( A ) or Formula ( I ) are selected from the group consisting of : 62 WO 2025/064848 PCT / US2024 / 0477 104a - ( ( 18,4S ) -7 - Amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro- 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N- dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine- 113a 142a 146a 2 - carboxamide - ( ( 18,4S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro- 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -3 - chloro- N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 18,4S ) -7 - Amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1- azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 18,4S ) -7 - Amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( ( R ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile 146b ( 18,4S ) -7 - Amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( ( S ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile 152a ( 18,4S ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( ( S ) -6 - oxa - 1- azaspiro [ 3.5 ] nonan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile 152b ( 18,4S ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( ( R ) -6 - oxa - 1- azaspiro [ 3.5 ] nonan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile 153a ( 18,4S ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( ( S ) -6 - oxa - 1- azaspiro [ 3.4 ] octan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile 153b ( 18,4S ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( ( R ) -6 - oxa - 1- azaspiro [ 3.4 ] octan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- 156a spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 18,4S ) -7 - amino - 4 ' - ( 2,2 - bis ( hydroxymethyl ) azeti din - 1 - yl ) -2'- ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile 63 WO 2025/064848 PCT / US2024 / 0477 LO or pharmaceutically acceptable salts thereof . In some embodiments , the compounds of Formula ( A ) or Formula ( I ) are selected from the group consisting of the compounds depicted in Table C1s of U.S. Provisional Application Serial Nos . 63 / 685,160 , filed August 20 , 2024 ; 63 / 675,512 , filed July 25 , 2024 ; 63 / 653,043 , filed May 29 , 2024 ; 63 / 650,239 , filed May 21 , 2024 ; 63 / 567,238 , filed March 19 , 2024 ; / 559,588 , filed February 29 , 2024 ; 63 / 614,278 , filed December 22 , 2023 ; and 63 / 539,749 , filed September 21 , 2023 , each Table C1 is incorporated by reference it its entirety herein .

Also provided herein are compounds of Formula ( B ) : R2a R2b R * B R2c R2d Formula ( B ) or pharmaceutically acceptable salts thereof , or prodrugs thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : -CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; SA²A b2 ( R7 ) ( ii ) wherein b2 is 0 , 1 , 2 , or 3 ; and A1 and A2 are independently selected from the group consisting of : N , CH , and CR7 ; ( iii ) -N ( ²R ) 2 , wherein each ²R is independently selected from the group consisting of : - H and C1-6 alkyl optionally substituted with 1-3 R ° ; and ( iv ) -H ; each R7 is independently selected from the group consisting of Ra and Rb ; R2a and R2b are independently selected from the group consisting of : -H , C1-3 alkyl , C1- haloalkyl , and C3-6 cycloalkyl ; or 64 LO WO 2025/064848 PCT / US2024 / 0477 R2a and R2b taken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring ; c²R and d²R are independently selected from the group consisting of : -H , halo , -CN , C1- alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; or R2c and R2d taken together with the ring carbon atom to which each is attached form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring ; ⁹R Ring B is : b1 ( R10 ) X3 - X R2a R2b .

' N ' R2c R2d , wherein the * marks the ring carbon atom common to , both Ring B and ¹X is selected from the group consisting of a bond , -S ( O ) 0-2- , -CH2- , -³RHC- , -C ( ¹R ) 2- and -O- ; ²X and ³X are independently selected from the group consisting of : -CH2- , -³RHC- , - C ( RL ) 2- , -O- , and -S ( O ) 0-2- , provided that no more than one of X1 , X2 , and ³X is selected from the group consisting of : -O- and -S ( O ) 0-2- ; b1 is 0 , 1 , or 2 ; R ' is selected from the group consisting of : -H , -OH , eRªRN- , and halo ; each R10 is independently selected from the group consisting of Ra and ³R ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , R ° R ° C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , C1-6 haloalkyl , and ﻭ or a pair of RY on the same or different carbon atom ( s ) taken together with the atom ( s ) 65 WO 2025/064848 PCT / US2024 / 0477 connecting them forms a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of F and C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) a 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR , ³R , ( b ) -NRdRe ; R ° R ° fore and Rox ; and each R ° is independently selected from the group consisting of : -H , -F , C1-3 alkyl , and C1-3 haloalkyl ; Rox is -H or C1-3 alkyl ; each ªR is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) C1-6 alkoxy ; ( f ) C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) -C ( = O ) C1-6 alkyl ; ( i ) -C ( = O ) C1-6 haloalkyl ; ( j ) -C ( = O ) OH ; ( k ) -C ( = O ) OC1-6 alkyl ; ( 1 ) -C ( = O ) OC1-6 haloalkyl ; ( m ) -C ( = O ) N ( ³R ) 2 , ( n ) -S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) -S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) -S ( O ) 1-2N ( R ) 2 ; and ( q ) C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 Rc ; 66 WO 2025/064848 PCT / US2024 / 0477 each Rb is independently selected from the group consisting of : - ( Lb ) ь - ¹³R and ¹bR , wherein : b is 1 , 2 , or 3 ; , each -Lb is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , -C ( = O ) - , and C1-3 alkylene ; and each ¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each R is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , RªRN- , -C ( = O ) C1-6 alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) OH , -C ( = O ) N ( ³R ) 2 , -S ( O ) 0-2 ( C1-6 alkyl ) , -S ( O ) 0-2 ( C1-haloalkyl ) , and -S ( O ) 1-2N ( R ) 2 ; each Rd and ªR is independently selected from the group consisting of : -H , -C ( = O ) C1-alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) N ( ³R ) 2 , - S ( O ) 1-2 ( C1-6 alkyl ) , -S ( O ) 1-2 ( C1-6 haloalkyl ) , -S ( O ) 1-2N ( R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : -H and C1-6 alkyl optionally substituted with 1-3 Rh ; ﻭ each R is independently selected from the group consisting of : ¹R , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2 .

The term " prodrug " as used herein refers to a derivative of a compound of Formula ( B ) which releases the Formula ( B ) compound under appropriate conditions ( e.g. , under in vivo conditions ) via non - enzymatic ( e.g. , chemical reduction , oxidation , or hydrolysis ( e.g. , acid catalyzed hydrolysis ) ) or enzymatic ( e.g. , esterase , nuclease , lipase , amidase , or protease catalyzed reactions ) processes . A prodrug can be used to change the biological distribution of a compound of Formula ( B ) or its pharmacokinetics . A variety of groups have been used to modify compounds to form prodrugs , such as esters ( e.g. , benzoates , acetates , etc. ) , ethers , carbamates , carbonates , N , O - acetals , phosphate esters / salts , etc. A compound of Formula ( B ) may form prodrugs at -NH2 ( e.g. , at R9 when R ' is -NH2 ) or -OH ( e.g. , at R7 when R7 is -OH 67 WO 2025/064848 PCT / US2024 / 0477 LO or C1-3 alkyl substituted with -OH ) functionalities . Further information on the use of prodrugs may be found in WO 2024/050640 ; ACS Omega 2023 , 8 , 7 , 7211-7221 , doi : 10.1021 / acsomega.3c00329 ; Nat Rev Drug Discov 7 , 255-270 ( 2008 ) , doi : 10.1038 / nrd246 ; Chem Biol Drug Des 82 : 643-668 ( 2013 ) , doi : 10.1111 / cbdd . 12224 ; Pro- drugs as Novel Delivery Systems , Vol . 14 , ACS Symposium Series ; Bioreversible Carriers in Drug Design , Pergamon Press , 1987 ( ed . E. B. Roche , American Pharmaceutical Association .

⁹R CN * Xﻭ wherein ³X is -CH2- , - In some embodiments of Formula ( B ) , Ring B is : -¹RHC , or -C ( ¹R ) 2- . In some embodiments , R9 is selected from the group consisting of : -OH , NRdRe ( e.g. , -OH and -NH2 ) . In some embodiments , each RL is independently C1-3 alkyl optionally substituted with 1-3 -F . NHCN * XIn some embodiments of Formula ( B ) , Ring B is : wherein ³X is -CH2- , - -¹RHC , or -C ( ¹R ) 2- . In some embodiments , each ¹R is independently C1-3 alkyl optionally substituted with 1-3 -F . NHCN In some embodiments of Formula ( B ) , Ring B is R be methyl , ethyl , or -CF3 . For example , RL can be methyl . For example , RL can NH.CN In some embodiments of Formula ( B ) , Ring B is In some embodiments of Formula ( B ) , Ring B is NHCN ₂HN CN PCT / US2024 / 0477 In some embodiments of Formula ( B ) , Ring B is In some embodiments of Formula ( B ) , ª²R , R2b , R2c , and R2d are each -H . In some embodiments of Formula ( B ) , ¹E is CH .

In some embodiments of Formula ( B ) , a²R , R2b , R2c , and R2d are each -H ; and ¹E is CH .

In some embodiments of Formula ( B ) , ª²R , R2b , R2c , and R2d are each -H ; ¹E is CH ; NHCN NH.CN ﻭ NHCN $ $ & and Ring B is : R ( e.g. , ) or ( R7 ) n( R7 ) nA In some embodiments of Formula ( B ) , ¹R is ﻭ wherein : Ring Al is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms ; n4 is 0 , 1 , or 2 ; and n5 is 0 , 1 , or 2 , provided that n4 + n5 is 0 , 1 , or 2. In some embodiments , n4 is 0. In some embodiments , n5 is 0. In some embodiments n4 is 0 ; and n5 is 0. In some embodiments , each R7 is independently selected from the group consisting of : -F , - OH , oxo , ¹bR , and C1-3 alkyl optionally substituted with 1-3 Rc , wherein the Rb1 is a 5-membered heteroaryl optionally substituted with 1-2 ºR . In some embodiments of Formula ( B ) , ¹R is selected from the group consisting of : N ( e.g. , or ) , and ( e.g. , or ) , each of which is optionally substituted with 1-2 R In some embodiments of Formula ( B ) , ¹R is a 4 - membered heterocyclyl optionally substituted with 1-4 R7 . In some embodiments , each R7 is independently selected from the WO 2025/064848 PCT / US2024 / 0477 group consisting of : -F , -OH , oxo , ¹¹R , and C1-3 alkyl optionally substituted with 1-3 R , wherein the ¹bR is a 5-6 membered heteroaryl optionally substituted with 1-2 R. optionally substituted with 1-4 ( e.g. , In some embodiments of Formula ( B ) , ¹R is 1-2 ) R7 . In some embodiments , each R7 is independently selected from the group consisting of : -F , oxo , -OH , Rb1 , and C1-3 alkyl optionally substituted with 1-3 RC , wherein the Rb1 is a 5- membered heteroaryl optionally substituted with 1-2 Rg . In some embodiments of Formula ( B ) , ¹R is selected from the group consisting of : -R and group consisting of : RRIn some embodiments , each R7 is independently selected from the Ro , ( a ) -F ; ( b ) cyano ; ( c ) -OH ; ( d ) Rb1 , wherein the ¹R is a 5-6 membered heteroaryl optionally substituted with 1- ( e ) C1-3 alkyl optionally substituted with 1-3 -F ; and ( f ) C1-3 alkyl substituted with -OH or C1-3 alkoxy .

-R7 R In some embodiments of Formula ( B ) , ¹R is ( e.g. , ) , wherein R7 is C1-3 alkyl substituted with -OH or C1-3 alkoxy ( e.g. , C1-3 alkyl substituted with -OH ) . In some embodiments , ¹R is OH OH ( e.g. , ☑ R7b -R7a In some embodiments of Formula ( B ) , ¹R is ﻭ wherein R7 is C1-3 alkyl substituted with -OH ( e.g. , HO₂HC- ) ; and R7b is selected from the group consisting of : C1-alkyl optionally substituted with 1-3 -F ( e.g. , methyl ) , and C1-3 alkyl substituted with -OH or C1-3 alkoxy . For example , ¹R can be OH -OH ﻡﺎﻣ 70 WO 2025/064848 PCT / US2024 / 0477 In some embodiments of Formula ( B ) , ¹R is R7 R N ' ' N ' ( e.g. , ) , wherein R7 is a 5 - membered heteroaryl optionally substituted with 1-3 ºR . In some embodiments , R7 is selected from the group consisting of pyrazolyl and oxazolyl , each of which is optionally substituted with 1-2 R. In some embodiments , R7 is pyrazolyl optionally substituted with 1- ³R ( e.g. , R7 is optionally substituted with one ºR ) . For example , ³R can be In some embodiments , R7 is oxazolyl optionally substituted with one Rg ( e.g. , R7 is optionally substituted with one ºR ) . For example , R7 can be HJ In some embodiments of Formula ( B ) , ²Y is -CH2- or -CD2- ( e.g. , -CH2- ) . In some embodiments of Formula ( B ) , ²Y is -CH2- or -CD2- ( e.g. , -CH2- ) ; and ³R is optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , -C1-3 alkoxy , and -C1-3 haloalkoxy . In some embodiments of Formula ( B ) , ²Y is -CH2- or -CD2- ( e.g. , -CH2- ) ; and ³R is a 9-14 ( e.g. , 9-12 ) membered heterocyclyl optionally substituted with 1-3 substituents R ° R ° In some independently selected from the group consisting of : ªR , Rb , and embodiments , ³R is a 9-12 membered heterocyclyl optionally substituted with 1-3 ªR . In some embodiments , ³R is a 9-12 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from the group consisting of : -F , C1-3 alkyl , and C1-3 alkoxy . For example , ³R can be selected from the group consisting of : N -N F LO N F ﻭ N ﻭ F N. .N N. ﻭ ﻭ and PCT / US2024 / 0477 ﻭ In some embodiments of Formula ( B ) , Y2 is - CH2- or - CD2- ( e.g. , -CH2- ) ; and R3 is an R ° R ° 8-12 membered heterocyclyl substituted with 1-2 and further optionally substituted with 1-2 independently selected R. In some embodiments , R3 is selected from the group Ro R ° -R ° ºR Ro -R ° Ro -R ° ºR . N consisting of : ( ªR ) ¯1-( Ra ) 0-1 R ° and For example , ³R can be selected from the group consisting of : ﻭ CN F ﻭ N and N , In some embodiments of Formula ( B ) , ²Y is -CH2- or -CD2- ( e.g. , -CH2- ) ; and ³R is an 8-12 membered heterocyclyl substituted with Rh and further optionally substituted with 1- substituents independently selected from the group consisting of : Ra and E -Rb R ° R ° In some embodiments , R3 is selected from the group consisting of : NRO , Ra- Rb ﻭ and R ° . R ° Rb PCT / US2024 / 0477 For example , R3 can be selected from the group consisting ﻭ CFﻭ OCF N CF, of : N N ﺞﻣﻭﺩ ﻪﻬﻬﻬﻫ , N- , ﻪﻣ N- N zaur ﻭ ﻢﻬﻤﻫ OCF3 , sayo N ﻪﻤﻫ N , LO ﻢﺤﻣﻭﺩ and , PCT / US2024 / 0477 In some embodiments of Formula ( B ) , ²Y is -CH2- or -CD2- ( e.g. , -CH2- ) ; and ³R is RaRaRaRaR ° R ° Ra ' N ' N ' N ' selected from the group consisting of : Ra( e.g. , Ra) or Ra( e.g. , R ° R ° Ra ' N ' Ra) , wherein each ³ªR is an independently selected C1-3 alkyl optionally substituted F F with 1-3 -F . For example , ³R can be selected from the group consisting of : F F $$$ ' N ' CD3DĊ and ﻭ , In some embodiments of Formula ( B ) , ²Y is -CH2- or -CD2- ( e.g. , -CH2- ) ; and ³R is E selected from the group consisting of : ( F ) o - 2 , N Ra, N Ra N Ra and Rb F .F ﻭ F Ra3 .F N Ra3 Ra, , N - ( F ) 0- ( F ) 0- F Ra F " F , , , wherein each ³aR is an independently selected C1-3 alkyl optionally substituted LO WO 2025/064848 PCT / US2024 / 0477 with 1-3 -F . For example , ³R can be selected from the group consisting of : F F # N ﻭ F N- N N and , F In some embodiments of Formula ( B ) , Y2 is a straight - chain C3-6 alkylene optionally substituted with 1-6 RY . In some embodiments , ²Y is selected from the group consisting of : F ﻢﻌﻫ , ﻭ and In some embodiments of Formula ( B ) , Y2 is a straight - chain C3-6 alkylene optionally substituted with 1-6 RY ; and ³R is -NRdRe . In some embodiments , ²Y is selected from the group consisting of : ﻊﻫ ﻝﺎﻣ F and , N N ( C1-3 alkyl ) 2 . For example , -O - ²Y - ³R can be : Lo ' N ' ' N ' ﻭ or -F ﻭ ; and ³R is - N ﻭ In some embodiments of Formula ( B ) , ²Y is a straight - chain C3-6 alkylene optionally substituted with 1-6 RY ; and ³R is a 4-8 membered heterocyclyl optionally substituted with 1- R ° R ° substituents independently selected from the group consisting of : Ra , Rox In some embodiments , Y2 is selected from the group consisting of : F strate ﻡا and and , ﺡﺩ ﻝﻭ ; and ³R is selected from the group consisting 75 WO 2025/064848 PCT / US2024 / 0477 R ° of : R ° , Rox For example , -O - ²Y - ³R can be : D D D D ót ' N ' ' N ' ' N ' ﻭ and may tra ' N ' ót ' N ' to F ' N ' ' N ' , or , LO Also provided herein is a KRas protein ( e.g. , a dysregulated KRas protein ( e.g. , a mutated KRas protein ) ) non - covalently bound with a compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof . In some embodiments , Gly10 of the KRas protein interacts non - covalently with the ¹R group of the compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , ( e.g. , via a hydrogen bond between the carbonyl of Gly 10 and an -OH group of ¹R and / or via a water mediated interaction between the -NH group of Gly 10 and an -OH group of ¹R ) . Without wishing to be bound by theory , in some embodiments , the interaction between Gly 10 of the KRas protein and the ¹R group of the compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I- c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , facilitates the inhibition of interaction between the KRas protein and Raf - RBD . In some embodiments , Arg68 of the KRas protein interacts non - covalently with the ¹R group of the compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I- c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , ( e.g. , via a hydrogen bond between the guanidine of Arg68 and a CN group of ¹R ) . Without wishing to be bound by theory , in some embodiments , the interaction between Arg68 of the KRas protein and the ¹R group of the compound of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I- a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) , or a pharmaceutically acceptable salt thereof , facilitates the inhibition of interaction between the 76 WO 2025/064848 PCT / US2024 / 0477 KRas protein and Raf - RBD .

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. , " = 0 " ) . 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-indicates that the group may have from 1 to 10 ( inclusive ) carbon atoms in it . Alkyl groups can either be unsubstituted or substituted with one or more substituents . Non - limiting examples include methyl , ethyl , iso - propyl , tert - butyl , n - hexyl . The term " saturated " as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein . The term " haloalkyl " refers to an alkyl , in which one or more hydrogen atoms is / are replaced with an independently selected halo ( e.g. , -CF3 , -CHF2 , or F₂HC- ) . The term " alkoxy " refers to an -O - alkyl radical ( e.g. , ³HCO- ) . 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 ) or on different ring atoms ( e.g. , ring carbon and / or nitrogen atoms ( e.g. , vicinal ring carbon and / or nitrogen atoms ) ) ( e.g. , ﻭ at hat 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 , C2-6 indicates 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 WO 2025/064848 PCT / US2024 / 0477 the indicated number of carbon atoms . For example , C2-6 indicates 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 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 bicyclo [ 1.1.0 ] butyl , fused / bridged cycloalkyl includes : bicyclo [ 1.1.1 ] pentyl , bicyclo [ 3.1.0 ] hexyl , bicyclo [ 4.1.0 ] heptyl , bicyclo [ 2.2.1 ] heptyl , bicyclo [ 2.1.1 ] hexyl , bicyclo [ 3.1.1 ] heptyl , bicyclo [ 2.1.0 ] pentyl , bicyclo [ 3.2.0 ] 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 , S ( inclusive of oxidized forms such as : toy or S = O ) , and P ( inclusive of oxidized forms such as : PCT / US2024 / 0477 ) ( e.g. , N , O , and S ( inclusive of oxidized forms such as : roy or ) ) 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. , ' N ' or , ) , pyrimidonyl ( e.g. , or ) , pyridazinonyl ( e.g. , or ' N ' ) , pyrazinonyl ( e.g. , or ) , and imidazolonyl ( e.g. , 79 LO WO 2025/064848 PCT / US2024 / 0477 ) , wherein each ring nitrogen adjacent to a carbonyl is tertiary ( i.e. , the oxo group ( i.e. , " = 0 " ) 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-heteroatoms if bicyclic , or 1-9 heteroatoms if tricyclic or polycyclic , said heteroatoms selected from O , N , S ( inclusive of oxidized forms such as : or and P ( inclusive of ﺶﻣا oxidized forms such as : toy or ) ( e.g. , N , O , and S ( 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 [ 3.1.0 ] hexyl , 5 - azabicyclo [ 2.1.1 ] hexyl , octahydrocyclopenta [ c ] pyrrole , azabicyclo [ 1.1.1 ] pentyl , - azabicyclo [ 4.1.0 ] heptyl , - azabicyclo [ 3.1.1 ] heptyl , 7 - azabicyclo [ 4.2.0 ] octyl , 3- 7- ﻦﻫ ﻦﻫ 2- azabicyclo [ 3.2.0 ] heptyl , azabicyclo [ 2.2.1 ] heptyl , 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- WO 2025/064848 PCT / US2024 / 0477 LO 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 , oxaspiro [ 5.5 ] undecyl , 3 - oxaspiro [ 5.5 ] undecyl , 3 - oxa - 9 - azaspiro [ 5.5 ] undecyl and the like . 1- 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 , ) , or ( iii ) a contiguous array of ring atoms ( bridged ring systems having all bridge lengths > 0 ) ( e.g. , 00.or ﻝا 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 81 WO 2025/064848 PCT / US2024 / 0477 limitation , isotopes of hydrogen include tritium and deuterium , and isotopes of carbon include 13C and 14C . 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 : HO 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 . Certain combinations of heteroatoms ( e.g. , N , O , S , or halo ) define compounds which are less stable under physiological conditions . Examples include ( 1 ) compounds containing acetal or aminal linkages ; ( 2 ) compounds containing acyclic N - O , N - N , or N - S ( O ) 0 bonds ; and ( 3 ) compounds containing O - O , O - S ( O ) 0-2 , N - halo , O - halo , and S ( O ) 0-2 - halo bonds . Accordingly , such compounds are less preferred . As used herein , " acyclic bonds " mean ' N ' ' N ' chemical bonds that are not part of a ring . Examples include the N - O bond in OH and OH For avoidance of doubt , acyclic N - O , N - N , or N - S ( O ) 0 bonds ( i.e. , those bonds that are not part of a ring ( e.g. , in or ) ) are less preferred , but compounds provided herein can include N - O , N - N , or N - S ( O ) o bonds that form part of a ring ( e.g. , the N - N bond in ) . 82 WO 2025/064848 PCT / US2024 / 0477 LO Methods of Treatment Indications Provided herein are methods for inhibiting a KRas protein . For example , provided herein are inhibitors of a KRas protein ( e.g. , a dysregulated KRas 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 ) ) ) useful for treating or preventing diseases or disorders associated with the KRas dysregulation ( i.e. , a KRas - associated disease or disorder ) , such as a cardiovascular disease , an inflammatory and / or autoimmune disease , or a cancer ( e.g. , a KRas - associated cancer ) . The term " KRas - associated disease or disorder " as used herein refers to diseases or disorders associated with or having a dysregulation of a KRAS gene , a KRas protein , or the expression or activity or level of any ( e.g. , one or more ) of the same ( e.g. , any of the types of dysregulations of a KRAS gene , a KRas protein , or the expression or activity or level of any of the same described herein ) . Non - limiting examples of a KRas - associated disease or disorder include , for example , cancer , a cardiovascular disease ( e.g. , arteriovenous malformations ) , endometriosis , and an inflammatory and / or autoimmune disease ( e.g. , a nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis ) . See , e.g. , Adashek et al . Genome Med . 2020 ; 12 : 16 , doi : 10.1186 / s13073-020-0714 - y ; Niemela et al . Blood . 2011 ; 117 ( 10 ) : 2883-6 , doi : 10.1182 / blood - 2010-07-295501 ; Nosan et al . Croat Med J. 2013 ; 54 ( 6 ) : 875–475 , doi : 10.3325 / cmj.2013.54.574 ; and Messina et al . Small GTPases 11.5 ( 2020 ) : 312- 319 , 10.1080 / 21541248.2018.1502591 . The term " mutant KRas - associated disease or disorder " as used herein refers to diseases or disorders associated with or having a KRas mutation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation ) . Non- limiting examples of a mutant KRas - associated disease or disorder include , for example , cancer , a cardiovascular disease ( e.g. , arteriovenous malformations ) , endometriosis , and an inflammatory and / or autoimmune disease ( e.g. , a nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis ) . See , e.g. , Adashek et al . Genome Med . 2020 ; 12 : 16 , doi : 10.1186 / s13073-020-0714 - y ; Niemela et al . Blood . 2011 ; 117 ( 10 ) : 2883-6 , doi : 10.1182 / blood- 2010-07-295501 ; Nosan et al . Croat Med J. Med J. 2013 ; 54 ( 6 ) : 574-578 , 10.3325 / cmj.2013.54.574 ; and Messina et al . Small GTPases 11.5 ( 2020 ) : 312-319 , 10.1080 / 21541248.2018.1502591 . doi : 83 WO 2025/064848 PCT / US2024 / 0477 LO gene that The phrase " dysregulation of a KRAS gene , a KRas protein , or the expression or activity or level of any of the same " refers to a genetic mutation ( e.g. , a mutation in a KRAS gene 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 . A " dysregulated KRas protein " as used herein refers to ( i ) a KRas protein having a mutation ( e.g. , a deletion of at least one amino acid as compared to a wild type KRas protein , one or more point mutations as compared to a wild type KRas protein , or an insertion of at least one amino acid as compared to a wild type KRas protein ) ; ( ii ) a KRas protein resulting from a gene duplication event , e.g. , of the gene encoding the KRas protein ( e.g. , the wild type KRas protein ) , thus resulting in an increased level and / or activity of the KRas protein ( e.g. , the wild type KRas protein ) in a cell ; ( iii ) a KRas 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 KRas protein ( e.g. , the wild type KRas protein ) in a cell ) ; ( iv ) a KRas protein resulting from 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 ( v ) a KRas protein resulting from increased expression ( e.g. , increased levels ) 84 WO 2025/064848 PCT / US2024 / 0477 LO 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 ) . In some embodiments , a dysregulated KRas protein is a dysregulated human KRas protein . A " mutant KRas protein " as used herein refers to a KRas protein including a substitution , an insertion , a deletion , a truncation and / or a fusion relative to the wild type human KRas sequence shown in SEQ ID NO : 1 . For example , a mutant human KRas protein includes a substitution at any amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G12X mutant protein " as used herein refers to a KRas protein including substitution of a glycine to any other amino acid at the twelfth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G12A mutant protein " as used herein refers to a KRas protein including a glycine to alanine substitution at the twelfth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G12C mutant protein " as used herein refers to a KRas protein including a glycine to cysteine substitution at the twelfth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G12D mutant protein " as used herein refers to a KRas protein including a glycine to aspartic acid substitution at the twelfth amino acid position ( relative to SEQ ID NO : ) . A " KRas G12R mutant protein " as used herein refers to a KRas protein including a glycine to arginine substitution at the twelfth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G12S mutant protein " as used herein refers to a KRas protein including a glycine to serine substitution at the twelfth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G12V mutant protein " as used herein refers to a KRas protein including a glycine to valine substitution at the twelfth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G13X mutant protein " as used herein refers to a KRas protein including substitution of a glycine to any other amino acid at the thirteenth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas G13C mutant protein " as used herein refers to a KRas protein including a glycine to cysteine substitution at the thirteenth amino acid position ( relative to SEQ ID NO : ) . A " KRas G13D mutant protein " as used herein refers to a KRas protein including a glycine to aspartic acid substitution at the thirteenth amino acid position ( relative to SEQ ID NO : 1 ) . 85 LO WO 2025/064848 PCT / US2024 / 0477 A " KRas G13V mutant protein " as used herein refers to a KRas protein including a glycine to valine substitution at the thirteenth amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas Q61X mutant protein " as used herein refers to a KRas protein including substitution of a glutamine to any other amino acid at the sixty - first amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas Q61E mutant protein " as used herein refers to a KRas protein including a glutamine to glutamic acid substitution at the sixty - first amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas Q61H mutant protein " as used herein refers to a KRas protein including a glutamine to histidine substitution at the sixty - first amino acid position ( relative to SEQ ID NO : 1 ) . A " KRas Q61K mutant protein " as used herein refers to a KRas protein including a glutamine to lysine substitution at the sixty - first amino acid position ( relative to SEQ ID NO : ) . A " KRas Q61L mutant protein " as used herein refers to a KRas protein including a glutamine to leucine substitution at the sixty - first amino acid position ( relative to SEQ ID NO : ) . A " KRas Q61P mutant protein " as used herein refers to a KRas protein including a glutamine to proline substitution at the sixty - first amino acid position ( relative to SEQ ID NO : ) . A " KRas Q61R mutant protein " as used herein refers to a KRas protein including a glutamine to arginine substitution at the sixty - first amino acid position ( relative to SEQ ID NO : ) . A " KRas inhibitor " as used herein includes any compound exhibiting KRas protein inactivation activity ( e.g. , inhibiting or decreasing KRas signaling activity ) . In some embodiments , a KRas inhibitor as described herein has an IC50 value of 1 Mμ or less in a nucleotide exchange assay as described herein , an IC50 value of 1 Mμ or less in a Raf kinase interaction assay as described herein , or both . In some embodiments , a KRas inhibitor inhibits the signaling activity of a wild type KRas protein . In some embodiments , a KRas inhibitor inhibits the signaling activity of a dysregulated KRas protein , for example , resulting in a decrease in activated Raf or other downstream effectors , such as ERK . In some embodiments , a KRas inhibitor inhibits the signaling activity of a mutant KRas protein . In some embodiments , a KRas inhibitor inhibits both the signaling activity of a wild - type KRas protein and the 86 WO 2025/064848 PCT / US2024 / 0477 LO signaling activity of one or more mutant KRas proteins and can be termed a " pan KRas inhibitor " . In some embodiments , a KRas inhibitor inhibits one or more mutant KRas proteins , and such a KRas inhibitor can be termed a " mutant KRas inhibitor " , and also termed by the mutant ( s ) it inhibits . For example , a KRas inhibitor that inhibits KRas G12R mutant protein could be termed a " KRas G12R inhibitor " . As another example , a KRas inhibitor that inhibits both KRas G12C mutant protein and KRas G12D mutant protein could be termed a " KRas G12C inhibitor " and / or a " KRas G12D inhibitor " . In some embodiments , a " mutant KRas inhibitor " inhibits two or more mutant KRas proteins and can be termed a " pan mutant KRas inhibitor " . In some embodiments , a pan mutant KRas inhibitor inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . For example , a " KRas G12X inhibitor " can inhibit two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . As yet another example , a KRas inhibitor that inhibits a KRas G13D mutant protein could be termed a " KRas G13D inhibitor " . In some embodiments , a KRas inhibitor can inhibit a KRas protein having one or more mutations , and such a KRas inhibitor can be termed a " mutant KRas inhibitor " whether or not the mutant KRas inhibitor also inhibits wild type KRas protein . In some embodiments , a KRas inhibitor is a mutant KRas inhibitor . In some embodiments , a KRas inhibitor is an allosteric inhibitor .

The term " compound ( s ) provided herein " refers to compound ( s ) of Formula ( A ) ( e.g. , Formula ( I ) ( e.g. , Formula ( I - a ) , ( I - b ) , ( I - c ) , ( I - c1 ) , ( I - c2 ) , ( I - c3 ) , ( I - c4 ) , ( I - d ) , or ( I - e ) ) ) or Formula ( B ) as disclosed herein . The compounds provided herein , or pharmaceutically acceptable salts thereof , are KRas inhibitors . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a mutant KRas inhibitor . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas 87 WO 2025/064848 PCT / US2024 / 0477 LO G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , or a combination thereof . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12V mutant protein , or a combination thereof . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12V mutant protein , or both . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12R mutant protein , a KRas G12V mutant protein , or both . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12C mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12S mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12X inhibitor . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a 88 WO 2025/064848 PCT / US2024 / 0477 LO pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits four or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits five or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits four or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , 89 WO 2025/064848 PCT / US2024 / 0477 LO inhibits a KRas G12D mutant protein , a KRas G12V mutant protein , or both . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12C mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , does not inhibit a KRas G12C mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , does not inhibit a KRas G12D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12S mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G13X inhibitor . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G13C mutant protein , a KRas G13D mutant protein , and a KRas G13V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G13C mutant protein , a KRas G13D mutant protein , and a KRas G13V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G13C mutant protein , a KRas G13D mutant protein , and a KRas G13V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G13C mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G13D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G13V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas Q61X inhibitor . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a 90 WO 2025/064848 PCT / US2024 / 0477 LO pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits four or more mutant KRas proteins selected from the group consisting of : a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits five or more mutant KRas proteins selected from the group consisting of : a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61E mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61H mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61K mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61P mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12X mutant protein , a KRas G13X mutant protein , and a KRas Q61X mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a 91 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12X mutant protein , a KRas G13X mutant protein , and a KRas Q61X mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant human KRas proteins selected from the group consisting of : a KRas G12X mutant protein , a KRas G13X mutant protein , and a KRas Q61X mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12X mutant protein , a KRas G13X mutant protein , and a KRas Q61X mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits four or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a 92 WO 2025/064848 PCT / US2024 / 0477 LO KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , five or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12V mutant protein , a KRas G13D mutant protein , and a KRas Q61H mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12V mutant protein , a KRas G13D mutant protein , and a KRas Q61H mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12V mutant protein , a KRas G13D mutant protein , and a KRas Q61H mutant protein . 93 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a bladder cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12V mutant protein , and a KRas G13D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12V mutant protein , and a KRas G13D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12V mutant protein , and a KRas G13D mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . 94 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12V mutant protein , or both . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a cervical cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected 95 WO 2025/064848 PCT / US2024 / 0477 LO from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a colorectal cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61H mutant protein , and a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61H mutant protein , and a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61H mutant protein , and a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a 96 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating an endometrial cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , and a KRas Q61H mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , and a KRas Q61H mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , and a KRas Q61H mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a 97 WO 2025/064848 PCT / US2024 / 0477 KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12V mutant protein , or both . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating an esophageal or stomach cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61E mutant protein , a KRas Q61H mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a 98 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a leukemia . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G13D mutant protein , a KRas G13V mutant protein , a KRas Q61K mutant protein , a KRas Q61L mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a 99 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12R mutant protein , or both . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a melanoma . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G13D mutant protein , and a KRas Q61L mutation . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G13D mutant protein , and a KRas Q61L mutation . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G13D mutant protein , and a KRas Q61L mutation . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12S mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12S mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D 100 WO 2025/064848 PCT / US2024 / 0477 LO mutant protein , a KRas G12R mutant protein , and a KRas G12S mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12C mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein , a KRas G12V mutant protein , or both . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating an ovarian cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas Q61H mutant protein , and a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas Q61H mutant protein , and a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas G13D mutant protein , a KRas Q61H mutant protein , and a KRas Q61L mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . 101 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12D mutant protein , and a KRas G12V mutant protein . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a lung cancer ( e.g. , non - small cell lung cancer ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas Q61H mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas Q61H mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas G13C mutant protein , a KRas Q61H mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a 102 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a pancreatic cancer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q6IR mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , a KRas G12V mutant protein , a KRas Q61L mutant protein , a KRas Q61P mutant protein , and a KRas Q61R mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and 103 WO 2025/064848 PCT / US2024 / 0477 LO a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits three or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits one or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits two or more mutant KRas proteins selected from the group consisting of : a KRas G12A mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12A mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein . In some some such embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating a testicular cancer ( e.g. , seminoma ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can bind to a KRas protein in the GTP - bound state . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can bind selectively to a KRas protein in the GTP - bound state . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can bind to a KRas protein in the GDP - bound state . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can bind selectively to a KRas protein in the GDP - bound state . An exemplary sequence of mature human KRas protein is shown below ( UniProtKB entry P01116 ) ( SEQ ID NO : 1 ) MTEYKLVVVG CLLDILDTAG AGGVGKSALT IQLIQNHFVD EYDPTIEDSY RKQVVIDGET QEEYSAMRDQ YMRTGEGFLC VFAINNTKSF EDIHHYREQI KRVKDSEDVP MVLVGNKCDL PSRTVDTKQA QDLARSYGIP FIETSAKTRQ RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCIIM 104 WO 2025/064848 PCT / US2024 / 0477 LO 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 . For example , if a compound provided herein , or a pharmaceutically acceptable salt thereof , binds " selectively " to a KRas G12X mutant protein over the wild type KRas protein as determined by a surface plasmon resonance ( SPR ) assay , then the compound provided herein , 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 - fold , or at least a 100 - fold ) smaller KD value for any one or more KRas mutant proteins selected from the group consisting of the KRas G12X mutant proteins than for the wild type KRas protein when measured by the SPR assay . As a further example , if a compound provided herein , or a pharmaceutically acceptable salt thereof , " selectively " reduces the viability of 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 ) smaller EC50 value 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 provided herein , or a pharmaceutically acceptable salt thereof , " selectively " inhibits a KRas G13X mutant protein over the wild type KRas protein as determined by a Raf kinase interaction assay , then the compound provided herein , 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 IC50 value for the KRas G13X protein than for the wild type KRas protein when measured by the Raf kinase interaction assay . As a further example , if a compound provided herein , or a pharmaceutically acceptable salt thereof , " selectively " inhibits the KRas G12R mutant protein over the wild type KRas protein as determined by a nucleotide exchange assay , then the compound provided herein , 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 IC50 value for the KRas G12R mutant protein than for the wild type KRas protein when measured by the nucleotide exchange assay . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a pan mutant KRas inhibitor ( i.e. , can inhibit two or more mutant KRas proteins ( e.g. , two or more of a KRas G12A mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , and a KRas G12V mutant protein ) ) . For example , such a compound can inhibit 105 WO 2025/064848 PCT / US2024 / 0477 LO each mutant KRas protein ( e.g. , two or more mutant KRas proteins ) with an IC50 of less than Mμ ( e.g. , less than 750 nM , less than 500 nM , or less than 200 nM ) . As another example , such a compound can inhibit ERK phosphorylation in cell lines each expressing a mutant KRas protein with an independent IC50 of less than 1 Mμ ( e.g. , less than 750 nM , less than 500 nM , or less than 200 nM ) in at least two of the cell lines . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a cell line expressing a KRas G12R mutant protein with an IC50 of less than 1 Mμ , and the compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a cell line expressing a KRas G12V mutant protein with an IC50 of less than Mμ . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a pan KRas inhibitor ( i.e. , the compound can inhibit wild type KRas and one or more mutant KRas proteins ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , does not inhibit certain KRas proteins ( e.g. , wild type KRas or one or more dysregulated KRas proteins ) . For example , such a compound can inhibit the interaction between a KRas protein ( e.g. , a dysregulated KRas protein ) and one or more Raf proteins with an IC50 of 1 Mμ or greater than 1 Mµ ( e.g. , greater than 2 Mµ , greater than Mμ , greater than 10 Mµ , or greater than 30 Mμ ) . As another example , such a compound can inhibit ERK phosphorylation in cell lines expressing the KRas protein ( e.g. , a dysregulated KRas protein ) with an IC50 of 1 Mμ or greater than 1 Mµ ( e.g. , greater than 2 Mµ , greater than Mμ , greater than 10 Mµ , or greater than 30 Mµ ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits a KRas G12D mutant protein and a KRas G12V mutant protein . In some such embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 that is within about 10 - fold , i.e. , within about 10 - fold less or within about 10 - fold more ( e.g. , within about 9 - fold less or within about 9 - fold more , within about 8 - fold less or within about 8 - fold more , within about 7 - fold less or within about 7 - fold more , within about 6 - fold less or within about 6 - fold more , within about 5 - fold less or within about 5 - fold more , or within about 2 - fold less or within about 2 - fold more ) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) . For example , if the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation 106 WO 2025/064848 PCT / US2024 / 0477 LO in a cell line expressing a KRas G12D mutant protein with an IC 50 of about 150 nM , then the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein would be within about 10 - fold more than about 150 nM , thus ranging from about 150 nM to about 1500 nM , or within about 10 - fold less than 150 nM , thus ranging from about 15 nM to about 150 nM . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about 10 - fold , i.e. , within about 10 - fold less or within about 10 - fold more ( e.g. , within about 9 - fold less or within about 9 - fold more , within about 8- fold less or within about 8 - fold more , within about 7 - fold less or within about 7 - fold more , within about 6 - fold less or within about 6 - fold more , within about 5 - fold less or within about - fold more , or within about 2 - fold less or within about 2 - fold more ) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 that is within about 10 - fold less ( e.g. , within about 9 - fold less , within about 8 - fold less , within about - fold less , within about 6 - fold less , within about 5 - fold less , or within about 2 - fold less ) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that within about 10 - fold less ( e.g. , within about 9 - fold less , within about 8 - fold less , within about - fold less , within about 6 - fold less , within about 5 - fold less , or within about 2 - fold less ) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 that is within about 10 - fold more ( e.g. , within about 9 - fold more , within about 8 - fold more , within about 7 - fold more , within about 6 - fold more , within about 5 - fold more , or within about 2 - fold more ) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a 107 WO 2025/064848 PCT / US2024 / 0477 LO GP2d cell line with an IC50 that is within about 10 - fold more ( e.g. , within about 9 - fold more , within about 8 - fold more , within about 7 - fold more , within about 6 - fold more , within about 5- fold more , or within about 2 - fold more ) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line . In some such embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . In some such further embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than nM ) . For example , the compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than nM , less than 50 nM , less than 30 nM ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 that is within about 10 - fold , i.e. , within about 10 - fold less or within about 10 - fold more ( e.g. , within about 9 - fold less or within about 9 - fold more , within about 8 - fold less or within about 8 - fold more , within about 7 - fold less or within about 7 - fold more , within about 6- fold less or within about 6 - fold more , within about 5 - fold less or within about 5 - fold more , or within about 2 - fold less or within about 2 - fold more ) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPANI , CAPAN2 , RKN , H441 , and SW480 ) , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in the cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , 108 WO 2025/064848 PCT / US2024 / 0477 LO CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than nM , less than 50 nM , less than 30 nM ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in the cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 of less than 250 nM ( e.g. , less than 2nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about - fold , i.e. , within about 10 - fold less or within about 10 - fold more ( e.g. , within about 9 - fold less or within about 9 - fold more , within about 8 - fold less or within about 8 - fold more , within about 7 - fold less or within about 7 - fold more , within about 6 - fold less or within about 6 - fold more , within about 5 - fold less or within about 5 - fold more , or within about 2 - fold less or within about 2 - fold more ) of the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 that is within about 10 - fold less ( e.g. , within about 9 - fold less , within about 8 - fold less , within about 7 - fold less , within about 6 - fold less , within about 5 - fold less , or within about 2- fold less ) than the IC 50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in the cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 109 WO 2025/064848 PCT / US2024 / 0477 LO 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than nM ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in the cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about - fold less ( e.g. , within about 9 - fold less , within about 8 - fold less , within about 7 - fold less , within about 6 - fold less , within about 5 - fold less , or within about 2 - fold less ) than the ICmeasured for inhibition of ERK phosphorylation by the compound in a SW620 cell line , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than nM , less than 30 nM ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and HPAC ) with an IC50 that is within about 10 - fold more ( e.g. , within about 9 - fold more , within about 8- fold more , within about 7 - fold more , within about 6 - fold more , within about 5 - fold more , or within about 2 - fold more ) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPANI , CAPAN2 , RKN , H441 , and SW480 ) , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in the cell line expressing a KRas G12V mutant protein ( e.g. , SW620 , H727 , CFPAC1 , CAPAN1 , CAPAN2 , RKN , H441 , and SW480 ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in the cell line expressing a KRas G12D mutant protein ( e.g. , AGS , ASPC1 , GP2D , LS180 , Panc04.03 , HPAFII , Panc02.03 , A427 , and 110 WO 2025/064848 PCT / US2024 / 0477 LO HPAC ) with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can inhibit ERK phosphorylation in a GP2d cell line with an IC50 that is within about - fold more ( e.g. , within about 9 - fold more , within about 8 - fold more , within about 7 - fold more , within about 6 - fold more , within about 5 - fold more , or within about 2 - fold more ) than the IC50 measured for inhibition of ERK phosphorylation by the compound in a SW620 cell line , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a SW620 cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than nM , less than 30 nM ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits ERK phosphorylation in a GP2d cell line with an IC50 of less than 250 nM ( e.g. , less than 200 nM , less than 150 nM , less than 125 nM , less than 100 nM , less than 75 nM , less than 50 nM , less than 30 nM ) . The ability of a compound provided herein , or a pharmaceutically acceptable salt thereof , to bind to a KRas 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 provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , binds ( for example , an antibody that binds to an N - terminal tag ) . It will be understood that the antibody and probe can be tagged with any appropriate FRET pair . See , e.g. , International Publication Nos . WO 2021/041671 , WO 2021/120890 , and U.S. Publication No. US 2021/0179633 .

In some cases , binding affinities ( e.g. , as measured by dissociation constant KD ) of the compounds provided herein , or pharmaceutically acceptable salts thereof with a KRas protein ( e.g. , a wild type KRas protein or a mutant KRas protein ) in the GDP - bound and / or GTP - bound state can be measured using methods known in the art ( e.g. , using SPR ( e.g. , using one or more 111 WO 2025/064848 PCT / US2024 / 0477 LO methods described herein ( e.g. , using the methods described in Example B1 or in Example B5 herein ) ) ) . Binding affinity with the KRas protein in the GDP - bound state can be measured by loading the KRas protein with GDP ( e.g. , at the concentrations described in Example Bor in Example B5 ) . Binding affinity with the KRas protein in the GTP - bound state can be measured by loading the KRas protein with GMPPNP ( e.g. , at the concentrations described in Example B1 ) . Another exemplary assay for determining the potency of a compound provided herein , or a pharmaceutically acceptable salt thereof , includes measuring the effect of the compound provided herein , 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 , CAPAN1 , CAPAN2 , CFPAC1 , GP2D , H358 , H441 , H460 , H727 , HCT116 , HKA1 , HPAC , HPAFII , HTK , HUPT3 , KMS20 , KP2 , LS123 , LS180 , MIAPaCa - 2 , MKN1 , NCI - H1993 , NCI - H211 , NCI - H424 , NCI - H526 , Panc02.03 , Panc04.03 , PATC50 , PC9 , PK8 , PSN1 , RKN , SW480 , SW620 , and / or TCCPAN2 . In some embodiments , the cell line can be AGS , A375 , A427 , ASPC1 , H727 , H441 , 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 provided herein , or a pharmaceutically acceptable salt thereof , measuring the cellular proliferation using an appropriate reagent ( e.g. , ®OLGRETITLLEC 3D ) , and then comparing the signal from the experiment with the compound provided herein , or a pharmaceutically acceptable salt thereof , to the signal from a control experiment ( e.g. , lacking a compound provided herein ) . 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 provided herein , or a pharmaceutically acceptable salt thereof , measuring the cellular proliferation using an appropriate reagent ( e.g. , ®OLGRETITLLEC ) , and then comparing the signal from the experiment with a compound provided herein , or a pharmaceutically acceptable salt thereof , to the signal from a control experiment ( e.g. , lacking a compound provided herein , or a pharmaceutically acceptable salt thereof ) . See , e.g. , Example B7 herein . In some embodiments , cellular proliferation can be assessed using a platform for live cell imaging ( e.g. , an ®ETYCUCNI SX5 Live - Cell Analysis Instrument ) . See also , e.g. , U.S. Publication No. US 2021/0179633 , US 2021/0230142 , and US 2019/0284144 . As another example , the potency and / or efficacy of a compound provided herein , or a 112 WO 2025/064848 PCT / US2024 / 0477 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 AGS , A375 , A427 , ASPC1 , H727 , H441 , RKN , and / or SW620 , or a patient - derived xenograft ( PDX ) model ) . See , e.g. , U.S. Publication No. US 2021/0179633 .

In some embodiments , the potency and / or efficacy of a compound provided herein , or a pharmaceutically acceptable salt thereof can be evaluated in a cell - derived xenograft ( CDX ) model . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is assessed in a CDX ( e.g. , H727 , RKN , or SW620 ) mouse model . For example , mice can be implanted with a cell line of interest ( e.g. , H727 , RKN , or SW620 ) and the tumor allowed to grow for a period of time , then the mice can be administered a compound provided herein , or a pharmaceutically acceptable salt thereof . The effect of the compound provided herein , or a pharmaceutically acceptable salt thereof , can be determined by measuring tumor growth ( or regression ) . An exemplary protocol follows . All the procedures related to animal handling , care , and treatment in the efficacy study are performed according to guidelines approved by the Institutional Animal Care and Use Committee ( IACUC ) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care ( AAALAC ) . 6-8 week old BALB / c nude female mice are inoculated subcutaneously on the right flank with 5 × 106 H727 , RKN , or SW6tumor cells in 0.1 mL of 1 : 1 medium / Matrigel for tumor development . Treatments start and groupings are assigned when the mean tumor volume reaches about 175-225 ³mm . Based on the tumor volume , mice are randomly assigned to respective groups such that the average starting tumor size is the same for each treatment group . Tumor - bearing mice are treated orally twice daily with a compound provided herein , or a pharmaceutically acceptable salt thereof ( e.g. , a dose of about 1 mg / kg to about 200 mg / kg , such as 1 mg / kg , 3 mg / kg , 5 mg / kg , mg / kg , 20 mg / kg , 30 mg / kg , 50 mg / kg , 75 mg / kg , 100 mg / kg , 150 mg / kg , or 200 mg / kg ) . The body weight of each animal is measured and recorded twice weekly throughout the study . The ﻭﻭ measurement of tumor size is conducted twice weekly with a caliper and recorded . The tumor volume ( ³mm ) is estimated using the formula : TV - a × ²b / 2 , where " a " and " b " are long and short diameters of a tumor , respectively . In some embodiments , the tumor volume is plotted as a function of time .

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 provided herein , or a pharmaceutically acceptable salt thereof ) stabilizes the 113 WO 2025/064848 PCT / US2024 / 0477 LO GTP - bound state or GDP - bound state of a KRas protein ( e.g. , a dysregulated KRas 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 ) ) . In such assays , the rate of hydrogen exchange of the backbone amide hydrogens can be measured for a KRas protein ( e.g. , a dysregulated KRas 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 ) ) bound to a non - hydrolyzable GTP mimic ( GMPPNP ) , GDP , or a compound provided herein , or a pharmaceutically acceptable salt thereof . See , e.g. , Lim et al . Angew Chem Int Ed Engl . 2014 ; 53 ( 1 ) : 402–991 , doi : 10.1002 / anie.201307387 .

In some embodiments , potency of a compound provided herein , or a pharmaceutically acceptable salt thereof , as provided herein can be determined by EC 50 value . A compound with a lower EC50 value , as determined under substantially similar conditions , is a more potent inhibitor relative to a compound with a higher EC50 value . In some embodiments , an EC50 value can be determined ( e.g. , using a KRas - 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 A375 , A427 , A549 , AGS , ASPC1 , CAL62 , CALU1 , CAPAN1 , CAPAN2 , CFPAC1 , GP2D , H358 , H441 , H460 , H727 , HCT116 , HKA1 , HPAC , HPAFII , HTK , HUPT3 , KMS20 , KP2 , LS123 , LS180 , MIAPaCa - 2 , MKN1 , NCI - H1993 , NCI - H211 , NCI - H424 , NCI - H526 , Panc02.03 , Panc04.03 , PATC50 , PC9 , PK8 , PSN1 , RKN , SW480 , SW620 , and / or TCCPAN2 ) expressing a KRas 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 , potency of a compound provided herein , or a pharmaceutically acceptable salt thereof , as provided herein can also be determined by IC50 value . A compound with a lower IC50 value , as determined under substantially similar conditions , is a more potent inhibitor relative to a compound with a higher IC50 value . In some embodiments , an IC50 value can be determined ( e.g. , using a KRas - 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 as A375 , A427 , A549 , AGS , ASPC1 , CAL62 , CALUI , CAPANI , CAPAN2 , CFPAC1 , GP2D , H358 , H441 , H460 , H727 , HCT116 , HKA1 , HPAC , HPAFII , HTK , HUPT3 , KMS20 , KP2 , LS123 , LS180 , MIAPaCa - 2 , MKN1 , NCI - H1993 , NCI - H211 , NCI - H424 , NCI - H526 , Panc02.03 , Panc04.03 , PATC50 , PC9 , PK8 , PSN1 , RKN , SW480 , SW620 , and / or TCCPAN2 ) expressing a KRas protein , such as a dysregulated KRas protein ( e.g. , a mutant KRas protein or an amplified KRas protein ) , or a fragment thereof ) . 114 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , measuring the potency of a compound provided herein , 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 , CAPAN1 , CAPAN2 , CFPAC1 , GP2D , H358 , H441 , H460 , H727 , HCT116 , HKA1 , HPAC , HPAFII , HTK , HUPT3 , KMS20 , KP2 , LS123 , LS180 , MIAPaCa - 2 , MKN1 , NCI - H1993 , NCI - H211 , NCI - H424 , NCI - H526 , Panc02.03 , Panc04.03 , PATC50 , PC9 , PK8 , PSN1 , RKN , SW480 , SW620 , and / or TCCPAN2 ( e.g. , AGS , A375 , A427 , ASPC1 , H727 , H441 , RKN , and / or SW620 ) ) . For example , cells can be contacted with a compound provided herein , 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 ®ERIFERUS p - ERK1 / 2 ( Thr202 / Tyr204 ) , or an ®FRTH Phospho- ERK ( Thr202 / Tyr204 ) cellular kit ( CisBio ) ) . In some embodiments , multiple concentrations of a compound provided herein , or a pharmaceutically acceptable salt thereof can be used to construct a dose response curve . See , e.g. , Example B6 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 . , An exemplary ERK phosphorylation protocol follows . In some embodiments , an ERK phosphorylation assay can be carried out using the AlphaLisa ®ERIFERUS Ultra Multiplex Phospho / Total ERK1 / 2 ( Thr202 / Tyr204 ) Assay Kit . In a plate ( e.g. , a white , opaque- bottom Perkin Elmer CulturPlate - 384 ( product number 6007680 ) ) , cells are seeded at the desired concentration one day prior to treatment with compounds provided herein , or pharmaceutically acceptable salts thereof , and incubated overnight in a standard 37 ° C , 5 % CO2 humidified incubator . The cells can be any cells of interest , such as MIAPaCa - 2 ( KRas G12C ) , H358 ( KRas G12C ) , AGS ( KRas G12D ) , ASPC1 ( KRas G12D ) , GP2D ( KRas G12D ) , LS180 ( KRas G12D ) , Panc04.03 ( KRas G12D ) , HPAFII ( KRas G12D ) , Panc02.03 ( KRas G12D ) , A427 ( KRas G12D ) , HPAC ( KRas G12D ) , TCCPAN2 ( KRas G12R ) , PSN1 ( KRas G12R ) , KP2 ( KRas G12R ) , LS123 ( KRas G12S ) , SW620 ( KRas G12V ) , H727 ( KRas G12V ) , CFPAC1 ( KRas G12V ) , CAPAN1 ( KRas G12V ) , CAPAN2 ( KRas G12V ) , RKN ( KRas G12V ) , H441 ( KRas G12V ) , SW480 ( KRas G12V ) , PACADD159 ( KRas G12V / G12S ) , HS766T ( KRas Q61H ) , H460 ( KRas Q61H ) , PANC0213 ( KRas Q61R ) , or A3735 ( KRas WT ) . 115 WO 2025/064848 PCT / US2024 / 0477 The day after seeding , compounds provided herein , or pharmaceutically acceptable salts thereof , are dispensed into the treatment plates ( e.g. , using a Tecan D300e compound printer in 9 - point DRC format ( 1 : 3 dilution ) , 10 - Mμ top concentration , in triplicate ) . Treatment plates are then returned to a standard 37 ° C , 5 % CO2 humidified incubator for the pre - determined treatment time . Following compound treatment , all media is removed from the treatment plate ( s ) , and the cells are subsequently lysed ( e.g. , using 1X Lysis Buffer in accordance with manufacturer protocol ) . Next , the Acceptor Mix ( prepared in accordance with manufacturer's protocol ) is added to each well of the assay plate and incubated on an orbital shaker at room temperature for 2 hours . Following incubation with the Acceptor Mix , the Donor Mix ( prepared in accordance with manufacturer protocol ) is added to each well of the assay plate , covered to protect from light , and incubated on an orbital shaker at room temperature overnight . Assay plates are read the following day ( e.g. , on a BMG Labtech PHERAstar FSX microplate reader ) . Data are then analyzed by calculating the ratio of ERK1 / 2 - phosphorylation relative to Total ERK1 / 2 for each individual well .

Ratio PERK1 / = 615nm Signal ( pERK1 / 2 ) 545nm Signal ( Total ERK1 / 2 ) The replicate ratios for each concentration are averaged and normalized to a DMSO control or other corresponding co - treatment before performing a variable slope ( 4 - parameter ) , non - linear regression curve fit for each compound of interest . Data can be reported as ICvalues .

In some embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , inhibit ERK phosphorylation in a cell line expressing a KRas protein ( e.g. , a dysregulated KRas 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 ) ) ) with an IC50 of less than 1 Mμ ( e.g. , less than 750 nM , less than 500 nM , or less than 200 nM ) . In some embodiments , the compounds inhibit ERK phosphorylation in a cell line expressing the KRas protein ( e.g. , a dysregulated KRas 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 ) ) ) with an IC 50 of less than 2nM ( e.g. , less than 150 nM , less than 200 nM , less than 100 nM , less than 10 nM , less than nM ) . For example , the compounds can inhibit ERK phosphorylation in a cell line expressing the KRas protein ( e.g. , a dysregulated KRas 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 ) ) ) with an IC50 of 0.1 nM to 100 nM , 0.1 nM to 50 nM , 1 nM to 50 nM , or 1 nM to 20 nM . In some cases , a KRas A59G mutant protein ( e.g. , as a single mutant or as a double 116 WO 2025/064848 PCT / US2024 / 0477 LO mutant with another mutation of interest , e.g. , KRas G12X ) can be used to " lock " the KRas protein in the GTP - bound state ( e.g. , by abrogating the GTPase activity of the protein ) ; such an assay can be useful , for example , to determine the affinity of a compound provided herein , or a pharmaceutically acceptable salt thereof for the GTP - bound state and / or to determine the effect of the compound on downstream signaling ( e.g. , interaction with an RBD and / or the phosphorylation of a downstream kinase , such as ERK ) , potentially independent of the GTP cycling of the KRas protein . See , e.g. , Hall , et al . Proceedings of the National Academy of Sciences 99.19 ( 2002 ) : 12138-12142 , doi : 10.1073 / pnas.192453199 ; Lu , et al . Biochemistry 57.3 ( 2018 ) : 324-333 , doi : 10.1021 / acs.biochem . 7b00974 ; and Lim , Shuhui , et al . Chemical Science 12.48 ( 2021 ) : 15975-15987 , doi : 10.1039 / D1SC05187C . In some embodiments , the potency of a compound provided herein , or a pharmaceutically acceptable salt thereof , as a KRas inhibitor can be evaluated by its effect on the nucleotide exchange of GDP for GTP . For example , nucleotide exchange can be measured via the increase in fluorescence of protein - bound N - methylanthraniloyl ( MANT ) -GDP upon the addition of an excess amount of a non - hydrolyzable GTP analog such as guanosine - 5'- [ ( u0000 , y ) -imido ] triphosphate ( GppNHp , sometimes also referred to as GMPPNP ) , when exchange is inhibited . See , e.g. , Kanie and Jackson , Bio Protoc . 2018 ; 8 ( 7 ) : e2795 , doi : 10.21769 / BioProtoc . 2795. As another example , nucleotide exchange can be measured via the decrease in fluorescence of an incubated mixture of KRas protein - bound fluorophore - tagged GDP ( e.g. , Bodipy - GDP ( e.g. , EDA - GTP - DY - 647P1 ) ) and a compound provided herein , or a pharmaceutically acceptable salt thereof , followed by treatment with unlabeled GTP . In such an assay , an exchange of fluorophore - tagged GDP ( e.g. , Bodipy - GDP ) for unlabeled GTP results in a reduced TR - FRET signal . As another example , nucleotide exchange can be measured via the increase in fluorescence of an incubated mixture of KRas protein - bound GDP and a compound provided herein , or a pharmaceutically acceptable salt thereof , followed by treatment with labeled GTP . In such an assay , an exchange of GDP for labeled GTP results in an increased FRET signal . See , e.g. , International Publication No. WO 2020/085493 and U.S. Publication Nos . US 2021/0122764 , US 2021/0269434 , and US 2018/0334454 . In some embodiments of nucleotide exchange assays , a guanine nucleotide exchange factor ( e.g. , SOS1 ) can be added to accelerate nucleotide exchange . Inhibition of SOS1 - catalyzed exchange of GDP for GTP on the KRas protein by compounds provided herein , or pharmaceutically acceptable salts thereof can be measured using methods known in the art ( e.g. , using one or more methods described herein ( e.g. , using 117 WO 2025/064848 PCT / US2024 / 0477 LO methods described in Example B2 herein ) ) . Additional examples of in vitro assays include assays that determine inhibition of the GTPase activity of KRas protein . In some embodiments , the potency of a compound provided herein , or a pharmaceutically acceptable salt thereof , can be evaluated by its effect on GTPase activity ( or lack thereof , as a decrease in GTPase activity is generally believed to be associated with aberrant signaling ) . For example , GTPase activity of a KRas protein can be measured using a phosphate assay system that continuously measures phosphate release . In some embodiments , a purine nucleoside phosphorylase - based ( PNP ) assay can be used to measure GTPase activity of a KRas protein . See , e.g. , Hunter et al . Mol Cancer Res . 2015 ; 13 ( 9 ) : 1325-35 , doi : 10.1158 / 1541-7786.MCR - 15-0203 . In some embodiments , an enzyme - linked immunosorbent assay ( ELISA ) can be used to measure the effect of a compound provided herein , or a pharmaceutically acceptable salt thereof , on the GTPase activity of a KRas protein ( e.g. , a dysregulated KRas 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 ) ) , for example , by detecting a change in the amount of GST - Ras - RBD that binds to the KRas protein following pull - down and antibody detection of the complex . See , e.g. , US 2021/0179633 .

An exemplary SOS1 - catalyzed nucleotide exchange assay protocol follows . GST - KRas G12R ( 1-169 ) loaded with GDP nucleotide is mixed with Anti - GST ( Cisbio ) antibody in assay buffer ( 20 mM HEPES pH 7.4 , 150 mM NaCl , 5 mM MgCl2 , 1 mM DTT , 0.005 % NP40 , 1 % DMSO ) to produce a 1.5x solution . 10 Lμ of the 1.5x KRas - Ab solution is added to wells of a black , low - volume 384 - well assay plate . Compounds provided herein , or pharmaceutically acceptable salts thereof , are added to wells using acoustic transfer technology . A 10 - point dose response of each compound is performed with a 30 Mμ top dose . The KRas / Ab - compound mixture is incubated 1 hour at room temperature . A 3x solution of SOS1 ( 564-1049 ) and EDA- GTP - DY - 647P1 ( Jena Bioscience ) is prepared in assay buffer . 5 Lμ of the SOS1 - labeled GTP solution is added to the wells to initiate the nucleotide exchange reaction . The final concentration of KRas G12R and SOS1 are 10 nM and 200 nM , respectively . 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 HTRF signal is calculated as = = = the ratio of fluorescence intensity [ emission 665 nm ] / [ emission 620 nm ] . IC50 values are calculated using a four - parameter , variable response sigmoidal dose response curve fit in Graphpad Prism software . 118 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits SOS1 - catalyzed exchange of GDP for GTP on the KRas protein with an IC50 of less than 1 Mμ ( e.g. , less than 750 nM , less than 500 nM , or less than 200 nM ) . In some embodiments , the compound inhibits SOS1 - catalyzed exchange of GDP for GTP on the KRas protein with an IC50 of less than 200 nM ( 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 compound can inhibit SOS1 - catalyzed exchange of GDP for GTP on the KRas protein with an IC50 of 0.001 nM to 500 nM , 0.005 nM to 100 nM , 0.025 nM to 100 nM , 0.1 nM to 50 nM , or 0.1 nM to 10 nM .

Additional assays for evaluating the potency of a compound provided herein , 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 KRas : nucleotide complexes for the Ras Binding Domain ( RBD ) of a RAF protein kinase ( e.g. , as impacted by a compound provided herein , or a pharmaceutically acceptable salt thereof ) . For example , FLAG tagged KRas protein can be preloaded with the GTP analog GppNHp and then incubated with biotinylated Raf - RBD to form complexes . A competition assay can then be performed by adding untagged KRas 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. , ⓇNEERCSAHPLA beads ) can be measured to determine the affinity of the KRas 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 ) : 402–991 , 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 provided herein , or pharmaceutically acceptable salts thereof , that may bind selectively to the GTP - bound state , His - tagged KRas protein can be preloaded with the GTP analog GppNHp and then incubated with a compound provided herein , 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 IC50 value . 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 119 WO 2025/064848 PCT / US2024 / 0477 LO nucleotide exchange assay ; for example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be incubated with a KRas protein ( e.g. , a dysregulated KRas 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 ) ) 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 KRas mixture , followed by introduction of donor beads ( e.g. , glutathione donor beads ) and measurement using ®NEERCSAHPLA technology . As an alternative to ®NEERCSAHPLA 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 KRas : nucleotide complex for a RBD is to incubate cells with a compound provided herein , or a pharmaceutically acceptable salt thereof , lyse the cells , then pull down non - RBD - bound KRas using an immobilized RBD . See , e.g. , U.S. Publication No. US 2019/0233440 . As another example , the effect of a compound provided herein , or a pharmaceutically acceptable salt thereof , on the interaction between KRas 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. , KRas 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 provided herein , or a pharmaceutically acceptable salt thereof , on the interaction between KRas 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. , KRas 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 provided herein , or a pharmaceutically acceptable salt thereof , is selective for a KRas protein ( e.g. , a dysregulated KRas 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 ) ) in the GDP - bound state or the GTP - bound state . 120 WO 2025/064848 PCT / US2024 / 0477 Inhibition of the interaction between the KRas protein and Raf - RBD by compounds provided herein , or pharmaceutically acceptable salts thereof , can be measured using methods known in the art ( e.g. , using one or more methods described herein ( e.g. , using methods described in Example B3 or Example B4 herein ) ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , modulates the interaction between the KRas protein and one or more Raf proteins . In some embodiments , the compound inhibits the interaction between the KRas protein and Raf - RBD with an IC50 of less than 1 Mμ ( e.g. , less than 750 nM , less than 500 nM , or less than 200 nM ) . In some embodiments , the compound inhibits the interaction between the KRas protein and Raf - RBD with an IC50 of 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.nM ) . For example , the compound inhibits the interaction between the KRas protein and Raf- RBD with an IC50 from 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 . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits the interaction between the KRas protein and Raf - RBD with an IC50 of less than 1 Mμ in the absence of cyclophilin A ( 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 KRas protein and Raf - RBD with an IC50 of less than 200 nM in the absence of cyclophilin A ( e.g. , e.g. , less than 150 nM , less than 200 nM , less than 100 nM , less than 10 nM , less than nM , less than 0.1 nM , or less than 0.01 nM ) . For example , the compounds inhibit the interaction between the KRas protein and Raf - RBD with an IC50 from 0.001 nM to 500 nM , from 0.0nM 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 in the absence of cyclophilin A. Another exemplary assay for evaluating the potency of a compound provided herein , 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 , CAPAN1 , CAPAN2 , CFPAC1 , GP2D , H358 , H441 , H460 , H727 , HCT116 , HKA1 , HPAC , HPAFII , HTK , HUPT3 , KMS20 , KP2 , LS123 , LS180 , MIAPaCa - 2 , MKN1 , NCI - H1993 , NCI - H211 , NCI - H424 , NCI - H526 , Panc02.03 , Panc04.03 , PATC50 , PC9 , PK8 , PSN1 , RKN , SW480 , SW620 , and / or TCCPAN2 ) . For example , cells can be contacted with a compound provided herein , or a pharmaceutically 121 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا 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 or MesoScale Discovery p / t ERK1 / 2 ) . In some embodiments , multiple concentrations of a compound provided herein , or a pharmaceutically acceptable salt thereof , can be used to construct a dose response curve . In some embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , inhibit ERK phosphorylation in a cell line expressing a KRas 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 ) ) with an IC50 of less than 1 Mµ ( e.g. , less than 750 nM , less than 500 nM , or less than 200 nM ) . In some embodiments , the compounds inhibit ERK phosphorylation in a cell line expressing a KRas 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 ) ) with an IC50 of less than 200 nM ( e.g. , less than 150 nM , less than 200 nM , less than 100 nM , less than 10 nM , less than 1 nM ) . For example , the compounds can inhibit ERK phosphorylation in a cell line expressing a KRas 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 ) ) with an IC50 from 0.1 nM to 100 nM , from 0.1 nM to 50 nM , from 1 nM to 50 nM , or from nM to 20 nM .

In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can selectively inhibit one or more mutant KRas proteins over wild type KRas protein . The selectivity between wild type KRas protein and a mutant KRas protein as described herein can be measured using cellular proliferation assays where cell proliferation is dependent on signaling activity . For example , HEK293 cells transfected with a suitable version of wild type KRas , or HEK293 cells transfected with KRas containing one or more mutations as described herein ( e.g. , a G12D mutation , a G12R mutation , or a G12V mutation ) can be used . Proliferation assays are performed at a range of inhibitor concentrations ( e.g. , 10 Mμ , 3 . Mμ , 1.1 Mμ , 330 nM , 110 nM , 33 nM , 11 nM , 3 nM , 1 nM ) and an EC50 is calculated . See also the assays described in International Publication Nos . WO 2021/120890 ; WO 2021/041671 ; and U.S. Publication Nos . US 2021/0130369 ; US 2021/0179633 ; US 2018/0334454 ; and US 2021/0122764 . The pharmacokinetic parameters of a compound provided herein , or a pharmaceutically acceptable salt thereof , can be evaluated in an animal model , for instance , a mouse model , a rat 122 WO 2025/064848 PCT / US2024 / 0477 LO model , a dog model , or a nonhuman primate ( e.g. , cynomolgus monkey ) model . Pharmacokinetics parameters , including clearance ( CL ) , volume of distribution ( Va ) , maximum plasma concentration ( Cmax ) , time of maximum plasma concentration ( tmax ) , half- life ( t1 / 2 ) , area under the curve ( AUC ) , and oral bioavailability ( % F ) can be calculated using , e.g. , a non - compartmental model . In some embodiments , a reference compound ( e.g. , a first KRas inhibitor ( e.g. , MRTX1133 ) ) may be used as a comparator . See , e.g. , Example ( " Pharmacokinetic experiments in mice " ) of International Publication No. WO 2023/098425 . Certain pharmacokinetic parameters of a compound provided herein , or a pharmaceutically acceptable salt thereof , can be evaluated in hepatocytes , such as in mouse , rat , dog , nonhuman primate ( e.g. , cynomolgus monkey ) , or human hepatocytes . Pharmacokinetics parameters , including clearance ( CL ) and half - life ( t1 / 2 ) , can be calculated . In some embodiments , a reference compound ( e.g. , a first KRas inhibitor ( e.g. , MRTX1133 ) ) may be used as a comparator . See , e.g. , Example VI ( " Liver microsomal metabolically stability " ) of International Publication No. WO 2023/284881 . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof can be assessed for its pharmacokinetic parameters and / or its ability to cause toxicity ( e.g. , skin toxicity ) in an animal model . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be administered to an animal ( e.g. , rat ) , and body fluid ( e.g. , blood ) samples can be taken at various time points and analyzed for the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining . As another example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be administered to an animal ( e.g. , rat ) , and the skin of the animal can be assessed for redness , scaling , and / or thickness . An exemplary protocol follows . Rats ( e.g. , male RNU Nude Rat or Sprague - Dawley IGS rats , 6-8 weeks of age ) are dosed with a compound provided herein , or a pharmaceutically acceptable salt thereof , once per day orally ( e.g. , via gavage ) for several days ( e.g. , 14 days ) . The compound provided herein , or a pharmaceutically acceptable salt thereof , is administered to the rat at a given dose level ( e.g. , 1 , 3 , 5 , 10 , 25 , 30 , 50 , or 100 mg / kg ) in a solution or suspension formulation ( e.g. , % DMSO / 90 % hydroxypropyl methylcellulose ) . The rats have access to food and water ad libitum .

Blood samples ( e.g. , 200 Lμ per sample ) from the rats are taken at predetermined intervals , such as 4 , 8 , or 24 hours after the first dose is administered . The blood is sampled via jugular vein puncture , then the blood samples ( e.g. , with K2EDTA as anticoagulant ) are 123 WO 2025/064848 PCT / US2024 / 0477 LO temporarily put on ice and then centrifuged ( e.g. , at 4 ° C and 4600 RPM for 5 minutes ) within minutes . Plasma samples can be diluted 1 : 1 v / v with acidified phosphate buffer and are put on dry ice . After the completion of the last sampling , all samples are stored at -80 ° C or analyzed in a short time following collection . The concentration of the compound provided herein , or a pharmaceutically acceptable salt thereof , measured in an acidified plasma sample ( e.g. , diluted 1 : 1 v / v with pH 3 phosphate buffer ) can be determined ( e.g. , via LC / MS / MS ) . For example , an acidified plasma sample is prepared for analysis using protein precipitation ( e.g. , by the addition of acetonitrile ) , and an internal standard is spiked in at a known concentration . The spiked sample is mixed , centrifuged , and the supernatant is used in an LC / MS / MS method . The LC / MS / MS method uses an ACQUITY UPLC BEH C18 1.7 mμ ( 2.1 * 50 mm ) column with a first mobile phase of 5 mM NH4OAc ( 0.05 % formic acid ( FA ) or 0.1 % FA ) and a second mobile phase of acetonitrile ( 0.1 % FA ) . Multiple reaction monitoring is used to measure the analyte ( s ) of interest . Using the concentration of the compound provided herein , or a pharmaceutically acceptable salt thereof , in the plasma sample , pharmacokinetic parameters of t1 / 2 ( hr ) , tmax ( hr ) , Cmax ( ng / mL ) , AUClast ( hr * ng / mL ) , AUC Inf ( hr * ng / mL ) , AUCExtr ( % ) , MRT Inf ( hr ) , AUC Inf / D ( hr * kg * ng / mL / mg ) , F ( % ) , are determined . The clinical signs , body weight and food consumption of the rats are tracked during dosing . The potential for skin rash is tracked intermittently before and during dosing using one or more methodologies . A skin scoring system is used to evaluate skin redness ( erythema ) or skin scaling on a gradation of 0-4 . Thickness of the back skin is measured using a micrometer ( MITUTOYO ABSOLUTE Digimatic Micrometer Series 227-211 ) . For the back skin , thickness measurement is performed by doing a skin folding of the applied area between the thumb and index fingers followed by measuring with the micrometer . The mice are then sacrificed and assessed for any abnormalities . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be tested for its potency in inhibiting hERG potassium channels . The cardiac potassium channel hERG is responsible for a rapid delayed rectifier current ( Ikr ) in human ventricle , and inhibition of rкI is the most common cause of cardiac action potential prolongation by non - cardiac drugs . Increased action potential duration causes prolongation of the QT interval that has been associated with a dangerous ventricular arrhythmia , torsade de pointes . There are several methods of testing hERG inhibition potency , including SyncroPatch hERG and manual patch clamp experiments . 124 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is tested for its potency in inhibiting hERG potassium channels using a SyncroPatch hERG assay . For example , in some embodiments , solutions or suspension of a compound provided herein , or a pharmaceutically acceptable salt thereof , at several concentrations ( 0.30 Mµ , 1.00 Mµ , 3.00 Mµ , 10.00 Mμ and 30.00 Mμ ) can be exposed to single CHO or HEK293 cells . The effect of the compound provided herein , or a pharmaceutically acceptable salt thereof , on the inhibition of hERG potassium channels can be measured in this system using an electrical pulse pattern , the data plotted , and an IC50 value calculated for the inhibition of hERG by the compound provided herein , or a pharmaceutically acceptable salt thereof . An exemplary protocol follows . hERG potassium channels are expressed in a Chinese Hamster Ovarian ( CHO ( Sophian Biosciences ) ) cell line that lacks endogenous rкI . See , e.g. , Brown , Arthur M. , and David Rampe . Pharmaceutical News 7.4 ( 2000 ) : 15-20 ; Weirich , gröJ , and H. Antoni , Basic Research in Cardiology 93 ( 1998 ) : s125 - s132 , doi : 10.1007 / s003950050236 ; Yap , Yee Guan , and A. J. Camm . Clinical & Experimental Allergy 29 ( 1999 ) : 174-181 , doi : 10.1046 / j.1365- 2222.1999.0290s3174.x ; Haraguchi , Yuji , et al . BMC Pharmacology and Toxicology ( 2015 ) : 1-6 , doi : 10.1186 / s40360-015-0042-9 ; and Walker , B. D. , et al . British Journal of Pharmacology 127.1 ( 1999 ) : 243-251 , 10.1038 / sj.bjp.0702502 . All chemicals used in solution preparations are purchased from a commercial supplier ( e.g. , Sigma - Aldrich ) and are of ACS reagent grade purity or higher . Stock solutions of the compound provided herein , or a pharmaceutically acceptable salt thereof , positive control compound ( s ) , and reference substance ( s ) are prepared in dimethyl sulfoxide ( DMSO ) and stored frozen . Solutions of each tested compound provided herein , or a pharmaceutically acceptable salt thereof , positive control compound ( s ) , and reference substance ( s ) are prepared fresh daily by diluting stock solutions into HEPES - buffered physiological saline solution ( HB- PS ; 140 mM NaCl , 4 mM KCl , 2.0 mM CaCl2 , 1 mM MgCl2 , 10 mM HEPES , and 5 mM glucose , pH 7.4 ) . Since previous results have shown that ≤ 0.3 % DMSO does not affect channel current , all test and control solutions can contain up to 0.3 % DMSO . In some embodiments , a positive control compound can be included in the experiment . In some such embodiments , the positive control compound can be amitriptyline ( Sigma- Aldrich ) , for example , in a HB - PS and 0.3 % DMSO solution . In some embodiments , a positive control compound can be included in the experiment . In some such embodiments , the positive control compound can be E - 4031 ( 4 ' - [ [ 1- [ 2- ( 6- 125 WO 2025/064848 PCT / US2024 / 0477 LO Methyl - 2 - pyridinyl ) ethyl - 4 - piperidinyl ] carbonyl ] methanesulfonanilide , Aldrich ) , for example , in a HB - PS and 0.3 % DMSO solution . 2HC1 ) ( Sigma- If necessary , solutions are sonicated to facilitate dissolution . Visible precipitate observed during preparation or exposure of formulations to the test system is noted for reference .

The effect of compounds provided herein , or a pharmaceutically acceptable salt thereof , is initially evaluated at 1 Mμ . Subsequent concentrations are evaluated based on the inhibition observed at this initial concentration .

The CHO cells , which are at least two days after plating and more than 75 % confluent , are used for experiments . Before testing , cells are harvested using TrypLE and resuspended in HB - PBS at room temperature . The HB - PBS and external solution ( 80 mM NaCl , 4 mM KCl , mM CaCl2 , 1 mM MgCl2 , 60 mM N - Methyl - D - glucamine ( NMDG ) , 10 mM HEPES , and mM glucose , pH 7.4 ) are prepared and stored up to 1 month . Voltage command protocol : From a holding potential of -80 mV , the voltage is first stepped to -50 mV for 80 ms for leak subtraction , and then stepped to +20 mV for 4800 ms to open hERG channels . After that , the voltage is stepped back down to -50 mV for 5000 ms , causing a " rebound " or tail current , which is measured and collected for data analysis . Finally , the voltage is stepped back to the holding potential ( -80 mV , 1000 ms ) . This voltage command protocol is repeated every 20,000 msec . This command protocol is performed continuously during the experiment . The hERG SyncroPatch assay is conducted at room temperature . The Setup , Prime Chip , Catch and Seal Cells , Amplifier Settings , Voltage and Application Protocols are established with Biomek Software ( Nanion ) . A single cell per well is clamped with the formation of a gigaseal . On one side of the seal , the cell is bathed in external solution . On the opposite side , addition of 40 Lμ of the vehicle ( e.g. , HB - PBS ) is applied , followed by a 300 s pause to create a baseline period . Then a dose of a compound provided herein , or a pharmaceutically acceptable salt thereof , is added ( 40 Lµ ) , and the process is repeated for different concentrations . The exposure of a compound provided herein , or a pharmaceutically acceptable salt thereof , at each concentration is no less than 300 s . The recording for the whole process must pass quality control criteria ( e.g. , seal quality , rundown attributes ) or the well is abandoned , and the compound is retested , all automatically set by exclusion criteria determined prior to experiment start . Five concentrations ( 0.30 Mμ , 1.00 Mμ , 3.00 Mμ , 10.00 Mμ , and 126 WO 2025/064848 PCT / US2024 / 0477 .00 Mμ ) are tested for each tested compound provided herein , or a pharmaceutically acceptable salt thereof . A minimum of 2 replicates per concentration are obtained . Data analysis is carried out using DataControl , Excel 2013 ( Microsoft ) and GraphPad Prism 5.0 .

Within each well recording , a percent of control values is calculated for each concentration of the compound provided herein , or a pharmaceutically acceptable salt thereof , with current response based on peak current in presence of a reference compound ( e.g. , E- 4031 ) ( current response / peak current ) × 100 % . The Dose - Response curves are fit to the standard Hill equation as shown below : Ipost compound Ipre compound = Bottom + - ( Top - Bottom ) + 10 ( LogIC 50 - X ) * Hillslope where X is the logarithm of concentration , Ipost compound / Ipre compound is the normalized peak current amplitude , Top is 1 , and Bottom is equal to 0 . Curve - fitting and IC50 calculations are performed by GraphPad Prism 5.0 . If the inhibition obtained at the lowest concentration tested is over 50 % , or at the highest concentration tested is less than 50 % , the IC50 is reported as less than the lowest concentration , or higher than the highest concentration , respectively . In some embodiments , a positive control can be included in the experiment . In some such embodiments , the positive control compound can be cisapride ( Tocris Bioscience ) , for example , in a 0.3 % DMSO solution . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is not a hERG inhibitor . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits hERG with an IC50 of greater than 60 nM ( e.g. , greater than 100 nM , 300 nM , 500 nM , 1 Mµ , 3 Mµ , 5 Mµ , 10 Mµ , 20 Mµ , or 30 Mµ ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits hERG with an IC50 of greater than 500 nM ( e.g. , 1 Mµ , 3 Mµ , 5 Mµ , 10 Mµ , 20 Mµ , or 30 Mμ ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits hERG with an IC50 of greater than 1 Mμ ( e.g. , greater than Mμ , 5 Mμ , 10 Mμ , 20 Mµ , or 30 Mμ ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits hERG with an IC50 of greater than 10 Mμ ( e.g. , greater than 20 Mμ or 30 Mμ ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , inhibits hERG with an IC50 of greater than 30 Mµ . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be assessed for its stability in hepatocytes ( e.g. , human hepatocytes ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is 127 WO 2025/064848 PCT / US2024 / 0477 LO assessed for stability in human hepatocytes , yielding a value for intrinsic hepatocyte clearance ( CLint ( hep ) ) , from which intrinsic liver clearance ( CLint ( liver ) ) can be estimated . For example , human hepatocytes can be incubated with a compound provided herein , or a pharmaceutically acceptable salt thereof , and aliquots at various time points can be removed and analyzed for the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining . First - order kinetics equations can then be used to determine half - life ( t1 / 2 ) and CLint ( hep ) . An exemplary protocol follows . A 1000X stock solution of a compound provided herein is prepared to a final concentration ( e.g. , 1 mM in DMSO ) . Similarly , 1000X stock solution ( s ) of positive control compound ( s ) ( e.g. , 7 - ethoxycoumarin and / or 7 - hydroxycoumarin ) is prepared to a final concentration ( e.g. , 3 mM in DMSO ) . 100X stock solutions are then made by dilution with acetonitrile .

To prepare a cell suspension ( e.g. , at 0.5 × 106 cells / mL ) , cryopreserved hepatocytes ( e.g. , human hepatocytes ) are thawed ( e.g. , in Williams ' Medium E containing 5 % fetal bovine serum and 30 % Percoll solution and other supplements ) , isolated , and suspended in incubation medium ( e.g. , Williams ' Medium E ( no phenol red ) containing 2 mM L - Glutamine and 25 mM HEPES ) , then diluted with pre - warmed incubation medium to 0.5 × 106 cells / mL . Pre - warmed cell suspension ( e.g. , 198 Lµ ) is added to a well in a testing plate ( e.g. , a 96 - well plate ) . A quenching plate is prepared by transferring stop solution ( e.g. , acetonitrile containing tolbutamide and labetalol as internal standards ) ( e.g. , 125 Lµ ) to a set of pre - labeled 96 - well plates , with one quenching plate for To and one plate per time point to be tested . To begin the experiment , 2 Lµ of the 100X dosing solution of the compound provided herein , or a pharmaceutically acceptable salt thereof , or 2 Lμ of the 100X dosing solution of a control compound is added to a well of the testing plate . This is performed in duplicate . For To samples , the plate is mixed to achieve a homogenous suspension ( e.g. , mixed for about 1 min ) , then an aliquot ( e.g. , 25 Lµ ) of each sample on the testing plates is immediately transferred into a well of a quenching plate containing ice - cold stop solution ( e.g. , 125 Lµ ) , followed by mixing . The testing plate is incubated ( e.g. , at 37 ° C in a 95 % humidified incubator at 5 % COwith constant shaking ) to start the reactions . At each time point of 15 , 30 , 60 and 90 minutes , the plate is mixed and then an aliquot of each sample ( e.g. , 25 Lµ ) is transferred to a well in a quenching plate containing ice - cold stop solution ( e.g. , 125 Lµ ) followed by mixing . 128 WO 2025/064848 PCT / US2024 / 0477 LO Medium Control ( MC ) sample plates ( at least one for the first and last time point ; additional time points are optional ) are prepared in the same way as the testing plate except that incubation medium is used instead of cell suspension . At each corresponding time point as the testing plate , the reactions are stopped by removing the corresponding MC plate from the incubator and mixing with ice - cold stop solution ( e.g. , 125 Lµ ) . Immediately after addition of stop solution to each plate , the plate is immediately vortexed ( e.g. , on a plate shaker at 600 RPM for 10 minutes ) . Then the plate is centrifuged ( e.g. , at 3220 x g for 20 min at 4 ° C ) . After centrifugation , supernatant from the plate ( e.g. , 80 Lµ / well ) is transferred to another plate ( e.g. , a corresponding 96 - well plate ) which contains ultra pure water ( 240 Lµ per well ) according to the plate map . This analytical plate is sealed and stored at 4 ° C until LC- MS / MS analysis . The percent remaining of the compound provided herein , or a pharmaceutically acceptable salt thereof , after incubation is calculated by the following equations . The equation of first order kinetics is used to calculate t1 / 2 and CLint : Equation of first order kinetics : Ct = Co x e - kxt When ₁C = ½ Co , then ₁t = Ct = CLint ( hep ) = k / million cells Ink per mL CLint ( liver ) = CLint ( hep ) * liver weight ( g / kg body weight ) x hepatocellularity Table 2 shows reference values for liver weight , liver blood flow , and hepatocellularity for various species . See , e.g. , Sohlenius - Sternbeck , Anna - Karin Toxicology in vitro 20.( 2006 ) : 1582-1586 , doi : 10.1016 / j.tiv.2006.06.003 ; Davies , Brian , and Tim Morris Pharmaceutical Research 10.7 ( 1993 ) : 1093-1095 ; and Obach , R. Scott , et al . Journal of Pharmacology and Experimental Therapeutics 283.1 ( 1997 ) : 46-58 .

Table 2 .

Species Liver Weight ( g / kg Body Weight ) Liver Blood Flow ( ml / min / kg ) Hepatocellularity ( million cells / g liver ) Mouse 90.0 1 Rat 40 55.2 1 Dog 30.9 2 129 WO 2025/064848 PCT / US2024 / 0477 Monkey 43.1 Human 20 20.7 1 Table 3 shows floor and ceiling values for the described assay . For example , if CLint ( hep ) falls below 6.4 Lµ / min / 106 cells , an experimental value may not be able to be accurately determined .

Table 3 .

Cut off Value in Hepatocyte Stability Assay Remainin t1 / Cell Conc . g ( % ) at Cut the Off CLint ( hep ) CLint ( liver ) ( mL / min / kg ) ( < ) maximum ( min ) Tmax ( min ) k incubatio n time ( × 106 ( Lμ / min / 10 ° cells cells / mL ) ( CV = 25 % ( > ) * Mouse Rat Dog ) Monkey Human ( < ) 75 % 216.8 0.0032 6.4 23 17.8 0.5 75.9 29.9 * Based on the first - order reaction , t1 / 2 cut - off = In2 / ( ( 1 / Tmax ) In ( 1 / remaining ) ) . t1 / 2 cut - off is a maximum measurable value at the maximum incubation time ( Tmax ) at which the reaction remaining is within an acceptable experimental variation .

Cell Conc . t1 / Cut Off CLint ( hep ) CLint ( liver ) ( mL / min / kg ) ( > ) T ( min ) Remainin g at the ( min ) k ( × 1cells / mL ) T( < ) 0.5 15 25 % 7.5 0.09 ( Lµ / min / 10 ° cells ) ( > ) 184.

Mouse Rat Dog Monkey Human 2195.9 : 865 : 1271.7 665.4 513.

In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof can be assessed for its stability in simulated human fluids ( e.g. , simulated gastric fluid or simulated intestinal fluid ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof can be incubated in a simulated human fluid ( e.g. , simulated gastric fluid ( e.g. , fed or fasted state ) or simulated intestinal fluid ( e.g. , fed or fasted state ) ) , and aliquots at various time points can be removed and analyzed for the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining . An exemplary protocol follows . 130 WO 2025/064848 PCT / US2024 / 0477 LO Fasted state simulated gastric fluid ( FaSSGF ) is prepared ( 0.02 mM lecithin , 0.08 mM sodium taurocholate , 0.1 mg / mL pepsin , 34.2 mM sodium chloride , 25.1 mM hydrochloric acid , and deionized water , pH 1.6 ± 0.05 ) . A working solution of a compound provided herein , or a pharmaceutically acceptable salt thereof is prepared ( e.g. , 2 Mμ in DMSO ) . Similarly , a working solution of a control compound ( e.g. , omeprazole ) is prepared ( e.g. 2 Mμ in DMSO ) . An aliquot ( e.g. , 2 Lµ ) of either working solution is transferred to a deep - well plate , one plate per time condition to be tested ( e.g. , 0 minutes , 60 minutes , 120 minutes , 360 minutes , and 1440 minutes ) . To the plates corresponding to the later time points ( e.g. , T60 , T120 , T360 , and T1440 ) , an aliquot ( e.g. , 198 Lµ ) of the FaSSGF is added , and the samples adjusted to have a final DMSO concentration of 1 % . The plates are incubated at 37 ° C with shaking at 600 RPM for the appointed amount of time . At the end of the appointed amount of time , the reaction is stopped by the addition of stop solution ( e.g. , 400 Lµ ) , and the resulting solution is mixed . A portion of this mixture ( e.g. , 2Lµ ) is removed and mixed with a further addition of stop solution ( e.g. , 400 Lµ ) . Similarly , the To samples are prepared by adding stop solution ( e.g. , 400 Lµ ) , mixing , then adding the FaSSGF ( e.g. , 200 Lµ ) and mixing again . The To samples are further prepared by removing a portion of this mixture ( e.g. , 200 Lµ ) and mixing with a further addition of stop solution ( e.g. , 400 Lμ ) . Following the second addition of stop solution at each time point , the samples are centrifuged ( e.g. , at 4000 RPM at 4 ° C for 20 min ) . A portion of the supernatant ( e.g. , 60 Lµ ) is removed and mixed with purified water ( e.g. , 180 Lµ ) for LC - MS / MS analysis . The LC- MS / MS analysis is performed using an ACQUITY UPLC BEH C18 1.7 um 2.1 * 50 mm ( Part No.186002350 ) column , with a mobile phase A ( 0.1 % formic acid in water ) and a mobile phase B ( 0.1 % formic acid in acetonitrile ) . The percent remaining of the compound provided herein , or a pharmaceutically acceptable salt thereof , at each incubation time is calculated based on peak area ratio of analyte to internal standard from the LC - MS / MS analysis using the equation below .

Percent remaining ( at an appointed time ) = PART PARO * 100 % Where PAR is the peak area ratio , the ratio of peak area of the analyte of interest and an internal standard ; PART is the peak area ratio at the appointed time ; and PARO is the peak area ratio at To . 131 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا Fed state simulated intestinal fluid ( FeSSIF ) is prepared ( 0.282 % ( w / v ) lecithin , 0.806 % ( w / v ) sodium taurocholate , 0.865 % ( w / v ) acetic acid , 1.52 % ( w / v ) potassium chloride , and deionized water , pH 5.0 ± 0.05 ) . A working solution of a compound provided herein , or a pharmaceutically acceptable salt thereof is prepared ( e.g. 2 Mµ in DMSO ) . Similarly , a working solution of a control compound ( e.g. , chlorambucil ) is prepared ( e.g. 2 Mµ in DMSO ) . An aliquot ( e.g. , 2 Lµ ) of either working solution is transferred to a deep - well plate , one plate per time condition to be tested ( e.g. , 0 minutes , 60 minutes , 120 minutes , 360 minutes , and 1440 minutes ) . To the plates corresponding to the later time points ( e.g. , T60 , T120 , T360 , and T1440 ) , an aliquot ( e.g. , 198 Lµ ) of the FeSSIF is added , and the samples are adjusted to have a final DMSO concentration of % . The plates are incubated at 37 ° C with shaking at 600 RPM for the appointed amount of time . At the end of the appointed amount of time , the reaction is stopped by the addition of stop solution ( e.g. , 400 Lµ ) , and the resulting solution is mixed . A portion of this mixture ( e.g. , 2Lµ ) is removed and mixed with a further addition of stop solution ( e.g. , 400 Lµ ) . Similarly , the To samples are prepared by adding stop solution ( e.g. , 400 Lµ ) , mixing , then adding the FeSSIF ( e.g. , 200 Lµ ) and mixing again . The To samples are further prepared by removing a portion of this mixture ( e.g. , 200 Lµ ) and mixing with a further addition of stop solution ( e.g. , 400 Lµ ) . Following the second addition of stop solution at each time point , the samples are centrifuged ( e.g. , at 4000 RPM at 4 ° C for 20 min ) . A portion of the supernatant ( e.g. , 60 Lµ ) is removed and mixed with purified water ( e.g. , 180 Lµ ) for LC - MS / MS analysis . The LC - MS / MS analysis is performed using an ACQUITY UPLC HSS T3 1.8 mμ 2.1 * 50 mm , ( Part No. 186003538 ) column , with a mobile phase A ( 0.1 % formic acid in water ) and a mobile phase B ( 0.1 % formic acid in acetonitrile ) . The percent remaining of the compound provided herein , or a pharmaceutically acceptable salt thereof , at each incubation time is calculated based on peak area ratio of analyte to internal standard from the LC - MS / MS analysis using the equation below .

Percent remaining ( at an appointed time ) = PART PARO * 100 % Where PAR is the peak area ratio , the ratio of peak area of the analyte of interest and an internal standard ; PART is the peak area ratio at the appointed time ; and PARO is the peak area ratio at To . 132 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا Fasted state simulated intestinal fluid ( FASSIF ) is prepared ( 0.056 % ( w / v ) lecithin , 0.161 % ( w / v ) sodium taurocholate , 0.39 % ( w / v ) monobasic potassium phosphate , 0.77 % ( w / v ) potassium chloride , and deionized water , pH 6.5 ± 0.05 ) . A working solution of a compound provided herein , or a pharmaceutically acceptable salt thereof is prepared ( e.g. 2 Mμ in DMSO ) . Similarly , a working solution of a control compound ( e.g. , chlorambucil ) is prepared ( e.g. 2 Mµ in DMSO ) . An aliquot ( e.g. , 2 Lµ ) of either working solution is transferred to a deep - well plate , one plate per time condition to be tested ( e.g. , 0 minutes , 60 minutes , 120 minutes , 360 minutes , and 1440 minutes ) . To the plates corresponding to the later time points ( e.g. , T60 , T120 , T360 , and T1440 ) , an aliquot ( e.g. , 198 Lµ ) of the FASSIF is added , and the samples adjusted to have a final DMSO concentration of 1 % . The plates are incubated at 37 ° C with shaking at 600 RPM for the appointed amount of time . At the end of the appointed amount of time , the reaction is stopped by the addition of stop solution ( e.g. , 400 Lµ ) , and the resulting solution is mixed . A portion of this mixture ( e.g. , 2Lµ ) is removed and mixed with a further addition of stop solution ( e.g. , 400 Lµ ) . Similarly , the To samples are prepared by adding stop solution ( e.g. , 400 Lµ ) , mixing , then adding the FaSSIF ( e.g. , 200 Lµ ) and mixing again . The To samples are further prepared by removing a portion of this mixture ( e.g. , 200 Lµ ) and mixing with a further addition of stop solution ( e.g. , 400 Lµ ) . Following the second addition of stop solution at each time point , the samples are centrifuged ( e.g. , at 4000 RPM at 4 ° C for 20 min ) . A portion of the supernatant ( e.g. , 60 Lµ ) is removed and mixed with purified water ( e.g. , 180 Lµ ) for LC - MS / MS analysis . The LC - MS / MS analysis is performed using an ACQUITY UPLC HSS T3 1.8 mµ 2.1 * 50mm , ( Part No.186003538 ) column , with a mobile phase A ( 0.1 % formic acid in water ) and a mobile phase B ( 0.1 % formic acid in acetonitrile ) . The percent remaining of the compound provided herein , or a pharmaceutically acceptable salt thereof , at each incubation time is calculated based on peak area ratio of analyte to internal standard from the LC - MS / MS analysis using the equation below .

Percent remaining ( at an appointed time ) = PART PARO * 100 % Where PAR is the peak area ratio , the ratio of peak area of the analyte of interest and an internal standard ; PART is the peak area ratio at the appointed time ; and PARO is the peak area ratio at To .

In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof can be assessed for its solubility in simulated human fluids ( e.g. , simulated gastric fluid or simulated intestinal fluid ) or aqueous solutions ( e.g. , water or pH 3.0 citrate buffer ) . 133 WO 2025/064848 PCT / US2024 / 0477 LO For example , a compound provided herein , or a pharmaceutically acceptable salt thereof can be incubated in a simulated human fluid ( e.g. , simulated gastric fluid or simulated intestinal fluid ) or an aqueous solution ( e.g. , water or pH 3.0 citrate buffer ) . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof can be incubated in a simulated human fluid ( e.g. , simulated gastric fluid ( e.g. , fed or fasted state ) or simulated intestinal fluid ( e.g. , fed or fasted state ) ) or an aqueous solution ( e.g. , water or pH 3.0 citrate buffer ) , and aliquots at various time points can be removed and analyzed for the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining . An exemplary protocol follows . Fasted state simulated gastric fluid ( FaSSGF ) is prepared ( 0.02 mM lecithin , 0.08 mM sodium taurocholate , 0.1 mg / mL pepsin , 34.2 mM sodium chloride , 25.1 mM hydrochloric acid , and deionized water , pH 1.6 ± 0.05 ) . The FaSSGF is equilibrated at 37 ° C . Fed state simulated intestinal fluid ( FeSSIF ) is prepared ( 0.282 % ( w / v ) lecithin , 0.806 % ( w / v ) sodium taurocholate , 0.865 % ( w / v ) acetic acid , 1.52 % ( w / v ) potassium chloride , and deionized water , pH 5.0 ± 0.05 ) . The FeSSIF is equilibrated at 37 ° C . Fasted state simulated intestinal fluid ( FaSSIF ) is prepared ( 0.056 % ( w / v ) lecithin , 0.161 % ( w / v ) sodium taurocholate , 0.39 % ( w / v ) monobasic potassium phosphate , 0.77 % ( w / v ) potassium chloride , and deionized water , pH 6.5 ± 0.05 ) . The FaSSIF is equilibrated at 37 ° C . Citrate buffer is prepared ( 100 mM sodium citrate , pH 3.07 ) . Solubility in citrate buffer and water is determined at room temperature . A compound provided herein , or a pharmaceutically acceptable salt thereof , ( e.g. , 6 mg ) is combined with FaSSGF , FeSSIF , FASSIF , citrate buffer , or water ( e.g. , 3 mL ) . The vials are stirred ( at 37 ° C for simulated human fluid or room temperature for citrate buffer and water ) , and at 30 minutes , 3 hours , and 24 hours , an aliquot is removed and filtered ( e.g. , using a 0.um syringe filter ) , then analyzed with HPLC ( e.g. , HPLC is conducted using an Agilent 12Infinity LC System equipped with a VWD ( Variable Wavelength Detector ) and an Agilent 1260 ELSD ( Evaporative Light Scattering Detector ) . Flow rate range of the instrument is –2.5.0 mL / min , operating pressure range is 0031–0 bar , temperature range is 5 ° C above ambient to 60 ° C , and wavelength range is 006–091 nm ; mobile phase A of 0.1 % trifluoroacetic acid ( TFA ) in distilled water ; mobile phase B of 0.1 % TFA in acetonitrile ; column Waters Acuity UPLC CSH C - 18 , 2.1 x 150 mm , 1.7 mµ ) to determine the dissolved concentration of the compound provided herein , or a pharmaceutically acceptable salt thereof . 134 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , the kinetic solubility of a compound provided herein , or a pharmaceutically acceptable salt thereof can be determined . In some embodiments , the kinetic solubility of a compound provided herein , or a pharmaceutically acceptable salt thereof , is determined at a physiologically relevant pH ( e.g. , 7.4 ) . For example , a stock solution of a compound provided herein , or a pharmaceutically acceptable salt thereof , can be prepared , and any solids separated ( e.g. , by centrifugation ) . The resulting mixture ( e.g. , supernatant ) can be subsequently filtered , and the dissolved concentration of the compound provided herein , or a pharmaceutically acceptable salt thereof , can be determined via liquid chromatography . An exemplary protocol follows . A stock solution ( e.g. , a 200 Mμ stock solution ) of a compound provided herein , or a pharmaceutically acceptable salt thereof , is diluted with buffer ( e.g. , phosphate buffer , pH 7.4 ) ( e.g. , 10 Lμ of the stock solution with 490 uL of the buffer ) . The diluted sample is vortexed for at least two minutes and then shaken ( e.g. , at 800 RPM ) on a shaker for 24 hours at room temperature . The sample is then centrifuged ( e.g. , at 4000 RPM for 10 minutes at 25 ° C ) . The supernatant is filtered ( e.g. , in a plate format by centrifugation for 5 minutes ) , and the concentration of the compound provided herein , or a pharmaceutically acceptable salt thereof , is determined by an LC - UV system ( e.g. , with a mobile phase A of 0.1 % TFA and 5 mM NH4OAc in water / MeCN ( v : v , 95 : 5 ) and a mobile phase B of 0.1 % TFA and 5 mM NH4OAc in water / MeCN ( v : v , 5:95 ) ) . In some embodiments , the chemical stability of a compound provided herein , or a pharmaceutically acceptable salt thereof , can be determined . For example , an aliquot of a solution of a compound provided herein , or a pharmaceutically acceptable salt thereof , is added to an acidic solution ( e.g. , pH 1.5 or pH 5 ) and incubated for a period of time . A sample of the incubation mixture can be taken , and the remaining amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , can be determined via liquid chromatography- mass spectrometry ( LCMS ) and / or nuclear magnetic resonance ( NMR ) . Exemplary protocols follow .

To prepare a pH 1.5 HCl solution , 1 N hydrogen chloride solution ( 1 mL ) is added to deionized water ( 99 mL ) and stirred for 5 minutes . The pH is adjusted , while stirring and monitoring by pH meter , to the desired pH using concentrated hydrochloric acid . To prepare a pH 5 HCl solution , 1 N hydrogen chloride solution ( 1 mL ) is added to deionized water . ( mL ) and stirred for 5 minutes . The pH is adjusted , while stirring and monitoring by pH meter , to the desired pH using 1N sodium hydroxide . 135 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا A portion ( e.g. , 10 Lµ ) of a stock solution ( e.g. , 10 mM ) of a compound provided herein , or a pharmaceutically acceptable salt thereof , is added the HCl solution at pH of 1.5 or pH ( e.g. , 90 Lµ ) in separate vials denoted for each timepoint ( e.g. , To , T30m , T60m , T90m , T240m , and T3d ) . The samples are incubated at 37 ° C for the desired timeframe and then immediately neutralized with 10 Lμ of HEPES buffer to pH of 7. The To timepoint is neutralized immediately upon preparation of the sample . The samples are then analyzed by LCMS to determine the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining . To prepare pH 1.5 and pH 5 DCl solutions , deuterium oxide ( 5 mL ) is adjusted to the desired pH of 1.5 or 5 , monitoring by pH meter , using 20 % DC1 in D2O and stirred at room temperature for 5 minutes . A compound provided herein , or a pharmaceutically acceptable salt thereof , is dissolved in the pH 1.5 or pH 5 DCl solution to achieve a 3 mg / mL solution . The resulting solution is incubated at 37 ° C to the desired timepoint ( To , T90m , T240m , T5d ) then an aliquot ( e.g. , 0.3 mL ) is taken and analyzed by ' H NMR to determine the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining and / or to determine the presence of a compound that is not the compound provided herein . At the same timepoints , 30 Lμ of the solution was neutralized with HEPES buffer to pH of 7 and analyzed by LCMS to determine the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining and / or to determine the presence of a compound that is not the compound provided herein .

In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be assessed as a potential substrate for efflux ( e.g. , as a potential substrate for p - glycoprotein ( P - gp ) ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is assessed as a substrate for efflux using efflux pump - expressing cells , such as MDCKII cells . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be applied to one side of a cell monolayer , incubated , and then the recovery of the compound on the opposite side of the cell monolayer can be measured to determine the permeability of the compound to the cell monolayer in that direction . An exemplary protocol follows . MDCKII cells ( e.g. , obtained from the Netherlands Cancer Institute ) are seeded onto polycarbonate membranes ( PC ) in 96 - well insert systems at 2.33 x 105 cells / ²mc for 4-7 days for confluent cell monolayer formation . 136 WO 2025/064848 PCT / US2024 / 0477 LO A solution of a compound provided herein , or a pharmaceutically acceptable salt thereof , is diluted with transport buffer ( e.g. , Hank's Balanced Salt Solution ( HBSS ) with mM HEPES , pH 7.4 ) from a DMSO stock solution to a final concentration ( e.g. , of 2.00 Mμ ( DMSO < 1 % ) ) and applied to the apical or basolateral side of the cell monolayer . Permeation of the compound provided herein , or a pharmaceutically acceptable salt thereof , from the A to B direction and the B to A direction is determined in duplicate . For control data , digoxin is tested at 10.0 Mμ from A to B direction or B to A direction , while nadolol and metoprolol are tested ( e.g. , at 2.00 Mμ ) in A to B direction in duplicate . The plate is incubated ( e.g. , for 2.hours in an incubator at 37.0 ° C , with 5 % CO2 at saturated humidity without shaking ) . The efflux ratio of each compound is then determined . The compound provided herein , or pharmaceutically acceptable salt thereof , and control compounds are quantified by LC - MS / MS analysis based on the peak area ratio of analyte / internal standard ( IS ) . The apparent permeability coefficient Papp ( cm / s ) is calculated using the equation : Papp = ( dCr / dt ) x Vr / ( A x Co ) Where dCr / dt is the cumulative concentration of compound in the receiver chamber as a function of time ; Vr is the solution volume in the receiver chamber ( 0.075 mL on the apical side , 0.25 mL on the basolateral side ) ; A is the surface area for the transport ( e.g. , 0.143 ²mc for the area of the monolayer ) ; and Co is the initial concentration in the donor chamber . The efflux ratio was calculated using the equation : = Efflux Ratio = Papp ( BA ) / Papp ( AB ) Without being bound by any particular theory , it is believed that the Efflux Ratio indicates how efficiently a tested compound is removed from the tested cell . Percent recovery was calculated using the equation : % Solution Recovery = 100 x [ ( Vr x Cr ) + ( Va x Cd ) ] / ( Va x Co ) Where Va is the volume in the donor chamber ( 0.075 mL on the apical side , 0.25 mL on the basolateral side ) ; Cd and Cr are the final concentrations of transport compound in donor and receiver chambers , respectively . Without being bound by any particular theory , it is believed that the percent recovery is informative of whether the tested compound could have a solubility issue , is stuck in the cellular membrane , metabolized , or a combination thereof . After the transport assay , a Lucifer yellow rejection assay is used to determine the cell monolayer integrity ( e.g. , to determine whether the cell monolayer from the efflux study is intact ) . Buffers are removed from both apical and basolateral chambers , followed by the 137 WO 2025/064848 PCT / US2024 / 0477 LO addition of lucifer yellow dye ( e.g. , 75 Lµ of a 100 Mμ solution in transport buffer ) and transport buffer ( e.g. , 250 Lμ ) in the apical and basolateral chambers , respectively . The plate is incubated ( e.g. , for 30 minutes at 37 ° C with 5 % CO2 and 95 % relative humidity without shaking ) . After incubation , a lucifer yellow ( e.g. , 20 Lµ ) sample is taken from the apical side , and transport buffer ( e.g. , 60 Lµ ) is added . A lucifer yellow sample ( e.g. , 80 Lµ ) is taken from the basolateral side . The relative fluorescence unit ( RFU ) of lucifer yellow is measured at 425/528 nm ( excitation / emission ) with an Envision plate reader . Percent of lucifer yellow in the basolateral well is calculated using the equation : V Basolateral X RFU Basolateral % Lucifer Yellow = ( VApical × RFU Apical ) + ( VBasolateral × RFU Basolateral ) where RFU Apical and RFUBasolateral are the relative fluorescence unit values of lucifer yellow in the apical and basolateral wells , respectively ; VApical and VBasolateral are the volume of apical and basolateral wells ( 0.075 mL and 0.25 mL ) , respectively . The % Lucifer Yellow should be less than 2.0 to indicate an intact cell monolayer . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be assessed for formation of metabolites . For example , a compound provided herein , or a pharmaceutically acceptable salt thereof can be incubated with hepatocytes ( e.g. , rat hepatocytes , dog hepatocytes , or human hepatocytes ) , and at the end of incubation , the sample can be analyzed for the amount of the compound provided herein , or a pharmaceutically acceptable salt thereof , remaining , as well as for the amount of any metabolite from Phase metabolism , Phase 2 metabolism , or a combination thereof . An exemplary protocol follows . A working solution of a compound provided herein , or a pharmaceutically acceptable salt thereof , is prepared ( e.g. 10 Mμ in DMSO ) . Similarly , a working solution of a control compound ( e.g. , 7 - ethoxycoumarin ) is prepared ( e.g. 30 Mμ in DMSO ) . An aliquot of each working solution of a compound provided herein , or a pharmaceutically acceptable salt thereof , or the working solution of the control compound is incubated with hepatocytes ( e.g. , 1.0 × 1cells / mL ) ( e.g. , rat hepatocytes , dog hepatocytes , or human hepatocytes ) in incubation medium ( e.g. , Williams ' Medium E with HEPES ( e.g. , 5.958 g / L ) glutamine ( e.g. , 0.292 g / L ) ) , to a total volume of 200 Lμ , for 0 minutes or 120 minutes at 37 ° C in 5 % CO2 / saturated humidity . After incubation , MeCN ( 800 Lµ ) is added to each sample , and the samples are centrifuged . The supernatants are dried under N2 gas , and the residue is reconstituted ( e.g. , with 200 Lμ of 10 % MeCN with 0.1 % FA ) . The reconstituted residue of the compound provided herein , or a pharmaceutically acceptable salt thereof , is subjected to LC - UV - MS ( e.g. , LC with a Mobile 138 WO 2025/064848 PCT / US2024 / 0477 LO Phase A of 0.1 % FA and 2 mM NH4FA in O₂H / MeCN ( v : v = 95 : 5 ) , a Mobile Phase B of : 0.1 % FA and 2 mM NH4FA in O₂H / MeCN ( v v = 5 : 95 ) using an ACQUITY ®CLPU HSS T3 2.1 × 100 mm , 1.8 mµ column ; a UV detector with λ : 190-500 nm ; and MS with a Xevo G2 Q - TOF instrument in ESI * mode with a scanning mode of MS / ²SM ) . The reconstituted residue of the control compound is subjected to LC - UV - MS ( e.g. , LC with a Mobile Phase A of 0.1 % FA in H2O , a Mobile Phase B of 0.1 % FA in MeCN using an ACQUITY ®CLPU HSS T3 2.1 × 100 mm , 1.8 mμ column ; a UV detector with λ : 190 ~ 500 nm ; and MS with a Xevo G2 Q - TOF instrument in ESI * mode with a scanning mode of MSE ) . The data is then analyzed to identify and , if desired , quantify the metabolites .

In some embodiments , a compounds provide herein , or a pharmaceutically acceptable salt thereof , can exhibit potent and selective inhibition of a dysregulated KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can selectively inhibit a dysregulated KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) over another GTPase or non - GTPase target . In some embodiments , a compound provided herein can exhibit nanomolar potency against a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) with minimal activity against related GTPases ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit at least 2 - fold , 3 - fold , 5 - fold , 10 - fold , 25- fold , 50 - fold , or 100 - fold greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , 139 WO 2025/064848 PCT / US2024 / 0477 LO and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit up to 10000 - fold greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 2 - fold to about 10 - fold greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 10 - fold to about 100 - fold greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 100 - fold to about 1000 - fold greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 1000 - fold to about 10000 - fold greater inhibition of a KRas protein ( e.g. , a wild - type KRas protein and / or a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of a related GTPase ( e.g. , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , can exhibit potent and selective inhibition of a dysregulated KRas protein ( e.g. , a 140 WO 2025/064848 PCT / US2024 / 0477 LO mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can selectively inhibit a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) over another GTPase or non - GTPase target . In some embodiments , the compounds provided herein can exhibit nanomolar potency against a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) with minimal activity against related GTPases ( e.g. , wild - type KRas protein , wild - type NRas protein , and / or wild - type HRas protein ) . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit greater inhibition of a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit at least 2 - fold , 3 - fold , 5 - fold , 10 - fold , 25 - fold , 50 - fold , or 100 - fold greater inhibition of a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit up to 10000 - fold greater inhibition of a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 2 - fold to about 10 - fold greater inhibition of a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 10 - fold to about 100 - fold greater inhibition of a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a 141 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 100 - fold to about 1000 - fold greater inhibition of a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 1000 - fold to about 10000 - fold greater inhibition of a mutant KRas protein ( e.ga KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) relative to inhibition of wild - type KRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit nanomolar potency against a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) with minimal activity against wild - type NRas protein and / or wild - type HRas protein In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild - type HRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit at least 2 - fold , 3 - fold , 5 - fold , 10 - fold , 25 - fold , 50 - fold or 100 - fold greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild - type HRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit up to 1000 - fold greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild - type HRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit up to 10000 - fold greater inhibition of a 142 WO 2025/064848 PCT / US2024 / 0477 LO dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild - type HRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 2 - fold to about 10 - fold greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild- type HRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 10 - fold to about 100 - fold greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type HRas protein and / or wild - type NRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 100 - fold to about 1000 - fold greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild - type HRas protein . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , can exhibit from about 1000- fold to about 10000 - fold greater inhibition of a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , and / or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein and / or a KRas G12V mutant protein ) ) ) relative to inhibition of wild - type NRas protein and / or wild - type HRas protein . Compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for treating diseases and disorders including cardiovascular disease ( e.g. , arteriovenous malformations or Noonan syndrome ) , endometriosis , an inflammatory and / or autoimmune disease ( e.g. , a nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis ) , proliferative disorders such as cancers , including hematological cancers and solid tumors ( e.g. , advanced solid tumors ) , and disorders of the MAPK pathway ( e.g. , neurofibromatosis type 1 ) . In some embodiments , the diseases and disorders are KRas- 143 WO 2025/064848 PCT / US2024 / 0477 LO associated diseases and disorders ( e.g. , mutant KRas - associated diseases or disorders ( e.g. , KRas G12D- , KRas G12R- , or G12V - associated diseases or disorders ) ) . In certain embodiments , compounds provided herein , or pharmaceutically acceptable salts thereof , are useful for preventing diseases and disorders as defined herein ( for example , a cardiovascular disease , endometriosis , and an inflammatory and / or autoimmune disease , or cancer ) . In some embodiments of any of the methods or uses described herein , the inflammatory and / or autoimmune disease is RAS - associated autoimmune leukoproliferative disease . See , e.g. , Niemela et al . Blood . 2011 ; 117 ( 10 ) : 2883-6 , doi : 10.1182 / blood - 2010-07-295501 . In some embodiments , the subject has been identified or diagnosed as having a cancer with a KRas dysregulation ( e.g. , a KRas 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 KRas dysregulation ( e.g. , a KRas 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 KRas dysregulation ( e.g. , a KRas mutation or amplification ) ( e.g. , identified as positive using a regulatory agency - approved , e.g. , FDA - approved , assay or kit ) . The subject can be a subject whose cancer ( e.g. , a tumor sample ) has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) ( e.g. , where the cancer ( e.g. , tumor sample ) is identified as such using a regulatory agency - approved , e.g. , FDA - approved , kit or assay ) . In some embodiments , the subject is suspected of having a mutant KRas - 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 KRas dysregulation ( e.g. , a KRas 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 ) . In some such embodiments , the cancer ( e.g. , a tumor sample ) has a KRas mutation selected from the group consisting of : a KRas G12X mutation , a KRas G13X mutation , and a KRas Q61X mutation . In some embodiments , a KRas mutation is selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . In some embodiments , a KRas mutation is selected from the group consisting 144 WO 2025/064848 PCT / US2024 / 0477 LO of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer ( e.g. , a tumor sample ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12D mutation , a KRas G12R mutation , and a KRas G12V mutation . In some embodiments , the cancer ( e.g. , a tumor sample ) has a KRas G12A mutation . In some embodiments , the cancer ( e.g. , a tumor sample ) has a KRas G12C 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 G12S mutation . In some embodiments , the cancer ( e.g. , a tumor sample ) has a KRas G12Vmutation . In some embodiments , the cancer ( e.g. , a tumor sample ) has a KRas G12D mutation , a KRas G12R mutation , or KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) . In some embodiments , the cancer ( e.g. , a tumor sample ) has a KRas G12D mutation or a 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 . The term " KRas - associated cancer " as used herein refers to cancers associated with or having a dysregulation of a KRAS gene , a KRas protein , or the expression or activity or level of any ( e.g. , one or more ) of the same ( e.g. , any of the types of dysregulations of a KRAS gene , a KRas protein , or the expression or activity or level of any of the same described herein ) . Non- limiting examples of a KRas - associated cancer are described herein . The term " mutant KRas - associated cancer " as used herein refers to cancers associated with or having a KRas mutation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation ) . Non - limiting examples of a mutant KRas - associated cancer are described herein . The term " KRas G12X - associated cancer " as used herein refers to cancers associated with or having a KRas G12X mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12X mutation in a KRas protein and / or a KRas protein having a G12X mutation ) . Non- limiting examples of a KRas G12X - associated cancer are described herein . The term " KRas G12A - associated cancer " as used herein refers to cancers associated with or having a KRas G12A mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12A mutation in a KRas protein and / or a KRas protein having a G12A mutation ) . Non- limiting examples of a KRas G12A - associated cancer are described herein . 145 WO 2025/064848 PCT / US2024 / 0477 The term " KRas G12C - associated cancer " as used herein refers to cancers associated with or having a KRas G12C mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12C mutation in a KRas protein and / or a KRas protein having a G12C mutation ) . Non- limiting examples of a KRas G12C - associated cancer are described herein . The term " KRas G12D - associated cancer " as used herein refers to cancers associated with or having a KRas G12D mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12D mutation in a KRas protein and / or a KRas protein having a G12D mutation ) . Non- limiting examples of a KRas G12D - associated cancer are described herein . The term " KRas G12R - associated cancer " as used herein refers to cancers associated with or having a KRas G12R mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12R mutation in a KRas protein and / or a KRas protein having a G12R mutation ) . Non- limiting examples of a KRas G12R - associated cancer are described herein . The term " KRas G12S - associated cancer " as used herein refers to cancers associated with or having a KRas G12S mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12S mutation in a KRas protein and / or a KRas protein having a G12S mutation ) . Non- limiting examples of a KRas G12S - associated cancer are described herein . The term " KRas G12V - associated cancer " as used herein refers to cancers associated with or having a KRas G12V mutation ( e.g. , a KRAS gene having a mutation corresponding to a G12V mutation in a KRas protein and / or a KRas protein having a G12V mutation ) . Non- limiting examples of a KRas G12V - associated cancer are described herein . The term " KRas G13X - associated cancer " as used herein refers to cancers associated with or having a KRas G13X mutation ( e.g. , a KRAS gene having a mutation corresponding to a G13X mutation in a KRas protein and / or a KRas protein having a G13X mutation ) . Non- limiting examples of a KRas G13X - associated cancer are described herein . The term " KRas G13C - associated cancer " as used herein refers to cancers associated with or having a KRas G13C mutation ( e.g. , a KRAS gene having a mutation corresponding to a G13C mutation in a KRas protein and / or a KRas protein having a G13C mutation ) . Non- limiting examples of a KRas G13C - associated cancer are described herein . The term " KRas G13D - associated cancer " as used herein refers to cancers associated with or having a KRas G13D mutation ( e.g. , a KRAS gene having a mutation corresponding to a G13D mutation in a KRas protein and / or a KRas protein having a G13D mutation ) . Non- limiting examples of a KRas G13D - associated cancer are described herein . The term " KRas G13V - associated cancer " as used herein refers to cancers associated 146 WO 2025/064848 PCT / US2024 / 0477 LO with or having a KRas G13V mutation ( e.g. , a KRAS gene having a mutation corresponding to a G13V mutation in a KRas protein and / or a KRas protein having a G13V mutation ) . Non- limiting examples of a KRas G13V - associated cancer are described herein . The term " KRas Q61X - associated cancer " as used herein refers to cancers associated with or having a KRas Q61X mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61X mutation in a KRas protein and / or a KRas protein having a Q61X mutation ) . Non- limiting examples of a KRas Q61X - associated cancer are described herein . The term " KRas Q61E - associated cancer " as used herein refers to cancers associated with or having a KRas Q61E mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61E mutation in a KRas protein and / or a KRas protein having a Q61E mutation ) . Non- limiting examples of a KRas Q61E - associated cancer are described herein . The term " KRas Q61H - associated cancer " as used herein refers to cancers associated with or having a KRas Q61H mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61H mutation in a KRas protein and / or a KRas protein having a Q61H mutation ) . Non- limiting examples of a KRas Q61H - associated cancer are described herein . The term " KRas Q61K - associated cancer " as used herein refers to cancers associated with or having a KRas Q61K mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61K mutation in a KRas protein and / or a KRas protein having a Q61K mutation ) . Non- limiting examples of a KRas Q61K - associated cancer are described herein . The term " KRas Q61L - associated cancer " as used herein refers to cancers associated with or having a KRas Q61L mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61L mutation in a KRas protein and / or a KRas protein having a Q61L mutation ) . Non- limiting examples of a KRas Q61L - associated cancer are described herein . The term " KRas Q61P - associated cancer " as used herein refers to cancers associated with or having a KRas Q61P mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61P mutation in a KRas protein and / or a KRas protein having a Q61P mutation ) . Non- limiting examples of a KRas Q61P - associated cancer are described herein . The term " KRas Q61R - associated cancer " as used herein refers to cancers associated with or having a KRas Q61R mutation ( e.g. , a KRAS gene having a mutation corresponding to a Q61R mutation in a KRas protein and / or a KRas protein having a Q61R mutation ) . Non- limiting examples of a KRas Q61R - associated cancer are described herein . 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- 147 WO 2025/064848 PCT / US2024 / 0477 LO 0203 .

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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof . In some embodiments , the subject is treatment evïan with respect to the cancer . In some embodiments , the subject has received one or more lines of previous therapy for the cancer . 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , as a monotherapy . In some embodiments , the subject is treatment evïan with respect to the cancer . In some embodiments , the subject has received one or more lines of previous therapy for the cancer . In some embodiments , the subject has received one or more lines of previous therapy for the cancer prior to administration of a compound provided herein . In some such embodiments , the subject has received previous chemotherapy for the cancer prior to administration of a compound provided herein . In some embodiments , the subject has received first or second - line chemotherapy prior to administration of a compound provided herein . In some embodiments , the subject has received standard of care chemotherapy prior to administration of a compound provided herein . In some embodiments , a subject with colorectal cancer has previously received one or more of capecitabine , fluorouracil ( 5 - FU ) , leucovorin , and oxaliplatin . In some embodiments , a subject with colorectal cancer has previously received FOLFOX ( fluorouracil , leucovorin , and oxaliplatin ) . In some embodiments , a subject with colorectal cancer has previously received FOLFIRI ( fluorouracil , leucovorin , and irinotecan ) . In some embodiments , a subject with a colorectal cancer has previously received FOLFIRINOX ( fluorouracil , leucovorin ( e.g. , leucovorin calcium ) , irinotecan ( e.g. , irinotecan hydrochloride ) , and oxaliplatin ) . In some embodiments , a subject with colorectal cancer has previously received CAPEOX ( capecitabine and oxaliplatin ) . In some embodiments , a subject with colorectal cancer has previously received FOLFIRI and one or more of bevacizumab , ziv - aflibercept , and ramucirumab . In some embodiments , a subject with colorectal cancer has previously received FOLFIRI and one or more of cetuximab or panitumumab . In some embodiments , a subject with colorectal cancer has previously received FOLFOX and one or more of bevacizumab , ziv - aflibercept , and 148 WO 2025/064848 PCT / US2024 / 0477 LO ramucirumab . In some embodiments , a subject with colorectal cancer has previously received FOLFOX and one or more of cetuximab or panitumumab . In some embodiments , a subject with colorectal cancer has previously received FOLFIRINOX and one or more of bevacizumab , ziv - aflibercept , and ramucirumab . In some embodiments , a subject with colorectal cancer has previously received FOLFIRINOX and one or more of cetuximab or panitumumab . In some embodiments , a subject with colorectal cancer has previously received CAPEOX and one or more of bevacizumab , ziv - aflibercept , and ramucirumab . In some embodiments , a subject with colorectal cancer has previously received CAPEOX and one or more of cetuximab or panitumumab . In some embodiments , a subject with endometrial cancer has previously received one or more of cisplatin , carboplatin , paclitaxel , capecitabine , mitomycin , and gemcitabine . In some embodiments , a subject with endometrial cancer has previously received cisplatin and radiation therapy . In some embodiments , a subject with endometrial cancer has previously received cisplatin and radiation therapy followed by carboplatin and paclitaxel . In some embodiments , a subject with endometrial cancer has previously received capecitabine and mitomycin . In some embodiments , a subject with endometrial cancer has previously received gemcitabine . In some embodiments , a subject with endometrial cancer has previously received paclitaxel . In some embodiments , a subject with endometrial cancer has previously received carboplatin and paclitaxel . In some embodiments , a subject with endometrial cancer has previously received carboplatin , paclitaxel , and pembrolizumab . In some embodiments , a subject with endometrial cancer has previously received carboplatin , paclitaxel , and dostarlimab ( e.g. , dostarlimab - gxly ) . In some embodiments , a subject with endometrial cancer has previously received carboplatin , paclitaxel , and trastuzumab . In some embodiments , a subject with endometrial cancer has previously received carboplatin , paclitaxel , and bevacizumab . In some embodiments , a subject with endometrial carcinoma has previously received megestrol acetate and tamoxifen . In some embodiments , a subject with endometrial carcinoma has previously received everolimus and letrozole . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received one or more of pembrolizumab , atezolizumab , cemiplimab ( e.g. , cemiplimiab - rwlc ) , durvalumab , nivolumab , ipilimumab , tremelimumab ( e.g. , tremelimumab - actl ) , carboplatin , cisplatin , pemetrexed , paclitaxel ( e.g. , albumin - bound paclitaxel ) , and bevacizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received pembrolizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has 149 WO 2025/064848 PCT / US2024 / 0477 LO previously received carboplatin , pemetrexed , and pembrolizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received cisplatin , pemetrexed , and pembrolizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received cemiplimab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received cemiplimab , pemetrexed , and carboplatin . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received cemiplimab , pemetrexed , and cisplatin . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received carboplatin , paclitaxel , bevacizumab , and atezolizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received carboplatin , paclitaxel ( e.g. , albumin - bound paclitaxel ) , and atezolizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received cemiplimab , paclitaxel , and carboplatin . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received cemiplimab , paclitaxel , and cisplatin . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received tremelimumab , durvalumab , carboplatin , and paclitaxel ( e.g. , albumin - bound paclitaxel ) . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received tremelimumab , durvalumab , carboplatin , and pemetrexed . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received tremelimumab , durvalumab , cisplatin , and pemetrexed . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received tremelimumab , durvalumab , carboplatin , and paclitaxel ( e.g. , albumin - bound paclitaxel ) . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received tremelimumab , durvalumab , carboplatin , and gemcitabine . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received tremelimumab , durvalumab , cisplatin , and gemcitabine . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received nivolumab and ipilimumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received carboplatin , paclitaxel ( e.g. , albumin - bound paclitaxel ) , and pembrolizumab . In some embodiments , a subject with lung cancer ( e.g. , NSCLC ) has previously received nivolumab , ipilimumab , paclitaxel , and carboplatin . In some embodiments , a subject with ovarian cancer has previously received one or more of paclitaxel , carboplatin , fluorouracil , leucovorin , oxaliplatin , capecitabine , docetaxel , and doxorubicin ( e.g. , liposomal doxorubicin ) . In some embodiments , a subject with ovarian cancer has previously received paclitaxel and carboplatin . In some embodiments , a subject with ovarian cancer has previously received fluorouracil , leucovorin , and oxaliplatin . In some 150 WO 2025/064848 PCT / US2024 / 0477 LO embodiments , a subject with ovarian cancer has previously received hormone therapy ( e.g. , an aromatase inhibitor such as anastrozole , letrozole , or exemestane ) . In some embodiments , a subject with ovarian cancer has previously received docetaxel and carboplatin . In some embodiments , a subject with ovarian cancer has previously received carboplatin and doxorubicin ( e.g. , liposomal doxorubicin ) . In some embodiments , a subject with ovarian cancer has previously received paclitaxel , carboplatin , and bevacizumab . In some embodiments , a subject with ovarian cancer has previously received fluorouracil , leucovorin , oxaliplatin , and bevacizumab . In some embodiments , a subject with ovarian cancer has previously received capecitabine , oxaliplatin , and bevacizumab . In some embodiments , a subject with pancreatic cancer has previously received one or more of capecitabine , fluorouracil , gemcitabine , irinotecan , leucovorin , paclitaxel ( e.g. , albumin - bound paclitaxel ) , and oxaliplatin . In some embodiments , a subject with pancreatic cancer has previously received FOLFIRINOX . In some embodiments , a subject with pancreatic cancer has previously received GEMOX ( gemcitabine and oxaliplatin ) . In some embodiments , a subject with pancreatic cancer has previously received gemcitabine . In some embodiments , a subject with pancreatic cancer has previously received gemcitabine and paclitaxel ( e.g. , albumin - bound paclitaxel ) . In some embodiments , a subject with pancreatic cancer has previously received NALIRIFOX ( liposomal irinotecan , fluorouracil , leucovorin , and oxaliplatin ) . Provided herein is use of a compound provided herein , 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 provided herein , 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 provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , for use as a medicament . Also provided herein is a compound provided herein , 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 . 151 WO 2025/064848 PCT / US2024 / 0477 Provided herein is a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , for use in treating a cancer , for example , any of the cancers provided herein . As used herein , " monotherapy " , when referring to a compound provided herein , or a pharmaceutically acceptable salt thereof , means that the compound provided herein , 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 , pruritis , 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 . As used herein , " the subject has received one or more lines of previous therapy " means that the subject has been previously administered one or more therapeutic agents or therapies ( e.g. , anticancer agent or therapy , such as chemotherapy , radiation , or surgery ) for the cancer other than a compound provided herein , or a pharmaceutically acceptable salt thereof , during a treatment cycle prior to administration of a compound provided herein . 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 . As used herein , " the subject is treatment evïan with respect to the cancer " means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer . 152 WO 2025/064848 PCT / US2024 / 0477 LO 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 . Provided herein is a method of treating a cancer in a subject in need of such treatment , the method comprising a ) detecting a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) in a sample from the subject ( e.g. , detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) ; and b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . Provided herein is a method of treating a cancer in a subject in need of such treatment , the method comprising a ) detecting a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) ) or amplification ) in a sample from the subject ( e.g. , detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) ; and b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . Also provided herein is a method of treating a KRas- associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12X- associated cancer ) ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a 153 WO 2025/064848 PCT / US2024 / 0477 LO pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . For example , provided herein are methods for treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V- associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) in a subject in need of such treatment , the methods comprising a ) detecting a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) in a sample from the subject ( e.g. , detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) ; and b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . For example , provided herein are methods for treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12X- associated cancer ) ) in a subject in need of such treatment , the methods comprising a ) detecting a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) or amplification ) in a sample from the subject ( e.g. , detecting a KRAS gene having a mutation corresponding to a mutation in KRas protein and / or detecting a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) ; and b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments of any of the methods or uses described herein , the cancer ( e.g. , KRas - associated cancer ( e.g. , mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated 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. , 154 WO 2025/064848 PCT / US2024 / 0477 LO anal cancer , bile duct cancer ( e.g. , cholangiocarcinoma ) , colorectal cancer ( e.g. , colon adenocarcinoma , rectal adenocarcinoma , mucinous adenocarcinoma , mucinous carcinoma ) , esophageal cancer ( e.g. , esophageal adenocarcinoma ) , gallbladder cancer , gastrointestinal carcinoid tumor , gastrointestinal stromal tumor , liver cancer ( e.g. , hepatocellular carcinoma , intrahepatic bile duct cancer ) , pancreatic cancer ( e.g. , pancreatic adenocarcinoma , pancreatic islet cell cancer ) , small intestine cancer , or stomach cancer ( e.g. , stomach adenocarcinoma , signet ring cell carcinoma of the stomach ) ) , genitourinary cancer ( e.g. , bladder cancer ( e.g. , bladder urothelial carcinoma ) , kidney cancer ( e.g. , renal clear cell carcinoma , renal papillary cell carcinoma , kidney chromophobe ) , prostate cancer ( e.g. , prostate adenocarcinoma ) , testicular cancer ( e.g. , testicular germ cell tumors , seminoma ) , or ureter cancer ) , gynecologic cancer ( e.g. , cervical cancer ( e.g. , cervical squamous cell carcinoma , endocervical adenocarcinoma , mucinous carcinoma ) , ovarian cancer ( e.g. , serous ovarian cancer , ovarian serous cystadenocarcinoma ) , uterine cancer ( e.g. , uterine carcinosarcoma , uterine endometrioid carcinoma , uterine serous carcinoma , uterine papillary serous carcinoma , uterine corpus endometrial carcinoma ) , or vulvar cancer ) , head and neck cancer ( e.g. , ear cancer ( e.g. , middle ear cancer ) , head and neck squamous cell carcinoma , nasal cavity cancer , oral cancer , pharynx cancer ( e.g. , hypopharynx cancer , nasopharynx cancer , oropharyngeal cancer ) , hematological cancer ( e.g. , leukemia ( e.g. , chronic lymphocytic leukemia ( CLL ) , acute lymphocytic leukemia ( ALL ) ( e.g. , Philadelphia chromosome positive ALL ) , acute myeloid leukemia ( AML ) ( e.g. , acute promyelocytic leukemia ( APL ) ) , chronic myeloid leukemia ( CML ) ) , lymphoma ( e.g. , Hodgkin lymphoma ( e.g. , nodular lymphocyte predominant Hodgkin lymphoma ( NLPHL ) ) , non - Hodgkin lymphoma ( e.g. , Burkitt lymphoma ( BL ) , diffuse large B- cell lymphoma ( DLBCL ) , diffuse histiocytic lymphoma ( DHL ) , follicular lymphoma ( FL ) , intravascular large B - cell lymphoma ( IVLBCL ) , mantle cell lymphoma ( MCL ) , small lymphocytic lymphoma ( SLL ) ) ) , or myeloma ( e.g. , multiple myeloma ) ) , Li - Fraumeni tumors , mesentery cancer ( e.g. , omentum cancer , peritoneal cancer ) , pleural cancer , respiratory cancer ( e.g. , larynx cancer , lung cancer ( e.g. , lung squamous cell carcinoma , lung adenocarcinoma , mesothelioma , non - small cell lung cancer ( NSCLC ) ) , tracheal cancer ) , sarcoma ( e.g. , bone cancer ( e.g. , osteosarcoma , chondrosarcoma ) or soft tissue sarcoma ( Ewing sarcoma , leiomyosarcoma , myxofibrosarcoma , rhabdomyosarcoma ) ) , skin cancer ( e.g. , melanoma ) , thymus cancer ( e.g. , thymoma ) , or a combination thereof . In some embodiments , the cancer ( e.g. , KRas - associated cancer ( e.g. , mutant KRas- associated cancer ) ) is a hematological cancer , a soft tissue cancer , bile duct cancer , bladder 155 WO 2025/064848 PCT / US2024 / 0477 ﺶﻣا 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 ( e.g. , KRas - associated cancer ( e.g. , mutant KRas- associated cancer ) ) is colorectal cancer ( e.g. , a colon cancer or a rectal cancer ) , endometrial cancer , lung cancer ( e.g. , NSCLC ) , ovarian cancer , or pancreatic cancer . In some embodiments , the cancer ( e.g. , KRas - associated cancer ( e.g. , mutant KRas- associated cancer ) ) is colon cancer , endometrial cancer , lung cancer , pancreatic cancer , and uterine cancer . In some embodiments , the cancer is a colorectal cancer ( e.g. , a colon cancer or a rectal cancer ) . In some such embodiments , the colorectal cancer has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) ) or amplification ) . In some embodiments , the cancer is an endometrial cancer . In some such embodiments , the endometrial cancer has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) ) or amplification ) . In some embodiments , the cancer is a lung cancer ( e.g. , NSCLC ) . In some such embodiments , the lung cancer ( e.g. , NSCLC ) has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) ) or amplification ) . In some embodiments , the cancer is an ovarian cancer . In some such embodiments , the ovarian cancer has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) ) or amplification ) . In some embodiments , the cancer is a pancreatic cancer . In some such embodiments , the pancreatic cancer has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12X mutation ) ) or amplification ) . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , a mutant KRas- associated cancer ( e.g. , a KRas G12X - associated 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 . 156 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , the cancer is brain cancer , colon cancer , lung cancer , pancreatic cancer , rectal cancer , testicular cancer ( e.g. , seminoma ) , or uterine cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is bladder cancer , breast cancer , cervical cancer , colon cancer , lung cancer , kidney cancer , liver cancer , or rectal cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a hematological cancer , brain 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 , thymus cancer , urothelial cancer , or uterine cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a hematological cancer , bladder cancer , bile duct cancer , colon cancer , ovarian cancer , pancreatic cancer , prostate cancer , rectal cancer , skin cancer , or testicular cancer . In some embodiments , the cancer is a KRas G12R - associated cancer .

In some embodiments , the cancer is colon cancer , lung cancer , pancreatic cancer , rectal cancer , stomach cancer , testicular cancer ( e.g. , seminoma ) , or uterine cancer . In some embodiments , the cancer is a KRas G12S - associated cancer In some embodiments , the cancer is a hematological cancer , bladder cancer , bile duct 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 , rectal cancer , skin cancer , stomach cancer , testicular cancer ( e.g. , seminoma ) , thymus cancer , or uterine cancer . In some embodiments , the cancer is a G12V- associated cancer . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , a mutant KRas- associated cancer ( e.g. , a KRas G13X - associated cancer ) ) ) is a hematological cancer , a soft tissue cancer , cervical cancer , colon cancer , endometrial cancer , liver cancer , lung cancer , pancreatic cancer , rectal cancer , skin cancer , stomach cancer , or urothelial cancer . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas Q61X - associated cancer ) ) is bladder cancer , colon cancer , lung cancer , ovarian cancer , rectal cancer , thyroid cancer , or uterine cancer . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , a cancer associated with KRas amplification ( e.g. , a cancer associated with wild - type KRas amplification ) ) is colorectal cancer , gastric cancer , 157 WO 2025/064848 PCT / US2024 / 0477 LO gastroesophageal cancer , head and neck squamous carcinoma , or lung cancer ( e.g. , NSCLC ) . See , e.g. , the public database cBioPortal . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , mutant KRas- associated cancer ) ) is pancreatic cancer or metastatic pancreatic cancer . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , mutant KRas - associated cancer ) ) is pancreatic ductal adenocarcinoma ( PDAC ) . In some such embodiments , the pancreatic cancer is a KRas G12R - associated cancer . In some embodiments , the cancer ( e.g. , a KRas - associated cancer ( e.g. , mutant KRas- associated cancer ) ) is advanced - stage lung adenocarcinoma . In some embodiments , the cancer is a solid tumor . In some embodiments , the solid tumor has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the solid tumor has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the solid tumor has a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation . In some embodiments , the solid tumor has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the solid tumor has a KRas G12A mutation . In some embodiments , the solid tumor has a KRas G12C mutation . In some embodiments , the solid tumor has a KRas G12D mutation . In some embodiments , the solid tumor has a KRas G12R mutation . In some embodiments , the solid tumor has a KRas G12S mutation . In some embodiments , the solid tumor has a KRas G12V mutation .

Also provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D or a KRas G12V 158 WO 2025/064848 PCT / US2024 / 0477 LO mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein .

Also provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically 159 WO 2025/064848 PCT / US2024 / 0477 LO acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as 160 WO 2025/064848 PCT / US2024 / 0477 described herein . Additionally provided herein is a method of treating an advanced solid tumor in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . As used herein , an " advanced solid tumor " is a solid tumor that has spread extensively to other anatomic sites and / or that is no longer responding to treatment . In some embodiments , classification of an advanced solid tumor can be made by the subject's physician . In some embodiments , the cancer is a bladder cancer . In some embodiments , the bladder cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the bladder cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12V mutation , a KRas G13D mutation , and a KRas Q61H mutation . As another example , the bladder cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , and a KRas G12V mutation . In some embodiments , the bladder cancer has a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation . In some embodiments , the bladder cancer has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the bladder cancer has a KRas G12C mutation . In some embodiments , the bladder cancer has a KRas G12D mutation . In some embodiments , the bladder cancer has a KRas G12R mutation . In some embodiments , the bladder cancer has a KRas G12V mutation .

Also provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12V mutation , a KRas G13D mutation , or a KRas Q61H mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas 161 WO 2025/064848 PCT / US2024 / 0477 LO G12C mutation , a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a bladder cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the cancer is a cervical cancer . In some embodiments , the cervical cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the cervical cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12V mutation , and a KRas G13D mutation . As another example , the cervical cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , and a KRas G12V mutation . In some embodiments , the cervical cancer has a KRas G12D mutation or a KRas G12V 162 WO 2025/064848 PCT / US2024 / 0477 LO mutation . In some embodiments , the cervical cancer has a KRas G12C mutation . In some embodiments , the cervical cancer has a KRas G12D mutation . In some embodiments , the cervical cancer has a KRas G12V mutation .

Also provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , a KRas G12V mutation , or a KRas G13D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a cervical cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) 163 WO 2025/064848 PCT / US2024 / 0477 LO administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein .

In some embodiments , the cancer is a colorectal cancer . In some embodiments , the colorectal cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the colorectal cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . As another example , the colorectal cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the colorectal cancer has a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation . In some embodiments , the colorectal cancer has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the colorectal cancer has a KRas G12A mutation . In some embodiments , the colorectal cancer has a KRas G12C mutation . In some embodiments , the colorectal cancer has a KRas G12D mutation . In some embodiments , the colorectal cancer has a KRas G12R mutation . In some embodiments , the colorectal cancer has a KRas G12S mutation . In some embodiments , the colorectal cancer has a KRas G12V mutation .

Also provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , or a KRas Q61R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically 164 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation , in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally 165 WO 2025/064848 PCT / US2024 / 0477 LO provided herein is a method of treating a colorectal cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein .

In some embodiments , the cancer is an endometrial cancer . In some embodiments , the endometrial cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the endometrial cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61H mutation , and a KRas Q61L mutation . As another example , the endometrial cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the endometrial cancer has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the endometrial cancer has a KRas G12A mutation . In some embodiments , the endometrial cancer has a KRas G12C mutation . In some embodiments , the endometrial cancer has a KRas G12D mutation . In some embodiments , the endometrial cancer has a KRas G12S mutation . In some embodiments , the endometrial cancer has a KRas G12V mutation .

Also provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61H mutation , or a KRas Q61L mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , or a 166 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an endometrial cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein .

In some embodiments , the cancer is an esophageal or stomach cancer . In some embodiments , the esophageal or stomach cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the esophageal or stomach cancer has a KRas 167 WO 2025/064848 PCT / US2024 / 0477 LO mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , and a KRas Q61H mutation . As another example , the esophageal or stomach cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the esophageal or stomach cancer has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the esophageal or stomach cancer has a KRas G12C mutation . In some embodiments , the esophageal or stomach cancer has a KRas G12D mutation . In some embodiments , the esophageal or stomach cancer has a KRas G12S mutation . In some embodiments , the esophageal or stomach cancer has a KRas G12V mutation . Also provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , or a KRas Q61H mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a 168 WO 2025/064848 PCT / US2024 / 0477 LO sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating an esophageal or stomach cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the cancer is a leukemia . In some embodiments , the leukemia has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the leukemia has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . For example , the leukemia has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the leukemia has a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation . In some embodiments , the leukemia has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the leukemia has a KRas G12A mutation . In some embodiments , the leukemia has a KRas G12C mutation . In some embodiments , the leukemia has a KRas G12D mutation . In some embodiments , the leukemia has a KRas G12R mutation . In some embodiments , the leukemia has a KRas G12S mutation . In some embodiments , the leukemia has a KRas G12V mutation . Also provided herein is a method of treating a leukemia in a subject in need thereof , the 169 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , or a KRas Q61R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound 170 WO 2025/064848 PCT / US2024 / 0477 LO provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a leukemia in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the cancer is a melanoma . In some embodiments , the melanoma has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the melanoma has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61K mutation , a KRas Q61L mutation , and a KRas Q61R mutation . As another example , the melanoma has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , and a KRas G12R mutation . In some embodiments , the melanoma has a KRas G12D mutation or a KRas G12R mutation . In some embodiments , the melanoma has a KRas G12C mutation . In some embodiments , the melanoma has a KRas G12D mutation . In some embodiments , the melanoma has a KRas G12R mutation . Also provided herein is a method of treating a melanoma in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a melanoma in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61K mutation , a KRas Q61L mutation , or a KRas Q61R mutation in a sample from the subject , and ( b ) administering to the subject a 171 WO 2025/064848 PCT / US2024 / 0477 LO therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a melanoma in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a melanoma in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a melanoma in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a melanoma in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the cancer is a lung cancer ( e.g. , non - small cell lung cancer ) . In some embodiments , the lung cancer ( e.g. , non - small cell lung cancer ) has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the lung cancer ( e.g. , non - small cell lung cancer ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas Q61H mutation , and a KRas Q61L mutation . For example , the lung cancer ( e.g. , non - small cell lung cancer ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the lung cancer has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the lung cancer has a KRas G12A mutation . In some embodiments , the lung cancer has a KRas G12C mutation . In some embodiments , the lung cancer has a KRas G12D mutation . In some embodiments , the lung cancer has a KRas G12S mutation . In some 172 WO 2025/064848 PCT / US2024 / 0477 embodiments , the lung cancer has a KRas G12V mutation . Also provided herein is a method of treating a lung cancer ( e.g. , non - small cell lung cancer ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a lung cancer ( e.g. , non - small cell lung cancer ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas Q61H mutation , or a KRas Q61L mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a lung cancer ( e.g. , non - small cell lung cancer ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a lung cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a lung cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a lung cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a lung cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the 173 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a lung cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a lung cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the cancer is a pancreatic cancer . In some embodiments , the pancreatic cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the pancreatic cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas Q61H mutation , and a KRas Q61R mutation . For example , the pancreatic cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the pancreatic cancer has a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation . In some embodiments , the pancreatic cancer has a KRas G12D mutation or a KRas G12V mutation . In some embodiments , the pancreatic cancer has a KRas G12A mutation . In some embodiments , the pancreatic cancer has a KRas G12C mutation . In some embodiments , the pancreatic cancer has a KRas G12D mutation . In some embodiments , the pancreatic cancer has a KRas G12R mutation . In some embodiments , the pancreatic cancer has a KRas G12S mutation . In some embodiments , the pancreatic cancer has a KRas G12V mutation .

Also provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method 174 WO 2025/064848 PCT / US2024 / 0477 LO comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas Q61H mutation , or a KRas Q61R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12C mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12D mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical 175 WO 2025/064848 PCT / US2024 / 0477 LO composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a pancreatic cancer in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the cancer is a testicular cancer ( e.g. , seminoma ) . In some embodiments , the testicular cancer ( e.g. , seminoma ) has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . For example , the testicular cancer ( e.g. , seminoma ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . As another example , the testicular cancer ( e.g. , seminoma ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the testicular cancer ( e.g. , seminoma ) cancer has a KRas G12R mutation or a KRas G12V mutation . In some embodiments , the testicular cancer ( e.g. , seminoma ) cancer has a KRas G12A mutation . In some embodiments , the testicular cancer ( e.g. , seminoma ) cancer has a KRas G12R mutation . In some embodiments , the testicular cancer ( e.g. , seminoma ) cancer has a KRas G12S mutation . In some embodiments , the testicular cancer ( e.g. , seminoma ) cancer has a KRas G12V mutation . Also provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . 176 WO 2025/064848 PCT / US2024 / 0477 LO Also provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas Q61L mutation , a KRas Q61P mutation , or a KRas Q61R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Also provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12A mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12R mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12S mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . Additionally provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need thereof , the method comprising : ( a ) detecting a KRas G12V mutation in a sample from the subject , and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein .

Also provided herein is a method of treating a bladder cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a 177 WO 2025/064848 PCT / US2024 / 0477 LO pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the bladder cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12V mutation , a KRas G13D mutation , and a KRas Q61H mutation . In some embodiments , the method further comprises determining that the bladder cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , and a KRas G12V mutation . In some such embodiments , the cancer is a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12V - associated cancer , a KRas G13D - associated cancer , or a KRas Q61H - associated cancer . In some such embodiments , the cancer is a KRas G12C - associated cancer , a KRas G12D- associated cancer , a KRas G12R - associated cancer , or a KRas G12V - associated cancer . In some aspects of this embodiment , the cancer is a KRas G12D - associated cancer , a KRas G12R- associated cancer , or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12R - associated cancer . In some embodiments , the cancer is a KRas G12V - associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12V inhibitor , a KRas G13D inhibitor , a KRas Q61H inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , and / or a KRas G12V inhibitor . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a cervical cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the cervical cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12V mutation , and a KRas G13D mutation . In some embodiments , the method further comprises determining that 178 WO 2025/064848 PCT / US2024 / 0477 LO the cervical cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12V- associated cancer , or a KRas G13D - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer , a KRas G12D - associated cancer , or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V- associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12V - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12V inhibitor , a KRas G13D inhibitor , or two or more thereof . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both .

Also provided herein is a method of treating a colorectal cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the colorectal cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . In some embodiments , the method further comprises determining that the colorectal cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , a KRas G12V - associated cancer , a KRas G13C - associated cancer , a KRas G13D - associated cancer , a KRas G13V- associated cancer , a KRas Q61E - associated cancer , a KRas Q61H - associated cancer , a KRas 179 WO 2025/064848 PCT / US2024 / 0477 LO Q61K - associated cancer , a KRas Q61L - associated cancer , a KRas Q61P - associated cancer , or a KRas Q61R - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer . In some aspects of this embodiment , the cancer is a KRas G12D - associated cancer , a KRas G12R- associated cancer , or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is a KRas G12C- associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12R - associated cancer . In some embodiments , the cancer is a KRas G12S - associated cancer . In some embodiments , the cancer is a KRas G12V- associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas G13C inhibitor , a KRas G13D inhibitor , a KRas G13V inhibitor , a KRas Q61E inhibitor , a KRas Q61H inhibitor , a KRas Q61K inhibitor , a KRas Q61L inhibitor , a KRas Q61P inhibitor , a KRas Q61R inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , and / or a KRas G12V inhibitor . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating an endometrial cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the endometrial cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61H mutation , and a KRas Q61L mutation . In some embodiments , the method further comprises determining that the endometrial cancer has 180 WO 2025/064848 PCT / US2024 / 0477 LO a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12S - associated cancer , a KRas G12V- associated cancer , a KRas G13C - associated cancer , a KRas G13D - associated cancer , a KRas G13V - associated cancer , a KRas Q61H - associated cancer , or a KRas Q61L - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12S - associated cancer , or a KRas G12V- associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12S - associated cancer . In some embodiments , the cancer is a KRas G12V- associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas G13C inhibitor , a KRas G13D inhibitor , a KRas G13V inhibitor , a KRas Q61H inhibitor , a KRas Q61L inhibitor , or two or more thereof . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both .

Also provided herein is a method of treating an esophageal or stomach cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the esophageal or stomach cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , and a KRas Q61H mutation . In some embodiments , the method further comprises determining that the esophageal or stomach cancer has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12S 181 WO 2025/064848 PCT / US2024 / 0477 LO mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12S - associated cancer , a KRas G12V - associated cancer , a KRas G13C - associated cancer , a KRas G13D - associated cancer , or a KRas Q61H - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12S - associated cancer , or a KRas G12V- associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12S - associated cancer . In some embodiments , the cancer is a KRas G12V - associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas G13C inhibitor , a KRas G13D inhibitor , a KRas Q61H inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a leukemia in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the leukemia has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61E mutation , a KRas Q61H mutation , a KRas Q61K mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . In some embodiments , the method further comprises determining that the leukemia has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12A- associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , a KRas G12V - associated cancer , a KRas G13C - associated cancer , a KRas G13D - associated cancer , a KRas G13V - associated 182 WO 2025/064848 PCT / US2024 / 0477 LO cancer , a KRas Q61E - associated cancer , a KRas Q61H - associated cancer , a KRas Q61K- associated cancer , a KRas Q61L - associated cancer , a KRas Q61P - associated cancer , or a KRas Q61R - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , and a KRas G12V - associated cancer . In some aspects of this embodiment , the cancer is a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12D- associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12R - associated cancer . In some embodiments , the cancer is a KRas G12S - associated cancer . In some embodiments , the cancer is a KRas G12V- associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas G13C inhibitor , a KRas G13D inhibitor , a KRas G13V inhibitor , a KRas Q61E inhibitor , a KRas Q61H inhibitor , a KRas Q61K inhibitor , a KRas Q61L inhibitor , a KRas Q61P inhibitor , a KRas Q61R inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , and / or a KRas G12V inhibitor . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a melanoma in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the melanoma has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G13D mutation , a KRas G13V mutation , a KRas Q61K mutation , a KRas Q61L mutation , and a KRas Q61R mutation . In some embodiments , the method further comprises determining that 183 WO 2025/064848 PCT / US2024 / 0477 LO the melanoma has a KRas mutation selected from the group consisting of : a KRas G12C mutation , a KRas G12D mutation , and a KRas G12R mutation . In some embodiments , the cancer is a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G13D - associated cancer , a KRas G13V - associated cancer , a KRas Q61K - associated cancer , a KRas Q61L - associated cancer , or a KRas Q61R - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer , a KRas G12D - associated cancer , or a KRas G12R - associated cancer . In some embodiments , the cancer is a KRas G12D- associated cancer or a KRas G12R - associted cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12R - associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G13D inhibitor , a KRas G13V inhibitor , a KRas Q61K inhibitor , a KRas Q61L inhibitor , a KRas Q61R inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , or both . Also provided herein is a method of treating a lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the lung cancer ( e.g. , NSCLC ) has a KRas mutation selected from the group consisting of : KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C - asociated cancer , a KRas G13D mutation , a KRas Q61H mutation , and a KRas Q61L mutation . In some embodiments , the method further comprises determining that the lung cancer ( e.g. , NSCLC ) has a KRas mutation selected from the group consisting of : KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D- associated cancer , a KRas G12S - associated cancer , a KRas G12V - associated cancer , a KRas G13C - asociated cancer , a KRas G13D - associated cancer , a KRas Q61H - associated cancer , or a KRas Q61L - associated cancer . In some embodiments , the cancer is a KRas G12A - associated 184 WO 2025/064848 PCT / US2024 / 0477 LO cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12S- associated cancer , or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is a KRas G12C- associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12S - associated cancer . In some embodiments , the cancer is a KRas G12V - associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas G13C - asociated cancer , a KRas G13D inhibitor , a KRas Q61H inhibitor , a KRas Q61L inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the pancreatic cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas G13C - asociated cancer , and a KRas Q61H mutation . In some embodiments , the method further comprises determining that the pancreatic cancer has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D- associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , a KRas G12V - associated cancer , a KRas G13C - asociated cancer , or a KRas Q61H - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S- associated cancer , or a KRas G12V - associated cancer . In some aspects of this embodiment , the cancer is a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V- 185 WO 2025/064848 PCT / US2024 / 0477 LO associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is a KRas G12C - associated cancer . In some embodiments , the cancer is a KRas G12D - associated cancer . In some embodiments , the cancer is a KRas G12R - associated cancer . In some embodiments , the cancer is a KRas G12S- associated cancer . In some embodiments , the cancer is a KRas G12V - associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas G13C inhibitor , a KRas Q61H inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , a KRas G12D inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , and / or a KRas G12V inhibitor . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some embodiments , the method further comprises determining that the testicular cancer ( e.g. , seminoma ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12R mutation , a KRas G12S mutation , a KRas G12V mutation , a KRas Q61L mutation , a KRas Q61P mutation , and a KRas Q61R mutation . In some embodiments , the method further comprises determining that the testicular cancer ( e.g. , seminoma ) has a KRas mutation selected from the group consisting of : a KRas G12A mutation , a KRas G12R mutation , a KRas G12S mutation , and a KRas G12V mutation . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12R - associated cancer , a KRas G12S- associated cancer , a KRas G12V - associated cancer , a KRas Q61L - associated cancer , a KRas Q61P - associated cancer , or a KRas Q61R - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer . In some aspects of this embodiment , the cancer is 186 WO 2025/064848 PCT / US2024 / 0477 LO a KRas G12R - associated cancer or a KRas G12V - associated cancer . In some embodiments , the cancer is a KRas G12A - associated cancer . In some embodiments , the cancer is a KRas G12R - associated cancer . In some embodiments , the cancer is a KRas G12S - associated cancer . In some embodiments , the cancer is a KRas G12V - associated cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , a KRas Q61L inhibitor , a KRas Q61P inhibitor , a KRas Q61R inhibitor , or two or more thereof . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12R inhibitor , a KRas G12S inhibitor , a KRas G12V inhibitor , or two or more thereof . In some aspects of this embodiment , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G12V inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , skin cancer ( e.g. , melanoma ) , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas G12D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas G12D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , skin cancer ( e.g. , melanoma ) , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , or both . Also provided herein is a method of treating bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , skin cancer ( e.g. , melanoma ) , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is 187 WO 2025/064848 PCT / US2024 / 0477 LO a KRas G12C - associated cancer or a KRas G12D - associated cancer , or both . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12D inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or kidney cancer . In some embodiments , the cancer has a KRas G12D mutation or a KRas G12V mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas G12V - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or kidney cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or kidney cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12V inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , leukemia , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12D mutation or a KRas G13D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G13D inhibitor , or both . 188 WO 2025/064848 PCT / US2024 / 0477 LO Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas G13D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , leukemia , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , leukemia , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D- associated cancer or a KRas G13D - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G13D inhibitor , or both .

In some embodiments , the KRas - associated cancer is bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas G12V mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas G12V - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12V inhibitor , or both . 189 LO WO 2025/064848 PCT / US2024 / 0477 Also provided herein is a method of treating bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas G12V - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12V inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12C mutation or a KRas G13D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas G13D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , liver cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas G13D - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G13D inhibitor , or both . 190 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12D mutation or a KRas Q61H mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61H inhibitor , or both .

Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas Q61H - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D - associated cancer or a KRas Q61H- associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61H inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12V mutation or a KRas G13D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating a KRas G12V - associated cancer or a KRas G13D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , cervical cancer , colorectal 191 WO 2025/064848 PCT / US2024 / 0477 LO cancer , endometrial cancer , esophageal or stomach cancer , leukemia , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating bladder cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12V - associated cancer or a KRas G13V- associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas G13D inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12V mutation or a KRas Q61H mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61H inhibitor , or both .

Also provided herein is a method of treating a KRas G12V - associated cancer or a KRas Q61H - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12V - associated cancer or a KRas Q61H- associated cancer . In some such embodiments , the compound provided herein , or a 192 WO 2025/064848 PCT / US2024 / 0477 LO pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61H inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas Q61H mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas Q61H - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating bladder cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas Q61H- associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61H inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12S mutation or a KRas G12V mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a KRas G12S - associated cancer or a KRas G12V - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , 193 WO 2025/064848 PCT / US2024 / 0477 LO or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G12V inhibitor , or both .

Also provided herein is a method of treating colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12S - associated cancer or a KRas G12V - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G12V inhibitor , or both .

In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12A mutation or a KRas G12S mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas G12S - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is 194 WO 2025/064848 PCT / US2024 / 0477 LO a KRas G12A - associated cancer or a KRas G12S - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12S inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12A mutation or a KRas G12V mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas G12V - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas G12V - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12V inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas G12S mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas G12S - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described 195 WO 2025/064848 PCT / US2024 / 0477 LO herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas G12S - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12S inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , skin cancer ( e.g. , melanoma ) , pancreatic cancer , or prostate cancer . In some embodiments , the cancer has a KRas G12D mutation or a KRas G12R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , or both . Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas G12R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , skin cancer ( e.g. , melanoma ) , pancreatic cancer , or prostate cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , or both . Also provided herein is a method of treating bladder cancer , colorectal cancer , skin cancer ( e.g. , melanoma ) , pancreatic cancer , or prostate cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12R inhibitor , or both . 196 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12D mutation or a KRas G12S mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas G12S - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D - associated cancer or a KRas G12S - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G12S inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , ovarian cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12R mutation or a KRas G12V mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas G12V - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , ovarian cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R 197 WO 2025/064848 PCT / US2024 / 0477 LO inhibitor , a KRas G12V inhibitor , or both . Also provided herein is a method of treating bladder cancer , colorectal cancer , ovarian cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12R - associated cancer or a KRas G12V - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G12V inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12S mutation or a KRas Q61H mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating a KRas G12S - associated cancer or a KRas Q61H - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , esophageal or stomach cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12S - associated cancer or a KRas Q61H - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61H inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , ovarian cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12V mutation or a KRas Q61L mutation . In some 198 WO 2025/064848 PCT / US2024 / 0477 LO such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating a KRas G12V - associated cancer or a KRas Q61L - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , ovarian cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , ovarian cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12V - associated cancer or a KRas Q61L - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61L inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12A mutation or a KRas G12C mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas G12C - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method 199 WO 2025/064848 PCT / US2024 / 0477 LO comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas G12C - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12C inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12A mutation or a KRas G12D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12D inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas G12D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12D inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas G12D - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12D inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12A mutation or a KRas G13C mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas 200 WO 2025/064848 PCT / US2024 / 0477 LO G13C - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas G13C - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G13C inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12A mutation or a KRas Q61H mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas Q61H - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61H inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer 201 WO 2025/064848 PCT / US2024 / 0477 LO or a KRas Q61H - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61H inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12A mutation or a KRas Q61L mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas Q61L - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas Q61L - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61L inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas G12R mutation . In some such embodiments , the compound provided herein , or pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12R inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas G12R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described 202 WO 2025/064848 PCT / US2024 / 0477 ﺶﻣا herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12R inhibitor , or both . Also provided herein is a method of treating bladder cancer , colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas G12R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G12R inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas G13C mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas G13C - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas G13C - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas G13C inhibitor , or both . 203 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12C mutation or a KRas Q61L mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas Q61L - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C- associated cancer or a KRas Q61L - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61L inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12D mutation or a KRas G13C mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas G13C - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a 204 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا KRas G13C inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D - associated cancer or a KRas G13C - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas G13C inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12D mutation or a KRas Q61L mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas Q61L - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , skin cancer ( e.g. , melanoma ) , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D- associated cancer or a KRas Q61L - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61L inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , ovarian cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12R mutation or a KRas Q61L mutation . In some such embodiments , 205 WO 2025/064848 PCT / US2024 / 0477 LO the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas Q61L - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , ovarian cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating colorectal cancer , skin cancer ( e.g. , melanoma ) , ovarian cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12R - associated cancer or a KRas Q61L - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61L inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12R mutation or a KRas Q61R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas Q61R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating colorectal cancer , skin cancer ( e.g. , melanoma ) , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such 206 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12R - associated cancer or a KRas Q61R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61R inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12S mutation or a KRas G13C mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating a KRas G12S - associated cancer or a KRas G13C - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12S - associated cancer or a KRas G13C - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G13C inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12S mutation or a KRas G13D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating a KRas G12S - associated cancer or a KRas 207 WO 2025/064848 PCT / US2024 / 0477 LO G13D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , esophageal or stomach cancer , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , esophageal or stomach cancer , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12S - associated cancer or a KRas G13D - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas G13D inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12S mutation or a KRas Q61L mutation . In some such embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating a KRas G12S - associated cancer or a KRas Q61L - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61L inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a 208 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12S - associated cancer or a KRas Q61L - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61L inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12V mutation or a KRas G13C mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating a KRas G12V - associated cancer or a KRas G13C - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas G13C inhibitor , or both . Also provided herein is a method of treating colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12V - associated cancer or a KRas G13C - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas G13C inhibitor , or both .

In some embodiments , the KRas - associated cancer is colorectal cancer , pancreatic cancer , testicular cancer ( e.g. , seminoma ) , or thyroid cancer . In some embodiments , the cancer has a KRas G12V mutation or a KRas Q61R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating a KRas G12V - associated cancer or a KRas Q61R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described 209 WO 2025/064848 PCT / US2024 / 0477 ﺶﻣا herein . In some such embodiments , the cancer is colorectal cancer , pancreatic cancer , testicular cancer ( e.g. , seminoma ) , or thyroid cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating colorectal cancer , pancreatic cancer , testicular cancer ( e.g. , seminoma ) , or thyroid cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12V- associated cancer or a KRas Q61R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12V inhibitor , a KRas Q61R inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12A mutation or a KRas G12R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12R inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas G12R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12R inhibitor , or both .

Also provided herein is a method of treating colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas G12R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G12R inhibitor , or both . 210 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا In some embodiments , the KRas - associated cancer is colorectal cancer , endometrial cancer , or lung cancer ( e.g. , NSCLC ) . In some embodiments , the cancer has a KRas G12A mutation or a KRas G13D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G13D inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas G13D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , endometrial cancer , or lung cancer ( e.g. , NSCLC ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G13D inhibitor , or both .

Also provided herein is a method of treating colorectal cancer , endometrial cancer , or lung cancer ( e.g. , NSCLC ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas G13D - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas G13D inhibitor , or both .

In some embodiments , the KRas - associated cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12A mutation or a KRas Q61R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating a KRas G12A - associated cancer or a KRas Q61R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61R 211 WO 2025/064848 PCT / US2024 / 0477 LO inhibitor , or both .

Also provided herein is a method of treating colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12A - associated cancer or a KRas Q61R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12A inhibitor , a KRas Q61R inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12C mutation or a KRas Q61R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating a KRas G12C - associated cancer or a KRas Q61R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12C - associated cancer or a KRas Q61R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12C inhibitor , a KRas Q61R inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer . In some embodiments , the cancer has a KRas G12D mutation or a KRas Q61R mutation . In some such embodiments , the compound provided 212 WO 2025/064848 PCT / US2024 / 0477 LO herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating a KRas G12D - associated cancer or a KRas Q61R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating colorectal cancer , skin cancer ( e.g. , melanoma ) , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12D - associated cancer or a KRas Q61R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12D inhibitor , a KRas Q61R inhibitor , or both .

In some embodiments , the KRas - associated cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12R mutation or a KRas G12S mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G12S inhibitor , or both . Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas G12S - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G12S inhibitor , or both .

Also provided herein is a method of treating colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising 213 WO 2025/064848 PCT / US2024 / 0477 LO administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12R - associated cancer or a KRas G12S - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G12S inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , or skin cancer ( e.g. , melanoma ) . In some embodiments , the cancer has a KRas G12R mutation or a KRas G13D mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G13D inhibitor , or both .

Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas G13D - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , or skin cancer ( e.g. , melanoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G13D inhibitor , or both .

Also provided herein is a method of treating bladder cancer , colorectal cancer , or skin cancer ( e.g. , melanoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12R - associated cancer or a KRas G13D - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas G13D inhibitor , or both . In some embodiments , the KRas - associated cancer is bladder cancer , colorectal cancer , or pancreatic cancer . In some embodiments , the cancer has a KRas G12R mutation or a KRas Q61H mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61H inhibitor , or both .

Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas 214 WO 2025/064848 PCT / US2024 / 0477 LO Q61H - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bladder cancer , colorectal cancer , or pancreatic cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61H inhibitor , or both .

Also provided herein is a method of treating bladder cancer , colorectal cancer , or pancreatic cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12R - associated cancer or a KRas Q61H- associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61H inhibitor , or both .

In some embodiments , the KRas - associated cancer is bile duct cancer ( e.g. , cholangiocarcinoma ) , colorectal cancer , or skin cancer ( e.g. , melanoma ) . In some embodiments , the cancer has a KRas G12R mutation or a KRas Q61K mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61K inhibitor , or both . Also provided herein is a method of treating a KRas G12R - associated cancer or a KRas Q61K - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is bile duct cancer ( e.g. , cholangiocarcinoma ) , colorectal cancer , or skin cancer ( e.g. , melanoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61K inhibitor , or both . Also provided herein is a method of treating bile duct cancer ( e.g. , cholangiocarcinoma ) , colorectal cancer , or skin cancer ( e.g. , melanoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a 215 WO 2025/064848 PCT / US2024 / 0477 LO KRas G12R - associated cancer or a KRas Q61K - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12R inhibitor , a KRas Q61K inhibitor , or both . In some embodiments , the KRas - associated cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some embodiments , the cancer has a KRas G12S mutation or a KRas Q61R mutation . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61R inhibitor , or both . Also provided herein is a method of treating a KRas G12S - associated cancer or a KRas Q61R - associated cancer in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61R inhibitor , or both .

Also provided herein is a method of treating colorectal cancer , pancreatic cancer , or testicular cancer ( e.g. , seminoma ) in a subject in need of such treatment , the method comprising administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition as described herein . In some such embodiments , the cancer is a KRas G12S - associated cancer or a KRas Q61R - associated cancer . In some such embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , is a KRas G12S inhibitor , a KRas Q61R inhibitor , or both .

Also provided herein is a method for treating a subject diagnosed with or identified as having a KRas - associated cancer , e.g. , any of the exemplary mutant KRas - associated cancers disclosed herein , comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , as defined herein . Also provided herein is a method for treating a subject diagnosed with or identified as having a cancer with a KRas dysregulation ( e.g. , a KRas mutation or amplification ) comprising administering to the subject a therapeutically effective amount of a compound provided herein or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , as defined herein . 216 LO WO 2025/064848 PCT / US2024 / 0477 Accordingly , provided herein are methods for treating a subject diagnosed with ( or identified as having ) a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) that include administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments , the subject that has been identified or diagnosed as having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) through the use of a regulatory agency - approved , e.g. , FDA - approved test or assay for identifying a dysregulation associated with KRas ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , in a subject or a biopsy sample from the subject or by performing any of the non - limiting examples of assays described herein . Accordingly , provided herein are methods for treating a subject diagnosed with ( or identified as having ) a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) that include administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments , the subject that has been identified or diagnosed as having a cancer with a KRas dysregulation ( e.g. , a KRas mutation or amplification ) through the use of a regulatory agency - approved , e.g. , FDA - approved test or assay for identifying a dysregulation associated with KRas ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , in a subject or a biopsy sample from the subject or by performing any of the non - limiting examples of assays described herein . In some embodiments , the subject that has been identified or diagnosed as having a KRas - associated cancer through the use of a regulatory agency - approved , e.g. , FDA - approved test or assay for identifying a KRas dysregulation ( e.g. , KRas mutation ) in a subject or a biopsy sample from the subject or by performing any of the non - limiting examples of assays described herein . In some embodiments , the test or assay is provided as a kit . Also provided are methods for treating cancer in a subject in need thereof , the methods comprising : ( a ) detecting a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V- 217 WO 2025/064848 PCT / US2024 / 0477 LO associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) in the subject ; and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof . Also provided are methods for treating cancer in a subject in need thereof , the method comprising : ( a ) detecting a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in the subject ; and ( b ) administering to the subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof . Some embodiments of these methods further include administering to the subject another anticancer agent ( e.g. , a second compound provided herein , or a pharmaceutically acceptable salt thereof , an immunotherapy , or any of the other anticancer agents described herein ) . In some embodiments , the subject was previously treated with another anticancer treatment , e.g. , chemotherapy or a kinase inhibitor ( e.g. , an EGFR inhibitor ) , at least partial resection of the tumor , radiation therapy , or a combination thereof . In some embodiments , the cancer in the subject is determined to have a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) ) through the use of a regulatory agency- approved , e.g. , FDA - approved test or assay for identifying a KRas mutation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , in a subject or a sample ( e.g. , a tumor sample or blood sample ) from the subject or by performing any of the non - limiting examples of assays described herein . In some embodiments , the subject that has been identified or diagnosed as having a cancer with a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12D mutation , a KRas G12R mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) ) through the use of a regulatory agency - approved , e.g. , FDA - approved test or assay for identifying a KRas dysregulation in a subject or a biopsy sample from the subject or by performing any of the non- limiting examples of assays described herein . In some embodiments , the test or assay is provided as a kit . Also provided are methods of treating a subject that include performing an assay on a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas 218 WO 2025/064848 PCT / US2024 / 0477 LO G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) ) , and administering ( e.g. , specifically or selectively administering ) a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , to the subject determined a cancer having a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) ) . In some embodiments , provided are methods of treating a subject that include performing an assay on a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , and administering ( e.g. , specifically or selectively administering ) a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , to the subject having a cancer determined to have a KRas dysregulation . Some embodiments of these methods further include administering to the subject another anticancer agent ( e.g. , a second compound provided herein , or a pharmaceutically acceptable salt thereof , chemotherapy , or immunotherapy ) . In some embodiments of these methods , the subject was previously treated with another anticancer treatment , e.g. , a first KRas inhibitor , chemotherapy , a kinase inhibitor ( e.g. , an EGFR inhibitor ) , at least partial resection of a tumor , radiation therapy , or a combination thereof . In some embodiments , the subject is a subject suspected of having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - assoicated cancer , or a KRas G12V- associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) , a subject presenting with one or more symptoms of a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S- associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) , or a subject having an elevated risk of developing a KRas- associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G12S - associated or a KRas G12V - associated cancer ( e.g. , a KRas 219 WO 2025/064848 PCT / US2024 / 0477 LO G12D - associated cancer or a KRas G12V - associated cancer ) ) ) . In some embodiments , the assay utilizes next generation sequencing , pyrosequencing , or immunohistochemistry . In some embodiments , the assay is a regulatory agency - approved assay , e.g. , FDA - approved kit . In some embodiments , the assay is a liquid biopsy . Additional , non - limiting assays that may be used in these methods are described herein . Additional assays are also known in the art . Also provided is a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , for use in treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S- associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) in a subject identified or diagnosed as having a KRas- associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G12S - associated cancer or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) through a step of performing an assay ( e.g. , an in vitro assay ) on a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation , where the presence of a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , identifies that the cancer in the subject has a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R- associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) . Also provided is a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof , for use in treating a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a subject identified or diagnosed as having a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) through a step of performing an assay ( e.g. , an in vitro assay ) on a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation , where the presence of a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , identifies that the cancer in the subject has a KRas 220 WO 2025/064848 PCT / US2024 / 0477 LO dysregulation . 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 ( dual specificity protein phosphatase 6 ) , and / or SPRY4 ( protein sprouty homolog 4 ) . See , e.g. , Riely , Gregory J. , et al . Journal of Thoracic Oncology 16.4 ( 2021 ) : S751 - S752 , doi : 10.1016 / S1556- 0864 ( 21 ) 01941-9 ; and Hallin , Jill , et al . Molecular Cancer Research 21.5_Supplement ( 2023 ) : B012 - B012 , doi : 10.1158 / 1557-3125.RAS23 - B012 . Determining the level ( e.g. , the protein expression level , the mRNA expression level , and / or the ctDNA level ) of a biomarker of response can be performed using any appropriate method , including consulting the subject's medical record ( i.e. , if a level ( e.g. , a baseline level ) of the biomarker of response was previously determined ) , and / or performing an assay , such as an immunohistochemical ( IHC ) assay , an immunofluorescence assay , a PCR assay ( e.g. , RT - qPCR assay or a digital droplet PCR assay ) , and / or a sequencing assay ( e.g. , a next - generation sequencing ( NGS ) assay ) . In some embodiments , the biomarker of response is a mutant KRas protein ( e.g. , a KRas G12D mutant protein , a KRas G12R mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V 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 ERK 221 WO 2025/064848 PCT / US2024 / 0477 LO and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , and the assay is an IHC assay or an immunofluorescence assay . In some embodiments , the biomarker of response is DUSP6 , and the assay is a PCR assay ( e.g. , RT - qPCR assay or a digital droplet PCR assay ) . In some embodiments , the biomarker of response is SPRY4 , and the assay is a PCR assay ( e.g. , RT- qPCR assay or a digital droplet PCR assay ) . See , e.g. , Holm , Matilda , et al . PLoS One 15.( 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.( 2018 ) : S153 - S154 , doi : 10.1016 / j.jtho.2018.07.024 ; and Thatikonda , Venu , et al . bioRxiv ( 2023 ) , doi : 10.1101 / 2023.01.23.525210 .

Accordingly , in some embodiments of the methods provided herein , the method includes ( a ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 , and / or SPRY4 ) . In some embodiments , determining the level ( e.g. , the protein expression level , the mRNA expression level , and / or the ctDNA level ) of a biomarker of response includes performing an assay on a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject . In some embodiments , prior to administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 , and / or SPRY4 ) 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 222 WO 2025/064848 PCT / US2024 / 0477 LO some embodiments of the methods provided herein , the method includes ( a ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 , and / or SPRY4 ; 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 ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 , and / or SPRY4 ; ( b ) after ( a ) , administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK2 ( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 , and / or SPRY4 ; 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments , the method includes ( e ) after ( c ) , administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a 223 WO 2025/064848 PCT / US2024 / 0477 LO compound provided herein , 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 ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) , ERK1 and / or ERK( e.g. , phosphoERK1 and / or phosphoERK2 ) , DUSP6 , and / or SPRY4 ; 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition comprising a compound provided herein , or a pharmaceutically acceptable salt thereof to the subject . Also provided is the use of a compound provided herein , or a pharmaceutically acceptable salt thereof , for the manufacture of a medicament for treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D- associated cancer or a KRas G12V - associated cancer ) ) ) in a subject identified or diagnosed as having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A- associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) through a step of performing an assay on a sample obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) where the presence of a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a 2224 WO 2025/064848 PCT / US2024 / 0477 LO KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , identifies that the subject has a KRas- associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R- associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) . Also provided is the use of a compound provided herein , or a pharmaceutically acceptable salt thereof , for the manufacture of a medicament for treating a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) in a subject identified or diagnosed as having a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) through a step of performing an assay on a sample obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) where the presence of a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , identifies that the subject has a cancer having a KRas dysregulation . Some embodiments of any of the methods or uses described herein further include recording in the subject's clinical record ( e.g. , a computer readable medium ) that the subject is determined to have a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) , through the performance of the assay , should be administered a compound provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof . In some embodiments , the assay utilizes next generation sequencing , pyrosequencing , or immunohistochemistry . In some embodiments , the assay is a regulatory agency - approved assay , e.g. , FDA - approved kit . In some embodiments , the assay is a liquid biopsy . Also provided is a compound provided herein , or a pharmaceutically acceptable salt thereof , for use in the treatment of a cancer in a subject in need thereof , or a subject identified or diagnosed as having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V- 225 WO 2025/064848 PCT / US2024 / 0477 LO associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) ( e.g. , any of the KRas - associated cancers described herein ) . Also provided is a compound provided herein , or a pharmaceutically acceptable salt thereof , for use in the treatment of a cancer in a subject in need thereof , or a subject identified or diagnosed as having a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . Also provided is the use of a compound provided herein , or a pharmaceutically acceptable salt thereof , for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A- associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) ( e.g. , any of the KRas - associated cancers described herein ) . Also provided is the use of a compound provided herein , or a pharmaceutically acceptable salt thereof , for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) In some embodiments , a mutant KRas- associated cancer is a cancer that was previously identified as having no KRas mutation ( e.g. , KRas wild - type ) , for example , in a cancer that was previously identified as having no KRas mutation and then , later , a KRas mutation ( e.g. , a resistance mutation ) was identified . In some embodiments , a subject is identified or diagnosed as having a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) through the use of a regulatory agency - approved , e.g. , FDA - approved , kit for identifying a KRas dysregulation , in a subject or a biopsy sample from the subject . In some embodiments , a subject is identified or diagnosed as having a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) through the use of a regulatory agency - approved , e.g. , FDA - approved , kit for identifying a KRas dysregulation , in a subject or a biopsy sample from the subject . As provided herein , a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) includes those described herein and known in the art . 226 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments of any of the methods or uses described herein , the subject has been identified or diagnosed as having a cancer with a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) . In some embodiments of any of the methods or uses described herein , the subject has a cancer ( e.g. , a tumor sample ) that is positive for a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) . In some embodiments of any of the methods or uses described herein , the subject can be a subject with a cancer ( e.g. , one or more tumor samples ) that is positive for a KRas dysregulation ( e.g. , KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) ) . In some embodiments of any of the methods or uses described herein , the subject is suspected of having a mutant KRas - associated cancer ( e.g. , a cancer that was previously identified a cancer having no KRas mutation ( e.g. , KRas wild type ) ) . In some embodiments , provided herein are methods for treating a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) in a subject in need of such treatment , the method comprising a ) detecting a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) in a sample from the subject ; and b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments , provided herein are methods for treating cancer having a KRas dysregulation in a subject in need of such treatment , the method comprising a ) detecting a KRas dysregulation ( e.g. , a KRAS gene having a mutation corresponding to a mutation in a KRas protein and / or a KRas protein having a mutation , a KRAS gene copy number increase , and / or an increase in KRas mRNA or protein expression ) in a sample from the subject ; and b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . 227 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , a mutant KRas - associated cancer is characterized by a mutation that arises from treatment with a first KRas inhibitor ; for example , a mutant KRas - associated cancer as described herein can include one or more KRas mutations that confer resistance to treatment with a first KRas inhibitor . For example , a subject can acquire one or more of the following KRas mutations as a resistance mutation to a KRas G12C inhibitor : G12D , G12R , G12V , G12W , G13D , Q61H , R68S , H95D , H95Q , H95R , or Y96C . See , e.g. , Awad et al . N Engl J Med . 2021 Jun 24 ; 384 ( 25 ) : 2382-2393 , doi : 10.1056 / NEJMoa2105281 . As used herein , a " first inhibitor of KRas " or " first KRas inhibitor " is a KRas inhibitor as defined herein , but which does not include a compound provided herein , or a pharmaceutically acceptable salt thereof , as defined herein . As used herein , a " second inhibitor of KRas " or a " second KRas inhibitor " is a KRas inhibitor as defined herein , but which does not include a compound provided herein , or a pharmaceutically acceptable salt thereof . When both a first and a second inhibitor of KRas are present in a method provided herein , the first and second inhibitors of KRas are different . In some embodiments , the first and / or second inhibitor of KRas bind in a different location than a compound provided herein , or a pharmaceutically acceptable salt thereof . Exemplary first and second inhibitors of KRas are described herein . In some embodiments , a first or a second inhibitor of KRas can be a KRas G12C inhibitor . In some embodiments , a first or second inhibitor of KRas can be selected from the group consisting of sotorasib , adragrasib , ARS - 853 , ARS - 1620 , ARS - 3248 , ATG - 012 , BI 1823911 , D - 1553 , ERAS - 3490 , GDC - 6036 , GFH925 , JAB - 21822 , JDQ - 443 , LY3537982 , MRTX - 1257 , RMC- 6291 , and combinations thereof . In some embodiments , a first or second inhibitor of KRas can be selected from the group consisting of sotorasib , adragrasib , ARS - 853 , ARS - 1620 , ARS- 3248 , ATG - 012 , BI 1823911 , D - 1553 , ERAS - 3490 , GDC - 6036 , GFH925 , JAB - 21822 , JDQ- 443 , LY3537982 , MRTX - 1133 , MRTX - 1257 , RMC - 6291 , RMC - 6236 , and combinations thereof .

In some embodiments , the methods provided herein include performing an assay on a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject to determine whether the cancer in the subject has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) . In some such embodiments , the method also includes administering to a subject determined to have a KRas dysregulation ( e.g. , a KRas mutation 228 WO 2025/064848 PCT / US2024 / 0477 LO ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments , the method includes determining that a cancer in a subject has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) via an assay performed on a sample obtained from the subject . In such embodiments , the method also includes administering to a subject a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . Some embodiments of these methods further include administering to the subject another anticancer agent ( e.g. , a second compound provided herein , or a pharmaceutically acceptable salt thereof , or immunotherapy ) . In some embodiments of any of the methods or uses described herein , an assay is used to determine whether the cancer in the subject has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) , using a sample ( e.g. , a tumor sample or a blood sample ) from a subject can include , for example , next generation sequencing , immunohistochemistry , fluorescence microscopy , Southern blotting , Western blotting , FACS analysis , Northern blotting , and PCR - based amplification ( e.g. , RT - PCR and quantitative real- time RT - PCR ) . As is well - known in the art , the assays are typically performed , e.g. , with at least one labelled nucleic acid probe or at least one labelled antibody or antigen - binding fragment thereof . Assays can utilize other detection methods known in the art for detecting a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) ( see , e.g. , the references cited herein ) . In some embodiments , the sample is tumor biopsy sample ( e.g. , a paraffin - embedded biopsy sample ) from the subject . In some embodiments , the subject is a subject suspected of having a KRas - associated cancer ( e.g. , mutant KRas- associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associateion , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V- 229 WO 2025/064848 PCT / US2024 / 0477 LO associated cancer ) ) ) , a subject having one or more symptoms of a KRas - associated cancer ( e.g. , mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C- associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) , and / or a subject that has an increased risk of developing a KRas - associated cancer ( e.g. , mutant KRas - associated cancer ( e.g. , a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) . In some embodiments , the subject is a subject suspected of having a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) , a subject having one or more symptoms of a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) , and / or a subject that has an increased risk of developing a cancer having a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . In some embodiments , a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) can be identified using a liquid biopsy ( variously referred to as a fluid biopsy or fluid phase biopsy ) . See , e.g. , Karachialiou et al . , " Real - time liquid biopsies become a reality in cancer treatment " , Ann . Transl . Med . , 3 ( 3 ) : 36 , 2016 , doi : 10.3978 / j.issn.2305-5839.2015.01.16 . Liquid biopsy methods can be used to detect total tumor burden and / or the KRas dysregulation ( e.g. , the KRas mutation or amplification ) . Liquid biopsies can be performed on biological samples obtained relatively easily from a subject ( e.g. , via a simple blood draw ) and are generally less invasive than traditional methods used to detect tumor burden and / or KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) . In some embodiments , liquid biopsies can be used to detect the presence of a KRas dysregulation ( e.g. , a KRas mutation or amplification ) at an earlier stage than traditional methods . In some embodiments , the biological sample to be used in a liquid biopsy can include , blood , plasma , urine , cerebrospinal fluid , saliva , sputum , broncho - alveolar lavage , bile , lymphatic fluid , cyst fluid , stool , ascites , and combinations thereof . In some embodiments , a liquid biopsy can be used to detect circulating tumor cells ( CTCs ) . In some embodiments , a 230 WO 2025/064848 PCT / US2024 / 0477 LO liquid biopsy can be used to detect cell - free DNA . In some embodiments , cell - free DNA detected using a liquid biopsy is circulating tumor DNA ( ctDNA ) that is derived from tumor cells . Analysis of ctDNA ( e.g. , using sensitive detection techniques such as , without limitation , next - generation sequencing ( NGS ) , traditional PCR , digital PCR , or microarray analysis ) can be used to identify a KRas dysregulation ( e.g. , KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) ) . Also provided is a method for modulating ( e.g. , decreasing ) KRas 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 provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , to a subject having a cell having a KRas protein ( e.g. , a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) ) ) . In some embodiments , the contacting is ex vivo , wherein the method comprises contacting a cell from a subject having a KRas protein ( e.g. , a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) ) ) with a compound provided herein , 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 KRas - associated cancer cell ( e.g. , a mutant KRas - associated cancer cell ( e.g. , a KRas G12A - associated cancer cell , a KRas G12C- associated cancer cell , a KRas G12D - associated cancer cell , a KRas G12R - associated cancer cell , a KRas G12S - associated cancer cell , or a KRas G12V - associated cancer cell ( e.g. , a KRas G12D - associated cancer cell or a KRas G12V - associated cancer cell ) ) ) . As used herein , the term " contacting " refers to the bringing together of indicated 231 WO 2025/064848 PCT / US2024 / 0477 LO moieties in an in vitro system , an in vivo system , or an ex vivo system . For example , " contacting " a KRas 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 KRas protein , as well as , for example , introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas protein . 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 provided herein , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition thereof as defined herein . 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 or a KRas G12V mutation . In some embodiments , the cell has a KRas G12A mutation . In some embodiments , the cell has a KRas G12C 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 G12S mutation . In some embodiments , the cell has a KRas G12V mutation . In some embodiments , the cell has a KRas amplification . 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 provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , in an amount effective to increase tumor cell death . 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 or a KRas G12V mutation . In some embodiments , the cell has a KRas G12A mutation . In some embodiments , the cell has a KRas G12C 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 G12S mutation . In some embodiments , the cell has a KRas G12V mutation . In some embodiments , the cell has a KRas amplification . When employed as pharmaceuticals , the compounds provided herein , or pharmaceutically acceptable salts thereof , can be administered in the form of pharmaceutical compositions as described herein . Also provided herein is a method for inhibiting a KRas protein in a mammalian cell , the method comprising contacting the mammalian cell with an effective amount of a compound 232 WO 2025/064848 PCT / US2024 / 0477 LO provided herein , or a pharmaceutically acceptable salt thereof . Also provided herein is a method for inhibiting a dysregulated KRas protein ( e.g. , a mutant KRas protein ( e.g. , a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , or a KRas G12V mutant protein ( e.g. , a KRas G12D mutant protein or a KRas G12V mutant protein ) ) ) in a mammalian cell , the method comprising contacting the mammalian cell with an effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof . In some embodiments , the mammalian cell is ex vivo .

Also provided herein is a method of treating a subject having a cancer , wherein the method comprises : administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , as a monotherapy or in conjunction with a first anticancer agent to the subject who has been administered one or more doses of the first anticancer agent to the subject for a period of time . Also provided herein is a method of treating a subject having a cancer , wherein the method comprises : ( a ) administering one or more doses of a first anticancer agent to the subject for a period of time ; ( b ) after ( a ) , determining whether a cancer cell in a sample ( e.g. , a tumor sample or a blood sample ) obtained from the subject has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) ; and ( c ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , as a monotherapy or in conjunction with a second anticancer agent to the subject if the subject has been determined to have a cancer cell that has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) ; or ( d ) administering additional doses of the first anticancer agent of step ( a ) to the subject if the subject has not been determined to have a cancer cell that has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) . Further provided herein is a method of treating a subject having a cancer , wherein the 233 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا method comprises : ( a ) determining whether a cancer cell in a sample ( e.g. , a tumor sample or a blood sample ) obtained from a subject having a cancer and previously administered one or more doses of a first anticancer agent has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) ; and ( b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , as a monotherapy or in conjunction with a second anticancer agent to the subject if the subject has been determined to have a cancer cell that has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) ; or ( c ) administering additional doses of the first anticancer agent to the subject if the subject has not been determined to have a cancer cell that has a KRas dysregulation ( e.g. , KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) . Also provided herein is a method of treating a subject having a cancer , wherein the method comprises : ( a ) determining that a cancer cell in a sample ( e.g. , a tumor sample or a blood sample ) obtained from a subject having a cancer and previously administered one or more doses of a first anticancer agent has a KRas dysregulation ( e.g. , a KRas mutation ( e.g. , a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation ( e.g. , a KRas G12D mutation or a KRas G12V mutation ) ) or amplification ) ; and ( b ) administering a therapeutically effective amount of a compound provided herein , or a pharmaceutically acceptable salt thereof , as a monotherapy or in conjunction with a second anticancer agent to the subject . In some embodiments of any of the methods described herein , the first anticancer agent can be a first KRas inhibitor . 234 WO 2025/064848 PCT / US2024 / 0477 When employed as pharmaceuticals , the compounds provided herein , or pharmaceutically acceptable salts thereof , can be administered in the form of pharmaceutical compositions as described herein .

Combinations In any of the indications described herein , a compound provided herein , or a pharmaceutically acceptable salt thereof , can be used as a monotherapy . In some embodiments , a compound provided herein , 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 provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , reduces the size of the tumor ( e.g. , the tumor burden ) prior to the at least partial resection of the tumor . In some embodiments , a subject in need thereof can be administered one or more doses of a compound provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , reduces the size of the tumor ( e.g. , the tumor burden ) prior to the one or more rounds of radiation therapy . In some embodiments , a subject has a cancer ( e.g. , a locally advanced or metastatic tumor ) that is refractory or intolerant to standard therapy ( e.g. , administration of a chemotherapeutic agent , such as a first KRas inhibitor , 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 first KRas inhibitor , 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 KRas inhibitor evïan . In some embodiments , a subject is not KRas inhibitor evïan . 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 KRas inhibitor , a RAF / MEK / PI3K pathway inhibitor , a MEK inhibitor , a Raf inhibitor , a YAP inhibitor , a proteasome inhibitor , a PI3K - AKT - mTOR pathway inhibitor , an ERK inhibitor , a pan - ErbB 235 WO 2025/064848 PCT / US2024 / 0477 LO inhibitor , a MET inhibitor , a farnesyl transferase inhibitor , a FAK inhibitor , a HSP90 inhibitor , or a combination thereof . In some embodiments of any the methods described herein , the compound provided herein , or a pharmaceutically acceptable salt thereof , is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic ( e.g. , chemotherapeutic ) agents . Non - limiting examples of additional therapeutic agents include : Ras pathway targeted therapeutic agents ( e.g. , Ras / RAF / MEK / PI3K pathway inhibitors or degraders , ( e.g. , Ras inhibitors or degraders , KRas - targeted therapeutic agents , SOS1 inhibitors or degraders , SOS1 / Ras protein - protein interaction inhibitors , SHP2 inhibitors or degraders , PI3K - AKT- mTOR pathway inhibitors or degraders ) ) , kinase - targeted therapeutics ( e.g. , MEK inhibitors or degraders , ERK inhibitors or degraders , Raf inhibitors or degraders ( e.g. , BRaf inhibitors or degraders ) , PI3K inhibitors or degraders , AKT inhibitors or degraders , mTOR inhibitors or degraders , CDK4 / 5 inhibitors or degraders , CDK4 / 6 inhibitors or degraders , MET inhibitors or degraders , FAK inhibitors or degraders , ErbB family inhibitors or degraders ( e.g. , EGFR inhibitors or degraders , Her2 inhibitors or degraders ) , Src inhibitors or degraders ) , Bcl - XL inhibitors or degraders , mTORC1 inhibitors or degraders , YAP inhibitors or degraders , TEAD inhibitors or degraders , proteasome inhibitors or degraders , farnesyl transferase inhibitors or degraders , HSP90 inhibitors or degraders , PTEN inhibitors or degraders , signal transduction pathway inhibitors or degraders , checkpoint inhibitors , modulators of the apoptosis pathway ( e.g. , venetoclax , navitoclax , obataclax ) , chemotherapeutics , angiogenesis - targeted therapies , immune - targeted agents including immunomodulatory imide drugs ( sometimes called " IMiDs " or " CELMODs " ) , immunotherapy ( e.g. , anti - PD1 , anti - PD - L1 , anti - CTLA4 , anti - LAG3 , anti- TIM3 , anti - B7 - H3 , anti - VISTA therapies , including antibodies ( e.g. , single - targeted antibodies targeting one or more of PD1 , PD - L1 , CTLA4 , LAG3 , TIM3 , B7 - H3 , or VISTA ; bispecific antibodies ( including bispecific T cell engagers ( BiTES ) ) targeting one or more of PD1 , PD- L1 , CTLA4 , LAG3 , TIM3 , B7 - H3 , or VISTA ; and antibody - drug conjugates ( ADCs ) incorporating one or more of PD1 , PD - L1 , CTLA4 , LAG3 , TIM3 , B7 - H3 , or VISTA ) or antigen - binding fragments thereof , a PD - 1 inhibitor , a PD - L1 inhibitor , or an ADORA2A 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 . 236 WO 2025/064848 PCT / US2024 / 0477 ﺶﻣا A " degrader " as used herein is a heterobifunctional molecule that induces degradation of a target protein , the degrader including a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase ( sometimes referred to as an E3 ligase or simply an E3 ) , these two moieties being optionally separated by a linker . Such degraders are sometimes known as " PROTACS " .

A " Ras pathway targeted therapeutic agent " as used herein includes any compound exhibiting inactivation activity of any protein in a Ras pathway ( e.g. , kinase inhibition , allosteric inhibition , inhibition of dimerization , and / or induction of degradation ) . Non - limiting examples of a protein in a Ras pathway include any one of the proteins in the Ras - RAF - MAPK pathway or PI3K / AKT pathway such as Ras ( e.g. , KRas , HRas , and NRas ) , RAF , BRAF , MEK , ERK , PI3K , AKT , and mTOR . In some embodiments , a Ras pathway modulator can be selective for a protein in a Ras pathway , e.g. , the Ras pathway modulator can be selective for Ras ( also referred to as a Ras modulator ) . In some embodiments , a Ras modulator is a covalent inhibitor . In some embodiments , a Ras pathway targeted therapeutic agent is a " KRas pathway modulator . " A KRas pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRas pathway ( e.g. , kinase inhibition , allosteric inhibition , inhibition of dimerization , and / or induction of degradation ) . Non - limiting examples of a protein in a KRas pathway include any one of the proteins in the KRas - RAF - MAPK pathway or PI3K / AKT pathway such as KRas , RAF , BRAF , MEK , ERK , PI3K , AKT , and mTOR . In some embodiments , a KRas pathway modulator is a KRas - targeted therapeutic agent . In some embodiments , the Ras pathway targeted therapeutic agent is a SOS1 inhibitor or a SHPinhibitor . Non - limiting examples of SOS1 inhibitors include MRTX - 0902 and RMC - 5845 . Non - limiting examples of SHP2 inhibitors include batoprotafib ( TNO - 155 ) , vociprotafib ( RMC - 4630 ) , ARRY - 558 , BBP - 398 , ENT - 03 , ERAS - 601 , ET - 0038 , GDC - 1971 ( RLY - 1971 ) , GH - 21 , HS - 10381 , ICP - 189 , JAB - 3068 , JAB - 3312 , and SH - 3809 . Non - limiting examples of KRas - targeted therapeutic agents ( e.g. , a first KRas inhibitor or a second KRas inhibitor ) 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 ) , garsorasib ( D - 1553 ) , glecirasib ( JAB - 21822 ) , olomorasib ( LY - 3537982 ) , sotorasib , ARS- 1620 , ARS - 3248 , ARS - 853 , ASP - 3082 , ATG - 012 , BI - 1701963 , BI - 1823911 , BPI - 421286 , ERAS - 3490 , GFH - 925 , GH - 35 , JDQ - 443 , MK - 1084 , MRTX - 1133 , MRTX - 1257 , RMC - 6236 , RMC - 6291 , RMC - 7977 , RMC - 9805 , RSC - 1255 , SHR - 1127 , or a combination thereof . 237 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , the KRas - targeted therapeutic agent is an agent that inhibits the interaction between KRas and SOS1 or SHP2 . Non - limiting examples of an agent that inhibits the interaction between SOS1 and KRas include BI - 3406 , BI - 1701963 , and BAY 293 . Additional KRas - targeted therapeutic agents ( e.g. , a first KRas inhibitor or a second KRas inhibitor ) include those disclosed in International Publication Nos . WO 2021/104431 ; WO WO2021 / 119343 ; WO2021 / 113595 ; WO 2021/107160 ; WO 2016/161361 ; WO 2016/17262 ; WO 2020/035031 ; WO 2021/041671 ; WO 2016/077793 ; WO 2020/180768 ; WO 2021/092115 ; WO 2020/180770 ; U.S. Patent Nos . US 10,898,487 ; US 10,829,487 ; US 10,858,359 ; US 10,561,655 ; US 10,532,042 ; U.S. Publication Nos . US 2021/0101870 ; US 2019/0231805 ; US 2020/0017517 ; US 2020/0017511 ; US 2020/0147058 ; US 2021/0009577 ; and Hillig et al . PNAS . 2019 ; 116 ( 7 ) : 2551-2560 , doi : 10.1073 / pnas.1812963116 . Further non - limiting examples of Ras pathway - targeted therapeutic agents include BRAF inhibitors , MEK inhibitors , ERK inhibitors , PI3K inhibitors , AKT inhibitors , and mTOR inhibitors .

In some embodiments , the BRAF inhibitor is avutometinib , dabrafenib ( e.g. , dabrafenib mesylate , ®RALNIFAT ) , encorafenib ( BRAFTOVI ™ ) , naporafenib , sorafenib ( e.g. , sorafenib tosylate ) , vemurafenib ( ®FAROBLEZ ) , ARQ 736 , AZ304 , BMS - 908662 ( XL281 ) , C17071479 - F , CHIR - 265 , FORE - 8394 , GDC - 0879 , GSK2118436 , HLX - 208 , HM95573 , LGX818 , LXH254 , PLX - 3603 , PLX - 4720 , PLX - 8394 , RAF265 , RO5126766 , RO5185426 , or a combination thereof . In some embodiments , the BRAF inhibitor is avutometinib , dabrafenib ( e.g. , dabrafenib mesylate ) , encorafenib , naporafenib , sorafenib ( e.g. , sorafenib tosylate ) , vemurafenib , C17071479 - F , CHIR - 265 , FORE - 8394 , HLX - 208 , or a combination thereof . In some embodiments , the MEK inhibitor is avutometinib , binimetinib ( ®ⓇIVOTKEM , MEK162 ) , cobimetinib ( e.g. , cobimetinib fumarate , ®CILLETOC ) , mirdametinib , pimasertib , refametinib , selumetinib ( e.g. , selumetinib sulfate , AZD6244 ) , trametinib ( e.g. , trametinib dimethyl sulfoxide , GSK - 1120212 ®TSINIKEM ) , zapnometinib , hypothemycin , CI10( PD184352 ) , CS3006 , FCN - 159 , MSC1936369B , NFX - 179 , PD0325901 , PD98059 , RO5126766 , SHR7390 , TAK - 733 , WX - 554 , or a combination thereof . In some embodiments , the MEK inhibitor is avutometinib , binimetinib , cobimetinib ( e.g. , cobimetinib fumarate ) , mirdametinib , nedometinib , pimasertib , refametinib , selumetinib ( e.g. , selumetinib sulfate ) , trametinib ( e.g. , trametinib dimethyl sulfoxide , GSK - 1120212 ) , tunlametinib , zapnometinib , FCN - 159 , NFX - 179 , TAK - 733 , or a combination thereof . In some 238 WO 2025/064848 PCT / US2024 / 0477 LO embodiments , the MEK inhibitor is a MEK - Raf protein - protein interaction stabilizer , such as NST - 628 or avutometinib ( VS6766 ) . In some embodiments , the ERK inhibitor is 25 - OH - D3-3 - BE ( B3CD , bromoacetoxycalcidiol ) , 5-7 - Oxozeaenol , 5 - iodotubercidin , AEZ - 131 ( AEZS - 131 ) , AEZS- 136 , ASN007 , AZ - 13767370 , BL - EI - 001 , CC - 90003 , FR148083 , FR - 180204 , FRI - 20 ( ON- 01060 ) , GDC0994 , GDC - 0994 ( RG - 7482 ) , KO - 947 , KO - 947 , LTT - 462 , LY - 3214996 , MK- 8353 ( SCH900353 ) , ONC201SCH772984 , ulixertinib ( BVD - 523 ) , VTX - 11e , or a combination thereof . In some embodiments , the ERK inhibitor is rineterkib , ulixertinib , or a combination thereof .

In some embodiments , PI3K inhibitor is alpelisib ( BYL719 ) , apitolisib ( GDC - 0980 ) , buparlisib ( BKM120 ) , copanlisib ( ALIQOPA ™ , BAY80-6946 ) , dactolisib ( NVP - BEZ235 , BEZ - 235 ) , gedatolisib ( PF - 05212384 , PKI - 587 ) , omipalisib ( GSK2126458 , GSK458 ) , pictilisib ( GDC - 0941 ) , pilaralisib ( XL147 , SAR245408 ) , rigosertib , serabelisib ( TAK - 117 , MLN1117 , INK 1117 ) , sonolisib ( PX - 866 ) , taselisib ( GDC - 0032 , RG7604 ) , voxtalisib ( XL756 , SAR245409 ) , wortmannin , AMG 511 , AMG319 , ASN003 , AZD8835 , BGT - 2( NVP - BGT226 ) , CH5132799 , CUDC - 907 , GDC - 0077 , GDC - 0084 ( RG7666 ) , GS - 9820 , GSK1059615 , GSK2636771 , KIN - 193 ( AZD - 6428 ) , LY2023414 , LY294002 , PF - 04691502 , PI - 103 , PKI - 402 , PQR309 , SAR260301 , SF1126 , VS - 5584 ( SB2343 ) , WX - 037 , XL - 765 , ZSTK474 , or a combination thereof . In some embodiments , the PI3K inhibitor is alpelisib , amdizalisib , apitolisib , bimiralisib , buparlisib , copanlisib ( e.g. , copanlisib dihydrochloride or a hydrate of copanlisib dihydrochloride ) , dactolisib , dezapelisib , dordaviprone , duvelisib ( e.g. , a hydrate of duvelisib ) , eganelisib , fimepinostat , gedatolisib , idelalisib , inavolisib , leniolisib ( e.g. , leniolisib phosphate ) , linperlisib , parsaclisib , paxalisib , risovalisib , seletalisib , serabelisib , sonolisib , tenalisib , umbralisib ( e.g. , umbralisib tosylate ) , zandelisib , PF- 04691502 , SHC - 014748 - M , TQ - B - 3525 , or a combination thereof . In some embodiments , the AKT inhibitor is 2- [ 4- ( 2 - aminoprop - 2 - yl ) phenyl ] -3- phenylquinoxaline , 3 - oxo - tirucallic acid , A - 443654 , A - 674563 , afuresertib , API - 1 , ARQ092 , AT13148 , AT7867 , AZD5363 , BAY 1125976 , boc - Phe - vinyl ketone , CCT128930 , DC120 , DM - PIT - 1 , edelfosine , erucylphophocholine , erufosine , GSK2141795 , GSK690693 , H - 89 , ipatasertib ( GDC - 0068 , RG7440 ) , lactoquinomycin , miltefosine ( ®OVIDAPMI ) , MK - 2206 , N- ( 4- ( 5- ( 3 - acetamidophenyl ) -2- ( 2 - aminopyridin - 3 - yl ) -3H - imidazo [ 4,5 - b ] pyridin - 3- yl ) benzyl ) -3 - fluorobenzamide , NL - 71-101 , ONC201 , OSU - A9 , Perifosine ( D - 21266 ) , PH- 316 , PHT - 427 , PIT - 1 , SR13668 , TCN , TCN - P , triciribine ( Triciribine Phosphate 239 WO 2025/064848 PCT / US2024 / 0477 Monohydrate ) , uprosertib , wortmannin , or a combination thereof . In some embodiments , the AKT inhibitor is afuresertib , capivasertib ( AZD - 5363 ) , miransertib ( e.g. , miransertib mesylate ) , pifusertib , uprosertib , MK - 2206 , SM - 020 , or a combination thereof . In some embodiments , the mTOR inhibitor is MLN0128 , AZD - 2014 , CC - 223 , AZD2014 , CC - 115 , everolimus ( RAD001 ) , temsirolimus ( CCI - 779 ) , ridaforolimus ( AP- 23573 ) , sirolimus ( rapamycin ) , or a combination thereof . In some embodiments , the mTOR inhibitor is apitolisib , bimiralisib , dactolisib , everolimus , fosciclopirox ( e.g. , fosciclopirox sodium ) , gedatolisib , onatasertib , paxalisib , sapanisertib , sirolimus , sodium 2- hydroxylinoleate , temsirolimus , umirolimus , zandelisib , zotarolimus , BI - 860585 , CC - 115 , PF- 04691502 , or a combination thereof . In some embodiments , the mTOR inhibitor is everolimus , sirolimus , temsirolimus , umirolimus , zotarolimus , or a combination thereof . In some embodiments , the mTOR inhibitor is everolimus , sirolimus , temsirolimus , umirolimus , zotarolimus , RMC5552 , or a combination thereof . In some embodiments , the farnesyl transferase inhibitor is lonafarnib , tipifarnib , BMS- 214662 , L778123 , L744832 , FTI - 277 , or a combination thereof . In some embodiments , the farnesyl transferase inhibitor is lonafarnib , tipifarnib , BMS - 214662 , or a combination thereof . In some embodiments , a chemotherapeutic agent includes a DNA replication inhibitor ( e.g. , a DNA intercalator ( e.g. , an anthracycline ) ) , a DNA crosslinker ( e.g. , cyclophosphamide , a mitomycin ( e.g. , mitomycin C ) , a platinum complex ) , a ribonucleotide - diphosphate reductase inhibitor ( e.g. , gemcitabine ) , or a topoisomerase inhibitor ) , an anti - microtubule agent ( e.g. , a taxane , a vinca alkaloid , or eribulin ) , or a combination thereof . Non - limiting examples of a taxane include paclitaxel , docetaxel , abraxane , and taxotere . In some embodiments , the anthracycline is selected from daunorubicin , doxorubicin , epirubicin , idarubicin , and combinations thereof . In some embodiments , the platinum - based agent is selected from carboplatin , cisplatin , oxaliplatin , nedplatin , triplatin tetranitrate , phenanthriplatin , picoplatin , satraplatin , and combinations thereof .

In some embodiments , the chemotherapy is a platinum complex , a microtubule inhibitor ( e.g. , a microtubule destabilizer or a microtubule stabilizer ) , a topoisomerase inhibitor , or an antibody - drug conjugate including any thereof . In some embodiments , the platinum complex is carboplatin , cisplatin , lobaplatin , miriplatin , oxaliplatin , or a combination thereof . In some embodiments , the microtubule inhibitor is cabazitaxel , colchicine , 240 WO 2025/064848 PCT / US2024 / 0477 LO desoxyepothilone B , docetaxel , eribulin , ixabepilone , nab - paclitaxel , paclitaxel , plinabulin , sabizabulin , tirbanibulin , vinblastine , vinflunine , vinorelbine , or a combination thereof . In some embodiments , the microtubule inhibitor is cabazitaxel , docetaxel , nab - paclitaxel , paclitaxel , or a combination thereof . In some embodiments , the topoisomerase inhibitor is aclarubicin , amsacrine , belotecan , camptothecin , daunorubicin , dexrazoxane , elliptinium , epirubicin , etoposide , gepotidacin , idarubicin , mitoxantrone , nemonoxacin , pirarubicin , pixantrone , razoxane , rubitecan , sobuzoxane , temozolomide , teniposide , topotecan , SN - 38 , or a combination thereof . In some embodiments , the hypomethylating agent is azacitidine , decitabine , or a combination thereof . In some embodiments , the chemotherapy is a platinum complex and a topoisomerase inhibitor ( e.g. , cisplatin and etoposide ) . In some embodiments , the antibody - drug conjugate including the microtubule inhibitor is belantamab mafodotin , brentuximab vedotin , cofetuzumab pelidotin , disitamab vedotin , enfortumab vedotin ( e.g. , enfortumab vedotin - ejfv , or a biosimilar thereof ) , mirvetuximab soravtansine ( e.g. , mirvetuximab soravtansine - gynx , or a biosimilar thereof ) , polatuzumab vedotin , telisotuzumab vedotin , tisotumab vedotin , trastuzumab emtansine ( e.g. , ado - trastuzumab emtansine , or a biosimilar thereof ) , tusamitamab ravtansine , upifitamab rilsodotin , zilovertamab vedotin , Alpha - Her2 - pAF1 - AS - 269 , BAT - 8001 , TAA - 013 , biosimilars thereof , or a combination thereof . In some embodiments , the antibody - drug conjugate including the microtubule inhibitor is enfortumab vedotin ( e.g. , enfortumab vedotin - ejfv , or a biosimilar thereof ) . In some embodiments , the antibody - drug conjugate including the microtubule inhibitor is mirvetuximab soravtansine ( e.g. , mirvetuximab soravtansine - gynx , or a biosimilar thereof ) . In some embodiments , the antibody - drug conjugate including the microtubule inhibitor is trastuzumab emtansine ( e.g. , ado - trastuzumab emtansine , or a biosimilar thereof ) . In some embodiments , the antibody - drug conjugate including the topoisomerase inhibitor is datopotamab deruxtecan , patritumab deruxtecan , sacituzumab govitecan ( e.g. , sacituzumab govitecan - hziy , or a biosimilar thereof ) , trastuzumab deruxtecan ( fam - trastuzumab deruxtecan- nxki , or a biosimilar thereof ) , or a combination thereof . In some embodiments , the antibody- drug conjugate including the topoisomerase inhibitor is sacituzumab govitecan ( e.g. , sacituzumab govitecan - hziy , or a biosimilar thereof ) . In some embodiments , the antibody - drug conjugate including the topoisomerase inhibitor is trastuzumab deruxtecan ( e.g. , fam- trastuzumab deruxtecan - nxki , or a biosimilar thereof ) . In some embodiments , the chemotherapy includes one or more of capecitabine , carboplatin , cisplatin , docetaxel , doxorubicin ( e.g. , liposomal doxorubicin ) , fluorouracil , 241 WO 2025/064848 PCT / US2024 / 0477 LO , gemcitabine , leucovorin , mitomycin , oxaliplatin , paclitaxel ( e.g. , albumin - bound paclitaxel ) , and pemetrexed . In some embodiments , the chemotherapy is FOLFOX . In some embodiments , the chemotherapy is FOLFIRI . In some embodiments , the chemotherapy is FOLFIRINOX . In some embodiments , the chemotherapy is CAPEOX . In some embodiments , the chemotherapy is GEMOX . In some embodiments , the chemotherapy is NALIRIFOX . In some embodiments , the chemotherapy is carboplatin and paclitaxel . In some embodiments , the chemotherapy is capecitabine and mitomycin . In some embodiments , the chemotherapy is fluorouracil , leucovorin , and oxaliplatin . In some embodiments , the chemotherapy is carboplatin and doxorubicin ( e.g. , liposomal doxorubicin ) . In some embodiments , the chemotherapy is gemcitabine . In some embodiments , the chemotherapy is gemcitabine and paclitaxel . In some embodiments , the BCL - XL inhibitor or degrader is foselutoclax ( UBX - 1325 ) , navitoclax , obatoclax , pelcitoclax , mirzotamab clezutoclax ( ABBV - 155 ) , ABBV - 637 , APG- 1252-12A , AZD - 0466 , DT - 2216 , PA - 15227 , UBX - 1967 , XZ - 739 , 753 - B , or a combination thereof .

In some embodiments , the CDK4 / 6 inhibitor is abemaciclib , birociclib , dalpiciclib , lerociclib , milciclib , palbociclib , ribociclib ( e.g. , ribociclib succinate ) , riviciclib , roniciclib , trilaciclib ( e.g. , trilaciclib dihydrochloride ) , BPI - 16350 , FCN - 437 , SPH - 4336 , or combination thereof . In some embodiments , the CDK4 / 6 inhibitor is palbociclib or ribociclib ( e.g. , ribociclib succinate ) . 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 , sutetinib , tesevatinib , vandetanib , varlitinib , zipalertinib , zorifertinib , BIBW - 2948 , BPI - 7711 , HA - 121-28 , SH - 1028 , or a combination thereof . In some embodiments , the EGFR inhibitor is an EGFR - targeting biologic . In some embodiments , the EGFR - targeting biologic is amivantamab ( e.g. , amivantamab - vmjw , or a biosimilar thereof ) , cetuximab ( e.g. , ®XUTIBRE ( cetuximab ) , or a biosimilar thereof ( e.g. , CMAB - 009 , CPGJ - 602 , or KL - 140 ) ) , cetuximab sarotalocan 2242 WO 2025/064848 PCT / US2024 / 0477 LO ( ®XULAKA ( cetuximab sarotalocan ) , or a biosimilar thereof ) , depatuxizumab , duligotuzumab , futuximab , imgatuzumab , modotuximab , necitumumab ( e.g. , ®AZZARTROP ( necitumumab ) , or biosimilar thereof ) , nimotuzumab ( e.g. , BIOMAb ⓇRFGE ( nimotuzumab ) , or a biosimilar thereof ) , panitumumab ( e.g. , ®XIBITCEV ( panitumumab ) , or a biosimilar thereof ) , tomuzotuximab , zalutumumab , EMD - 55900 , EMD - 82633 , GC - 1118 , HLX - 07 , ICR - 62 , SCT - 200 , SI - B - 001 , biosimilars thereof , or a combination thereof . In some embodiments , the EGFR - targeting biologic is cetuximab or panitumumab . In some embodiments , the EGFR - targeting biologic is cetuximab . In some embodiments , the EGFR- targeting biologic is panitumumab . In some embodiments , the PARP inhibitor is iniparib , niraparib , olaparib ( ®AZRAPNYL ) , pamiparib ( BGB - 290 ) , rucaparib , talazoparib , veliparib , 2X - 121 , ABT - 767 , BMN 673 , BSI - 201 , CEP 9722 , E7016 , IMP4297 , INO - 1001 , JPI - 289 , KU - 00594( AZD2281 ) , NOV1401 , PF - 01367338 , and RBN - 2397 . In some embodiments , the PARP inhibitor is fuzuloparib ( fluzoparib ) , niraparib ( e.g. , niraparib tosylate monohydrate ) , olaparib , pamiparib , rucaparib ( e.g. , rucaparib camsylate ) , saruparib ( AZD5305 ) , senaparib , stenoparib , talazoparib ( e.g. , talazoparib tosylate ) , veliparib , CEP - 9722 , JPI - 289 , NMS - 03305293 , or a combination thereof . In some embodiments , the PARP inhibitor is a PARP1 inhibitor . In some embodiments , the PARP1 inhibitor is saruparib ( AZD5305 ) , NMS - 03305293 , or a combination thereof .

Non - limiting examples of immunotherapy include immune checkpoint therapies . Non- limiting examples of immune checkpoint therapies include antibodies and / or inhibitors that target CTLA - 4 , PD - 1 , PD - L1 , BTLA , LAG - 3 , ADORA2A , TIM - 3 , B7 - H3 , VISTA , IDO , and combinations thereof .

In some embodiments , the anti - CTLA4 therapy is abatacept ( e.g. , ®AICNERO ( abatacept ) , or a biosimilar thereof ) , botensilimab , cadonilimab , erfonrilimab , goti stobart , ipilimumab ( e.g. , ®YOVREY ( ipilimumab ) , or a biosimilar thereof ) , nurulimab , quavonlimab , tremelimumab ( ticilimumab ) ( e.g. , ®ODUIMI ( tremelimumab ) , or a biosimilar thereof ) , volrustomig , vudalimab , zalifrelimab , BMS - 986218 , PSB - 205 , biosimilars thereof , or a combination thereof . In some embodiments , the anti - CTLA4 therapy is ipilimumab or tremelimumab . In some embodiments , the anti - CTLA4 therapy is ipilimumab . In some embodiments , the anti - CTLA4 therapy is tremelimumab . In some embodiments , the anti- CTLA4 therapy is used in combination with anti - PD1 or anti - PD - L1 therapy . 243 WO 2025/064848 PCT / US2024 / 0477 LO In some embodiments , the anti - PD1 therapy is balstilimab , budigalimab , cadonilimab , camrelizumab , cemiplimab ( e.g. , cemiplimab - rwlc , or a biosimilar thereof ) , cetrelimab , dostarlimab ( e.g. , dostarlimab - gxly , or a biosimilar thereof ) , enlonstobart ( SG - 001 ) , ezabenlimab , geptanolimab , ivonescimab , nivolumab ( e.g. , ®OVIDPO ( nivolumab ) , or a biosimilar thereof ) , nofazinlimab , pembrolizumab ( e.g. , ®ADURTYEK ( 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 , BAT - 1308 , biosimilars thereof , or a combination thereof . In some embodiments , the anti - PD1 therapy is cemiplimab , nivolumab , or pembrolizumab . In some embodiments , the anti - PD1 therapy is cemiplimab . In some embodiments , the anti - PD1 therapy is nivolumab . In some embodiments , the anti - PD1 therapy is pembrolizumab . In some embodiments , the anti - PD1 therapy is used in combination with anti - CTLA4 therapy . In some embodiments , the anti - PD - L1 therapy is adebrelimab , atezolizumab ( e.g. , ⓇQIRTNECET ( atezolizumab ) , or a biosimilar thereof ) , avelumab ( e.g. , ®OICNEVAB ( avelumab ) , or a biosimilar thereof ) , benmelstobart ( APL - 502 ) , bintrafusp alfa , cosibelimab , danburstotug , durvalumab ( e.g. , ®IZNIFMI ( durvalumab ) , or a biosimilar thereof ) , envafolimab ( e.g. , ®ADIEWNE ( envafolimab ) , or a biosimilar thereof ) , erfonrilimab , lesabelimab , pacmilimab , socazolimab , sugemalimab ( e.g. , ®YLMEJEC ( sugemalimab ) , or a biosimilar thereof ) , tagitanlimab ( A - 167 ) , AUPM - 170 , BNT - 311 , SHR - 1701 , biosimilars thereof , or a combination thereof . In some embodiments , the anti - PD - L1 therapy is atezolizumab or durvalumab . In some embodiments , the anti - PD - L1 therapy is atezolizumab . In some embodiments , the anti - PD - L1 therapy is durvalumab . In some embodiments , the anti- PD - L1 therapy is used in combination with anti - CTLA4 therapy . In some embodiments , the PD - L1 inhibitor is INCB - 086550 or INCB - 099280 . In some embodiments , the anti - LAG3 therapy is eftilagimod alfa , favezelimab , fianlimab , ieramilimab , miptenalimab , negalstobart ( IBI - 110 ) , relatlimab ( e.g. , relatlimab- rmbw , or a biosimilar thereof ) , tebotelimab , tobemstomig ( RG - 6139 ) , tuparstobart ( INCAGN- 02385 ) , HLX - 26 , LBL - 007 , SHR - 1802 , biosimilars thereof , or a combination thereof . In some embodiments , the ADORA2A inhibitor is etrumadenant , inupadenant , istradefylline , mefloquine ( e.g. , mefloquine ) , taminadenant , CPI - 444 , PBF - 999 , or a 244 WO 2025/064848 PCT / US2024 / 0477 combination thereof . In some embodiments , the ADORA2A inhibitor is etrumadenant , inupadenant , istradefylline , mefloquine ( e.g. , mefloquine ) , taminadenant , PBF - 999 , or a combination thereof .

In some embodiments , the anti - TIM3 therapy is cobolimab , sabatolimab ( MBG - 453 ) , surzebiclimab , AZD - 7789 , INCAGN - 02390 , TQB - 2618 , or a combination thereof . In some embodiments , the anti - B7 - H3 therapy is omburtamab , enoblituzumab , or a combination thereof .

In some embodiments , the anti - VISTA therapy is onvatilimab ( JNJ - 61610588 ) , HMBD - 002 , K01401-020 , KVA - 12.1 , SNS - 101 , or a combination thereof . In some embodiments , the IDO inhibitor ( e.g. , IDO1 and / or IDO2 inhibitor ) is 3- deazaguanine , beta - lapachone , diindolylmethane , epacadostat , indole - 3 - carbinol , indoximod , linrodostat , sertaconazole ( e.g. , sertaconazole nitrate ) , or a combination thereof . See , for example , Marin - Acevedo , et al . , J Hematol Oncol . 11 : 39 ( 2018 ) , doi : 10.1186 / s13045-018- 0582-8 .

In some embodiments , the additional therapy or therapeutic agent is a combination of atezolizumab and nab - paclitaxel . Accordingly , also provided herein is a method of treating cancer , comprising administering to a subject in need thereof ( a ) a compound provided herein , 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 provided herein , or a pharmaceutically acceptable salt thereof , and the additional therapeutic agent are together effective in treating the cancer . In some embodiments , the additional therapeutic agent ( s ) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a KRas dysregulation ( e.g. , a KRas mutation or amplification ) . In some embodiments , the additional therapeutic agent ( s ) includes any one of the above listed therapies or therapeutic agents which are standards of care in a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) . These additional therapeutic agents may be administered with one or more doses of the compound provided herein , or a pharmaceutically acceptable salt thereof , or pharmaceutical 2245 WO 2025/064848 PCT / US2024 / 0477 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 . Also provided herein is ( i ) a pharmaceutical composition for treating a cancer in a subject in need thereof , which comprises ( a ) a compound provided herein , or pharmaceutically acceptable salt thereof , ( b ) at least one additional therapeutic agent ( e.g. , any of the exemplary additional therapeutic agents described herein or known in the art ) , 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 provided herein , or a pharmaceutically acceptable salt thereof , and of the additional therapeutic agent are together effective in treating the cancer ; ( ii ) the use of such a composition for the preparation of a medicament for the treatment of cancer ; and ( iii ) a commercial package or product comprising such a composition for simultaneous , separate or sequential use . In some embodiments , the cancer is a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V- associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) ) . Accordingly , also provided herein is a method of treating a cancer , comprising administering to a subject in need thereof ( a ) a compound provided herein , or a pharmaceutically acceptable salt thereof , and ( b ) an additional therapeutic agent , wherein the compound provided herein , or a pharmaceutically acceptable salt thereof , and the additional therapeutic agent are administered simultaneously , separately or sequentially , wherein the amounts of the compound provided herein , or a pharmaceutically acceptable salt thereof , and the additional therapeutic agent are together effective in treating the cancer . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , and the additional therapeutic agent are administered simultaneously as separate dosages . In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , and the additional therapeutic agent are administered as separate dosages sequentially in any order , in jointly therapeutically effective amounts , e.g. , in daily or intermittently dosages . In some embodiments , the compound provided herein , or a pharmaceutically acceptable salt thereof , and the additional therapeutic agent are administered simultaneously as a combined dosage . In some embodiments , the cancer is a KRas - associated cancer ( e.g. , a mutant KRas - associated cancer ( e.g. , a KRas G12D - associated cancer , a KRas G12R- associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or 246 WO 2025/064848 PCT / US2024 / 0477 LO a KRas G12V - associated cancer ) ) ) The term " wild type " or " wild - type " describes a nucleic acid ( e.g. , a KRAS gene or a KRas mRNA ) or protein ( e.g. , a KRas 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 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 . The term " wild type KRas " or " wild - type KRas " describes a KRas nucleic acid ( e.g. , a KRAS gene or a KRas mRNA ) or protein ( e.g. , a KRas protein ) that is found in a subject that does not have a KRas - associated disease , e.g. , a KRas - associated cancer ( and optionally also does not have an increased risk of developing a KRas - associated disease and / or is not suspected of having a KRas - associated disease ) , or is found in a cell or tissue from a subject that does not have a KRas - associated disease , e.g. , a KRas - associated cancer ( and optionally also does not have an increased risk of developing a KRas - associated disease and / or is not suspected of having a KRas - associated disease ) . Although a wild type KRas nucleic acid or protein sequence is the sequence that is typically found in a subject that does not have a KRas - associated disease or disorder , it is not necessarily the case that a subject that has a KRas - associated disease or disorder lacks the wild type KRas sequence . For example , a subject with a KRas gene duplication may have the wild type sequence but could still have a KRas - associated disease or disorder due to the duplication event . As another example , a subject with a KRas - associated disease or disorder may have one allele that encodes wild type KRas protein , and another allele that encodes a mutant KRas protein . 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 . 247 WO 2025/064848 PCT / US2024 / 0477 LO " Treatment " can also mean prolonging survival as compared to expected survival if not receiving treatment . As used herein , treatment of a cancer can include treatment of a primary tumor ( i.e. , non - metastatic cancer ) ( e.g. , as first , second , third , or later line of therapy , including , but not limited to , the relapsed / refractory setting ) , treatment of a metastatic ( or secondary ) tumor , neoadjuvant therapy ( e.g. , before treatment with an additional therapy or therapeutic agent , such as surgery , radiation , chemotherapy , or a line of therapy ) , adjuvant therapy ( e.g. , following treatment with an additional therapy or therapeutic agent , such as surgery , radiation , chemotherapy , or a line of therapy ) , or maintenance therapy ( e.g. , treatment following response to an additional therapy or therapeutic agent , such as surgery , radiation , chemotherapy , or a line of therapy ) . As used herein , the terms " subject , " " individual , " or " patient , " are used interchangeably and refer 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 . In some embodiments , the subject is a pediatric subject . 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 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 248 LO WO 2025/064848 PCT / US2024 / 0477 than 10 years of age , from 6 years of age to less than 13 years of age , from less than 15 years of age , or from 15 years of age to less than 22 years of age . years of age to The term " activating mutation " in reference to KRas describes a mutation in a KRas gene that results in the expression of a KRas protein that has decreased GTPase activity and / or increased effector activation activity , e.g. , as compared to a wild type KRas protein , e.g. , when assayed under identical conditions . For example , an activating mutation can be a mutation in a KRAS gene that results in the expression of a KRas protein that has one or more ( e.g. , two , three , four , five , six , seven , eight , nine , or ten ) amino acid substitutions ( e.g. , any combination of any of the amino acid substitutions described herein ) that has decreased GTPase activity , e.g. , as compared to a wild type KRas protein , e.g. , when assayed under identical conditions . In another example , an activating mutation can be a mutation in a KRAS gene that results in the expression of a KRas protein that has one or more ( e.g. , two , three , four , five , six , seven , eight , nine , or ten ) amino acids deleted , e.g. , as compared to a wild type KRas protein , e.g. , when assayed under identical conditions . In another example , an activating mutation can be a mutation in a KRAS gene that results in the expression of a KRas protein that has at least one ( e.g. , at least 2 , at least 3 , at least 4 , at least 5 , at least 6 , at least 7 , at least 8 , at least 9 , at least , at least 12 , at least 14 , at least 16 , at least 18 , or at least 20 ) amino acid inserted as compared to a wild type KRas protein , e.g. , the exemplary wild type KRas protein described herein , e.g. , when assayed under identical conditions . Additional examples of activating mutations are known in the art .

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 . 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 ) . 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 KRas- associated disease or disorder ( e.g. , a mutant KRas - associated disease or disorder ( e.g. , a KRas G12D - associated cancer , a KRas G12R - associated cancer , or a KRas G12V - associated cancer ( e.g. , a KRas G12D - associated cancer or a KRas G12V - associated cancer ) ) , ( 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 provided herein , or a pharmaceutically acceptable 2249 WO 2025/064848 PCT / US2024 / 0477 salt thereof , that will correspond to such an amount will vary depending upon factors such as the particular compound , disease condition and its severity , the identity ( e.g. , weight ) of the subject in need of treatment , but can nevertheless be routinely determined by one skilled in the art .

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 .

Pharmaceutical Compositions and Administration General In some embodiments , a compound provided herein , or a pharmaceutically acceptable salt thereof , is administered as a pharmaceutical composition that includes the compound , or a pharmaceutically acceptable salt thereof , and one or more pharmaceutically acceptable excipients , and optionally one or more additional therapeutic agents as described herein . In some embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , can be administered in combination with one or more conventional pharmaceutical excipients . Pharmaceutically acceptable excipients include , but are not limited to , ion exchangers , alumina , aluminum stearate , lecithin , self - emulsifying drug delivery systems ( SEDDS ) such as d - 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 , sodium - chloride , zinc salts , colloidal silica , magnesium trisilicate , polyvinyl pyrrolidone , cellulose - based substances , polyethylene glycol , sodium carboxymethyl cellulose , polyacrylates , waxes , polyethylene - polyoxypropylene - block polymers , and wool fat . Cyclodextrins such as -α , -u0000 , and y - cyclodextrin , or chemically modified derivatives such as hydroxyalkylcyclodextrins , including 2- and 3 - hydroxypropyl - -u0000 cyclodextrins , or other solubilized derivatives can also be used to enhance delivery of compounds described herein . Dosage forms or compositions containing a compound provided herein , or a pharmaceutically acceptable salt thereof , as described herein in the range of 0.005 % 250 WO 2025/064848 PCT / US2024 / 0477 LO 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 provided herein , 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 , 22nd Edition ( Pharmaceutical Press , London , UK . 2012 ) .

Routes of Administration and Composition Components In some embodiments , the compounds provided herein , or pharmaceutically acceptable salts thereof , or a pharmaceutical composition comprising a compound provided herein , or a pharmaceutically acceptable salt thereof , can be administered to a subject in need thereof by any accepted route of administration . Acceptable routes of administration include , but are not limited to , buccal , cutaneous , endocervical , endosinusial , endotracheal , enteral , epidural , interstitial , intra - abdominal , intra - arterial , intrabronchial , intrabursal , intracerebral , intracisternal , intracoronary , intradermal , intraductal , intraduodenal , intradural , intraepidermal , intraesophageal , intragastric , intragingival , intraileal , intralymphatic , intramedullary , intrameningeal , intramuscular , intraovarian , intraperitoneal , intraprostatic , intrapulmonary , intrasinal , intraspinal , intrasynovial , intratesticular , intrathecal , intratubular , intratumoral , intrauterine , intravascular , intravenous , nasal , nasogastric , oral , parenteral , percutaneous , peridural , rectal , respiratory ( inhalation ) , subcutaneous , sublingual , submucosal , topical , transdermal , transmucosal , transtracheal , ureteral , urethral and vaginal . In certain embodiments , a preferred route of administration is parenteral ( e.g. , intratumoral ) . In some embodiments , a compound provided herein , 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 . 251 WO 2025/064848 PCT / US2024 / 0477 LO The preparation of such formulations will be known to those of skill in the art in light of the present disclosure . 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 . 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 . 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 . 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 252 WO 2025/064848 PCT / US2024 / 0477 LO 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 caprylocaprate , 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 . In certain embodiments , suppositories can be prepared by mixing a compound provided herein , 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 . 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 . ) . Solid dosage forms for oral administration include capsules , tablets , pills , powders , and granules . In such solid dosage forms , the compound provided herein , 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 . 253 WO 2025/064848 PCT / US2024 / 0477 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 . 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 provided herein , 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 provided herein , 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 . 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 . 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 . 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 provided herein , 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 . Examples include upper - GI targeting techniques , e.g. , Accordion Pill ( Intec Pharma ) , floating capsules , and materials capable of adhering to mucosal walls . Other examples include lower - GI targeting techniques . For targeting various regions in the intestinal tract , several enteric / pH - responsive coatings and excipients are available . These 254 WO 2025/064848 PCT / US2024 / 0477 LO 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 . 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. ) ) . 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 . In any of the foregoing embodiments , pharmaceutical compositions described herein can include one or more one or more of the following : lipids , interbilayer crosslinked multilamellar vesicles , biodegradable poly ( D , L - lactic - co - glycolic acid ) [ PLGA ] -based or poly anhydride - based nanoparticles or microparticles , and nanoporous particle - supported lipid bilayers .

Dosages 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 255 WO 2025/064848 PCT / US2024 / 0477 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 . 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.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 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 ) .

Regimens 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 ) . 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 , weeks , 11 weeks , 12 weeks , 4 months , 5 months , 6 months , 7 months , 8 months , 9 months , 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 , days , 10 days , 11 days , 12 days , 13 days , 14 days , 3 weeks , 4 weeks , 5 weeks , 6 weeks , weeks , 8 weeks , 9 weeks , 10 weeks , 11 weeks , 12 weeks , 4 months , 5 months , 6 months , 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 256 WO 2025/064848 PCT / US2024 / 0477 LO 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 day , 2 days , 3 days , 4 days , 5 days , 6 days , 7 days , 8 days , 9 days , 10 days , 11 days , 12 days , days , 14 days , 3 weeks , 4 weeks , 5 weeks , 6 weeks , 7 weeks , 8 weeks , 9 weeks , 10 weeks , weeks , 12 weeks , 4 months , 5 months , 6 months , 7 months , 8 months , 9 months , 10 months , 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 , days , 10 days , 11 days , 12 days , 13 days , 14 days , 3 weeks , 4 weeks , 5 weeks , 6 weeks , weeks , 8 weeks , 9 weeks , 10 weeks , 11 weeks , 12 weeks , 4 months , 5 months , 6 months , months , 8 months , 9 months , 10 months , 11 months , 12 months , or more . The term " acceptable " with respect to a formulation , composition , or ingredient , as used herein , means having no persistent detrimental effect on the general health of the subject being treated .

" API " refers to an active pharmaceutical ingredient . The term " excipient " or " pharmaceutically acceptable excipient " means a pharmaceutically acceptable material , composition , or vehicle , such as a liquid or solid filler , diluent , carrier , solvent , or encapsulating material . In one embodiment , each component is " pharmaceutically acceptable " in the sense of being compatible with the other ingredients of a pharmaceutical formulation , and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity , irritation , allergic response , immunogenicity , or other problems or complications , commensurate with a reasonable benefit / risk ratio . See , e.g. , Remington : The Science and Practice of Pharmacy , 21st ed .; Lippincott Williams & Wilkins : Philadelphia , PA , 2005 ; Handbook of Pharmaceutical Excipients , 6th ed .; Rowe et al . , Eds .; The Pharmaceutical Press and the American Pharmaceutical Association : 2009 ; Handbook of Pharmaceutical Additives , 3rd ed .; Ash and Ash Eds .; Gower Publishing Company : 2007 ; Pharmaceutical Preformulation and Formulation , 2nd ed .; Gibson Ed .; CRC Press LLC : Boca Raton , FL , 2009 . The term " pharmaceutically acceptable salt " refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound . In certain instances , pharmaceutically acceptable salts are obtained by reacting a compound described herein , with acids such as hydrochloric acid , hydrobromic acid , sulfuric acid , nitric acid , phosphoric acid , methanesulfonic acid , ethanesulfonic acid , p - toluenesulfonic acid , salicylic acid , and the like . 257 WO 2025/064848 PCT / US2024 / 0477 LO 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 . In some embodiments , a pharmaceutically acceptable salt is an anion salt selected from the group consisting of : a mesylate salt , a besylate salt , an acetate salt , a benzenesulfonate salt , a benzoate salt , a bicarbonate salt , a bitartrate salt , a bromide salt , a calcium edetate salt , a camsylate salt , a carbonate salt , a chloride salt , a citrate salt , a dihydrochloride salt , an edetate salt , an edisylate salt , an estolate salt , an esylate salt , a fumarate salt , a gluceptate salt , a gluconate salt , a glucuronate salt , a glutamate salt , a glycollylarsanilate salt , a hexylresorcinol salt , a hydramine salt , a hydrobromide salt , a hydrochloride salt , a hydroxynaphthoate salt , an iodide salt , an isethionate salt , a lactate salt , a lactobionate salt , a malate salt , a maleate salt , a mandelate salt , a mesylate salt , a methylbromide salt , a methylnitrate salt , a methylsulfate salt , a mucate salt , a napsylate salt , a nitrate salt , a pamoate ( embonate ) salt , a pantothenate salt , a phosphate / diphosphate salt , a polygalacturonate salt , a salicylate salt , a stearate salt , a subacetate salt , a succinate salt , a sulfate salt , an oleate salt , a tannate salt , a tartrate salt , a teoclate salt , and a triethiodide salt . In some embodiments , a pharmaceutically acceptable salt is a cation salt selected from the group consisting of : a benzathine salt , a chloroprocaine salt , a choline salt , a tromethamine salt , a diethanolamine salt , an ethylenediamine salt , a meglumine salt , a procaine salt , an 258 WO 2025/064848 PCT / US2024 / 0477 LO aluminum salt , a calcium salt , a lithium salt , a magnesium salt , a potassium salt , a sodium salt , and a zinc salt .

Examples of pharmaceutically acceptable salts also include those disclosed in e.g. , Berge , Stephen M. , Lyle D. Bighley , and Donald C. Monkhouse . " Pharmaceutical salts . " Journal of pharmaceutical sciences 66.1 ( 1977 ) : 1-19 doi : 10.1002 / jps.2600660104 , Bharate , Sonali S. " Recent developments in pharmaceutical salts : FDA approvals from 2015 to 2019. " Drug Discovery Today 26.2 ( 2021 ) : 384-398 doi : 10.1016 / j.drudis.2020.11.016 , and Bharate , Sonali S. " Modulation of biopharmaceutical properties of drugs using sulfonate counterions : A critical analysis of FDA - approved pharmaceutical salts . " Journal of Drug Delivery Science and Technology 66 ( 2021 ) : 102913 doi : 10.1016 / j.jddst.2021.102913 . The term " pharmaceutical composition " refers to a mixture of a compound described herein with other chemical components ( referred to collectively herein as " excipients " ) , such as carriers , stabilizers , diluents , dispersing agents , suspending agents , and / or thickening agents . The pharmaceutical composition facilitates administration of the compound to a subject . Multiple techniques of administering a compound exist in the art including , but not limited to : rectal , oral , intravenous , aerosol , parenteral , ophthalmic , pulmonary , and topical administration .

Compound Preparation The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials , compounds known in the literature , or from readily prepared intermediates , by employing standard synthetic methods and procedures either known to those skilled in the art , or in light of the teachings herein . Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field . Although not limited to any one or several sources , classic texts such as R. Larock , Comprehensive Organic Transformations , VCH Publishers ( 1989 ) ; L. Fieser and M. Fieser , Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons ( 1994 ) ; Smith , M. B. , March , J. , March's Advanced Organic Chemistry : Reactions , Mechanisms , and Structure , 5th edition , John Wiley & Sons : New York , 2001 ; and Greene , T.W. , Wuts , P.G. M. , Protective Groups in Organic Synthesis , 3rd edition , John Wiley & Sons : New York , 1999 , are useful and recognized reference textbooks of organic synthesis known to those in the art . The following descriptions of synthetic methods are 259 WO 2025/064848 PCT / US2024 / 0477 LO designed to illustrate , but not to limit , general procedures for the preparation of compounds of the present disclosure . The synthetic processes disclosed herein can tolerate a wide variety of functional groups ; therefore , various substituted starting materials can be used . The processes generally provide the desired final compound at or near the end of the overall process , although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof . Scheme 1 depicts exemplary methods for preparing compounds of Formula ( I ) : OH CI So X Eb1 ( R10 ) ⁹R ( R10 ) b * R ²x $ CI X R1 - H REa , b b1 ( R* XX' N ' S b1 ( R10 ) * X' N ' ²x S ⁹R Rd E1 ⁹R - H ³R ³R b1 ( R10 ) . e , f ³X ²x S X* - Formula ( I ) Scheme 1. Exemplary Conditions : a . LDA , THF , Cº87- ; b . H3PO4 , toluene , reflux ; or TPP , DIAD , THF or TSCI , nBuLi , THF ; c . DIPEA or TEA , EtOH or 1,4 - dioxane ; d . BrettPhos Pd G4 , 3OC₂sC , 1,4 - dioxane , 80 ° C ; or Pd ( OAc ) 2 , Xantphos , ³OC₂sC , 1,4 - dioxane , 80 ° C ; e . Oxone or mCPBA , DCM ; f . NaH or tBuONa or t - amylONA , THF Referring to Scheme 1 , compound S0 is treated with a base ( e.g. , LDA ( e.g. , in THF at ° C ) ) , followed by S1 to provide an intermediate which is converted into S2 under appropriate conditions ( e.g. , H3PO4 in toluene under reflux ; or TPP and DIAD in THF ; or TsCl and nBuLi in THF ) , wherein ¹E ( e.g. , ¹E is CH or CF ) , ¹X , ²X , ³X , b1 , and R10 are as defined for Formula ( I ) ; and X is halo ( e.g. , -Br ) . S2 is then reacted with ¹R - H , wherein ¹R is as defined for Formula ( I ) ( e.g. , ¹R is attached to the pyrimidine ring via a nitrogen atom ) , to provide Sunder appropriate conditions ( e.g. , in the presence of a base ( e.g. , triethylamine or N , N- diisopropylethylamine ) in an appropriate solvent ( e.g. , EtOH , 1,4 - dioxane , or DMF ) ) . S3 is then reacted with a compound having Formula ºR - H , wherein R2 is as defined for Formula ( I ) , to provide a S4 under appropriate conditions ( e.g. , in the presence of a palladium catalyst and optionally a ligand and / or a base ( e.g. , Pd ( OAc ) 2 , XantPhos , Cs2CO3 , in 1,4 - dioxane at 80 ° C ; 260 WO 2025/064848 PCT / US2024 / 0477 or BrettPhos Pd G4 , Cs2CO3 , in 1,4 - dioxane at 80 ° C ) ) . Subsequently , the thioether group in the compound of S4 is oxidized ( e.g. , with Oxone or mCPBA ) . This is followed by coupling with ³R - ²Y - OH , wherein ³R and ²Y are as defined for Formula ( I ) , to provide a compound of Formula ( I ) .

Scheme 2 depicts exemplary methods for synthesizing G13 , which are examples of S1 : R b1 ( R10 ) G OH G⁹R b1 ( R10 ) G R b , c b1 ( R10 ) G Scheme 2. Exemplary Conditions : a . Pd ( OAc ) 2 , LICI , LIOAc , NчuB * ¯IC , b . NaClO2 , NaH2PO4 ; c . AICI 3 , oxalyl chloride , DMF Referring to Scheme 2 , Compound G10 is reacted with compound G11 to provide compound G12 under appropriate conditions ( e.g. , in the presence of a palladium catalyst ( e.g. , Pd ( OAc ) 2 , LiCl , LiOAc , tetrabutylammonium chloride ) , wherein R , b1 , and º¹R are as defined for Formula ( I ) ( e.g. , R is halo such as -Br ) ; and ³X is CH2 , CHRL , or C ( RL ) 2 wherein ¹R is as defined for Formula ( I ) ( e.g. , ³X is CH2 or ¹RHC ) . The aldehyde group in compound Gis subsequently oxidized ( e.g. , under Pinnick oxidation conditions ( e.g. , with NaClO2 , NaH2PO4 ) ) . The oxidized product is then cyclized to provide compound G13 ( e.g. , with AlCl3 , oxalyl chloride , DMF ) . 261 WO 2025/064848 PCT / US2024 / 0477 Scheme 3 depicts exemplary methods for synthesizing G6 , which are intermediates useful in the synthesis of compounds of Formula ( I ) ( e.g. , in place of S2 of Scheme 1 ) : Br G Br Br HO Br ) 1-G G Br ) 1- HO Rel G11- CI . -Rel Br ) 1-11-G5 G Scheme 3. Exemplary Conditions : a . NaH , LDA , THF , -78 to 10 ° C ; b . DMA - DMF ; 2tEOu00003FB , DCM ; c . L- Selectride , THF ; d . see e.g. , Chemistry of Heterocyclic Compounds 42 ( 2006 ) : 765-775 . e . POCl3 , MeCN , reflux Referring to Scheme 3 , methyl 3 - oxobutanoate is treated with a base ( e.g. , NaH ) followed by reaction with G1 , e.g. , in the presence of a second base ( e.g. , LDA , - 70 to 10 ° C ) to provide compound G2 . The reaction of compound G2 with DMA - DMF in the presence of BF3 etherate ( e.g. , in DCM ) provides compound G3 which is then reduced ( e.g. , with L- Selectride in THF ) to provide compound G4 . Reaction of G4 under appropriate conditions provides G5 , wherein Rel is OH , O ( C1-3 alkyl ) , SH , S ( C1-3 alkyl ) , or a leaving group ( e.g. , halo ) . For example , G4 can be converted to G5 wherein Rel is OH using methods described in Ukrainets , I. V. , et al . Chemistry of Heterocyclic Compounds 42 ( 2006 ) : 765-775 . The reaction of G5 with a chlorinating agent ( e.g. , POCl3 ) in an appropriate solvent ( e.g. , acetonitrile ) under heat ( e.g. , reflux in acetonitrile ) then provides compound G6 . may Variations to the reaction sequences in Schemes 1-3 are also contemplated . For example , to provide certain compounds of Formula ( I ) wherein R ' is halo , step d in Scheme be bypassed ( i.e. , S3 can be directly reacted with ³R - ²Y - OH under steps e and f ) . For example , in the preparation of certain compounds of Formula ( I ) according to Scheme 1 , wherein R ' is NH2 , the R ' group can be protected with one or two nitrogen protecting groups ( e.g. , the NH2 can be protected as NBn2 or NHBoc ) during the reaction sequence e.g. , in Sand / or ⁹R - H of step d , followed by the appropriate deprotection steps ( e.g. , HCl in 1,4 - dioxane for NHBoc group ; or Pd ( OAc ) 2 / H2 for NBn2 ) . Representative examples of nitrogen protecting 262 WO 2025/064848 PCT / US2024 / 0477 groups include : acetyl ( Ac ) , benzoyl ( Bz ) , benzyl ( Bn ) , benzyloxycarbonyl ( Cbz ) , formyl , phenylsulfonyl , pivaloyl , tert - butoxycarbonyl ( Boc ) , tert - butyl acetyl , ethyloxycarbonyl , trifluoroacetyl , triphenylmethyl ( trityl ) , and triisopropylsilane . See : T. W. Greene and P. G. M. Wuts in " Protective groups in organic chemistry " John Wiley and Sons , 4th Edition , 2006 . The final product and / or intermediates in Schemes 1-3 can be subjected to standard functional group transformation ( s ) to provide additional examples of compounds of Formula ( I ) . For example , a compound of Formula ( I ) as provided in Scheme 1 can be converted into a second compound of Formula ( I ) having a different ³R and / or R10 group . For example , a compound of Formula ( I ) wherein R ' is -NHC ( O ) O'Bu can be converted into a second compound of Formula ( I ) wherein R ' is -NH2 upon treatment with an acid ( e.g. , HCl in 1,4- dioxane ) . For example , a compound of Formula ( I ) wherein one R10 is -Br can be converted into a second compound of Formula ( I ) wherein the corresponding R10 is -CN under standard conditions ( e.g. , with CuCN under elevated temperature ( e.g. , at 120 ° C in DMF ) ) . Scheme 4 provides exemplary methods for preparing compounds of Formula ( I ) : ⁹R OH CI E $ b1 ( R10 ) a , b ²x ⁹R $ CI b1 ( R10 ) E³R X²x X S ⁹R R⁹R CI Spa - åpS b1 ( R10 ) . X3 X²x E Formula ( I ) Scheme 4. Exemplary Conditions : a . LDA , THF , -78 ° C ; ³R R1 - H ₁b ( R10 ) .

S b . ( TsCI , nBuLi , THF ) or ( H3PO4 , toluene , reflux ) or ( TPP , DIAD , THF ) ; ³R c . ( Pd2dba3 , BINAP , CS2CO3 , 90-100 ° C ) or ( BrettPhos Pd G4 , Cs2CO3 , 1,4 - dioxane , 80 ° C ) or ( Pd ( OAc ) 2 , Xantphos , Cs2CO3 , 1,4 - dioxane , 80 ° C ) ; d . Pd2dba3 , BINAP , CS2CO3 , 90-100 ° C - Referring to Scheme 4 , compound S10 is treated with a base ( e.g. , LDA ( e.g. , in THF at - 78 ° C ) ) , followed by S11 to provide an intermediate which is converted into S12 under 263 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا appropriate conditions ( e.g. , with TsCl , nBuLi , and THF ; or with H3PO4 and toluene under reflux ; or with TPP , DIAD , and THF ) , wherein ¹E , X1 , X2 , ³X , b1 , R2 , and R10 are as defined for Formula ( I ) ; and Y is -Cl , -F , or -SMe . For example , ¹E can be CH or CF , wherein the CH is optionally protected with a silyl group , e.g. , as C - Si ( Me ) 3 . The silyl group can then be removed e.g. , with TBAF in THF , e.g. , prior to step c . Alternatively , compound S12 wherein ¹E is protected as C - Si ( Me ) 3 can be transformed into an analog wherein ¹E is C - F ( e.g. , with a fluorinating agent such as NFSI ) . S12 is then reacted with a compound of Formula ³R - ²Y - OH , wherein ³R and ²Y are as defined for Formula ( I ) to provide S13 . For example , when Y is -C1 , S12 can be reacted with ³R - ²Y - OH in the presence of a palladium catalyst ( e.g. , with Pd2dba3 , BINAP , Cs2CO3 at 90- 100 ° C , or with BrettPhos Pd G4 , Cs2CO3 , 1,4 - dioxane at 80 ° C , or with Pd ( OAc ) 2 , Xantphos , Cs2CO3 , 1,4 - dioxane , 80 ° C ) to provide $ 13 . S13 is then reacted with a compound of Formula ¹R - H , wherein ¹R is as defined for Formula ( I ) ( e.g. , ¹R is attached to the pyridine ring via a nitrogen atom ) under appropriate conditions ( e.g. , in the presence of a palladium catalyst ( e.g. , with Pd2dba3 , BINAP , Cs2CO3 at 90-100 ° C ) ) to provide a compound of Formula ( I ) . The final product and / or intermediates in Scheme 4 can be subjected to standard functional group transformation ( s ) to provide additional examples of compounds of Formula ( I ) . For example , a compound of Formula ( I ) wherein ¹E is CH can be converted into a second compound of Formula ( I ) wherein ¹E is CR4 , wherein R4 is as defined herein ( e.g. , R4 is -F ) . As another example , a compound of Formula ( I ) as provided in Scheme 4 can be converted into a second compound of Formula ( I ) having a different R2 and / or R10 group . For example , a compound of Formula ( I ) wherein one R10 is -Br can be converted into a second compound of Formula ( I ) wherein the corresponding R10 is -CN under standard conditions ( e.g. , with CuCN under elevated temperature ( e.g. , at 120 ° C in DMF ) ) . Variations to the reaction sequences in Scheme 4 are also contemplated . For example , in the preparation of certain compounds of Formula ( I ) according to Scheme 4 , wherein ⁹R is NH2 , the R ' group can be protected with one or two nitrogen protecting groups ( e.g. , the NHcan be protected as NBn2 or NHBoc ) during the reaction sequence followed by the appropriate deprotection steps ( e.g. , HCl in 1,4 - dioxane for NHBoc group ; or Pd ( OAc ) 2 / H2 for NBn2 ) . Representative examples of nitrogen protecting groups include : acetyl ( Ac ) , benzoyl ( Bz ) , benzyl ( Bn ) , benzyloxycarbonyl ( Cbz ) , formyl , phenylsulfonyl , pivaloyl , tert - butoxycarbonyl ( Boc ) , tert - butyl acetyl , ethyloxycarbonyl , trifluoroacetyl , triphenylmethyl ( trityl ) , and 264 WO 2025/064848 PCT / US2024 / 0477 triisopropylsilane . See : T. W. Greene and P. G. M. Wuts in " Protective groups in organic chemistry " John Wiley and Sons , 4th Edition , 2006 .

Scheme 5 provides exemplary methods for preparing compounds of Formula ( I - c ) : Br CI N₂nB b4 ( R10 ) .

HO S' N ' CI a , b S b4 ( R10 ) . b4 ( R10 ) .

Bn Bn ' N ' RBr E' N ' X$ X²x Bn Bn ' N ' CI Br b4 ( R10 ) . E³R ³X ' N ' XCI S ¹R - H b4 ( R10 ) .

Bn . Bn ' N ' CI Br ' E X3 X³R $ Bn . - Bn ' N ' RNHCN RCN ' Eb4 ( R10 ) . f ' N ' X³R X²x $ * X²x X³R Formula ( I - C ) LO Scheme 5. Exemplary Conditions : a . LDA , THF , -78 ° C ; b . ( TsCl , nBuLi , THF ) or ( H3PO4 , toluene , reflux ) or ( TPP , DIAD , THF ) ; c . ( Pd2dba3 , BINAP , 3OC₂sC , 90-100 ° C ) or ( BrettPhos Pd G4 , Cs2CO3 , 1,4 - dioxane , 80 ° C ) or ( Pd ( OAc ) 2 , Xantphos , Cs2CO3 , 1,4 - dioxane , 80 ° C ) ; d . 3abd₂dP , BINAP , CS2CO3 , 90-100 ° C ; e . CuCN , DMF , 100 ° C ; f . Pd ( OH ) 2 , H2 .

Referring to Scheme 5 , compound S20 is treated with a base ( e.g. , LDA ( e.g. , in THF at 78 ° C ) ) , followed by S21 to provide an intermediate which is converted into S22 under appropriate conditions ( e.g. , with TsCl , nBuLi , and THF ; or with H3PO4 and toluene under reflux ; or with TPP , DIAD , and THF ) , wherein ¹E , ¹X , ²X , ³X , b4 , and R10 are as defined for Formula ( I - c ) . For example , ¹E can be CH or CF , wherein the CH is optionally protected with 265 WO 2025/064848 PCT / US2024 / 0477 LO a silyl group , e.g. , as C - Si ( Me ) 3 . The silyl group can then be removed e.g. , with TBAF in THF , e.g. , prior to step c . Alternatively , compound S22 wherein ¹E is protected as C - Si ( Me ) 3 can be transformed into an analog wherein ¹E is C - F ( e.g. , with a fluorinating agent such as NFSI ) . S22 is then reacted with a compound of Formula ³R - ²Y - OH , wherein ³R and Y2 are as defined for Formula ( I - c ) to provide S23 . For example , S22 can be reacted with ³R - ²Y - OH in the presence of a palladium catalyst ( e.g. , with Pd2dba3 , BINAP , Cs2CO3 at 90-100 ° C , or with BrettPhos Pd G4 , Cs2CO3 , 1,4 - dioxane at 80 ° C , or with Pd ( OAc ) 2 , Xantphos , Cs2CO3 , 1,4- dioxane , 80 ° C ) to provide $ 23 . S23 is then reacted with a compound of Formula ¹R - H , wherein ¹R is as defined for Formula ( I - c ) ( e.g. , ¹R is attached to the pyrimidine ring via a nitrogen atom ) under appropriate conditions ( e.g. , in the presence of a palladium catalyst ( e.g. , with Pd2dba3 , BINAP , CS2CO3 at 90-100 ° C ) ) to $ 24 . S24 is then treated with CuCN ( e.g. , in DMF at 100 ° C ) to provide S25 which is then subjected to hydrogenolysis to remove the benzyl protecting groups ( e.g. , with Pd ( OH ) 2 under hydrogen atmosphere ) to provide a compound of Formula ( I - c ) . The final product and / or intermediates in Scheme 5 can be subjected to standard functional group transformation ( s ) to provide additional examples of compounds of Formula ( I - c ) . For example , a compound of Formula ( I - c ) wherein ¹E is CH can be converted into a second compound of Formula ( I - c ) wherein ¹E is CR4 , wherein R4 is as defined herein ( e.g. , R4 is -F ) .

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 orl , 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 : 266 WO 2025/064848 PCT / US2024 / 0477 LO 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 orl 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 : and 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 orl 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 : and 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. , or 1 or or 2 ) notations in its structural formula in Table C1 .

When two stereogenic centers are labelled orl and orl 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 oror these stereogenic centers ) . For example , the chemical name of is ( ( 2R * , 3S , 4R * ) - - cyclopropyl - 1,4 - dimethylpyrrolidin - 2 - yl ) methanol . This name , taken together with the 267 WO 2025/064848 PCT / US2024 / 0477 structural formula , represents one stereoisomer selected from the group consisting of : N and N When two stereogenic centers are labelled orl 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 oror 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 S N group consisting of : S " , N , and N When the chemical name of a compound having only one stereogenic center contains the prefix " rac , " a mixture of enantiomers ( e.g. , racemic mixture ) is provided , thereby corresponding to an & 1 enhanced stereochemical notation at the corresponding stereogenic center in its structural formula . For example , the chemical name rac- ( R ) - ( 1 - methylpyrrolidin- N N 2 - yl ) methanol represents a mixture of : and When one stereogenic center is designated " RS " or " SR " in the chemical name of a compound having more than one stereogenic centers , a mixture of stereoisomers differing at this stereogenic center is provided , thereby corresponding to an & 1 enhanced stereochemical notation at the corresponding stereogenic center in its structural formula . For example , the 268 chemical name HO & ( ( 2RS , 4R ) -1,4 - dimethylpyrrolidin - 2 - yl ) methanol H.

PCT / US2024 / 0477 ( corresponding to represents a mixture of : and 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 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 ( ( 2RS , 3S , 4RS ) -3 - cyclopropyl - 1,4 - dimethylpyrrolidin - 2 - yl ) methanol . This name , is taken together with the structural formula , represents a mixture of two stereoisomers : N and 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 ) , & & is This name , taken ( S , R ) , ( R , R ) , and ( S , S ) stereoisomers ) . For example , the chemical name of ( ( 2R , 3S , 4RS ) -3 - cyclopropyl - 1,4 - dimethylpyrrolidin - 2 - yl ) methanol . 269 LO WO 2025/064848 PCT / US2024 / 0477 together with the structural formula , represents a mixture of four stereoisomers : , til and ' General Analytical Methods : Method A : VanGuard Pre - Column CSH C18 , 1.7 mμ , 2.1 × 5 mm , Pre - run : 1 mL / min for 0.7 minutes . Column : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 × 30 mm , Flow rate : 0.mL / min , 5 to 100 % MeCN / O₂H ( + 0.1 % formic acid ) for 3 minutes .

Method B : VanGuard Pre - Column CSH C18 , 1.7 mµ , 2.1 × 5 mm , Pre - run : 1 mL / min for 0.7 minutes . Column : Acquity UPLC , CSH C18 , 1.7 mµ , 2.1 × 30 mm , Flow rate : 0.mL / min , 5 to 100 % MeCN / O₂H ( + 10 mM ammonium bicarbonate ) for 3 minutes .

Method C : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 × 30 mm , Mobile phase A : 0.1 % formic acid in H2O ; Mobile phase B : 0.1 % formic acid in MeCN ( v / v ) ; Gradient : 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN in 2.0 minutes , hold at 5 % H20 / 95 % MeCN to 2.minutes . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 0.5 minutes . Flow rate : 0.6 mL / min .

Method D : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 × 30 mm , Mobile phase A : 0.1 % ammonium hydroxide in H2O ; Mobile phase B : 0.1 % ammonium hydroxide in MeCN ( v / v ) ; Gradient : 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN in 2.0 minutes , hold at 5 % O₂H / 95 % MeCN to 2.50 minutes . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 0.5 minutes . Flow rate : 0.6 mL / min .

Method E : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 × 30 mm , Mobile phase A : 0.1 % formic acid in H2O ; Mobile phase B : 0.1 % formic acid in MeCN ( v / v ) ; Gradient : 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN in 4.0 minutes , hold at 5 % O₂H / 95 % MeCN to 4.minutes . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 0.5 minutes . Flow rate : 0.6 mL / min . 270 WO 2025/064848 PCT / US2024 / 0477 Method F : Poroshell SB - C18 , 4.6 × 150 mm , Mobile phase A : 0.1 % TFA in O₂H ( v / v ) , Mobile phase B : 0.1 % TFA in MeCN ( v / v ) , Gradient : 30-95 % Mobile phase B over 15 minutes .

Method G : Chiralpak IB - U ( 3.0 × 100 mm , 1.6 mM , P / N 81U83 ) Method H : ®xeteniK EVO C18 2.1 × 30 mm 5 mμ , Mobile phase A : 0.0375 % TFA in H2O ( v / v ) , Mobile phase B : 0.01875 % TFA in MeCN ( v / v ) , Gradient : 95 % O₂H / 5 % MeCN linear to 5 % H20 / 95 % MeCN in 0.6 minutes , hold at 5 % O₂H / 95 % MeCN to 0.78 minutes . Flow rate : 2.0 mL / min . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 0.minutes . Flow rate : 2.0 mL / min .

Method I : VanGuard Pre - Column CSH C18 , 1.7 mµ , 3.0 × 50 mm , Pre - run : 0.mL / min for 2.5 minutes . Column : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 × 75 mm , Flow rate : 0.6 mL / min , 5 to 100 % MeCN / O₂H ( + 10 mM ammonium bicarbonate ) for 7.5 minutes .

Method J : Column : Chiralcel OD - 3R ( 2.1 × 100 mm , 3 mµ , P / N 14893 ) ; Mobile phase A = 0.1 % v / v ammonium hydroxide in H2O , 0.1 % v / v ammonium hydroxide in MeCN ; Gradient : 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN in 8.0 minutes , hold at 5 % O₂H / 95 % MeCN to 9.00 minutes . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 1.0 minute .

Method K : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 x 30 mm , Mobile phase A : 0.1 % TFA in H2O ; Mobile phase B : 0.1 % formic acid in MeCN ( v / v ) ; Gradient : 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN in 4.0 minutes , hold at 5 % O₂H / 95 % MeCN to 4.50 minutes . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 0.5 minutes . Flow rate : 0.mL / min .

Method L : Acquity UPLC , CSH C18 , 1.7 mμ , 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 % O₂H / 5 % MeCN hold to 0.5 min , 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN to 4.0 min , hold at % O₂H / 95 % MeCN to 0.50 min . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN hold for 0.5 min . Flow : 0.6 mL / min . 271 WO 2025/064848 PCT / US2024 / 0477 Method M : Acquity UPLC , CSH C18 , 1.7 mμ , 2.1 × 30 mm , Mobile phase A : 0.1 % TFA in H2O ; Mobile phase B : 0.1 % TFA in MeCN ( v / v ) ; Gradient : 95 % O₂H / 5 % MeCN linear to 5 % O₂H / 95 % MeCN in 2.0 minutes , hold at 5 % O₂H / 95 % MeCN to 2.50 minutes . Then 5 % O₂H / 95 % MeCN linear to 95 % O₂H / 5 % MeCN in 0.5 minutes . Flow rate : 0.6 mL / min .

Table of Abbreviations : Abbreviation Definition Ac Acyl BINAP Bn Benzyl Boc BrettPhos BrettPhos Pd G 2,2 ' - bis ( diphenylphosphino ) -1,1 ' - binaphthyl tert - Butoxycarbonyl 2- ( Dicyclohexylphosphino ) 3,6 - dimethoxy - 2 ' , 4 ' , 6 ' - triisopropyl - 1,1'- biphenyl ( SP - 4-3 ) - [ Dicyclohexyl [ 3,6 - dimethoxy - 2 ' , 4 ' , 6 ' - tris ( 1- methylethyl ) [ 1,1 ' - biphenyl ] -2 - yl ] phosphine - Pк ] ( methanesulfonato- Oк ) [ 2 ' - ( methylamino - Nк ) [ 1,1 ' - biphenyl ] -2 - yl - Cк ] BSA Bovine Serum Albumin Bz Benzoyl Cbz Benzyloxycarbonyl CSH Charged Surface Hybrid Da DBU DCM Daltons 1,8 - Diazabicyclo [ 5.4.0 ] undec - 7 - ene Dicholoromethane DEA Diethylamine DIAD Diisopropyl azodicarboxylate DIBAL - H Diisobutylaluminium hydride DIPEA Diisopropylethylamine DMA Dimethylacetamide DMF Dimethylformamide DMSO Dimethylsulfoxide DTT Dithiothreitol ee Enantiomeric excess eq equivalents ESI Electrospray Ionization EtOAc Ethyl acetate EtOH Ethanol GDP Guanosine diphosphate GMPPNP ' - Guanylyl imidodiphosphate GTP Guanosine triphosphate HEPES HPLC LCMS LDA 4- ( 2 - Hydroxyethyl ) -1 - piperazineethanesulfonic acid High - performance liquid chromatography Liquid chromatography mass spectroscopy Lithium diisopropylamide 272 m / z MCPBA Mass to charge meta - Chloroperoxybenzoic acid MeCN Acetonitrile MeOD Deuterated methanol ( CD3OD ) MeOH Methanol nBuLi n - Butyl lithium NMR Nuclear magnetic resonance NMP Pd ( dppf ) ₂lC PCT / US2024 / 0477 Pd2dbaPDA psi PvBOP N - Methyl - 2 - Pyrrolidone [ 1,1 ' - Bis ( diphenylphosphino ) ferrocene ] dichloropalladium ( II ) Tris ( dibenzylideneacetone ) dipalladium ( 0 ) Photodiode array Pounds per square inch Benzotriazol - 1 - yloxytripyrrolidinophosphonium hexafluorophosphate Resonance units - Dicyclohexylphosphino - 2 ' , 6 ' - diisopropoxybiphenyl Supercritical fluid chromatography Nucleophilic aromatic substitution Son of sevenless homolog 2 - Di - tert - butylphosphino - 2 ' , 4 ' , 6 ' - triisopropylbiphenyl Tetra - n - butylammonium fluoride Tris ( 2 - carboxyethyl ) phosphine Triethylamine RU RuPhos SFC SNAr SOStBuXPhos TBAF TCEP TEA TFA THF TPP tR or TR Retention time TR - FRET Trityl TsCl UPLC Ultra performance liquid chromatography Trifluoroacetic acid Tetrahydrofuran Triphenylphosphine Time - resolved fluorescence resonance energy transfer Triphenylmethyl p - Toluenesulfonyl chloride wt % XantPhos XPhos Percent by weight ( 9,9 - Dimethyl - 9H - xanthene - 4,5 - diyl ) bis ( diphenylphosphane ) Dicyclohexyl [ 2 ' , 4 ' , 6 ' - tris ( propan - 2 - yl ) [ 1,1 ' - biphenyl ] -2 - yl ] phosphane Example P. Synthesis of Intermediates Intermediate 1 : 8 - Bromo - 7- ( dibenzylamino ) -3,4 - dihydronaphthalen - 1 ( 2H ) -one Br Step 1 : 7 - Amino - 8 - bromo - 3,4 - dihydronaphthalen - 1 ( 2H ) -one 273 WO 2025/064848 PCT / US2024 / 0477 LO A solution of 1 - bromopyrrolidine - 2,5 - dione ( 2.86 g , 1 equiv , 16.1 mmol ) in DMF ( mL ) was added dropwise to a solution of 7 - amino - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 2.59 g , equiv , 16.1 mmol ) in DMF ( 20 mL ) at 0 ° C . The resulting mixture was stirred for 4 hours at room temperature and then poured into water . The mixture was extracted with DCM three times , and the combined extracts were washed with water . The combined organic phases were dried over sodium sulfate and passed through a Celite pad . The filtrate was concentrated to a residue which was purified by column chromatography ( 80 g , 0-20 % hexane / EtOAc ) to afford 7 - amino - 8 - bromo - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 3.31 g ) . LCMS : m / z ( ESI ) [ M + H ] * 239.9 , tR = 1.02 minutes ( Method A ) . ' H NMR ( 400 MHz , CDC13 ) : 8 7.01 ( d , 1H ) , 6.88 ( d , 1H ) , 4.30 ( s , 2 H ) , 2.86 ( t , 2 H ) , 2.66 ( t , 2H ) , 2.03-2.09 ( m , 2 H ) .

Step 2 : 8 - Bromo - 7- ( dibenzylamino ) -3,4 - dihydronaphthalen - 1 ( 2H ) -one Potassium carbonate ( 5.36 g , 3.5 equiv , 38.8 mmol ) was added to 7 - amino - 8 - bromo- 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 2.66 g , 1 equiv , 11.1 mmol ) in anhydrous DMF ( 55.4 mL ) followed by the dropwise addition of ( bromomethyl ) benzene ( 4.71 mL , 3.5 equiv , 38.mmol ) at room temperature . The resulting mixture was stirred at 70 ° C for 16 hours . Water was added , and the aqueous layer was extracted with EtOAc three times . The combined extracts were washed with brine , dried over sodium sulfate , filtered , and evaporated to a residue , which was purified by column chromatography ( 80 g silica , 0-5 % hexane / EtOAc ) to afford 8 - bromo- 7- ( dibenzylamino ) -3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 4.25 g ) . LCMS : m / z ( ESI ) [ M + H ] * 422.2 , tr = 1.99 minutes ( Method A ) .

Intermediate 2a : ( R ) -7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one Br Aluminum chloride ( 20.8 g , 2.5 equiv . , 156 mmol ) was stirred rapidly as 4 - methyl - 3,4- dihydronaphthalen - 1 ( 2H ) -one ( 10.0 g , 1 equiv . , 62.4 mmol ) was added dropwise by syringe over 20 minutes . The resulting dark - red mass was heated at 85 ° C until it melted , at which point Br2 ( 12.0 g , 3.86 mL , 1.2 equiv . , 74.9 mmol ) was added dropwise by syringe over minutes . The mixture was stirred for 1 hour at 85 ° C . The reaction mixture was cooled to room temperature , added to ice - water ( 500 mL ) and concentrated HCl ( 100 mL ) . The resulting 274 WO 2025/064848 PCT / US2024 / 0477 LO mixture was extracted with ethyl acetate ( 4 × 300 mL ) , and the combined organic layers were filtered through Celite . The filtrate was washed with saturated aqueous sodium bicarbonate solution ( 250 mL ) , water ( 250 mL ) and brine ( 250 mL ) , dried over sodium sulfate , filtered , and concentrated to give a residue . The residue was purified by reverse - phase HPLC ( 0.1 % formic acid condition ) to give 7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 10.5 g ) . LCMS : m / z ( ESI ) [ M + H ] * 240.9 , tr = 0.462 minutes ( Method H ) .

The enantiomers of 7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 5 g , 20.mmol ) were separated by chiral SFC ( Column : Chiralpak AD - 3 50 × 4.6 mm I.D. , 3 mµ Mobile phase : Phase A for CO2 , and Phase B for MeOH ( 0.05 % DEA ) , Gradient elution : B in A from % to 40 % Flow rate : 3 mL / min , Detector : PDA , Column Temp : 35 ° C , Back Pressure : 1bar ) to afford ( R ) -7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( Intermediate 2a ) and ( S ) -7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( Intermediate 2b ) .

Intermediate 2a : First eluting peak , tr = 1.027 minutes ( 1780 mg ) ' H NMR ( 400 MHz , CD3OD ) § 8.03 ( d , 1H ) , 7.69 ( dd , 1H ) , 7.36 ( d , 1H ) , 3.15 - 3.( m , 1H ) , 2.84 - 2.74 ( m , 1H ) , 2.66 - 2.55 ( m , 1H ) , 2.31 - 2.20 ( m , 1H ) , 1.96 - 1.84 ( m , 1H ) , 1.40 ( d , 3H ) .

Intermediate 2b : ( S ) -7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ﺶﻣا Br Intermediate 2b : Second eluting peak , tr = 1.167 minutes ( 1549 mg ) ' H NMR ( 400 MHz , CD3OD ) § 8.03 ( d , 1H ) , 7.69 ( dd , 1H ) , 7.36 ( d , 1H ) , 3.17 - 3.( m , 1H ) , 2.85 - 2.73 ( m , 1H ) , 2.69 - 2.53 ( m , 1H ) , 2.31 - 2.20 ( m , 1H ) , 1.96 - 1.82 ( m , 1H ) , 1.40 ( d , 3H ) .

Intermediate dihydronaphthalen - 1 ( 2H ) -one 3 : ( S ) -8 - bromo - 7- ( dibenzylamino ) -4 - methyl - 3,4- 275 Br Bn2N PCT / US2024 / 0477 ﺶﻣا Step 1 : ( S ) -7 - amino - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one NMP ( 27.9 mL ) and ammonium hydroxide ( 29.3 g , 32.4 mL , 20 equiv , 836 mmol ) were delivered to a pressure vessel charged with ( S ) -7 - bromo - 4 - methyl - 3,4 - dihydronaphthalen- ( 2H ) -one ( Intermediate 2b ) ( 10.0 g , 1.00 equiv , 41.8 mmol ) and copper ( I ) oxide ( 598 mg , 0.10 equiv , 4.18 mmol ) under nitrogen . The pressure vessel was sealed , and the reaction mixture was stirred at 80 ° C for 17 hours . The reaction mixture was cooled to ambient temperature and poured into a separatory funnel charged with water ( 100 mL ) and EtOAc ( 2mL ) . The layers were separated , and the aqueous phase was extracted with EtOAc ( 3 x 1mL ) . The combined organic extracts were dried over sodium sulfate , filtered , and concentrated to a residue . The crude residue was purified by silica gel chromatography ( 2 to 45 % heptane / EtOAc ) to afford ( S ) -7 - amino - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 6.79 g ) . = ' H NMR ( 400 MHz , CDC13 ) 8 7.34 ( d , 1H ) , 7.16 ( d , 1H ) , 6.94 – 6.86 ( m , 1H ) , 3.68 ( bs , 2H ) , 3.07 2.95 ( m , 1H ) , 2.88 - 2.72 ( m , 1H ) , 2.64 – 2.52 ( m , 1H ) , 2.28 – 2.16 ( m , 1H ) , 1.– 1.80 ( m , 1H ) , 1.37 ( d , 3H ) . – LCMS : m / z ( ESI ) [ M + H ] * 176.2 , tr = 1.51 minutes ( Method E ) Step 2 : ( S ) -7 - amino - 8 - bromo - 4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one A solution of N - bromosuccinimide ( 6.90 g , 1.0 equiv , 38.8 mmol ) in DMF ( 25.9 mL ) was delivered dropwise to a flask containing ( S ) -7 - amino - 4 - methyl - 3,4 - dihydronaphthalen- ( 2H ) -one ( 6.79 g , 1.00 equiv , 38.79 mmol ) in DMF ( 51.7 mL ) at 0 ° C , under nitrogen . The resulting mixture was stirred at 0 ° C for 5 minutes . The mixture was then warmed to room temperature and stirred for 2 hours . The reaction mixture was quenched by the addition of water ( 150 mL ) and EtOAc ( 200 mL ) . The layers were separated , and the aqueous phase was extracted with EtOAc ( 3 x 150 mL ) . The combined organic extracts were dried over sodium sulfate , filtered , and concentrated to give a residue , which was purified by silica gel chromatography ( 0 to 30 % heptane / EtOAc ) to afford ( S ) -7 - amino - 8 - bromo - 4 - methyl - 3,4- dihydronaphthalen - 1 ( 2H ) -one ( 7.96 g ) . ' H NMR ( 400 MHz , CDC13 ) 8 7.07 ( d , 1H ) , 6.92 ( d , 1H ) , 4.15 ( bs , 2H ) , 3.05 -2.91 ( m , 1H ) , 2.86 – 2.74 ( m , 1H ) , 2.68 – 2.56 ( m , 1H ) , 2.25 – 2.12 ( m , 1H ) , 1.90 – 1.77 ( m , 1H ) , 1.- ( d , 3H ) . 276 WO 2025/064848 PCT / US2024 / 0477 one LCMS : m / z ( ESI ) [ M + H ] * 254.1 , tr = 2.47 minutes ( Method E ) Step 3. ( S ) -8 - bromo - 7- ( dibenzylamino ) -4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) - Benzyl bromide ( 16.1 g , 11.2 mL , 3 equiv , 94.0 mmol ) and potassium carbonate ( 15.g , 3.5 equiv , 110 mmol ) were sequentially delivered to a solution of ( S ) -7 - amino - 8 - bromo - 4- methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 7.96 g , 1.0 equiv , 31.3 mmol ) in MeCN ( 313 mL ) at room temperature . The resulting mixture was stirred vigorously at reflux for 18 hours at which point the reaction mixture was cooled to room temperature . The solids were filtered and rinsed with EtOAc . The filtrate was concentrated , and the remaining crude residue was purified by silica gel chromatography ( 1 to 35 % heptane / EtOAc ) to afford ( S ) -8 - bromo - 7- ( dibenzylamino ) -4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 12.5 g ) . 1H NMR ( 400 MHz , CDC13 ) 87.36 - 7.19 ( m , 10H ) , 7.09 - 6.97 ( m , 2H ) , 4.24 - 4.( m , 4H ) , 3.03 – 2.90 ( m , 1H ) , 2.89 – 2.76 ( m , 1H ) , 2.73 – 2.61 ( m , 1H ) , 2.24 – 2.12 ( m , 1H ) , 1.901.77 ( m , 1H ) , 1.30 ( d , 3H ) .

– LCMS : m / z ( ESI ) [ M + H ] * 434.3 , tr = 3.78 minutes ( Method E ) Intermediate 4 : ( 1S , 4S ) -4 ' - Chloro - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ' N ' Br CI gand Step 1 : ( 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3 ' - ( trimethylsilyl ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 520 To a solution of ( 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) pyridin - 3 - yl ) methanol mg , 1.97 mmol , 1 equiv . ) in THF ( 13.1 mL ) at -78 ° C was added dropwise LDA ( 464 mg , 4.mL , 4.33 mmol , 2.2 equiv . ) . The resulting mixture was stirred at this temperature for 1 hour . Then , ( S ) -8 - bromo - 7- ( dibenzylamino ) -4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 940 mg , 2.16 mmol , 1.1 equiv . ) in THF ( 4 mL ) was dropwise added at -78 ° C . The resulting mixture 2 WO 2025/064848 PCT / US2024 / 0477 LO was stirred at -78 ° C for 15 minutes . p - Toluenesulfonyl chloride ( 563 mg , 450 Lµ , 2.95 mmol , 1.5 equiv . ) in THF ( 5 mL ) was dissolved while maintaining the temperature below -70 ° C . The reaction was allowed to warm to room temperature and stirred for 2 hours . The reaction was then quenched with saturated aqueous sodium bicarbonate ( 25 mL ) and the aqueous layer was washed with EtOAc . The combined organic layers were dried over sodium sulfate , filtered , and concentrated . The crude material was purified by flash silica gel chromatography ( 0 to 5 % ethyl acetate / heptanes ) to afford ( 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3'- ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 730 mg ) as a yellow solid . = LCMS : m / z ( ESI ) [ M + H ] * 679.3 tR = 2.19 min ( Method K ) The stereoisomers were separated by the chiral SFC ( purification : ChiralPak AD - H x 250 mm ; Isocratic 70 % A : carbon dioxide ; Mobile phase in 30 % B : Isopropanol ( v / v ) . Flow mL / min ; back pressure = 100 bar ) to afford ( 1S , 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro- - methyl - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridin ] -7 - amine ( Peak 1 ) and ( 1R , 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3'- ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( Peak 2 ) . Analytical method - Chiral SFC purification : ChiralPak AD - H 4.6 x 100 mm ; Isocratic % A : carbon dioxide ; Mobile phase in 30 % B : Isopropanol ( v / v ) . Flow 2.5 mL / min ; back pressure 140 bar ; temperature 40 ° C = Peak 1 : ' H NMR ( 400 MHz , CDC13 ) 8 7.36 – 7.16 ( m , 10H ) , 6.96 ( d , 1H ) , 6.86 ( d , 1H ) , 5.( d , 1H ) , 4.77 ( d , 1H ) , 4.18 ( d , 2H ) , 4.14 – 4.01 ( m , 3H ) , 3.01 – 2.88 ( m , 2H ) , 2.14 ( m , 1H ) , - 2.00 – 1.85 ( m , 2H ) , 1.70 – 1.58 ( m , 1H ) , 1.30 ( d , 3H ) , 0.55 ( s , 9H ) . Peak 2 : ' H NMR ( 400 MHz , CDC13 ) 8 7.36 – 7.16 ( m , 10H ) , 7.13 ( d , 1H ) , 6.88 ( d , 1H ) , 4.( d , 1H ) , 4.72 ( d , 1H ) , 4.25 – 4.11 ( m , 5H ) , 3.06 – 2.80 ( m , 2H ) , 2.12 – 2.03 ( m , 1H ) , 1.96 – 1.85 ( m , 2H ) , 1.51 – 1.40 ( m , 1H ) , 1.28 ( d , 3H ) , 0.54 ( s , 9H ) .

= Step : ( 18,48 ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine To a solution of ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3'- ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine 278 WO 2025/064848 PCT / US2024 / 0477 LO ( 270 mg , 0.397 mmol , 1 equiv . ) in THF ( 1.59 mL ) was added dropwise TBAF ( 104 mg , 3Lμ , 397 lomμ , 1 equiv . ) . The mixture was stirred at room temperature for 3 hours . Water ( mL ) and EtOAc ( 5 mL ) were then added . The layers were separated and the aqueous extracted twice more with EtOAc ( 5 mL each ) . The combined organic layers were dried with sodium sulfate , filtered , and concentrated to afford ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4- methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine mg ) as a white solid . LCMS : m / z ( ESI ) [ M + H ] * 607.2 tr = 4.49 min ( Method K ) ( 2 Step : ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2- ﺶﻣا fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine A mixture of ( ( 2R , 7aS ) -2 - Fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methanol ( 94.mg , 592 lomμ , 2 equiv . ) , ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 180 mg , 296 lomμ , equiv . ) , BINAP ( 73.7 mg , 118 lomµ , 0.4 equiv . ) , ³abd2dP ( 54.2 mg , 59.2 lomμ , 0.2 equiv . ) , and cesium carbonate ( 193 mg , 592 lomµ , 2 equiv . ) was evacuated and backfilled with ₂N three times . Toluene ( 2.96 mL ) was then added and degassed for 5 minutes by bubbling ₂N through . The mixture was stirred in a heating block at 110 ° C for 3 hours . BINAP ( 73.7 mg , 118 lomµ , 0.4 equiv . ) , ³abd2dP ( 54.2 mg , 59.2 lomµ , 0.2 equiv . ) , and cesium carbonate ( 193 mg , 592 lomµ , equiv . ) were added again , and the mixture was stirred at 120 ° C for 2 more hours . The crude was purified by flash silica gel chromatography ( 0 to 50 % ethyl acetate / DCM ) to give ( 18,48 ) - N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] - - amine ( 500 mg ) as a yellow solid . LCMS : m / z ( ESI ) [ M + H ] * 730.4 tR = 3.36 min ( Method K. ) - ' H NMR ( 400 MHz , CDCl3 ) 8 7.37 – 7.16 ( m , 10H ; obscured by CDCl3 ) , 6.96 ( d , 1H ) , 6.84 ( d , 1H ) , 6.69 ( s , 1H ) , 5.36 – 5.30 ( m , 1H ) , 5.30 ( s , 3H ) , 5.22 – 5.16 ( m , OH ) , 4.98 ( d , 1H ) , 4.78 ( d , 1H ) , 4.21 – 4.06 ( m , 4H ; obscured by residual EtOAc ) , 4.06 – 3.91 ( m , 3H ) , 3.26 ( s , 1H ) , 3.21 ( d , 1H ) , 3.17 – 3.08 ( m , 1H ) , 2.98 ( q , 2H ) , 2.81 ( d , 1H ) , 2.19 ( d , 1H ) , 2.15 – 2.08 ( m , 2H ) , 1.97 – 1.79 ( m , 2H ) , 1.57 ( s , 2H ) , 1.30 ( d , 3H ) . 279 WO 2025/064848 PCT / US2024 / 0477 Step 4 : ( 18,4S ) -4 ' - Chloro - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile To a suspension of ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 1.0 g , 1.37 mmol , 1 equiv . ) and molecular sieves ( Å4 , 500 mg ) in DMF ( 10 mL ) was added copper ( I ) cyanide ( 613 mg , 6.mmol , 5 equiv . ) . The resulting mixture was degassed with N2 for 10 minutes and then stirred at 100 ° C for 3 hours . Aqueous ammonium hydroxide ( 10 mL ) and EtOAc ( 10 mL ) were added , and the mixture was stirred at room temperature for 30 minutes . The mixture was extracted with EtOAc ( 60 mL ) and the combined organic layers were washed with brine ( 45 mL ) , dried over sodium sulfate , filtered , and concentrated to a residue . The residue was purified by reverse phase chromatography ( MeOH / water with 1 % ammonium bicarbonate ) to afford ( 1S , 4S ) -4'- chloro - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] - - carbonitrile ( 862 mg ) as a yellow solid . LCMS : m / z ( ESI ) [ M + H ] * 677.4 tr = 2.29 min ( Method B ) 1H NMR ( 400 MHz , CDC13 ) 8 7.35 - 7.20 ( m , 10H ) , 7.13 ( d , 1H ) , 6.90 ( d , 1H ) , 6.( s , 1H ) , 5.26 ( d , 1H ) , 5.06 ( d , 1H ) , 4.82 ( d , 1H ) , 4.29 ( q , 4H ) , 4.13 ( d , 1H ) , 3.98 ( d , 1H ) , 3.( d , 1H ) , 3.33 3.20 ( m , 2H ) , 3.20 3.07 ( m , 1H ) , 3.02 - 2.85 ( m , 4H ) , 2.24 - 2.13 ( m , 1H ) , - 2.13 – 1.76 ( m , 7H ) , 1.65 ( d , 1H ) , 1.27 ( d , 3H ) . 19F NMR ( CHCl3 - d , 376 MHz ) : SF - 172.

Example 1 : 5 - ( ( SR ) -7 - Amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- 280 WO 2025/064848 PCT / US2024 / 0477 pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( Compound 108b ) NH & ' N ' -N N.

LO Step 1 : Ethyl 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) nicotinate n - Butyl lithium ( 2.16 M in hexanes , 4.35 mL , 1.1 equiv . , 9.40 mmol ) was added to a solution of ethyl 4,6 - dichloro - 2 - methylnicotinate ( 2.00 g , 1.0 equiv . , 8.54 mmol ) in THF ( mL ) at -78 ° C over 20 minutes , while ensuring the internal temperature was maintained below -70 ° C . The resulting red mixture was stirred at -78 ° C for 30 minutes and then chlorotrimethylsilane ( 1.08 mL , 1.0 equiv . , 8.54 mmol ) was added dropwise at -78 ° C , while ensuring the internal temperature was maintained below -70 ° C during the addition . The resulting reaction mixture was stirred at -78 ° C for 2 hours . Saturated sodium bicarbonate ( mL ) was added , and the resulting reaction was slowly warmed to room temperature . The aqueous phase was separated and extracted with ethyl acetate ( 3 × 30 mL ) . The combined organic layers were washed with brine ( 20 mL ) , dried over sodium sulfate , and concentrated to a residue , which was purified by column chromatography ( SiO2 , 0-3 % ethyl acetate in hexanes ) to afford ethyl 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) nicotinate ( 1.4 g ) . ' H NMR ( 400 MHz , CDCl3 ) 8 4.44 ( q , 2H ) , 2.48 ( d , 3H ) , 1.40 ( t , 3H ) , 0.51 ( s , 9H ) . ethyl Step 2 : ( 4,6 - Dichloro - 2 - methyl - 5- ( trimethylsilyl ) pyridin - 3 - yl ) methanol DIBAL - H ( 25 wt % in toluene , 6.1 mL , 2 equiv . , 9.1 mmol ) was added to a solution of 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) nicotinate ( 1.4 g , 1 equiv . , 4.6 mmol ) in THF ( mL ) at 0 ° C . The internal temperature was maintained below 5 ° C during the addition . The reaction mixture was stirred at 0 ° C for 10 minutes , and then slowly warmed to room temperature . The resulting mixture was stirred at room temperature for 14 hours . The mixture was cooled to 0 ° C and DIBAL - H ( 25 % wt in toluene , 6.1 mL , 2 equiv . , 9.1 mmol ) was added , while maintaining the internal temperature below 5 ° C . The reaction mixture was stirred for 4.5 hours and then quenched with Rochelle salts solution ( 100 mL ) . The biphasic mixture was 281 WO 2025/064848 PCT / US2024 / 0477 extracted with ethyl acetate ( 2 × 100 mL ) . The combined organic layers were washed with brine ( 50 mL ) , dried over sodium sulfate , and concentrated to yield ( 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) pyridin - 3 - yl ) methanol ( 1.3 g ) , which was used without purification . ' H NMR ( 400 MHz , CDC13 ) 8 4.84 ( d , 2H ) , 2.64 ( s , 3H ) , 1.85 ( t , 1H ) , 0.51 ( s , 9H ) ( contains residual EtOAc and toluene ) .

Step 3 : rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine LDA in THF : hexanes ( 12 mL , 1 M , 2.2 equiv . , 12 mmol ) was added dropwise to a solution of ( 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) pyridin - 3 - yl ) methanol ( 1500 mg , 1 equiv . , 5.68 mmol ) in THF ( 20 mL ) at -78 ° C . The reaction mixture was stirred at -78 ° C for 1 hour then a solution of 8 - bromo - 7- ( dibenzylamino ) -3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 2.625 g , 1.equiv . , 6.245 mmol ) in THF ( 5 mL ) was added dropwise over 5 minutes . The internal temperature was maintained below -70 ° C during the addition . The mixture was stirred at -° C for 15 minutes , then a solution of toluenesulfonyl chloride ( 1.62 g , 1.5 equiv . , 8.mmol ) in THF ( 5 mL ) was added dropwise over 5 minutes . The internal temperature was maintained below -70 ° C during the additions . The mixture was stirred at -78 ° C for 1 hour then slowly warmed to room temperature and stirred at room temperature for 2 hours . The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate solution ( 20 mL ) and extracted with EtOAc ( 3 × 20 mL ) . The combined organic phases were washed with brine ( 20 mL ) , dried over sodium sulfate and concentrated to a residue , which was purified by flash column chromatography ( 40 g cartridge , 5-40 % EtOAc in hexanes ) to yield rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 1.52 g ) as a white foam . LCMS : m / z ( ESI ) [ M + H ] * 667.2 , tr = 2.66 minutes ( Method B ) .

Step 4 : rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine Tetrabutylammonium fluoride ( 1 M in THF , 4.35 mL , 1 M , 2 equiv . , 4.35 mmol ) was added to a solution of rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3 ' - ( trimethylsilyl ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 1.45 g , equiv . , 2.18 mmol ) in THF ( 15 mL ) at 22 ° C . After 20 minutes , the stir bar was removed , and silica ( 10 g ) was added . The solvent was evaporated under reduced pressure and the resulting 282 WO 2025/064848 PCT / US2024 / 0477 solid was purified by flash column chromatography ( 40 g cartridge , with 100 % chloroform ) to yield rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 1.26 g ) as a white foam . H¹ ' H NMR ( 400 MHz , CDC13 ) 8 7.37 – 7.16 ( m , 10H ) , 6.92 ( d , 1H ) , 6.83 ( d , 1H ) , 5.( d , 1H ) , 4.78 ( d , 1H ) , 4.20 – 4.02 ( m , 6H ) , 2.98 ( d , 1H ) , 2.92 – 2.71 ( m , 2H ) , 2.07 ( d , 1H ) , 1.– 1.83 ( m , 2H ) , 1.79 – 1.64 ( m , 1H ) .

Step 5 : ( SR ) -N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -7 - amine A degassed solution of rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 650 mg , 1 equiv . , 1.mmol ) in toluene ( 10 mL ) was added to ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methanol ( 348 mg , 2.0 equiv . , 2.19 mmol ) , BINAP ( 272 mg , 0.4 equiv . , 437 lomµ ) , and cesium carbonate ( 1.43 g , 4 equiv . , 4.37 mmol ) . зabd2dP ( 200 mg , 0.2 equiv . , 2lomµ ) was added , and the resulting solution was degassed over 20 minutes in a sonicator . The reaction mixture was then stirred at 90 ° C for 5 hours . The reaction mixture was cooled to room temperature and diluted with water and EtOAc . The layers were separated , and the aqueous layer was extracted twice more with EtOAc . The combined organics were dried with sodium sulfate , filtered , and concentrated to a residue , which was purified by column chromatography ( Redi Sep ®dloG Silica Gel eluting 0 to 100 % EtOAc in DCM ) to afford ( SR ) -N , N - dibenzyl - 8- bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 400 mg ) .

LCMS : m / z ( ESI ) [ M + H ] * 718.3 , tr = 2.50 minutes ( Method B ) .

Step 6 : 5 - ( ( SR ) -8 - Bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide Pd2dba3 ( 19.2 mg , 0.2 equiv . , 20.9 lomμ ) was added to a degassed suspension of ( RS ) - N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine 283 LO WO 2025/064848 PCT / US2024 / 0477 ( 75.0 mg , 1 equiv . , 105 lomμ ) , N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 43.6 mg , 2 equiv . , 209 lomμ ) , 2,2'- bis ( diphenylphosphaneyl ) -1,1 ' - binaphthalene ( 26.0 mg , 0.4 equiv . , 41.8 lomμ ) , and cesium carbonate ( 170 mg , 5 equiv . , 523 lomμ ) in DMF ( 3.8 mL ) . The resulting suspension was degassed with nitrogen for 5 minutes then heated at 100 ° C for 16 hours . The reaction mixture was then diluted with water ( 20 mL ) and EtOAc ( 20 mL ) . The organic layer was separated , and the organics were extracted with EtOAc ( 4 × 15 mL ) . The combined organic layers were washed with brine ( 3 × 15 mL ) , dried over sodium sulfate , and concentrated to a residue , which was purified by flash column chromatography ( 30 g cartridge , C - 18 , liquid injection with 10- % methanol / water containing 1 % NH4HCO3 ) to yield 5 - ( ( SR ) -8 - bromo - 7- ( dibenzylamino ) - ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H- pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 64.9 mg ) . LCMS : m / z ( ESI ) [ M + H ] * 889.9 , tr = 1.55 minutes ( Method A ) .

Step 7 : 5 - ( ( SR ) -8 - Cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide - ( ( SR ) -8 - Bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4'- yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( mg , 1 equiv . , 73 lomμ ) and copper ( I ) cyanide ( 65 mg , 10 equiv . , 0.73 mmol ) in DMF ( 3 mL ) was degassed with nitrogen for 10 minutes , and then the mixture was heated at 100 ° C for hours . 10 % Aqueous ammonium hydroxide ( 5 mL ) and EtOAc ( 5 mL ) were added , and the resulting mixture was stirred at 22 ° C for 30 minutes . The organic layer was separated , and the organics were extracted with EtOAc ( 4 × 5 mL ) . The combined organic layers were washed with brine ( 3 × 5 mL ) , dried over sodium sulfate , and dried to a residue , which was purified by flash column chromatography ( 12 g cartridge , dry inject with 0-15 % methanol / DCM ) to yield 5- ( ( SR ) -8 - cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N- dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 47 mg ) as a light brown solid . 284 WO 2025/064848 PCT / US2024 / 0477 LCMS : m / z ( ESI ) [ M + H ] * 835.5 , tR = 2.01 minutes ( Method B ) .

Step 8 : 5 - ( ( SR ) -7 - Amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridin - 4 - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2- carboxamide Pd ( OH ) 2 on carbon ( 59 mg , 20 wt % , 1.5 equiv . , 84 lomμ ) was added to a solution of 5- ( ( SR ) -8 - cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N- dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 47 mg , equiv . , 56 lomμ ) in methanol ( 2 mL ) . EtOAc ( 3 mL ) was added to the reaction mixture under an argon balloon . The reaction flask was then purged with hydrogen three times and stirred under hydrogen ( 1 atm ) for 3 hours . The suspension was filtered and the solid washed with DCM / methanol ( 10 mL , 1 : 1 by volume ) . Then 3 drops of 30 % aqueous NH4HCO3 were added . The solvent was evaporated to a residue , which was purified by column chromatography ( ( 12 ) g cartridge ; C - 18 , liquid loading ) with 10-70 % methanol / water with 1 % NH4HCO3 ) to yield 5- ( ( SR ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl- 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 19 mg ) as a white solid . LCMS : m / z ( ESI ) [ M + H ] * 655.5 , tr = 3.95 and 4.02 minutes ( Method I ) . 19F NMR ( 376 MHz , CDCl3 ) 8-172.86 ( dd ) . ' H NMR ( 400 MHz , CDCl3 ) 8 7.04 ( d , 1H ) , 6.63 ( d , 1H ) , 6.52 ( s , 1H ) , 6.26 ( d , 1H ) , 5.25 ( d , 1H ) , 4.93 – 4.71 ( m , 2H ) , 4.42 ( d , 4H ) , 4.21 – 4.03 ( m , 3H ) , 4.01 – 3.89 ( m , 1H ) , 3.( d , 2H ) , 3.33 ( s , 3H ) , 3.23 ( d , 2H ) , 3.15 ( s , 1H ) , 3.08 ( s , 3H ) , 2.95 ( d , 2H ) , 2.68 ( d , 2H ) , 2.- 1.97 ( m , 6H ) , 1.88 ( s , 3H ) , 1.74 ( d , 2H ) .

Example 1a : 5 - ( ( R ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( Compound 108c ) 285 ' N ' NH' N ' F PCT / US2024 / 0477 The diastereomers of 5 - ( ( SR ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridin - 4 - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2- carboxamide were separated by chiral SFC ( Column : Daicel Chiralpak IA 30 x 250 mm , mµ ; part number 80455 ; Mobile phase : Phase A for CO2 , and Phase B for MeOH ( 0.25 % DEA ) , Isocratic elution : B in A from 40 % Flow rate : 50 mL / min , Detector : PDA , Column Temp : 40 ° C , Back Pressure : 120 bar ) to afford 5 - ( ( R ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H- pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( Peak 1 ) and Peak 2 .

Peak 1 : LCMS : m / z ( ESI ) [ M + H ] * 655.5 , tr = 1.41 minutes ( Daicel Chiralpak IA , 4.6mm ID x 100mmL , mμ5 particle size , part number 80423 ; for chiral separation , MeOH with 0.25 % DEA , 40 % B isocratic . Flow rate = 4.0 mL / minute ; runtime = 8.0 minutes ) ' H NMR ( 400 MHz , MeOD ) 8 7.07 ( d , 1H ) , 6.72 ( d , 1H ) , 6.46 ( s , 1H ) , 6.27 ( s , 1H ) , 5.33 5.13 ( m , 1H ) , 4.86 – 4.73 ( m , 3H ) , 4.63 ( d , 1H ) , 4.47 – 4.38 ( m , 2H ) , 4.26 ( d , 1H ) , 4.21 ( d , 1H ) , 3.97 ( d , 1H ) , 3.88 ( d , 1H ) , 3.50 – 3.41 ( m , 2H ) , 3.26 ( s , 3H ) , 3.22 ( d , 1H ) , 3.- 3.03 ( m , 3H ) , 2.98 ( s , 3H ) , 2.94 ( d , 1H ) , 2.91 – 2.83 ( m , 1H ) , 2.74 – 2.61 ( m , 2H ) , 2.19 - 1.96 ( m , 6H ) , 1.90 – 1.72 ( m , 6H ) . 19F NMR ( 376 MHz , CD3CN ) 8-173.61 .

- Example 1b : 5 - ( ( S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( Compound 108a ) 286 NHCN ' N ' -N ' N ' PCT / US2024 / 0477 - ( ( S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N- dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide was obtained from Example 1a as Peak 2 . Peak 2 : LCMS : m / z ( ESI ) [ M + H ] * 655.5 , tr = 2.32 minutes ( Daicel Chiralpak IA , 4.6mm ID x 100mmL , mμ5 particle size , part number 80423 ; for chiral separation , MeOH with 0.25 % = DEA , 40 % B isocratic . Flow rate = 4.0 mL / minute ; runtime = 8.0 minutes ) ' H NMR ( 400 MHz , MeOD ) § 7.07 ( d , 1H ) , 6.72 ( d , 1H ) , 6.46 ( s , 1H ) , 6.27 ( s , 1H ) , 5.33 5.14 ( m , 1H ) , 4.85 - 4.74 ( m , 3H ) , 4.62 ( d , 1H ) , 4.46 - 4.38 ( m , 2H ) , 4.26 ( d , 1H ) , 4.21 ( d , 1H ) , 3.97 ( d , 1H ) , 3.89 ( d , 1H ) , 3.49 – 3.42 ( m , 2H ) , 3.26 ( s , 3H ) , 3.22 ( d , 1H ) , 3.- - – 3.03 ( m , 3H ) , 2.98 ( s , 3H ) , 2.94 ( d , 1H ) , 2.91 – 2.84 ( m , 1H ) , 2.72 – 2.61 ( m , 2H ) , 2.19 - 1.96 ( m , 6H ) , 1.91 – 1.73 ( m , 6H ) . 19F NMR ( 376 MHz , CD3CN ) 8-173.58 .

Example 2 : ( SR ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile , 3 trifluoroacetic acid ( Compound 107b ) NH' N ' & ' N ' 287 WO 2025/064848 PCT / US2024 / 0477 LO Step 1 : rac- ( S ) -N , N - dibenzyl - 8 - bromo - 2 ' - chloro - 4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine 1,4 - Oxazeapne ( 25.5 mg , 28.1 Lµ , 1.5 equiv . , 252 lomμ ) was added to a suspension of rac- ( S ) -N , N - Dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 100 mg , 1 equiv . , 168 lomµ ) , and cesium carbonate ( 110 mg , equiv . , 336 lomμ ) in DMF ( 561 Lµ ) . The reaction mixture was then heated to 145 ° C and stirred overnight . The reaction was diluted with ether and 10 % LiCl solution . The layers were separated , and the aqueous layer was extracted twice more with ether and the combined organics were dried with sodium sulfate , filtered , and concentrated to a residue , which was purified via silica gel chromatography ( 0 to 50 % EtOAc in heptane ) to yield rac- ( S ) -N , N- dibenzyl - 8 - bromo - 2 ' - chloro - 4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 25 mg ) as a yellow solid . LCMS : m / z ( ESI ) [ M + H ] * 658.1 tr = 3.37 minutes ( Method K ) Step 2 : ( SR ) -N , N - dibenzyl - 8 - bromo - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine To a vial containing rac- ( S ) -N , N - dibenzyl - 8 - bromo - 2 ' - chloro - 4 ' - ( 1,4 - oxazepan - 4 - yl ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 20 mg , equiv . , 30 lomµ ) , ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methanol ( 9.7 mg , equiv . , 61 lomµ ) , BINAP ( 7.6 mg , 0.4 equiv . , 12 lomμ ) , Pd2dba3 ( 5.6 mg , 0.2 equiv . , 6.lomμ ) , and cesium carbonate ( 20 mg , 2 equiv . , 61 lomμ ) were added . The vial was evacuated and backfilled three times with nitrogen . In a separate vial , toluene was degassed by bubbling nitrogen through for 30 minutes . Toluene ( 0.30 mL ) from this degassed vial was added to the vial containing the solids and this mixture was degassed further for 5 minutes . The reaction mixture was then set to a heating block to stir at 120 ° C . After 2 hours , the reaction was diluted with water and EtOAc , the layers were separated , and the aqueous layer extracted twice more with EtOAc . The combined organics were dried with sodium sulfate , filtered , and concentrated to an orange oil , which was purified via silica gel chromatography ( eluting first with 0 → 50 % EtOAc in DCM followed by a 30 % methanol in DCM flush ) to yield ( SR ) -N , N - dibenzyl - 8- bromo - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan- - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 15.3 mg ) as a yellow oil . 288 WO 2025/064848 PCT / US2024 / 0477 LO LCMS : m / z ( ESI ) [ M + H ] * 781.4 tr = 2.70 minutes ( Method K ) Step 3 : ( SR ) -7- ( Dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile To a vial containing ( SR ) -N , N - dibenzyl - 8 - bromo - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 15.3 mg , 1 equiv . , 19.6 lomµ ) , cuprous cyanide ( 8.76 mg , 3.01 Lµ , 5 equiv . , 97.8 lomµ ) , and DMF ( 280 Lµ ) were added . The vial was evacuated , backfilled three times with nitrogen , and stirred at 100 ° C for 2 hours . The reaction mixture was then cooled to room temperature and a 10 % aqueous NH4OH solution ( 5 mL ) was added . The resulting reaction mixture was extracted with ethyl acetate ( 3 × 5 mL ) . The combined organics were dried with sodium sulfate , filtered , and concentrated to yield ( SR ) -7- ( Dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4- oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8- carbonitrile ( 12 mg ) , which was carried forward without further purification . LCMS : m / z ( ESI ) [ M + H ] * 728.6 tr = 2.60 minutes ( Method K ) Step 4 : ( SR ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile , 3 trifluoroacetic acid To a vial containing ( SR ) -7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 6 mg , 1 equiv . , lomμ ) , palladium hydroxide on carbon ( 0.02 g , 20 % wt , 3 equiv . , 0.02 mmol ) was added . The vial was evacuated and backfilled three times with nitrogen . Methanol ( 0.50 mL ) was added followed by acetic acid ( 0.01 g , 9 Lµ , 20 equiv . , 0.2 mmol ) . Hydrogen gas from a balloon was then bubbled through the solution for 30 minutes ( solvent re - filled , if needed ) and then the mixture was left to stir for 2 hours . The reaction was filtered through a frit and the filtrate was stirred with sodium carbonate ( 100 mg ) and then filtered a second time . The reaction mixture was concentrated and purified via HPLC to afford ( SR ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( 1,4 - oxazepan - 4 - yl ) -3,4,5 ' , 8'- 289 WO 2025/064848 PCT / US2024 / 0477 tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile , 3 trifluoroacetic acid ( 1.5 mg ) as a yellow oil . LCMS : m / z ( ESI ) [ M + H ] * 548.4 tr = 1.72 minutes ( Method K ) ' H NMR ( 400 MHz , MeOD ) : 8 7.10 ( d , 1H ) , 6.77 ( d , 1H ) , 6.36 ( s , 1H ) , 5.56 ( d , 1H ) , 5.00 ( d , 1H ) , 4.84 ( d , 1H ) , 4.63 – 4.48 ( m , 2H ) , 3.98 – 3.76 ( m , 8H ) , 3.73 – 3.52 ( m , 4H ) , 3.- – 3.41 ( m , 1H ) , 3.14 – 3.05 ( m , 1H ) , 2.78 – 2.68 ( m , 2H ) , 2.60 – 2.53 ( m , 1H ) , 2.48 – 2.23 ( m , 3H ) , 2.23 1.71 ( m , 8H ) . - Example 3 : - ( ( SR ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridin - 4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2- carboxamide ( Compound 106b ) NH' N ' & ' N ' Step 1 : rac- ( S ) -7 - Bromo - 2 ' , 4 ' - dichloro - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] LDA in THF : hexanes ( 0.9 g , 8 mL , 1 M , 2.2 equiv . , 8 mmol ) was added dropwise over minutes to a solution of ( 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) pyridin - 3 - yl ) methanol ( g , 1 equiv . , 4 mmol ) in THF ( 20 mL ) at -78 ° C in a dry ice / acetone bath . The internal temperature was maintained below -70 ° C during the addition and the mixture turned orange / yellow . The mixture was stirred at -78 ° C for 1 hour , and then a solution of 7 - bromo- 3,4 - dihydronaphthalen - 1 ( 2H ) -one ( 0.9 g , 1.1 equiv . , 4 mmol ) in THF ( 5 mL ) was added dropwise over 5 minutes . The internal temperature was maintained below -70 ° C . The mixture was stirred at -78 ° C for 15 minutes then a solution of toluenesulfonyl chloride ( 1 g , 1.5 equiv . , mmol ) in THF ( 5 mL ) was added dropwise over 5 minutes while stirring under nitrogen and maintaining the internal temperature below -70 ° C . The mixture was stirred at -78 ° C for hour , slowly warmed to room temperature , and stirred at room temperature overnight . The reaction was quenched by adding saturated aqueous sodium bicarbonate solution ( 10 mL ) and extracted with EtOAc ( 3 × 20 mL ) . The combined organic phases were washed with brine ( 290 WO 2025/064848 PCT / US2024 / 0477 mL ) , dried over sodium sulfate and concentrated to a residue , which was purified using silica gel column chromatography ( gradient of EtOAc in hexanes ) to provide rac- ( S ) -7 - bromo - 2 ' , 4'- dichloro - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridine ] ( 1.06 g ) as a slightly yellow oil . LCMS : m / z ( ESI ) [ M + H ] * 472.1 tr = 2.43 minutes ( Method A ) Step : rac- ( S ) -7 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] TBAF ( 1 M in THF ) ( 1.18 g , 4.50 mL , 1 M , 2 equiv . , 4.50 mmol ) was added dropwise over 2 minutes to a solution of rac- ( S ) -7 - bromo - 2 ' , 4 ' - dichloro - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] ( 1.06 g , 1 equiv . , 2.25 mmol ) in THF ( 10 mL ) at room temperature . The mixture was stirred at room temperature for 10 minutes then concentrated to a residue , which was purified via silica gel column chromatography ( gradient of EtOAc in hexanes ) to provide rac- ( S ) -7 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro- 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] ( 600 mg ) as a white solid . LCMS : m / z ( ESI ) [ M + H ] * 399.8 tR = 2.13 minutes ( Method A ) Step : rac- ( S ) -7 - Bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -1 ' - oxide TFA ( 486 mg , 328 Lµ , 5 equiv . , 4.26 mmol ) and H2O2 ( 483 mg , 435 Lµ , 30 % wt , equiv . , 4.26 mmol ) were added to a solution of rac- ( S ) -7 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] ( 340 mg , 1 equiv . , 852 lomμ ) in DCM ( 20 mL ) at room temperature . The resulting biphasic mixture was stirred at room temperature for 24 hours . The reaction mixture was quenched with saturated aqueous sodium bicarbonate solution ( 10 mL ) and extracted with DCM ( 3 × 10 mL ) . The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to yield crude rac- ( S ) -7 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridine ] -1 ' - oxide ( 350 mg ) as an off - white solid which was used directly in the next step . = LCMS : m / z ( ESI ) [ M + H ] * 416.1 tr = 1.70 minutes ( Method A ) Step 4 : ( SR ) -7 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridine ] -1 ' - oxide 291 WO 2025/064848 PCT / US2024 / 0477 LO NaH ( 60 % dispersion in mineral oil ) ( 50.6 mg , 60 % wt , 1.5 equiv . , 1.26 mmol ) was added to a solution of ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methanol ( 2mg , 1.5 equiv . , 1.26 mmol ) in DMF ( 4 mL ) at room temperature . The mixture was stirred at room temperature for 5 minutes . This mixture was then added in a single portion to a suspension of rac- ( S ) -7 - bromo - 2 ' , 4 ' - dichloro - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridine ] -1 ' - oxide ( 350 mg , 1 equiv . , 843 lomμ ) in DMF ( 4 mL ) while stirring at room temperature under nitrogen . The reaction mixture turned dark brown instantly . The reaction was quenched with saturated aqueous sodium bicarbonate solution ( 50 mL ) and extracted with EtOAc ( 3 × 50 mL ) . The combined organic phases were washed with brine ( 2 × mL ) , dried over sodium sulfate and concentrated to a residue , which was purified via silica gel column chromatography ( eluant DCM : methanol : NH4OH 85 : 13.5 : 1.5 ) to provide ( SR ) -7- bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -1 ' - oxide ( 215 mg ) as a light brown solid . . LCMS : m / z ( ESI ) [ M + H ] * 538.9 tr = 1.13 minutes ( Method A ) Step 5 : ( SR ) -7 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridine ] Hypodiboric acid ( 52.5 mg , 1.5 equiv . , 586 lomµ ) was added to a solution of ( SR ) -7- bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -1 ' - oxide ( 210 mg , equiv . , 390 lomµ ) in DMF ( 5 mL ) at room temperature . After 20 minutes , the reaction was quenched with a saturated aqueous sodium bicarbonate solution ( 50 mL ) and extracted with EtOAc ( 3 × 50 mL ) . The combined organic phases were washed with brine ( 2 × 20 mL ) , dried over sodium sulfate , and concentrated to a residue , which was purified using silica gel column chromatography ( eluant DCM : methanol : NH4OH 85 : 13.5 : 1.5 ) to provide ( SR ) -7 - bromo - 4'- chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] ( 200 mg ) as an off - white solid . LCMS : m / z ( ESI ) [ M + H ] * 521.0 tR = 1.30 minutes ( Method A ) 292 WO 2025/064848 PCT / US2024 / 0477 LO Step 6 : tert - Butyl ( ( SR ) -4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridin ] -7 - yl ) carbamate Nitrogen was bubbled through a mixture of ( SR ) -7 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] ( 200 mg , 1 equiv . , 383 lomμ ) , tert - butyl carbamate ( 53.9 mg , 1.2 equiv . , 460 lomμ ) and cesium carbonate ( 250 mg , 2 equiv . , 766 lomµ ) in DMF ( 2 mL ) at room temperature for 5 minutes . BrettPhos Pd G4 ( 35.3 mg , 0.1 equiv . , 38.lomμ ) was added and nitrogen was bubbled through the mixture at room temperature for another 5 minutes . The reaction mixture was heated at 70 ° C while stirring under nitrogen for hours . The reaction was then quenched with saturated aqueous sodium bicarbonate solution ( 50 mL ) and extracted with EtOAc ( 3 × 50 mL ) . The combined organic phases were washed with brine ( 2 × 20 mL ) , dried over sodium sulfate , and concentrated to a residue , which was purified using silica gel column chromatography ( eluant DCM : methanol : NH4OH 85 : 13.5 : 1.5 ) to provide tert - butyl ( ( SR ) -4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7- yl ) carbamate ( 88 mg ) as a light brown solid . LCMS : m / z ( ESI ) [ M + H ] * 558.2 tr = 1.32 minutes ( Method A ) Step 7 : tert - butyl ( ( SR ) -4 ' - ( 2- ( dimethylcarbamoyl ) -7,8 - dihydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepin - 5 ( 6H ) -yl ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7- yl ) carbamate Nitrogen was bubbled through a mixture of tert - butyl ( ( SR ) -4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - yl ) carbamate ( 40.0 mg , 1 equiv . , 71.7 lomµ ) , N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide hydrochloride ( 35.1 mg , 2 equiv . , 143 lomµ ) and cesium carbonate ( 117 mg , 5 equiv . , 3lomμ ) in DMF ( 2 mL ) at room temperature for 5 minutes . BINAP ( 17.9 mg , 0.4 equiv . , 28.lomμ ) and Pd2dba3 ( 13.1 mg , 0.2 equiv . , 14.3 lomμ ) were added and nitrogen was bubbled through the mixture while stirring at room temperature for another 5 minutes . The reaction mixture was heated under nitrogen while stirring at 100 ° C for 14 hours . The reaction mixture was then diluted with water ( 10 mL ) and extracted with EtOAc ( 3 × 30 mL ) . The combined 293 WO 2025/064848 PCT / US2024 / 0477 LO ﺶﻣا organic phases were washed with brine ( 2 × 20 mL ) , dried over sodium sulfate , and concentrated to a residue , which was purified using silica gel column chromatography ( eluant DCM : methanol : NH4OH 85 : 13.5 : 1.5 ) to provide tert - butyl ( ( SR ) -4 ' - ( 2- ( dimethylcarbamoyl ) - 7,8 - dihydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepin - 5 ( 6H ) -yl ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridin ] -7 - yl ) carbamate ( 6 mg ) as a yellow solid . LCMS : m / z ( ESI ) [ M + H ] * 730.3 tr = 1.18 minutes ( Method A ) Step 8 : 5 - ( ( SR ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4'- yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide p - Toluenesulfonic acid monohydrate ( 8 mg , 6 Lμ , 5 equiv . , 0.04 mmol ) was added to a solution of tert - butyl ( ( SR ) -4 ' - ( 2- ( dimethylcarbamoyl ) -7,8 - dihydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepin - 5 ( 6H ) -yl ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7- yl ) carbamate ( 6 mg , 1 equiv . , 8 lomµ ) in MeCN ( 0.2 mL ) and heated to 60 ° C . After 1 hour , the solvent was removed under reduced pressure , NH4OH : methanol 1 : 9 ( 1 mL ) was added , and the mixture was concentrated again . The crude material was purified by reverse phase purification ( C18 silica , gradient of MeCN in aqueous 10 mM ammonium bicarbonate buffer ) provide 5 - ( ( SR ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - to yl ) methoxy ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N- dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 2 mg ) as an off - white solid LCMS : m / z ( ESI ) [ M + H ] * 630.2 tr = 1.42 minutes and tR = diastereomers ( Method B ) – 1.45 minutes , ' H NMR ( 400 MHz , CDC13 ) 8 6.92 ( d , 1H ) , 6.74 – 6.68 ( m , 1H ) , 6.62 – 6.55 ( m , 1H ) , 6.46 ( s , 1H ) , 6.22 ( s , 1H ) , 5.38 – 5.16 ( m , 1H ) , 4.63 ( d , 1H ) , 4.57 – 4.47 ( m , 1H ) , 4.47 – 4.( m , 2H ) , 4.14 ( d , 2H ) , 3.99 ( s , 1H ) , 3.52 – 3.36 ( m , 1H ) , 3.23 ( d , 5H ) , 3.07 ( s , 3H ) , 3.03 - 2. - ( m , 2H ) , 2.88 – 2.64 ( m , 2H ) , 2.29 – 1.65 ( m , 16H ) . 19F NMR ( 376 MHz , CDCl3 ) : 8-172.9 .

Example 4 : 5 - ( ( 1S , 4S ) -7 - Amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- 294 WO 2025/064848 PCT / US2024 / 0477 pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( Compound 104a ) ' N ' NH' N ' F Step 1 : ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3 ' - ( trimethylsilyl ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine To a stirred solution of ( 4,6 - dichloro - 2 - methyl - 5- ( trimethylsilyl ) pyridin - 3 - yl ) methanol ( 520 mg , 1 equiv . , 1.97 mmol ) in THF ( 13.1 mL ) at -78 ° C was added LDA ( 464 mg , 4.33 mL , M , 2.2 equiv . , 4.33 mmol ) . The resulting mixture was stirred at 87− ° C for 1 hour . To this mixture was added ( S ) -8 - bromo - 7- ( dibenzylamino ) -4 - methyl - 3,4 - dihydronaphthalen - 1 ( 2H ) - one ( 940 mg , 1.1 equiv . , 2.16 mmol ) dropwise as a solution in 4 mL of THF . The resulting mixture was then stirred at -78 ° C for 15 minutes . p - Toluenesulfonyl chloride ( 563 mg , 4Lµ , 1.5 equiv . , 2.95 mmol ) was then dissolved in 5 mL of THF and added to the reaction mixture dropwise , maintaining a temperature below -70 ° C . The reaction was then warmed to room temperature and was stirred for 1 hour . The reaction was quenched with saturated ammonium chloride ( 30 mL ) , and the aqueous layer was extracted with DCM ( 2 × 30 mL ) . The organic layers were combined , dried over sodium sulfate , filtered , and concentrated . The crude material was purified via silica gel chromatography ( 0 to 5 % EtOAc in heptanes ) to give ( 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro- 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 730 mg ) . LCMS : m / z ( ESI ) [ M + H ] * 679.3 tr = 2.19 minutes ( Method L ) The diastereomers of ( 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3'- ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine were separated by chiral SFC purification ( ChiralPak AD - H 21 x 250 mm ; Isocratic 70 % A : carbon dioxide ; Mobile phase in 30 % B : Isopropanol ( v / v ) . Flow 70 mL / min ; back pressure = 100 bar ) to afford ( 1S , 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3 ' - ( trimethylsilyl ) - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( Peak 1 ) ( 287. 295 WO 2025/064848 PCT / US2024 / 0477 mg ) and ( 1R , 4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3 ' - ( trimethylsilyl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( Peak 2 ) ( 138.2 mg ) . Analytical method - Chiral SFC purification : ChiralPak AD - H 4.6 x 100 mm ; Isocratic % A : carbon dioxide ; Mobile phase in 30 % B : Isopropanol ( v / v ) . Flow 2.5 mL / min ; back pressure 140 bar ; temperature 40 ° C = Peak 1 : ' H NMR ( 400 MHz , CDCl3 ) 8 7.36 – 7.16 ( m , 10H ) , 6.96 ( d , 1H ) , 6.86 ( d , 1H ) , 5.( d , 1H ) , 4.77 ( d , 1H ) , 4.18 ( d , 2H ) , 4.14 – 4.01 ( m , 3H ) , 3.01 – 2.88 ( m , 2H ) , 2.14 ( m , 1H ) , 2.00 – 1.85 ( m , 2H ) , 1.70 – 1.58 ( m , 1H ) , 1.30 ( d , 3H ) , 0.55 ( s , 9H ) . SFC Peak 1 : tr = 1.562 min Peak 2 : ' H NMR ( 400 MHz , CDC13 ) 8 7.36 – 7.16 ( m , 10H ) , 7.13 ( d , 1H ) , 6.88 ( d , 1H ) , 4.= ( d , 1H ) , 4.72 ( d , 1H ) , 4.25 – 4.11 ( m , 5H ) , 3.06 – 2.80 ( m , 2H ) , 2.12 – 2.03 ( m , 1H ) , 1.96 – - 1.85 ( m , 2H ) , 1.51 – 1.40 ( m , 1H ) , 1.28 ( d , 3H ) , 0.54 ( s , 9H ) . SFC Peak 2 : tr = 1.732 min Step 2 : ( 18,48 ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine To a 20 mL vial was added ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3'- ( trimethylsilyl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 270 mg , 0.397 mmol , 1 equiv . ) followed by THF ( 1.59 mL ) . To this reaction , TBAF ( 104 mg , 397 Lµ , 1 M , 1 equiv . , 397 lomµ ) was added dropwise . The resulting reaction was stirred for hours at room temperature . After 3 hours , 5 mL of water and 5 mL of EtOAc were added . The layers were separated , and the aqueous layers were extracted with EtOAc ( 10 mL ) . The combined organic layers were dried with sodium sulfate , filtered , and concentrated to afford ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 233 mg ) , which was used without further purification . LCMS : m / z ( ESI ) [ M + H ] * 607.2 tr = 4.49 min ( Method K ) 296 WO 2025/064848 PCT / US2024 / 0477 Step : ( 1S , 4S ) -N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( ( 2R , 7aS ) -2 - Fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methanol ( 94.2 mg , 2 equiv . , 592 lomμ ) , ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 2 ' , 4 ' - dichloro - 4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 180 mg , 1 equiv . , 296 lomμ ) , BINAP ( 73.7 mg , 0.4 equiv . , 118 lomμ ) , Pd2dba3 ( 54.2 mg , 0.2 equiv . , 59.2 lomµ ) , and cesium carbonate ( 193 mg , 2 equiv . , 592 lomμ ) were added to a vial which was evacuated and backfilled with nitrogen three times . Toluene ( 2.96 mL ) was then added , and the reaction was degassed for 5 minutes by bubbling nitrogen through the mixture . The reaction mixture was then stirred at 110 ° C for 3 hours . To this mixture was added BINAP ( 73.7 mg , 0.4 equiv . , 1lomμ ) , зabd2dP ( 54.2 mg , 0.2 equiv . , 59.2 lomµ ) , and cesium carbonate ( 193 mg , 2 equiv . , 5lomμ ) to the vial . The mixture was degassed again by bubbling nitrogen through for minutes . The reaction was stirred for another two hours at 120 ° C . The reaction mixture was purified by silica gel column chromatography ( 0 → 50 % EtOAc in DCM ) to yield ( 18,4S ) - N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] - - amine ( 97 mg ) . LCMS : m / z ( ESI ) [ M + H ] * 730.4 tr = 3.36 min ( Method K ) Step 4 : 5 - ( ( 18,4S ) -8 - Bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 18,4S ) -N , N - Dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 50 mg , 1 equiv . , 68 lomµ ) , N , N - dimethyl - 5,6,7,8 - tetrahydro- 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 28 mg , 2 equiv . , 0.14 mmol ) , cesium carbonate ( 67 mg , 3 equiv . , 0.21 mmol ) , ³abd2dP ( 6.3 mg , 0.1 equiv . , 6.8 lomµ ) , and RuPhos ( 6.4 mg , 0.2 equiv . , 14 lomμ ) were combined in a 2 dram vial with 700 Lμ of toluene . This vial was then degassed by bubbling nitrogen through the reaction mixture for 30 minutes . The mixture was then stirred at 90 ° C and monitored for conversion . After three hours , the reaction mixture was diluted with water and EtOAc ( 10 mL ) . The layers were separated , and the 297 WO 2025/064848 PCT / US2024 / 0477 LO aqueous layer was extracted twice with EtOAc ( 5 mL each ) . The combined organics were dried with sodium sulfate , filtered , and concentrated . The crude mixture was purified via silica gel chromatography ( 0 → 10 % MeOH in DCM ) to yield 5 - ( ( 18,4S ) -8 - bromo - 7- ( dibenzylamino ) - ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8- tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 26.2 mg , 0.029 mmol ) . LCMS : m / z ( ESI ) [ M + H ] * 902.5 tr = 2.99 min ( Method E ) Step 5 : 5 - ( ( 1S , 4S ) -8 - Cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide - ( ( 1S , 4S ) -8 - Bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 57 mg , 80 % wt , 1 equiv . , 51 lomμ ) and copper ( I ) cyanide ( mg , 7.8 Lμ , 5 equiv . , 0.25 mmol ) were added to a 40 mL scintillation vial . The vial was evacuated and backfilled with nitrogen three times . DMF ( 0.51 mL ) was added , and the resulting reaction mixture was left to stir at 90 ° C . After 2 hours , the temperature was increased to 95 ° C , and the reaction was stirred for 8 hours . The reaction mixture was quenched by the addition of 10 % NH4OH solution in water and EtOAc ( 10 mL ) . The layers were separated , and the aqueous layer was extracted twice with EtOAc . The combined organics were dried with sodium sulfate , filtered , and concentrated . The crude was purified on a 5.5 g C18 column reverse phase chromatography ( 10 ⇒ 90 % MeCN in water ( 0.1 % formic acid modifier ) ) . The fraction containing the product was concentrated to remove MeCN , and then diluted with saturated sodium bicarbonate solution and EtOAc . The layers were separated and the aqueous was extracted two more times with EtOAc . The combined organic layers were washed with brine , dried with sodium sulfate , filtered , and concentrated to afford 5 - ( ( 1S , 4S ) -8 - cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4- methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N- dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 11.0 mg ) . LCMS : m / z ( ESI ) [ M + H ] * 849.5 tr = 1.71 min ( Method L ) 298 WO 2025/064848 PCT / US2024 / 0477 Step 6 : 5 - ( ( 18,4S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide - ( ( 1S , 4S ) -8 - Cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 11 mg , 1 equiv . , 13 lomμ ) and Pd ( OH ) 2 on carbon ( 18 mg , % wt , 2 equiv . , 26 lomμ ) were added to a 40 mL scintillation vial . This vial was evacuated and backfilled with nitrogen three times . MeOH ( 0.25 mL ) was added followed by acetic acid ( 7.8 mg , 7.4 Lμ , 10 equiv . , 0.13 mmol ) . Hydrogen was then bubbled through the mixture for minutes . The mixture was stirred at room temperature and monitored for conversion of starting material . After 2 hours of additional stirring , acetic acid ( 7.8 mg , 7.4 Lµ , 10 equiv . , 0.13 mmol ) was added , and the reaction was stirred once more after bubbling through hydrogen again for 3 minutes . After 4 hours of stirring , acetic acid ( 7.8 mg , 7.4 Lμ , 10 equiv . , 0.13 mmol ) was added , and hydrogen was again bubbled through the mixture . After 7 hours , the mixture was diluted with MeOH ( 10 mL ) and filtered through a frit and pad of celite . The celite and filter cake were washed with MeOH and DCM . The filtrate was dried over sodium carbonate and filtered once more . The filtrate was concentrated , and the crude mixture was purified via HPLC . The fractions containing the product were combined and concentrated . The aqueous solution was then neutralized with a saturated solution of sodium bicarbonate and extracted three times with EtOAc ( 10 mL each ) . The combined organic layers were dried with sodium sulfate , filtered , and concentrated to yield 5 - ( ( 18,4S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H- pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 3.2 mg ) . LCMS : m / z ( ESI ) [ M + H ] * 669.6 tr = 1.88 min ( Method K ) ' H NMR ( 400 MHz , CDCl3 ) : 8 7.01 ( d , 1H ) , 6.59 ( d , 1H ) , 6.47 ( s , 1H ) , 6.19 ( s , 1H ) , 5.20 ( d , 1H ) , 4.79 ( d , 1H ) , 4.72 ( d , 1H ) , 4.45 – 4.30 ( m , 4H ) , 4.10- 4.01 ( m , 3H ) , 3.93 – 3.( m , 1H ) , 3.40 – 3.06 ( m , 9H ) , 3.05 – 2.75 ( m , 6H ) , 2.17 – 1.77 ( m , 11H ) , 1.61-1.54 ( m , 1H ) , 1.17 ( d , 3H ) – 299 LO WO 2025/064848 PCT / US2024 / 0477 Example 5 : 5 - ( ( 18,4S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -3 - chloro - N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( Compound 113a ) -N CI NH' N ' CN ' N ' F Step 1 : 5 - ( ( 1S , 4S ) -8 - bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -3 - chloro - N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H- pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 175 mg , 1 equiv . , 239 lomμ ) , 3 - chloro - N , N - dimethyl - 5,6,7,8- tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide ( 116 mg , 2 equiv . , 479 lomμ ) , cesium carbonate ( 234 mg , 3 equiv . , 718 lomµ ) , and RuPhos Pd G3 ( 40.0 mg , 0.2 equiv . , 47.lomμ ) were combined in a vial that was then evacuated and backfilled three times with nitrogen . The contents were dissolved in toluene ( 2.4 mL ) . The resulting mixture was stirred at 90 ° C for 5 hours . The mixture was then diluted with water ( 5 mL ) and EtOAc ( 5 mL ) . The layers were separated , and the aqueous layer was extracted with EtOAc ( 5 mL ) . The combined organics were dried with sodium sulfate , filtered , and concentrated to a residue which was purified by reverse phase chromatography ( 12 g C18 column eluting with 10 to 90 % MeCN in water with 0.1 % formic acid modifier ) . The fractions containing the product were combined and concentrated to remove MeCN . The aqueous layer was then neutralized with saturated sodium bicarbonate solution and extracted three times with EtOAc ( 10 mL ) . The combined organics were dried with sodium sulfate , filtered , and concentrated to yield 5 - ( ( 18,4S ) -8- bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] - 300 WO 2025/064848 PCT / US2024 / 0477 4 ' - yl ) -3 - chloro - N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2- carboxamide ( 71 mg ) . LCMS : m / z ( ESI ) [ M + H ] * 936.4 tr = 2.88 minutes ( Method K ) Step : - Chloro - 5 - ( ( 18,4S ) -8 - cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro- 4H - pyrazolo [ 1,5 - a ] [ 1,4 ] diazepine - 2 - carboxamide - ( ( 18,4S ) -8 - Bromo - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -3 - chloro - N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 68 mg , 1 equiv . , 73 lomμ ) and copper ( I ) cyanide ( 32 mg , Lµ , 5 equiv . , 0.36 mmol ) were combined in a 40 mL vial , which was evacuated and back filled three times with nitrogen . To this mixture , DMF ( 0.73 mL ) was added . The resulting reaction mixture was stirred at 100 ° C for 3 hours . The reaction was diluted with 10 % NH4OH solution and EtOAc ( 5 mL ) . The layers were separated , and the aqueous layer was extracted with EtOAc . The combined organic layers were dried over sodium sulfate , filtered , and concentrated to afford 3 - chloro - 5 - ( ( 1S , 4S ) -8 - cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 63 mg ) which was used in the next step without further purification . LCMS : m / z ( ESI ) [ M + H ] * 883.5 tr = 2.77 minutes ( Method K ) Step 3 : 5 - ( ( 18,4S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -3 - chloro - N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide - Chloro - 5 - ( ( 18,4S ) -8 - cyano - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 55 mg , 1 equiv . , 62 lomµ ) and Pd ( OH ) 2 on carbon ( 87 mg , % wt , 2 equiv . , 0.12 mmol ) were combined in a 40 mL vial , which was evacuated and back 301 WO 2025/064848 PCT / US2024 / 0477 LO filled three times with nitrogen . To this mixture , MeOH ( 0.52 mL ) and acetic acid ( 0.11 g , 0.mL , 30 equiv . , 1.9 mmol ) were added . Hydrogen was bubbled through the resulting mixture for 10 minutes and then the mixture was stirred at room temperature for 2.5 hours under a ₂H atmosphere . The reaction was diluted with MeOH ( 10 mL ) and filtered through a frit and a celite pad . The frit and filter cake were thoroughly washed with methanol and DCM . Sodium carbonate ( 100 mg ) was added to the filtrate . The filtrate was then filtered again and concentrated . The crude product was purified via HPLC . The fractions containing the product were combined and concentrated under reduced pressure . The aqueous solution was then neutralized with a saturated solution of sodium bicarbonate and extracted three times with EtOAc ( 10 mL each ) . The combined organic layers were dried with sodium sulfate , filtered , and concentrated to yield 5 - ( ( 18,4S ) -7 - amino - 8 - cyano - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridin ] -4 ' - yl ) -3 - chloro - N , N - dimethyl - 5,6,7,8 - tetrahydro - 4H - pyrazolo [ 1,5- a ] [ 1,4 ] diazepine - 2 - carboxamide ( 12 mg ) .

- LCMS : m / z ( ESI ) [ M + H ] * 703.6 tr = 1.95 minutes ( Method K ) - - - ' H NMR ( 400 MHz , CDC13 ) : 8 7.07 ( d , 1H ) , 6.66 ( d , 1H ) , 6.25 ( s , 1H ) , 5.26 ( d , 1H ) , 4.92 – 4.79 ( m , 2H ) , 4.52 – 4.35 ( m , 4H ) , 4.17 – 4.05 ( m , 3H ) , 3.96 ( d , 1H ) , 3.52 – 3.37 ( m , 2H ) , 3.33 3.05 ( m , 10H ) , 3.02 - 2.81 ( m , 3H ) , 2.26 - 2.06 ( m , 4H ) , 2.00 – 1.81 ( m , 7H ) , 1.– 1.56 ( m , 1H ) , 1.22 ( d , 3H ) .

Example 6 : ( 18,4S ) -7 - Amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro- 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( Compound 142a ) NHF Step 1 : ( 18,48 ) -N , N - dibenzyl - 8 - bromo - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 18,4S ) -N , N - dibenzyl - 8 - bromo - 4 ' - chloro - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- 302 WO 2025/064848 PCT / US2024 / 0477 LO pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 50 mg , 1 equiv . , 68 lomµ ) , 6 - oxa - 1 - azaspiro [ 3.3 ] heptane , oxalic acid ( 20 mg , 2 equiv . , 0.14 mmol ) , cesium carbonate ( 89 mg , 4 equiv . , 0.mmol ) , Pd2 ( dba ) 3 ( 6.3 mg , 0.1 equiv . , 6.8 lomμ ) , and XPhos ( 6.5 mg , 0.2 equiv . , 14 lomμ ) were combined in a 2 dram vial . The reaction vessel was evacuated and backfilled three times with nitrogen . Toluene ( 0.68 mL ) was then added to the vial containing the solids , and the solution was degassed again for 10 minutes by bubbling argon through . This mixture was then stirred at 95 ° C for 90 minutes . The reaction mixture was then quenched by the addition of water ( mL ) and EtOAc ( 5 mL ) . The layers were separated . The aqueous phase was extracted twice more with EtOAc . The combined organic phases were dried with sodium sulfate , filtered , and concentrated to a residue , which was purified by column chromatography ( silica gel column eluting with 0 → 50 % ( 20 % MeOH , 2.5 % NH4OH in DCM mixture ) in DCM to yield ( 18,4S ) - N , N - dibenzyl - 8 - bromo - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) - - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene- 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 39 mg , 49 lomμ ) . LCMS : m / z ( ESI ) [ M + H ] * 793.5 tr = 2.69 min ( Method K ) Step 2 : ( 18,4S ) -7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 18,4S ) -N , N - Dibenzyl - 8 - bromo - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridin ] -7 - amine ( 76 mg , 1 equiv . , lomμ ) and copper ( I ) cyanide ( 43 mg , 15 Lµ , 5 equiv . , 0.48 mmol ) were combined in a 40 mL vial , which was evacuated and backfilled three times with nitrogen . To this mixture , DMF ( 0.mL ) was added , and the reaction was stirred for 10 hours at 90 ° C . The reaction was diluted with EtOAc ( 5 mL ) and aqueous 10 % ammonium hydroxide ( 5 mL ) . The layers were separated , and the aqueous layer was extracted with EtOAc ( 10 mL ) . The combined organics were dried with sodium sulfate , filtered , and concentrated to afford ( 18,4S ) -7- ( dibenzylamino ) - ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1- azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3- b ] pyridine ] -8 - carbonitrile ( 76 mg ) , which was used without further purification . LCMS : m / z ( ESI ) [ M + H ] * 740.5 tr = 2.56 min ( Method K ) 303 WO 2025/064848 PCT / US2024 / 0477 Step 3 : ( 18,4S ) -7 - Amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 18,4S ) -7- ( Dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 76 mg , 1 equiv . , 0.10 mmol ) was dissolved in methanol ( 900 Lµ ) and acetic acid ( 100 Lµ ) . The vial was purged with nitrogen followed by the addition of Pd ( OH ) 2 on carbon ( 72 mg , 20 % wt , 1 equiv . , 0.10 mmol ) . Hydrogen was then bubbled through the solution for 20 minutes and then left to stir at room temperature for 8 hours under a hydrogen atmosphere . The reaction mixture was filtered through celite , rinsed with MeOH , and concentrated to a residue , which was purified by reverse phase chromatography ( loaded directly onto preparative HPLC C18 20 × 150 mm column , eluting with 15-35 % MeCN in water ( 0.1 % TFA modifier ) ) . The fractions containing product were concentrated , and the remaining aqueous layer was neutralized with sodium bicarbonate and then extracted three times with EtOAc . The combined organics were dried with sodium sulfate , filtered , and concentrated to afford ( 18,4S ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro- 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 4 ' - ( 6 - oxa - 1 - azaspiro [ 3.3 ] heptan - 1 - yl ) -3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 5.5 mg , 9.lomμ ) . LCMS : m / z ( ESI ) [ M + H ] * 560.3 tr = 1.76 min ( Method K ) ' H NMR ( 400 MHz , CDCl3 ) : 8 7.07 ( d , 1H ) , 6.65 ( d , 1H ) , 6.41 ( s , 1H ) , 5.44 – 5.16 ( m , 3H ) , 5.09 ( d , 1H ) , 4.94 ( d , 1H ) , 4.79 – 4.70 ( m , 2H ) , 4.43 ( s , 2H ) , 4.26 – 4.29 ( m , 1H ) , 4.- - 4.07 ( m , 2H ) , 3.93 ( d , 1H ) , 3.33 – 3.11 ( m , 4H ) , 2.99 – 2.90 ( m , 1H ) , 2.90 – 2.79 ( m , 2H ) , 2.- 2.41 ( m , 2H ) , 2.30 – 1.78 ( m , 9H ) , 1.65 – 1.57 ( m , 1H ) , 1.22 ( d , 3H ) .

Example 25 : ( 18,4S ) -7 - Amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin- 7a ( 5H ) -yl ) methoxy ) -4 ' - ( ( R ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8'- tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( Compound 146a ) 304 OH NH PCT / US2024 / 0477 Step 1 : ( 18,4S ) -7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H- pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( ( R ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl- 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile To a suspension of ( 18,4S ) -4 ' - chloro - 7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2- fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 50 mg , 74 lomμ , 1 equiv . ) with ( R ) -azetidin - 2 - ylmethanol ( 36 mg , 0.41 mmol , 5.6 equiv . ) and cesium carbonate ( 0.12 g , 0.mmol , 5 equiv . ) in toluene ( 0.74 mL ) was added RuPhos Pd G3 ( 19 mg ) . The mixture was degassed by bubbling N2 through the mixture for 30 minutes , and then the mixture was stirred at 100 ° C for 3 hours . The reaction was stored at -20 ° C for 65 hours , diluted with EtOAc , and filtered through celite . The combined organic layers were concentrated to afford ( 18,4S ) -7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( ( R ) - 2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 105 mg ) as a white solid . LCMS : m / z ( ESI ) [ M + H ] * 728.6 tr = 2.52 min ( Method K ) Step 2 : ( 18,4S ) -7 - amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 ' - ( ( R ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile Palladium hydroxide on carbon ( 100 mg , 0.15 mmol , 20 wt % , 2.0 equiv . ) was added to ( 18,4S ) -7- ( dibenzylamino ) -2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) - yl ) methoxy ) -4 ' - ( ( R ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H- spiro [ naphthalene - 1,7 ' - pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 105 mg , 0.14 mmol ) in a mixture of MeOH ( 0.70 mL ) and AcOH ( 0.10 mL ) . The suspension was stirred under a ₂H atmosphere for 16 hours . An additional amount of Pd ( OH ) 2 on carbon ( 50 mg , 0.15 mmol , 20 % wt , 2.0 equiv . ) was then added . The reaction mixture was stirred at room temperature for hours . The mixture was then filtered through celite . Tetraalkylammonium carbonate ( polymer- bound ) ( 300 mg ) was added to the methanol solution and the resulting mixture was stirred for 305 WO 2025/064848 PCT / US2024 / 0477 LO minutes . The resulting suspension was filtered , and the filtrate was concentrated under reduced pressure to give a residue , which was purified by prep - HPLC to afford ( 18,48 ) -7- amino - 2 ' - ( ( ( 2R , 7aS ) -2 - fluorotetrahydro - 1H - pyrrolizin - 7a ( 5H ) -yl ) methoxy ) -4 ' - ( ( R ) -2- ( hydroxymethyl ) azetidin - 1 - yl ) -4 - methyl - 3,4,5 ' , 8 ' - tetrahydro - 2H - spiro [ naphthalene - 1,7'- pyrano [ 4,3 - b ] pyridine ] -8 - carbonitrile ( 25.5 mg ) as a yellow solid .

- LCMS : m / z ( ESI ) [ M + H ] * 548.5 tr = 1.70 min ( Method K ) ' H NMR ( 400 MHz , MeOD ) 8 7.15 ( d , 1H ) , 6.80 ( d , 1H ) , 6.15 ( s , 1H ) , 5.71 – 5.42 ( m , 1H ) , 5.16 ( d , 1H ) , 4.91 ( d , 1H ) , 4.80 ( dd , 1H ) , 4.60 – 4.45 ( m , 4H ) , 4.06 – 3.98 ( m , 1H ) , 3.- - – 3.89 ( m , 2H ) , 3.87 – 3.83 ( m , 1H ) , 3.83 – 3.74 ( m , 1H ) , 3.52 – 3.40 ( m , 1H ) , 3.26 ( s , 1H ) , 2.98 – 2.84 ( m , 2H ) , 2.72 – 2.60 ( m , 1H ) , 2.57 ( s , 1H ) , 2.62 – 2.51 ( m , 1H ) , 2.47 – 2.24 ( m , 4H ) , 2.24 – 2.19 ( m , 1H ) , 2.08 – 1.86 ( m , 3H ) , 1.74 – 1.64 ( m , 1H ) , 1.24 ( d , 3H ) .

The following examples were synthesized using methods similar to those described in the examples above : Example Compound LCMS ( ESI ) Method No. No. 109a LCMS : m / z ( ESI ) [ M + H ] * 689.4 , tr = 1.minutes Method B LCMS : m / z ( ESI ) [ M + H ] * 703.3 , tR = 1.8 113b Method E minutes 109b LCMS : m / z ( ESI ) [ M + H ] * 689.4 , tr = 4.and 4.75 minutes Method I LCMS : m / z ( ESI ) [ M + H ] * 512.5 , tr = 4.10 120a Method I minutes 119a LCMS : m / z ( ESI ) [ M + H ] * 689.4 , tr = 4.and 4.75 minutes Method I 12 110b LCMS : m / z ( ESI ) [ M + H ] * 707.2 , tr = 1.minutes Method C LCMS : m / z ( ESI ) [ M + H ] * 689.5 , tr = 1.13 109d Method B minutes 143a LCMS : m / z ( ESI ) [ M + H ] * 467.2 , tr 1.78 / 1.80 minutes Method E LCMS : m / z ( ESI ) [ M + H ] + 585.5 , tr = 1.15 137a Method B minutes 102b LCMS : m / z ( ESI ) [ M + H ] + 673.3 , tr = 2.15 / 2.20 minutes Method K LCMS : m / z ( ESI ) [ M + H ] * 463.6 , tr = 2.17 138a Method K minutes LCMS : m / z ( ESI ) [ M + H ] + 520.4 , tR = 1.18 126a Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 614.4 , tr = 1.19 121a Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 492.4 , tr = 1.20 124a Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 498.4 , tr = 1.21 123a Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 628.5 , tr = 1.22 122a Method B minutes 306 WO 2025/064848 PCT / US2024 / 0477 Example Compound LCMS ( ESI ) Method No. No. 127a 224 136a LCMS : m / z ( ESI ) [ M + H ] * 534.4 , tr = 1.minutes LCMS : m / z ( ESI ) [ M + H ] + 571.4 , tr = 1.minutes Method B Method B 27 149a LCMS : m / z ( ESI ) [ M + H ] * 701.4 , tr = 4.and 4.31 minutes Method I 28 148a LCMS : m / z ( ESI ) [ M + H ] * 659.4 , tr = 1.minutes Method B 29 146b LCMS : m / z ( ESI ) [ M + H ] * 548.5 , tr = 1.minutes Method B 147a LCMS : m / z ( ESI ) [ M + H ] * 645.4 , tr = 1.minutes Method B 31 125a LCMS : m / z ( ESI ) [ M + H ] + 506.5 , tr = 4.minutes Method I 32 145a LCMS : m / z ( ESI ) [ M + H ] + 671.5 , tR = 1.minutes Method B LCMS : m / z ( ESI ) [ M + H ] * 572.5 , tr = 1.33 144a Method K minutes LCMS : m / z ( ESI ) [ M + H ] * 542.5 , tr = 1.34 140a Method K minutes 141a LCMS : m / z ( ESI ) [ M + H ] * 546.4 , tr = 4.minutes Method I 36 150a LCMS : m / z ( ESI ) [ M + H ] * 576.4 , tr = 1.minutes Method E LCMS : m / z ( ESI ) [ M + H ] + 576.3 , tr = 1.37 150b Method E minutes LCMS : m / z ( ESI ) [ M + H ] + 560.5 , tr = 4.38 151a Method I minutes LCMS : m / z ( ESI ) [ M + H ] * 560.5 , tr = 4.39 151b Method I minutes LCMS : m / z ( ESI ) [ M + H ] + 560.4 , tr = 4.40 151c Method I minutes LCMS : m / z ( ESI ) [ M + H ] * 588.9 , tr = 2.41 152a Method D minutes LCMS : m / z ( ESI ) [ M + H ] * 588.9 , tr = 2.42 152b Method D minutes LCMS : m / z ( ESI ) [ M + H ] * 701.5 , tr = 4.43 149b Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 701.5 , tr = 4.44 149c Method B minutes LCMS : m / z ( ESI ) [ M + H ] + 574.5 , tr = 2.45 153a Method K minutes LCMS : m / z ( ESI ) [ M + H ] * 574.5 , tr = 2.46 153b Method K minutes LCMS : m / z ( ESI ) [ M + H ] * 477.5 , tr = 4.47 154a Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 562.4 , tR = 1.48 155a Method M minutes LCMS : m / z ( ESI ) [ M + H ] * 578.4 , tr = 3.49 156a Method I minutes LCMS : m / z ( ESI ) [ M + H ] + 562.4 , TR = 1.50 155b Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 535.4 , tr = 1.51 139a Method B minutes LCMS : m / z ( ESI ) [ M + H ] * 561.5 , tr = 1.52 157a Method B minutes 307 WO 2025/064848 PCT / US2024 / 0477 Example Compound LCMS ( ESI ) Method No. No. 157b 54 139b LCMS : m / z ( ESI ) [ M + H ] + 561.5 , tr = 1.minutes LCMS : m / z ( ESI ) [ M + H ] * 535.4 , tr = 1.minutes Method B Method B LO Example B1 . Surface Plasmon Resonance Methods herein pertain to Cytiva ( formerly Biacore ) instrumentation and consumables and are applicable to other SPR - based systems . A Series S Streptavidin or Neutravidin chip is docked into a Biacore 8K . The instrument is then primed into an appropriate running buffer ( for example , 20 mM HEPES , pH 7.4 , 150 mM NaCl , 5 mM MgCl2 , 1 mM TCEP , 0.005 % Tween - 20 , and 2 % DMSO ) supplemented with either 5 Mμ GDP or GMPPNP to match the nucleotide state of the KRas state being tested ( GDP for KRas in the GDP - bound state ; and GMPPNP for KRas in the GTP - bound state ) . Biotinylated - KRas loaded with the appropriate nucleotide state ( e.g. , GDP or GMPPNP ) is then captured to between 500-2000 RU to provide adequate signal for small molecules of interest , typically in a range of 300-600 Da , as well as to accommodate a range of potencies , when appropriate . The remaining biotin binding sites can be blocked with Biocytin . Compounds are injected over both a reference surface ( Streptavidin or Neutravidin alone ) as well as the active surface ( KRas captured to Neutravidin or Streptavidin ) , and all curves are double - referenced before analysis ( specifically , a signal subtraction of the reference flow cell from the active flow cell as well as a buffer subtraction ) . Where appropriate , a solvent correction is applied to all curves to account for differential bulk effects from DMSO on the reference and active surfaces . Data is then analyzed using the Biacore software fitting kinetics if resolvable , or fitting via a Langmuir isotherm model if no kinetics are resolvable , to report a binding affinity as a dissociation constant , ĎK .

Example B2 . SOS1 - Catalyzed Nucleotide Exchange Assay KRas G12R and WT : 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 30 Mμ top dose . Biotinylated KRas WT ( 1-169 ) or KRas G12R ( 1-169 ) loaded with GDP nucleotide is mixed with Streptavidin - Tb cryptate ( Cisbio ) in assay buffer ( 20 mM HEPES pH 7.4 , 150 mM NaCl , 2 mM MgCl2 , and 0.005 % CA680 ) to produce a 1.5x solution . 10 Lµ of the 1.5x KRas - cryptate solution is added to wells of a black , low- volume 384 - well assay plate . The KRas / cryptate - compound mixture is incubated for 1 hour at room temperature . A 3x solution of SOS1 ( 564-1049 ) and EDA - GTP - DY - 647P1 ( Jena 308 WO 2025/064848 PCT / US2024 / 0477 LO - Bioscience ) is prepared in assay buffer . 5 Lμ of the SOS1 - labeled GTP solution is added to the wells to initiate the nucleotide exchange reaction . The final concentration of KRas G12R and SOS1 are 10 nM and 200 nM , respectively . The final concentration of KRas WT and SOS1 are nM and 10 nM , respectively . The plate is allowed to incubate for 1 hr , then 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 ] / [ emission 620 nm ] . IC 50 values are calculated using a four - parameter , variable response sigmoidal dose response curve fit in PerkinElmer Signals Vitro Vivo .

KRas G12V : Compounds were pre - dispensed via Echo liquid handling ( acoustic , touch - free ) to generate assay ready plates ( ARP ) . More precisely , a 10 - point concentration response curve for each compound was prepared with appropriate top concentration ( 1 Mμ , 10 . Mµ , 100 Mµ ) . Biotinylated KRas G12V ( aa 1-169 ) loaded with GDP nucleotide and Streptavidin - Europium ( SA - EU , Columbia Biosciences ) were preincubated in assay buffer ( 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 SOS1 ( aa 546-1049 ) and EDA - GTP - DY647P1 ( Jena Bioscience ) were preincubated in assay buffer on ice for 30 min . After 30 minutes of incubation for the assay components , 5 Lμ buffer and 5 Lμ of KRas G12V - SA - Eu were added to each well of the ARP . After a further 30 min , 5 Lμ of SOS1 - EDA - GTP - D467P1 was added to start the nucleotide exchange reaction . Final concentration in the assay were 5 nM KRas G12V , nM SOS1 ( aa 564-1049 ) . The reaction was allowed to proceed for 60-90 minutes after which the plate was read on a plate reader . After normalization of the raw data , the data was fit to a four - parameter logistic curve . For some compounds , data was collected at multiple sites , and the geometric mean value is presented in Table B1 below with two significant figures . The results are summarized in Table B1 , below : Table B1 .

Compound KRas G12V No. IC50 ( uM ) 102b 1.104a 0.00106b 0. 309 Compound No. KRas G12V IC50 ( Mμ ) 107b 0.0108a 0.00108b 0.00108c 1.109a < 0.00109b 0.00109d 0.110b > 113a < 0.00113b 8.119a 2.120a 0.00121a 0.0122a 0.00123a 0.00124a 0.00125a 0.00126a 0.00127a 0.00136a 0.00137a 0.00138a 0.00140a 0.00141a 0.00142a 0.00143a 1.144a 0.00145a 0.00146a < 0.00146b 0.00147a 0.0148a 0.0149a 0.00149b 0.00149c 0.00150a 0.0150b > 151a 0.00151b < 0.00151c 0.00152a 0.003 PCT / US2024 / 047734 Compound No. KRas G12V IC50 ( uM ) 152b 0.00153a < 0.00153b < 0.00154a 0.155a 0.00155b 0.00156a < 0.00157a 0.157b 0.0 PCT / US2024 / 0477 Example B3 . 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 Mμ03 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 Lµ 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 Lμ 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 Lμ 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 ] . IC50 values are calculated using a four - parameter , variable response sigmoidal dose response curve fit in PerkinElmer Signals VitroVivo .

== Example B4 . KRas - cRAF Protein - Protein Interaction ( PPI ) Assay = Version 1 : 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 311 WO 2025/064848 PCT / US2024 / 0477 performed with a Mμ03 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- , 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 Lμ buffer and 5 Lμ 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 Signal 665mm / Signal620nm ) the data is fit to a four - parameter logistic curve in GraphPad Prism ( v9.4.1 ) . Version 2 : Compounds are pre - dispensed via Echo liquid handling ( acoustic , touch- free ) to generate assay ready plates ( ARP ) . More precisely , a 10 - point concentration response curve for each compound is prepared with appropriate top concentration ( e.g. , 1 Mμ or 30 Mμ ) . 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 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 Lµ of KRas G12V - SA - Eu is added to each well of the ARP . After a 30 min equilibration phase at room temperature , 5 Lμ of GST - cRAF - anti - GST - APC is added to each well . Final concentrations in the assay are 5 nM KRas G12V , 5 nM CRAF . The reaction is allowed to proceed for 60-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 Signal 665 nm / Signal 620nm ) the data is fit to a four - parameter logistic curve . Version 3 : Compounds are pre - dispensed via Echo liquid handling ( acoustic , touch- free ) to generate assay ready plates ( ARP ) . More precisely , a 10 - point concentration response curve for each compound is prepared with appropriate top concentration ( e.g. , 1 Mμ or 30 Mμ ) . Biotinylated KRas G12D ( 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 min . Separately , GST - tagged CRAF ( 1-149 ) and anti - GST - APC antibody ( Columbia 312 WO 2025/064848 PCT / US2024 / 0477 LO Biosciences ) are preincubated in assay buffer on ice for 30 min . After incubation , 5 Lμ of KRas G12D - SA - Eu is added to each well of the ARP . After a 30 min equilibration phase at room temperature , 5 Lμ of GST - CRAF - anti - GST - APC is added to each well . Final concentrations in the assay are 4 nM KRas G12D , 4 nM CRAF . The reaction is allowed to proceed for 60-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 Signal 665 nm / Signal 620nm ) the data is fit to a four - parameter logistic curve .

Example B5 . Surface Plasmon Resonance ( SPR ) Biacore 8K buffer line was placed into 1 L of Immobilization buffer ( 20 mM HEPES pH 7.5 / 150 mM NaCl / 5 mM MgCl2 / 0.5 mM TCEP / 0.005 % P20 / 500 nM GDP ) and Change Solutions was performed . A Biacore Series S SA chip ( Cytiva 29104992 ) was inserted and Change Solutions was performed 3 times . The chip surface was conditioned by injecting conditioning solution ( 40 mM NaOH / 1 mM NaCl ) in four pulses of 30 seconds at 30 uL / min . These pulses were followed by pulses of running buffer injected for 30 seconds at 30 uL / min . Normalization was run using the BiaNormalize solution ( Cytiva 29207950 ) . 300 nM Biotinylated KRas G12V 1-169 was injected over all active flow cells at a flow rate of 5 uL / min until reaching a response of 1000 RUs . The buffer line was switched into Running Buffer ( mM HEPES pH 7.5 / 150 mM NaCl / 5 mM MgCl2 / 0.5mM TCEP / 0.005 % P20 / 500 nM GDP / 2 % DMSO ) and Change Solutions was performed . Compounds were plated into a Greiner v - bottom 384 - well Microplate ( Greiner 781280 ) in 8 - point dose - response with a log- fold dilution with a final volume of 2 uL in DMSO . 98uL of non - DMSO containing buffer was backfilled into all compound wells ( final volume of 100 uL with 2 % DMSO ) . Solvent corrections of 1 % , 1.5 % , 2 % , 2.5 % , and 3 % DMSO were plated into a Greiner U - bottom 96- well microplate ( Greiner 650201 ) . The SPR method was run with both flow cell and sample compartment at 20 ° C or 37 ° C with 5 startup cycles of 30 second association , and 30 second dissociation at a flow rate of 70 uL / min . An eight - point single cycle kinetics ( SCK ) analysis was run with 30 second association time , 1600 second dissociation time , 70 uL / min flow rate , 1600 sec stability period , and a 50 % DMSO wash after injection . Solvent corrections were run at the end of the method . Results were analyzed with the Biacore Insights Evaluation Software using the Single Cycle Kinetics analysis method . Sensorgrams are fit using a 1 : 1 binding model . KD values , as an average of multiple runs , if applicable , are reported in Table B2 with two significant figures . 313 Table B2 .

Compound No. KRas G12V GDP KD ( nM ) , 20 ° C KRas G12V GDP KD ( nM ) , 37 ° C 102b > 50104a 0.13 0.106b 1107b 108a 0.48 6.108b 0.62 9.108c > 50109a 0.27 2.109b 0.109d > 50110b > 5000 > 50113a 0.20 0.113b > 5000 > 50119a > 5000 > 50120a 0.33 6.121a 14 1122a 1.6 123a 6.0 124a 5.1 125a 0.29 7.126a 1.9 127a 0.36 7.136a 8.7 137a 1.8 138a 0.80 139a 139b > 5140a 0.054 0.141a 2.142a 0.077 0.143a 11144a 0.13 0.145a 0.59 6.146a 0.018 0.146b 147a 37 3148a 149a 5.3 PCT / US2024 / 047734 Compound KRas G12V GDP KRas G12V GDP KD ( nM ) , 37 ° C No. KD ( nM ) , 20 ° C 149b 6.149c 150a 3150b > 5151a 151b 0.151c 1.152a 152b 0.153a 0.0153b 0.154a 7155a 3.155b 156a 0.157a > 5157b PCT / US2024 / 0477 Example B6 . Measurement of cellular phospho- and total - ERK1 / In a white , opaque - bottom Revvity CulturPlate - 384 , SW620 [ SW - 620 ] ( ATCC CCL- 227 ™ ) cells were seeded at previously determined seeding densities such that the well would be approximately 80 % confluent at the end of the assay , and incubated overnight in a standard ° C , 5 % CO2 humidified incubator . The day after seeding , compounds were dispensed into the treatment plates using a Tecan D300e compound printer in 9 - point DRC format , 10- micromolar top concentration , in triplicate . Treatment plates were then returned to a 37 ° C , % CO2 humidified incubator for 2 hours unless otherwise stated . Following compound treatment , phosphoERK and total ERK were measured using the Alpha SureFire Ultra Multiplex Phospho / Total ERK1 / 2 Assay Kit ( Revvity ) . All media was removed from the treatment plate ( s ) and the cells subsequently lysed using 1X Lysis Buffer in accordance with manufacturer protocol . Next , the Acceptor Mix ( prepared in accordance with manufacturers protocol ) was added to each well of the assay plate and incubated on an orbital shaker at room temperature for 2 hours . Following Acceptor incubation , the Donor Mix ( prepared in accordance with manufacturer protocol ) was added to each well of the assay plate , covered to protect from light and incubated on an orbital shaker at room temperature overnight . Assay plates were read the following day on a BMG Labtech PHERAstar FSX microplate reader . 315 WO 2025/064848 PCT / US2024 / 0477 Data were then analyzed by calculating the ratio of ERK 1 / 2 - phosphorylation relative to Total ERK1 / 2 for each individual well . 615nm Signal ( pERK1 / 2 ) Ratio PERK1 / == 545nm Signal ( Total ERK1 / 2 ) The replicate ratios for each concentration were averaged and normalized to DMSO control or other corresponding co - treatment before performing a variable slope ( 4 - parameter ) , non - linear regression curve fit for each compound of interest . IC50 values , as a geometric mean of multiple runs , if applicable , are reported in Table B3 with two significant figures .

Table B3 .

Compound No. PERK SW6IC50 ( uM ) 104a 0.00107b 0.108a 0.0108b 0.0109a 0.0113a 0.00119a 3.120a 0.0121a 2.122a 0.123a 0.124a 0.125a 0.0126a 0.127a 0.136a 0.137a 0.0138a 0.140a 0.00141a 0.0142a 0.000144a 0.00145a 0.146a 0.00146b 0.0 316 Compound No. PERK SW6IC50 ( Mμ ) 147a 3.148a 1.149a 0.149b 0.0149c 0.150a 0.151a 0.151b 0.00151c 0.00152a 0.0152b 0.00153a 0.000153b 0.00155a 0.00155b 0.0156a 0.00 PCT / US2024 / 0477 Example B7 . Measurement of cellular proliferation In black , clear - bottom 384 - well tissue culture treated plates , SW620 [ SW - 620 ] ( ATCC CCL - 227 ™ M ) or MIAPaCa - 2 ( Sigma cb_85062806 ) cells were seeded at previously determined seeding densities such that the well would be approximately 80 % confluent at the end of the assay . Immediately after seeding , compounds were dispensed into the treatment plates using a Tecan D300e compound printer in 9 - point DRC format , 10- micromolar top concentration , in triplicate . Treatment plates were then transferred to a 37 ° C , 5 % CO2 humidified incubator for hours unless otherwise stated . After the completion of treatment , CELLTITER - ®OLG 2.reagent ( Promega ) was added directly to each well . The plates were covered to protect from light and incubated on an orbital shaker at room temperature for 30 minutes . Immediately before reading the assay plates , an opaque seal was attached to the bottom of each clear - bottom plate ; assay plates were then read on a BMG Labtech PHERAstar FSX microplate reader . Data were analyzed by calculating the ratio of signal from treated wells relative to negative control- treated wells . The replicates were averaged and a variable slope ( 4 - parameter ) , non - linear regression curve was fitted for each compound of interest . IC50 values , as a geometric mean of multiple runs , if applicable , are reported in Table B4 with two significant figures . 317 Table B4 .

Compound No. Proliferation SW6IC50 ( uM ) Proliferation MIA - PaCa - IC50 ( uM ) 104a 0.033 0.107b 5.3 8.108a 0.36 0.108b 0.23 0.109a 0.095 0.113a 0.024 0.0119a > 10 > 120a 0.28 0.122a 1.8 2.125a 0.23 0.127a 1.8 2.136a 4.1 5.137a 2.3 > 138a 0.43 0.140a 0.034 0.141a 0.073 0.142a 0.0096 0.0144a 0.044 0.145a 3.7 7.146a 0.014 0.0146b 0.39 0.147a 8.4 > 148a 4.6 7.149a 0.89 1.149b 1.0 3.149c 1.0 3.150a > 10 > 151a 0.17 0.151b 0.030 0.0151c 0.20 0.152a 1.1 0.152b 0.040 0.0153a 0.0047 0.0153b 0.041 0.

PCT / US2024 / 047734 Compound No. Proliferation SW6IC50 ( uM ) Proliferation MIA - PaCa - IC 50 ( Mμ ) 155a 0.13 0.155b 0.80 1.156a 0.093 0.0157b 2.0 6.

PCT / US2024 / 0477 LO Example B8 . Protein Production A KRas construct of amino acid residues 1-169 , harboring the G12V mutation , a C- terminal Avi tag , and an N - terminal 6x Histidine tag followed by a tobacco etch virus ( TEV ) protease site was expressed in E. coli BL21 ( DE3 ) . A single colony was inoculated in 100 mL LB with 100 gμ / mL ampicillin and incubated at 37 ° C overnight on an orbital shaker at 2rpm . The overnight strain was inoculated into 2L TB with 100 gµ / mL ampicillin at a ratio of : 100 . The culture was grown at 37 ° C on an orbital shaker until the OD600 reached 0.8 . The culture was cooled to 18 ° C , induced with IPTG at a final concentration of 0.2 mM and grown hours at 18 ° C on an orbital shaker at 180 rpm . Cells were harvested at 13,600 × g for minutes at 4 ° C .

The KRas G12V protein was purified by affinity chromatography using NiNTA resin . The cell pellet resuspended in 20 mM Tris pH 8.0 , 500 mM NaCl , 2 mM beta - mercaptoethanol supplemented with EDTA - free protease inhibitor ( Roche ) . Cells were sonicated at a power of 350 W with 3 s on and 3 s off pulses for a total of 300 cycles . The lysate was centrifuged at 13,600 x g at 4 ° C for 30 min . The supernatant was collected and centrifuged a second time with the same parameters . 5 mL NiNTA resin was pre - equilibrated with 20 mM Tris pH 8.0 , 500 mM NaCl , 2 mM beta - mercaptoethanol , added to the cleared lysate , and incubated for 2 h at 4 ° C on a rotator . The resin was washed in succession with 20 mM Tris pH 8.0 , 500 mM NaCl , 10 mM imidazole , 2 mM beta - mercaptoethanol , and then 20 mM Tris pH 8.0 , 500 mM NaCl , 20 mM imidazole , 2 mM beta - mercaptoethanol . Finally , the protein was eluted from the resin using 20 mM Tris pH 8.0 , 500 mM NaCl , 250 mM imidazole , 2 mM beta- mercaptoethanol . The 6x Histidine tag was removed from the KRas G12V protein by overnight incubation with TEV protease at 4 ° C while dialyzing against 20 mM HEPES pH 7.5 , 150 mM NaCl . The Avi tag on the C terminus was specifically labeled with biotin using recombinant 319 WO 2025/064848 PCT / US2024 / 0477 BirA enzyme during the tag cleavage process . 16 mg of recombinant BirA enzyme , 1 mM biotin , 7 mM ATP , and 7.5 mM MgCl2 was added to the 4 ° C overnight reaction . KRas G12V protein was subsequently mixed with NiNTA resin pre - equilibrated with 20 mM HEPES PH 7.5 , 150 mM NaCl - the cleaved and biotinylated protein was collected in the flow - through . KRas G12V protein was subsequently loaded with nucleotide by adding 10 mM EDTA and 2 mM GDP . The mixture was incubated on a rotator overnight at 4 ° C . 20 mM MgCl2 was added to quench loading and stabilize the protein . KRas G12V was further purified and excess GDP nucleotide was removed by size exclusion chromatography . The protein was loaded on a Superdex 75 pg 16/600 column equilibrated with 20 mM HEPES pH 7.5 , 150 mM NaCl and eluted with an isocratic flow . Biotin incorporation and GDP loading was confirmed by mass spectrometry on an Agilent 1290 Infinity II UPLC connected to an Agilent 6545XT qTOF .

P01 Exemplary Embodiments EMBODIMENTS Embodiment 1 . A compound of Formula ( A ) R B N Formula ( A ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; and -N A²A b2 ( R7 ) . ( ii ) wherein b2 is 0 , 1 , 2 , or 3 ; and A1 and A2 are independently selected from the group consisting of : N , CH , and CR7 ; each R7 is independently selected from the group consisting of Ra and Rb ; 320 ⁹R x Ring B is : b1 ( R10 ) * 3- PCT / US2024 / 0477 , wherein the * marks the ring carbon atom common to both Ring B and O ; H ' N ' E 1✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , CHRL , C ( RL ) 2 , and X2 and ³X are independently selected from the group consisting of : ₂HC , ¹RHC , C ( ¹R ) 2 , O , and S ( O ) 0-2 , provided that no more than one of X1 , ²X , and ³X is selected from the group consisting of : O and S ( O ) 0-2 ; b1 is 0 , 1 , or 2 ; , ﻭ R ' is selected from the group consisting of : H , OH , eRªRN , and halo ; each R10 is independently selected from the group consisting of Ra and ³R ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 ºR ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe ; 321 each ªR is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) -C1-6 alkoxy ; ( f ) -C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) C ( = O ) C1-6 alkyl ; ( i ) C ( = O ) C1-6 haloalkyl ; ( j ) C ( = O ) OH ; ( k ) C ( = O ) OC1-6 alkyl ; ( 1 ) C ( = O ) OC1-6 haloalkyl ; ( m ) C ( = O ) N ( ³R ) 2 ; ( n ) S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) PCT / US2024 / 0477 ( q ) S ( O ) 1-2N ( R ) 2 ; and C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 ºR ; each ³R is independently selected from the group consisting of : - ( Lb ) ¹ыR- and ¹³R- wherein : b is 1 , 2 , or 3 ; each -Lb is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , C ( = O ) , and C1-3 alkylene ; and each ¹¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each R is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NRdRe , C ( = O ) C1-6 alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) OH , C ( = O ) N ( ³R ) 2 , S ( O ) 0-2 ( C1-6 alkyl ) , S ( O ) 0-2 ( C1-6 haloalkyl ) , and S ( O ) 1-2N ( R ) 2 ; each Rd and Re is independently selected from the group consisting of : H , C ( = O ) C1- 322 WO 2025/064848 PCT / US2024 / 0477 alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) N ( ³R ) 2 , S ( O ) 1- ( C1-6 alkyl ) , S ( O ) 1-2 ( C1-6 haloalkyl ) , S ( O ) 1-2N ( ³R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each ³R is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2- .

Embodiment 2 . compound of Formula ( I ) : The compound of Embodiment 1 , wherein the compound is a b1 ( R10 ) - ⁹R R -Spa X* E ' N ' ³R Formula ( I ) or a pharmaceutically acceptable salt thereof .

Embodiment 3. The compound of Embodiment 1 or 2 , wherein R is selected from the group consisting of : OH and NRdRe .

Embodiment 4 . The compound of any one of Embodiments 1-3 , wherein R9 is NRdRe Embodiment 5 . NH2 . or 2 .

The compound of any one of Embodiments 1-4 , wherein ⁹R is Embodiment 6 . The compound of any one of Embodiments 1-5 , wherein b1 is 323 WO 2025/064848 PCT / US2024 / 0477 Embodiment 7 . The compound of any one of Embodiments 1-6 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Re ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 8 . compound is a compound of Formula ( I - a ) : The compound of any one of Embodiments 1-6 , wherein the NH b1 ( R10 ) .

-Spa R E ³R Formula ( I - a ) or a pharmaceutically acceptable salt thereof , wherein : b1 is 1 or 2 .

Embodiment 9. The compound of Embodiment 8 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 10 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - b ) : ⁹R RCN b4 ( R10 ) . E + 2- Formula ( I - b ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 R ° ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

NH2 ) . Embodiment 11. The compound of Embodiment 10 , wherein R is eRªRN ( e.g. , 324 LO WO 2025/064848 PCT / US2024 / 0477 Embodiment 12. The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - c ) : NHRCN b4 ( R10 ) - E ³R Formula ( I - c ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 13 . The compound of any one of Embodiments 1-12 , wherein ¹X is CH2 .

Embodiment 14. The compound of any one of Embodiments 1-13 , wherein ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( ¹R ) 2 , and O.

Embodiment 15. The compound of any one of Embodiments 1-14 , wherein ¹X is CH2 ; and ²X and ³X are both CH2 .

Embodiment 16. The compound of any one of Embodiments 1-14 , wherein ¹X is CH2 ; ²X is CH2 ; and ³X is CHRL .

Embodiment 17. The compound of any one of Embodiments 1-14 , wherein X1 is CH2 ; ²X is -O- ; and ³X is selected from the group consisting of : CH2 , ¹RHC , and C ( ¹R ) 2 ( e.g. , ³X is CH2 or ¹RHC ) .

Embodiment 18. The compound of any one of Embodiments 1-17 , wherein each RL is independently selected from the group consisting of : CH3 , CF3 , CHF2 , and F₂HC . 325 LO WO 2025/064848 PCT / US2024 / 0477 Embodiment 19. The compound of any one of Embodiments 1-12 , wherein X1 is CHRL ; ²X is O or CH2 ; and ³X is ³RHC , wherein the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

Embodiment 20 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - d ) : ⁹R R b1 ( R10 ) . E ' N ' ³R Formula ( I - d ) or a pharmaceutically acceptable salt thereof , wherein : ¹X is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and O ; and ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that : at least one of X1 , X2 , and ³X is CHRL or C ( RL ) 2 , and no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 .

Embodiment 21 . CH2 ; and X3 is CHRL . The compound of Embodiment 20 , wherein ¹X is CH2 ; X2 is Embodiment 22 . The compound of Embodiment 20 or 21 , wherein RL is selected from the group consisting of : CH3 , CF3 , CHF2 , and CH2F .

Embodiment 23 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - e ) : ⁹R R b1 ( R10 ) . E Formula ( I - e ) or a pharmaceutically acceptable salt thereof , wherein : 326 WO 2025/064848 PCT / US2024 / 0477 LO 0 ; 1✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , CHRL , C ( ¹R ) 2 , and ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( ¹R ) 2 , O , and S ( O ) 0-2 , provided that 2-3 of X1 , X2 , and ³X are independently CHRL or C ( ¹R ) 2 , wherein : one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; and each additional ¹R is independently selected from the group consisting of : C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 24 . The compound of Embodiment 23 , wherein X2 is CH2 or O ( e.g. , CH2 ) .

Embodiment 25. The compound of Embodiment 23 or 24 , wherein ¹X is CHRL ; ³X is ¹RHC ; and the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

Embodiment 26 . The compound of any one of Embodiments 20-25 , wherein Ris NRdRe ( e.g. , NH2 ) .

Embodiment 27 . The compound of any one of Embodiments 20-26 , wherein b1 is or 2 ; and each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 28. The compound of any one of Embodiments 20-27 , wherein the ⁹R b1 ( R10 ) - NHCN b4 ( R10 ) . moiety is ﻭ wherein b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 ºR ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 29. The compound of any one of Embodiments 1-28 , wherein ¹E is CH . 327 LO WO 2025/064848 PCT / US2024 / 0477 Embodiment 30 . The compound of any one of Embodiments 1-28 , wherein ¹E is CR Embodiment 31 . The compound of any one of Embodiments 1-28 or 30 , wherein ¹E is C - F .

Embodiment 32 . The compound of any one of Embodiments 1-31 , wherein ²Y is -CH2- ; and ³R is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-additional ring heteroatom selected from the group consisting of oxygen and nitrogen , wherein the heterocyclyl is optionally substituted with 1-6 Ra .

F Embodiment 33. The compound of any one of Embodiments 1-32 , wherein ³R is F b2 ( R7 ) . ( e.g. , Embodiment 34 .

' N ' N = A ²A The compound of any one of Embodiments 1-33 , wherein ¹R is , wherein b2 is 0 , 1 , or 2 , and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 .

Embodiment 35 . RThe compound of any one of Embodiments 1-34 , wherein ¹R is ﮧﻳں ﻢﻳں ' N ' or Embodiment 36 . R7a The compound of any one of Embodiments 1-35 , wherein ¹R is R7a or R7b wherein : 328 WO 2025/064848 PCT / US2024 / 0477 R7a is selected from the group consisting of : C ( = O ) N ( R ) 2 , C ( O ) N ( C1-3 alkyl ) ¹³R , - C ( O ) N ( H ) Rb1 , Rb1 , and C ( O ) Rb1 ; and R7b is selected from the group consisting of : halo , cyano , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

Embodiment 37. The compound of Embodiment 36 , wherein ª7R is selected from the group consisting of : ( a ) C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh ; ﻭ ( b ) C ( O ) N ( C1-3 alkyl ) ¹ыR or -C ( O ) N ( H ) ¹ыR , wherein : Rb1 is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 Rg ; and ( c ) C ( O ) Rb1 , wherein R1 is 4-10 membered heterocyclyl optionally substituted with 1-3 Rg , wherein Rb1 is attached to the C ( O ) via a ring nitrogen atom . , Embodiment 38. The compound of any one of Embodiments 35-37 , wherein R7a is C ( = O ) N ( ³R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh Embodiment 39 . is halo ( e.g. , -CI ) .

Embodiment 40 .

The compound of any one of Embodiments 35-38 , wherein R7b The compound of any one of Embodiments 1-39 , wherein ¹R is 3 Rh ' N ' Rf ' N ' Rf ﻭ wherein each Rf is independently C1-3 alkyl optionally substituted with 1- Embodiment 41. The compound of any one of Embodiments 1-40 , wherein ¹R is ' N ' 329 PCT / US2024 / 0477 ﺖﻤﺳﺎﺣ LO Embodiment 42. The compound of any one of Embodiments 1-33 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R7 .

Embodiment 43 . The compound of Embodiment 42 , wherein ¹R is optionally substituted with 1-4 R7 at one or more ring carbon atoms ( e.g. , ¹R is Embodiment 44. The compound of Embodiment 42 or 43 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Re , wherein : each RC present on R7 is independently selected from the group consisting of : -F , -OH , and -CN .

Embodiment 45. The compound of any one of Embodiments 1-33 , wherein ¹R is a 4-10 membered heterocyclyl substituted with -CN , - ( C1-3 alkylene ) -CN , or - ( C3-cycloalkylene ) -CN on a ring carbon atom , wherein the heterocyclyl is further optionally substituted with 1-3 R7 . Embodiment 46. The compound of any one of Embodiments 1-33 or 45 , wherein ¹R is a 6-8 membered heterocyclyl substituted with -CN or - ( C1-3 alkylene ) -CN on a ring carbon atom , wherein : the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom ; and the heterocyclyl is further optionally substituted with 1-3 R7 .

Embodiment 47. The compound of Embodiment 45 or 46 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) . 330 WO 2025/064848 PCT / US2024 / 0477 Embodiment 48. The compound of any one of Embodiments 1-47 , wherein the ring carbon atom labelled with * has ( S ) -stereochemistry .

Embodiment 49 . The compound of any one of Embodiments 1-47 , wherein the E' N ' E LO moiety is Embodiment 50. The compound of Embodiment 1 or 2 , wherein the compound of Formula ( A ) or Formula ( I ) is selected from the group consisting of Compound Nos . 101 , 101a , 102 , 102a , 103 , 103a , 104 , 104a , 105 , 105a , 106 , 106a , 107 , 107a , 108 , 108a , 109 , 109a , 110 , 110a , 111 , 111a , 112 , 112a , 113 , 113a , 114 , 114a , 115 , 115a , 116 , 116a , 117 , 117a , 118 , and ﻭ ﻭ 118a , as depicted in Table C1 , or a pharmaceutically acceptable salt thereof .

Embodiment 51. A pharmaceutical composition comprising a compound of any one of Embodiments 1-50 , or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable excipient .

Embodiment 52. A dysregulated KRas protein non - covalently bound with a compound of any one of Embodiments 1-50 , or a pharmaceutically acceptable salt thereof .

Embodiment 53. A method for treating a KRas - associated 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 Embodiments 1-50 , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 51 .

Embodiment 54. A method for treating a KRas - associated cancer in a subject in need thereof , the method comprising ( a ) determining that the cancer in the subject has a KRas dysregulation ; and ( b ) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-50 , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 51 . 331 WO 2025/064848 PCT / US2024 / 0477 LO Embodiment 55. A method of treating a KRas - associated cancer in a subject , the method comprising administering to a subject identified or diagnosed as having a cancer having a KRas dysregulation a therapeutically effective amount of a compound of any one of Embodiments 1-50 or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 51 .

Embodiment 56. A method of treating a KRas - associated cancer in a subject , the method comprising : ( a ) ( b ) determining that the cancer in the subject has a KRas dysregulation ; and administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-50 or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 51 .

Embodiment 57. The method of any one of Embodiments 53-56 , wherein the KRas - associated cancer is a mutant KRas - associated cancer .

Embodiment 58. The method of Embodiment 57 , wherein the mutant KRas- associated cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer .

Embodiment 59. The method of Embodiment 58 , wherein the mutant KRas- associated cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer .

Embodiment 60. The method of Embodiment 58 , wherein the mutant KRas- associated cancer is a KRas G12D - associated cancer .

Embodiment 61. The method of Embodiment 58 , wherein the mutant KRas- associated cancer is a KRas G12R - associated cancer .

Embodiment 62. The method of Embodiment 58 , wherein the mutant KRas- associated cancer is a KRas G12V - associated cancer . 332 WO 2025/064848 PCT / US2024 / 0477 Embodiment 63. The method of any one of Embodiments 54 or 56 , wherein the step of determining that the cancer in the subject has a KRas dysregulation includes performing an assay to detect the KRas dysregulation ( e.g. , a KRas mutation ) in a tumor sample from the subject .

Embodiment 64. The method of Embodiment 63 , wherein detecting the KRas dysregulation includes detecting a KRAS gene having a mutation corresponding to a substitution of glycine 12 in a KRas protein and / or a KRas protein having a substitution of glycine 12 .

, Embodiment 65. The method of Embodiment 64 , wherein the substitution of glycine 12 is a substitution to alanine , cysteine , aspartic acid , arginine , serine , or valine .

Embodiment 66. The method of Embodiment 65 , wherein the substitution of glycine 12 is a substitution to aspartic acid .

Embodiment 67. The method of Embodiment 65 , wherein the substitution of glycine 12 is a substitution to arginine .

Embodiment 68. The method of Embodiment 65 , wherein the substitution of glycine 12 is a substitution to valine .

Embodiment 69. The method of any one of Embodiments 63-68 , comprising obtaining a tumor sample from the subject .

Embodiment 70 . The method of Embodiment 69 , wherein the tumor sample is a biopsy sample .

Embodiment 71. The method of any one of Embodiments 63-70 , wherein the assay is selected from the group consisting of sequencing , immunohistochemistry , and enzyme - linked immunosorbent assay , and fluorescence in situ hybridization ( FISH ) . 333 WO 2025/064848 PCT / US2024 / 0477 Embodiment 72. The method of Embodiment 71 , wherein the sequencing is pyrosequencing or next generation sequencing .

Embodiment 73. The method of any one of Embodiments 53-72 , wherein the KRas - associated 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 .

Embodiment 74 . cancer is pancreatic cancer . The method of Embodiment 73 , wherein the KRas - associated Embodiment 75. The method of Embodiment 73 , wherein the KRas - associated cancer is selected from the group consisting of : a hematological cancer , brain cancer , cervical cancer , colon cancer , endometrial cancer , esophageal cancer , kidney cancer , liver cancer , lung cancer , mucinous carcinoma , pancreatic cancer , prostate cancer , rectal cancer , skin cancer , stomach cancer , thymus cancer , urothelial cancer , and uterine cancer .

Embodiment 76. The method of Embodiment 73 , wherein the KRas - associated cancer is selected from the group consisting of : the cancer is a hematological cancer , bladder cancer , bile duct 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 , rectal cancer , skin cancer , stomach cancer , testicular cancer ( e.g. , seminoma ) , thymus cancer , and uterine cancer .

Embodiment 77. The method of Embodiment 73 , wherein the KRas - associated cancer is selected from the group consisting of : bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , and kidney cancer . 334 WO 2025/064848 PCT / US2024 / 0477 Embodiment 78. The method of any one of Embodiments 53-77 , comprising administering an additional therapy or therapeutic agent to the subject .

Embodiment 79. The method of Embodiment 78 , wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway targeted therapeutic agents , kinase - targeted therapeutics , mTORC1 inhibitors or degraders , YAP inhibitors or degraders , proteasome inhibitors or degraders , HSP90 inhibitors or degraders , farnesyl 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 .

Embodiment 80. A method for a method for modulating KRas protein activity in a mammalian cell , the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-50 , or a pharmaceutically acceptable salt thereof .

Embodiment 81 . The method of Embodiment 80 , wherein the contacting occurs in vivo .

Embodiment 82 . The method of Embodiment 80 , wherein the contacting occurs in vitro .

Embodiment 83 . The method of Embodiment 80 , wherein the contacting occurs ex vivo .

Embodiment 84. The method of any one of Embodiments 80-83 , wherein the mammalian cell is a mammalian cancer cell .

Embodiment 85. The method of any one of Embodiments 80-83 , wherein the KRas protein is a mutant KRas protein . 335 WO 2025/064848 PCT / US2024 / 0477 Embodiment 86. The method of Embodiment 85 , wherein the mutant KRas protein is a mutant KRas protein selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . P03 Exemplary Embodiments Embodiment 1 . A compound of Formula ( A ) R E ' B ' N ' Formula ( A ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; ( ii ) b2 ( R7 ) ' N ' N A²A ﻭ wherein b2 is 0 , 1 , 2 , or 3 ; and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 ; ( iii ) -N ( ²R ) 2 , wherein each ²R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rc ; and ( iv ) -H ; each R7 is independently selected from the group consisting of Ra and ³R ; 336 ⁹R Ring B is : b1 ( R10 ) X E ﻭ PCT / US2024 / 0477 wherein the * marks the ring carbon atom common to both Ring B and 0 % ¹X is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , CHRL , C ( ¹R ) 2 , and X2 and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( ¹R ) 2 , O , and S ( O ) 0-2 , provided that no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 ; b1 is 0 , 1 , or 2 ; R ' is selected from the group consisting of : H , OH , ªRªRN , and halo ; each R10 is independently selected from the group consisting of Ra and Rb ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; or ﻭ one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe : each Ra is independently selected from the group consisting of : ( a ) halo ; 337 ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) -C1-6 alkoxy ; ( f ) -C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) C ( = O ) C1-6 alkyl ; ( i ) C ( = O ) C1-6 haloalkyl ; ( j ) C ( = O ) OH ; ( k ) C ( = O ) OC1-6 alkyl ; ( 1 ) C ( = O ) OC1-6 haloalkyl ; ( m ) C ( = O ) N ( R ) 2 ; ( n ) S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) S ( O ) 1-2N ( R ) 2 ; and ( q ) PCT / US2024 / 0477 C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 ºR ; each Rb is independently selected from the group consisting of : - ( ³L ) ¹³R- and ¸¹³R- wherein : b is 1 , 2 , or 3 ; each -Lb is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , C ( = O ) , and C1-3 alkylene ; and , each ¹¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each Re is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , eRªRN- , C ( = O ) C1-6 alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) OH , C ( = O ) N ( ³R ) 2 , S ( O ) 0-2 ( C1-6 alkyl ) , S ( O ) 0-2 ( C1-6 haloalkyl ) , and S ( O ) 1-2N ( R ) 2 ; each Rd and Re is independently selected from the group consisting of : H , C ( = O ) C1-alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) N ( ³R ) 2 , S ( O ) 1- ( C1-6 alkyl ) , S ( O ) 1-2 ( C1-6 haloalkyl ) , S ( O ) 1-2N ( ³R ) 2 , and C1-6 alkyl optionally substituted with 338 WO 2025/064848 PCT / US2024 / 0477 1-3 Rh each R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rh ; ﻭ each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2- .

Embodiment 2 . The compound of Embodiment 1 , wherein the compound is a compound of Formula ( I ) : ⁹R R b1 ( R10 ) .

Formula ( I ) ' N ' ³R or a pharmaceutically acceptable salt thereof .

Embodiment 4 . The compound of any one of Embodiments 1-3 , wherein R ' is NRdRe Embodiment 5 . The compound of any one of Embodiments 1-4 , wherein R9 is NH2 .

Embodiment 6 . The compound of any one of Embodiments 1-5 , wherein b1 is or 2 ( e.g. , 1 ) .

Embodiment 7 . The compound of any one of Embodiments 1-6 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) . 339 LO ﺶﻣا Embodiment 8 .

PCT / US2024 / 0477 The compound of any one of Embodiments 1-6 , wherein the compound is a compound of Formula ( I - a ) : NHR b1 ( R10 ) . E ³R Formula ( I - a ) or a pharmaceutically acceptable salt thereof , wherein : b1 is 1 or 2 .

Embodiment 9. The compound of Embodiment 8 , wherein each R10 is independently selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 10 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - b ) : ⁹R RCN b4 ( R10 ) . E N ³R X Formula ( I - b ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 11 . The compound of Embodiment 10 , wherein R ' is eRªRN ( e.g. , NH2 ) .

Embodiment 12 . a compound of Formula ( I - c ) : The compound of Embodiment 1 or 2 , wherein the compound is 340 LO b4 ( R10 ) .

NHR.CN ²Y- ³R Formula ( I - c ) PCT / US2024 / 0477 or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ( e.g. , 0 ) ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

CH2 . Embodiment 13 . The compound of any one of Embodiments 1-12 , wherein ¹X is Embodiment 14 . The compound of any one of Embodiments 1-13 , wherein ²X and ³X are independently selected from the group consisting of : CH2 , CHRL , C ( RL ) 2 , and O.

Embodiment 15. The compound of any one of Embodiments 1-14 , wherein ¹X is CH2 ; and X2 and ³X are both CH2 .

Embodiment 17. The compound of any one of Embodiments 1-14 , wherein ¹X is CH2 , X2 is -O- ; and ³X is selected from the group consisting of : CH2 , CHRL , and C ( RL ) 2 ( e.g. , ³X is ₂HC or ¹RHC ) .

Embodiment 18. The compound of any one of Embodiments 1-17 , wherein each ¹R is independently selected from the group consisting of : CH3 , CF3 , CHF2 , and CH2F ( e.g. , CH3 ) .

Embodiment 19. The compound of any one of Embodiments 1-12 , wherein ¹X is CHRL ; ²X is O or CH2 ; and ³X is ¹RHC , wherein the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring . 341 Embodiment 20 . a compound of Formula ( I - d ) : PCT / US2024 / 0477 The compound of Embodiment 1 or 2 , wherein the compound is ⁹R R ₁b ( R10 ) . ' E ﻡا Formula ( I - d ) or a pharmaceutically acceptable salt thereof , wherein : 1✗ is selected from the group consisting of a bond , S ( O ) 0-2 , ₂HC , ¹RHC , C ( ¹R ) 2 , and O ; and ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( R ) 2 , O , and S ( O ) 0-2 , provided that : at least one of ¹X , ²X , and ³X is ¹RHC or C ( ¹R ) 2 , and no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 .

Embodiment 21 . CH2 ; and X3 is CHRL The compound of Embodiment 20 , wherein ¹X is CH2 ; ²X is Embodiment 22 . The compound of Embodiment 20 or 21 , wherein RL is selected from the group consisting of : CH3 , CF3 , CHF2 , and CH2F ( e.g. , CH3 ) .

Embodiment 23 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - e ) : ⁹R R b1 ( R10 ) . E ' N ' ³R Formula ( I - e ) or a pharmaceutically acceptable salt thereof , wherein : ¹✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and C ( RL ) 2 , : 342 WO 2025/064848 PCT / US2024 / 0477 ²X and ³X are independently selected from the group consisting of : CH2 , ¼RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that 2-3 of X1 , X2 , and ³X are independently CHRL or C ( RL ) 2 , wherein : one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; and each additional ¹R is independently selected from the group consisting of : C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 ºR ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 24 . The compound of Embodiment 23 , wherein X2 is CH2 or O ( e.g. , CH2 ) . ﻭ Embodiment 25. The compound of Embodiment 23 or 24 , wherein ¹X is CHRL ; ³X is ¹RHC ( e.g. , C ( H ) CH3 ) ; and the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

Embodiment 26 . The compound of any one of Embodiments 20-25 , wherein R ' is NRdRe ( e.g. , NH2 ) .

Embodiment 27 . The compound of any one of Embodiments 20-26 , wherein b1 is or 2 ; and each R10 is independently selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 28. The compound of any one of Embodiments 20-27 , wherein the ⁹R b1 ( R10 ) .

NHCN b4 ( R10 ) - moiety is ﻭ wherein b4 is 0 or 1 ( e.g. , 0 ) ; and R10 is selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

CH . Embodiment 29. The compound of any one of Embodiments 1-28 , wherein ¹E is 343 WO 2025/064848 PCT / US2024 / 0477 Embodiment 30 . The compound of any one of Embodiments 1-28 , wherein ¹E is CR Embodiment 31 . The compound of any one of Embodiments 1-28 or 30 , wherein LO 5 ¹E is C - F .

Embodiment 32 . The compound of any one of Embodiments 1-31 , wherein Y2 is -CH2- ; and ³R is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-additional ring heteroatom selected from the group consisting of oxygen and nitrogen , wherein the heterocyclyl is optionally substituted with 1-6 ªR .

Embodiment 33. The compound of any one of Embodiments 1-32 , wherein ²Y is F -CH2- ; and ³R is optionally substituted with 1-2 -F ( e.g. , ³R is , or F F $ Embodiment 34 . The compound of any one of Embodiments 1-33 , wherein ³R is ( e.g. , -N Embodiment 35. The compound of any one of Embodiments 1-34 , wherein ¹R is = A-N ²A b2 ( R7 ) . ' N ' wherein b2 is 0 , 1 , or 2 , and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 . 344 WO 2025/064848 PCT / US2024 / 0477 Embodiment 36 . R-N The compound of any one of Embodiments 1-35 , wherein ¹R is R ' N ' or R LO ' N ' Embodiment 37 . R7a or -N The compound of any one of Embodiments 1-36 , wherein ¹R is R7a ☑ ' N ' R7b ﻭ wherein : R7 is selected from the group consisting of : C ( = O ) N ( ³R ) 2 , C ( O ) N ( C1-3 alkyl ) ¹³R , - C ( O ) N ( H ) ¹bR , Rb1 , and C ( O ) Rb1 ; and R7b is selected from the group consisting of : halo , cyano , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

Embodiment 38. The compound of Embodiment 37 , wherein R7a is selected from the group consisting of : ( d ) C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh ; ﻭ ( e ) C ( O ) N ( C1-3 alkyl ) ¹³R or -C ( O ) N ( H ) Rb1 , wherein : ¹bR is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 ºR ; and ( f ) C ( O ) Rb1 , wherein ¹¹R is 4-10 membered heterocyclyl optionally substituted with 1-3 Rg , wherein Rb1 is attached to the C ( O ) via a ring nitrogen atom .

Embodiment 39. The compound of any one of Embodiments 36-38 , wherein R7a is C ( = O ) N ( R ) 2 , wherein each Rf is independently H or C1-3 alkyl optionally substituted with 1-3 Rh Embodiment 40. The compound of any one of Embodiments 36-39 , wherein R7b is halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) .

Embodiment 41. The compound of any one of Embodiments 36-40 , wherein R7b is halo ( e.g. , -CI ) . 345 WO 2025/064848 PCT / US2024 / 0477 Embodiment 42. The compound of any one of Embodiments 1-39 , wherein ¹R is roç ' N ' Rf Rf or Rf N Rf ﻦﮩﻳں R7b ﻭ wherein each Rf is independently C1-3 alkyl optionally substituted with 1-3 Rh ; and R7 is halo or C1-3 alkyl ( e.g. , R7b is halo ( e.g. , -C1 ) ) .

-N Embodiment 43. The compound of any one of Embodiments 1-42 , wherein ¹R is or * CI Embodiment 44. The compound of any one of Embodiments 1-34 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R Embodiment 45. The compound of any one of Embodiments 1-34 or 44 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered monocyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered monocyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

Embodiment 46 . The compound of Embodiment 44 or 45 , wherein ¹R is optionally substituted with 1-4 R7 at one or more ring carbon atoms .

Embodiment 47. The compound of any one of Embodiments 44-46 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl 346 WO 2025/064848 PCT / US2024 / 0477 optionally substituted with 1-3 R ° , wherein each R ° present on R7 is independently selected from the group consisting of : -F , -OH , and -CN .

Embodiment 48 . The compound of any one of Embodiments 1-34 or 44-46 , wherein ¹R is ' N ' Embodiment 49 . -RThe compound of any one of Embodiments 1-34 or 44-46 , R ' N ' wherein ¹R is ( e.g. , optionally substituted with 1-3 Rg . ) , wherein R7 is a 5 - membered heteroaryl Embodiment 50. The compound of Embodiment 49 , wherein R7 is pyrazolyl optionally substituted with 1-2 Rg ( e.g. , R7 is optionally substituted with one ºR ) ; or optionally wherein R7 is oxazolyl optionally substituted with one Rg ( e.g. , R7 is substituted with one R ) . or Embodiment 51 . The compound of Embodiment 49 or 50 , wherein R7 is N Embodiment 52. The compound of any one of Embodiments 1-34 or 44 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

Embodiment 53 . The compound of any one of Embodiments 1-34 , 44 , or 52 , wherein ¹R is which is optionally substituted with 1-2 R7 . 347 WO 2025/064848 PCT / US2024 / 0477 Embodiment 54 . The compound of any one of Embodiments 1-34 , 44 , or 52-53 , wherein ¹R is Embodiment 55 . The compound of any one of Embodiments 1-34 , wherein ¹R is a 4-10 membered heterocyclyl substituted with -CN , - ( C1-3 alkylene ) -CN , or - ( C3-cycloalkylene ) -CN on a ring carbon atom , wherein the heterocyclyl is further optionally substituted with 1-3 R7 .

Embodiment 56. The compound of any one of Embodiments 1-34 or 55 , wherein ¹R is a 6-8 membered heterocyclyl substituted with -CN or - ( C1-3 alkylene ) -CN on a ring carbon atom , wherein : the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom ; and the heterocyclyl is further optionally substituted with 1-3 R7 .

Embodiment 57. The compound of Embodiment 55 or 56 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

Embodiment 58. The compound of any one of Embodiments 1-34 or 55-57 , N wherein ¹R is ' N ' ' N ' ( e.g. , The compound of any one of Embodiments 1-34 , wherein ¹R is Embodiment 59 . -N ( ²R ) 2 .

Embodiment 60. The compound of Embodiment 59 , wherein each ²R is independently methyl or ethyl , each optionally substituted with 1-3 Rc , wherein each RC present on ²R is independently selected from the group consisting of : -F , cyano , -OH , -C1-6 alkoxy , and -C1-6 haloalkoxy .

Embodiment 61. The compound of any one of Embodiments 1-34 or 59-60 , 348 LO WO 2025/064848 PCT / US2024 / 0477 wherein ¹R is selected from the group consisting of : -N ( Me ) 2 , -N ( Et ) 2 , and N− ( Me ) Et .

Embodiment 62. The compound of any one of Embodiments 1-61 , wherein the ring carbon atom labelled with * has ( S ) -stereochemistry .

Embodiment 63 . The compound of any one of Embodiments 1-61 , wherein the ' N ' E moiety is Embodiment 64 .

E Formula ( I - c ) is a compound of Formula ( I - c1 ) or ( I - c2 ) : The compound of Embodiment 12 , wherein the compound of R7a N NH' N ' .CN b4 ( R10 ) . E` N ' X Formula ( I - c1 ) R7a N R7b NHCN b4 ( R10 ) . E³R Formula ( I - c2 ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is CH ; b4 is 0 or 1 ( e.g. , 0 ) ; R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; ¹X is CH2 ; and ²X and ³X are independently selected from the group consisting of : O , CH2 , ¹RHC , and 349 WO 2025/064848 PCT / US2024 / 0477 C ( RL ) 2 ; R7a is selected from the group consisting of : ( a ) C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh ; , ( b ) C ( O ) N ( C1-3 alkyl ) ¹bR or -C ( O ) N ( H ) Rb1 , wherein : ¹bR is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 Rg ; and ( c ) C ( O ) Rb1 , wherein ¹¹R is 4-10 membered heterocyclyl optionally substituted with 1-3 Rg , wherein Rb1 is attached to the C ( O ) via a ring nitrogen atom ; and R7b is halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) .

Embodiment 65 . CH2 or CHRL The compound of Embodiment 64 , wherein ²X is CH2 ; and X3 is Embodiment 66 . ³X is CH2 . The compound of Embodiment 64 or 65 , wherein ²X is CH2 ; and Embodiment 67 . ³X is CHRL The compound of Embodiment 64 or 65 , wherein X2 is CH2 ; and Embodiment 68 . ²X is CH2 ; and ³X is CHMe .

Embodiment 69 .

The compound of any one of Embodiments 64-65 or 67 , wherein , The compound of any one of Embodiments 64-68 , wherein R7a is C ( = O ) N ( R ) 2 , wherein each R is an independently selected C1-3 alkyl ; and R7 is -F , -Cl , or methyl .

Embodiment 70. The compound of any one of Embodiments 64-69 , wherein R7a is C ( = O ) N ( Me ) 2 ; and R7 is -F , -Cl , or methyl . Embodiment 71 . The compound of any one of Embodiments 64-70 , wherein Y2 is -CH2- ; and ³R is optionally substituted with 1-2 -F . 350 WO 2025/064848 PCT / US2024 / 0477 F Embodiment 72. The compound of any one of Embodiments 64-71 , wherein ³R is F $$ -N ( e.g. , -N Embodiment 73 . The compound of any one of Embodiments 64-72 , wherein the ' N ' moiety is The compound of Embodiment 1 or 2 , wherein the compound of Formula ( A ) or Formula ( I ) is selected from the group consisting of Compound Nos . 101 , 101a , 102 , 102a , 102b , 103 , 103a , 104 , 104a , 104b , 105 , 105a , 106 , 106a , 106b , 107 , 107a , 107b , 108 , 108a , 108b , 108c , 109 , 109a , 109b , 109c , 109d , 110 , 110a , 110b , 111 , 111a , 112 , 112a , 113 , 113a , 113b , 114 , 114a , 115 , 115a , 116 , 116a , 117 , 117a , 118 , 118a , 119 , 119a , 120 , 120a , 121 , 121a , 122 , 122a , 123 , 123a , 124 , 124a , 125 , 125a , 126 , 126a , 127 , 127a , 128 , 128a , 129 , 129a , 130 , 130a , 131 , 131a , 132 , 132a , 133 , 133a , 134 , 134a , 135 , 135a , 136 , 136a , 137 , 137a , 138 , 138a , 140 , 140a , 141 , 141a , 142 , and 142a , as depicted in Table C1 , or a pharmaceutically acceptable salt thereof .

P05 Exemplary Embodiments Embodiment 1 . A compound of Formula ( A ) B R ' N Formula ( A ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; 351 WO 2025/064848 PCT / US2024 / 0477 ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; -N = A²A b2 ( R7 ) ( ii ) wherein b2 is 0 , 1 , 2 , or 3 ; and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 ; ( iii ) -N ( ²R ) 2 , wherein each ²R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 RC ; and ( iv ) -H ; each R7 is independently selected from the group consisting of Ra and ³R ; ⁹R X * 3- * Ring B is : b1 ( R10 ) E , wherein the * marks the ring carbon atom common to both Ring B and O ; ¹✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , CHRL , C ( RL ) 2 , and X2 and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( ¹R ) 2 , O , and S ( O ) 0-2 , provided that no more than one of ¹X , ²X , and ³X is selected from the group consisting of : O and S ( O ) 0-2 , b1 is 0 , 1 , or 2 ; ⁹R is selected from the group consisting of : H , OH , eRªRN , and halo ; each R10 is independently selected from the group consisting of Ra and Rb ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 ºR ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; 352 LO WO 2025/064848 PCT / US2024 / 0477 each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe ; each ªR is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) Oxo ; ( e ) -C1-6 alkoxy ; ( f ) -C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) C ( = O ) C1-6 alkyl ; ( i ) C ( = O ) C1-6 haloalkyl ; ( j ) C ( = O ) OH ; ( k ) C ( = O ) OC1-6 alkyl ; ( 1 ) C ( = O ) OC1-6 haloalkyl ; ( m ) C ( = O ) N ( R ) 2 ; ( n ) S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) S ( O ) 1-2N ( R ) 2 ; and ( q ) wherein : C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 Rc ; each Rb is independently selected from the group consisting of : - ( ³L ) ¹¹R- and ¸¹³R- b is 1 , 2 , or 3 ; 353 WO 2025/064848 PCT / US2024 / 0477 LO each -L is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , C ( = O ) , and C1-3 alkylene ; and each ¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg : each R is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , ºRdRN- , C ( = O ) C1-6 alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) OH , C ( = O ) N ( ³R ) 2 , S ( O ) 0-2 ( C1-6 alkyl ) , S ( O ) 0-2 ( C1-6 haloalkyl ) , and S ( O ) 1-2N ( R ) 2 ; each Rd and ªR is independently selected from the group consisting of : H , C ( = O ) C1-alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) N ( ³R ) 2 , S ( O ) 1- ( C1-6 alkyl ) , S ( O ) 1-2 ( C1-6 haloalkyl ) , S ( O ) 1-2N ( ³R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh each R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rh ; ﻭ each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2- .

Embodiment 2. The compound of Embodiment 1 , wherein the compound is a compound of Formula ( I ) : b1 ( R10 ) .

¹R -8+ - + ' N ' ³R or a pharmaceutically acceptable salt thereof .

Embodiment 3 .

Formula ( I ) The compound of Embodiment 1 or 2 , wherein R is selected from the group consisting of : OH and NRdRe . 354 Embodiment 4 . NRdRe .

NH2 . Embodiment 5 .

Embodiment 6 . or 2 ( e.g. , 1 ) .

PCT / US2024 / 0477 The compound of any one of Embodiments 1-3 , wherein Ris The compound of any one of Embodiments 1-4 , wherein R ' is The compound of any one of Embodiments 1-5 , wherein b1 is Embodiment 7 . The compound of any one of Embodiments 1-6 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

The compound of any one of Embodiments 1-6 , wherein the Embodiment 8 . compound is a compound of Formula ( I - a ) : NH b1 ( R10 ) - -Spa ' N ' E R Formula ( I - a ) or a pharmaceutically acceptable salt thereof , wherein : b1 is 1 or 2 .

³R Embodiment 9. The compound of Embodiment 8 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 10. The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - b ) : 355 b4 ( R10 ) .

⁹R RCN E ' N ' X Formula ( I - b ) PCT / US2024 / 0477 or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 11 . The compound of Embodiment 10 , wherein R is NRdRe ( e.g. , NH2 ) .

Embodiment 12 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - c ) : NHRCN b4 ( R10 ) . E ³R Formula ( I - c ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ( e.g. , 0 ) ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 R ° ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 13 . The compound of any one of Embodiments 1-12 , wherein X1 is CH2 .

Embodiment 14 . The compound of any one of Embodiments 1-13 , wherein ²X and ³X are independently selected from the group consisting of : CH2 , CHRL , C ( ¹R ) 2 , and O. 356 WO 2025/064848 PCT / US2024 / 0477 Embodiment 15. The compound of any one of Embodiments 1-14 , wherein X1 is CH2 ; and X2 and ³X are both CH2 .

Embodiment 16 . The compound of any one of Embodiments 1-14 , wherein X1 is LO CH2 ; X2 is CH2 ; and ³X is CHRL .

Embodiment 17. The compound of any one of Embodiments 1-14 , wherein X1 is CH2 ; ²X is -O- ; and ³X is selected from the group consisting of : CH2 , ¹RHC , and C ( ¹R ) 2 ( e.g. , ³X is CH2 or CHRL ) .

Embodiment 19. The compound of any one of Embodiments 1-12 , wherein ¹X is CHRL ; ²X is O or CH2 ; and ³X is ¹RHC , wherein the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

Embodiment 20. The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - d ) : Eb1 ( R10 ) .

⁹R R ﺲﻤﻳﺓ N Formula ( I - d ) or a pharmaceutically acceptable salt thereof , wherein : ¹X is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and O ; and ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( R ) 2 , O , and S ( O ) 0-2 , provided that : at least one of X1 , X2 , and ³X is CHR or C ( RL ) 2 , and no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 . 357 LO WO 2025/064848 PCT / US2024 / 0477 Embodiment 21 . CH2 , and X3 is CHRL . The compound of Embodiment 20 , wherein X1 is CH2 ; X2 is Embodiment 22 . The compound of Embodiment 20 or 21 , wherein RL is selected from the group consisting of : CH3 , CF3 , CHF2 , and CH2F ( e.g. , CH3 ) .

Embodiment 23 . a compound of Formula ( I - e ) : The compound of Embodiment 1 or 2 , wherein the compound is b1 ( R10 ) ⁹R R E X-Y³R Formula ( I - e ) O ; or a pharmaceutically acceptable salt thereof , wherein : ¹X is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and ²X and ³X are independently selected from the group consisting of : CH2 , ³RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that 2-3 of X1 , X2 , and ³X are independently CHRL or C ( RL ) 2 , wherein : one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; and each additional ¹R is independently selected from the group consisting of : C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 24 . The compound of Embodiment 23 , wherein ²X is CH2 or O ( e.g. , CH2 ) .

Embodiment 25. The compound of Embodiment 23 or 24 , wherein ¹X is CHRL ; ³X is ¹RHC ( e.g. , C ( H ) CH3 ) ; and the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

Embodiment 26. The compound of any one of Embodiments 20-25 , wherein R ' is NRdRe ( e.g. , NH2 ) . 358 LO WO 2025/064848 PCT / US2024 / 0477 Embodiment 27. The compound of any one of Embodiments 20-26 , wherein bl is or 2 ; and each R10 is independently selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) . b1 ( R10 ) - Embodiment 28 . ⁹R Xmoiety is The compound of any one of Embodiments 20-27 , wherein the b4 ( R10 ) .

NH X CN * ﻭ wherein b4 is 0 or 1 ( e.g. , 0 ) ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 R ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

CH .

CR Embodiment 29 . The compound of any one of Embodiments 1-28 , wherein ¹E is Embodiment 30 . The compound of any one of Embodiments 1-28 , wherein ¹E is Embodiment 31 . ¹E is C - F . The compound of any one of Embodiments 1-28 or 30 , wherein Embodiment 32 . The compound of any one of Embodiments 1-31 , wherein Y2 is -CH2- ; and ³R is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-additional ring heteroatom selected from the group consisting of oxygen and nitrogen , wherein the heterocyclyl is optionally substituted with 1-6 Ra .

Embodiment 33. The compound of any one of Embodiments 1-32 , wherein Y2 is -CH2- and ³R is optionally substituted with 1-2 substituents each independently 359 WO 2025/064848 PCT / US2024 / 0477 selected from the group consisting of : -F , -C1-3 alkoxy , and -C1-3 haloalkoxy ( e.g. , ³R is optionally substituted with 1-2 -F ( e.g. , ³R is " -N ﻭ F -N or Embodiment 34. The compound of any one of Embodiments 1-33 , wherein ³R is F ( e.g. , -N Embodiment 35. The compound of any one of Embodiments 1-34 , wherein ¹R is b2 ( R7 ) - ' N ' N ¹A ²A wherein b2 is 0 , 1 , or 2 , and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 .

Embodiment 36. The compound of any one of Embodiments 1-35 , wherein ¹R is R7 R ' N ' or ' N ' R Embodiment 37. The compound of any one of Embodiments 1-36 , wherein ¹R is R7a or R7a ☑ R7b ﻭ wherein : R7a is selected from the group consisting of : C ( = O ) N ( ³R ) 2 , C ( O ) N ( C1-3 alkyl ) ¹³R , - C ( O ) N ( H ) ¹¹R , ¹bR , and C ( O ) ¹³R ; and 360 LO WO 2025/064848 PCT / US2024 / 0477 R7b is selected from the group consisting of : halo , cyano , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

Embodiment 38 . 7a The compound of Embodiment 37 , wherein ª7R is selected from the group consisting of : ( a ) C ( = O ) N ( ¹R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh ; ﻭ ( b ) C ( O ) N ( C1-3 alkyl ) ¹³R or -C ( O ) N ( H ) ¹³R , wherein : ¹bR is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 Rg ; and ( c ) C ( O ) Rb1 , wherein R1 is 4-10 membered heterocyclyl optionally substituted with 1-3 Rg , wherein R1 is attached to the C ( O ) via a ring nitrogen atom .

Embodiment 39. The compound of any one of Embodiments 36-38 , wherein R7a is C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh Embodiment 40. The compound of any one of Embodiments 36-39 , wherein R7b is halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) .

Embodiment 41 . is halo ( e.g. , -Cl ) . The compound of any one of Embodiments 36-40 , wherein R7b Embodiment 42 .

' N ' ﮦﻭ Rf Rf The compound of any one of Embodiments 1-39 , wherein ¹R is Rf N ' N ' -N R7b Rf or ﻭ wherein each R is independently C1-3 alkyl optionally substituted with 1-3 Rh ; and R7 is halo or C1-3 alkyl ( e.g. , R7b is halo ( e.g. , -CI ) ) . 361 ' N ' PCT / US2024 / 0477 Embodiment 43. The compound of any one of Embodiments 1-42 , wherein ¹R is N. ' N ' -N or CI ' N ' ' N ' Embodiment 44 . The compound of any one of Embodiments 1-34 , wherein ¹R is , a 7-10 ( e.g. , 7 ) membered heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R7 .

Embodiment 45. The compound of any one of Embodiments 1-34 or 44 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered monocyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered monocyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

' N ' Embodiment 46. The compound of Embodiment 44 or 45 , wherein ¹R is optionally substituted with 1-4 R7 at one or more ring carbon atoms .

Embodiment 47. The compound of any one of Embodiments 44-46 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein each Rc present on R7 is independently selected from the group consisting of : -F , -OH , and -CN .

Embodiment 48. The compound of any one of Embodiments 1-34 or 44-46 , wherein ¹R is 362 WO 2025/064848 PCT / US2024 / 0477 Embodiment 49 . The compound of any one of Embodiments 1-34 or 44-46 , ﻡﺭﺪﻣ ( e.g. , ﺱﻮﻣ R wherein ¹R is optionally substituted with 1-3 Rg . ) , wherein R7 is a 5 - membered heteroaryl Embodiment 50. The compound of Embodiment 49 , wherein R7 is pyrazolyl optionally substituted with 1-2 ºR ( e.g. , R7 is H N optionally substituted with one ³R ) ; or N- optionally wherein R7 is oxazolyl optionally substituted with one Rg ( e.g. , R7 is substituted with one ºR ) . or N Embodiment 51 . The compound of Embodiment 49 or 50 , wherein R7 is Embodiment 52. The compound of any one of Embodiments 1-34 or 44 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

Embodiment 53. The compound of any one of Embodiments 1-34 , 44 , or 52 , ( R7 ) n( R7 ) nA wherein ¹R is ﻭ wherein : Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms ; n4 is 0 , 1 , or 2 ; and n5 is 0 , 1 , or 2 , provided that n4 + n5 is 0 , 1 , or 2 .

Embodiment 54. The compound of any one of Embodiments 1-34 , 44 , or 52-53 , wherein ¹R is ﻭ which is optionally substituted with 1-2 R7 . 363 Embodiment 55 . wherein ¹R is PCT / US2024 / 0477 The compound of any one of Embodiments 1-34 , 44 , or 52-54 , Embodiment 56 . The compound of any one of Embodiments 1-34 , 44 , or 52-53 , wherein ¹R is or , each of which is optionally substituted with 1-2 R Embodiment 57 . The compound of any one of Embodiments 1-34 , 44 , 52-53 , or X ☑ , wherein ¹R is ( e.g. , or ) or ( e.g. , or Embodiment 58. The compound of any one of Embodiments 1-34 , wherein ¹R is a 4 - membered heterocyclyl optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

Embodiment 59. The compound of any one of Embodiments 1-34 or 58 , wherein ¹R is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . ﺶﻣا Embodiment 60. The compound of any one of Embodiments 1-34 or 58-59 , -R7 " RR' Rwherein ¹R is ( e.g. , ) or H Embodiment 61. The compound of any one of Embodiments 58-60 , wherein each R7 is independently selected from the group consisting of : -F , -cyano , -OH , -Rb1 , wherein the Rb1 is a 5-6 membered heteroaryl optionally substituted with 1-2 R , C1-3 alkyl optionally substituted with 1-3 F , 364 LO WO 2025/064848 PCT / US2024 / 0477 C1-3 alkyl substituted with -OH or C1-3 alkoxy , and C ( = O ) N ( R ) 2 .

Embodiment 62. The compound of any one of Embodiments 1-34 or 58-60 , wherein ¹R is + -R ( e.g. , ' R ) , wherein R7 is C1-3 alkyl substituted with -OH or C1- alkoxy ( e.g. , C1-3 alkyl substituted with -OH ) .

Embodiment 63. The compound of any one of Embodiments 1-34 , 58-60 , or 62 , OH OH wherein ¹R is ( e.g. , ) .

Embodiment 64. The compound of any one of Embodiments 1-34 or 58-60 , R-R wherein ¹R is of : ﻭ wherein each R7 is independently selected from the group consisting C1-3 alkyl optionally substituted with 1-3 F ; and C1-3 alkyl substituted with -OH or C1-3 alkoxy .

Embodiment 65 . wherein ¹R is HO₂HC- ) ; and R7b -R7a T☑ ( e.g. , The compound of any one of Embodiments 1-34 , 58-60 , or 64 , R7b R7a ) , wherein R7a is C1-3 alkyl substituted with -OH ( e.g. , R7b is selected from the group consisting of : C1-3 alkyl optionally substituted with 1-3 F ( e.g. , methyl ) , and C1-3 alkyl substituted with -OH or C1-3 alkoxy .

Embodiment 66. The compound of any one of Embodiments 1-34 , 58-60 , or 64- -OH , wherein ¹R is + ( e.g. , HO✗ -OH -OH ) or 365 WO 2025/064848 PCT / US2024 / 0477 Embodiment 67. The compound of any one of Embodiments 1-34 , wherein ¹R is a 4-10 membered heterocyclyl substituted with -CN , - ( C1-3 alkylene ) -CN , or - ( C3-cycloalkylene ) -CN on a ring carbon atom , wherein the heterocyclyl is further optionally substituted with 1-3 R7 .

Embodiment 68. The compound of any one of Embodiments 1-34 or 67 , wherein ¹R is a 6-8 membered heterocyclyl substituted with -CN or - ( C1-3 alkylene ) -CN on a ring carbon atom , wherein : the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom ; and the heterocyclyl is further optionally substituted with 1-3 R7 .

Embodiment 69. The compound of Embodiment 67 or 68 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

Embodiment 70 . N The compound of any one of Embodiments 1-34 or 67-69 , N ןוו ןוו wherein ¹R is -N ( ²R ) 2 . ( e.g. , Embodiment 71 .

' N ' The compound of any one of Embodiments 1-34 , wherein ¹R is Embodiment 72. The compound of Embodiment 71 , wherein each ²R is independently methyl or ethyl , each optionally substituted with 1-3 RC , wherein each Re present on ²R is independently selected from the group consisting of : -F , cyano , -OH , -C1-6 alkoxy , and -C1-6 haloalkoxy .

Embodiment 73. The compound of any one of Embodiments 1-34 or 71-72 , wherein ¹R is selected from the group consisting of : -N ( Me ) 2 , -N ( Et ) 2 , and -N ( Me ) Et .

Embodiment 74. The compound of any one of Embodiments 1-73 , wherein the ring carbon atom labelled with * has ( S ) -stereochemistry . 366 WO 2025/064848 PCT / US2024 / 0477 Embodiment 75. The compound of any one of Embodiments 1-73 , wherein the soty ' N ' moiety is Jo E ' N ' Embodiment 76. The compound of Embodiment 12 , wherein the compound of Formula ( I - c ) is a compound of Formula ( I - c1 ) or ( I - c2 ) : b4 ( R10 ) - NH X CN R7a -N Formula ( I - c1 ) NHCN b4 ( R10 ) — X Formula ( I - c2 ) ³R R7a -N R7b ³R or a pharmaceutically acceptable salt thereof , wherein : ¹E is CH ; b4 is 0 or 1 ( e.g. , 0 ) ; R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; ¹X is CH2 ; and , ²X and ³X are independently selected from the group consisting of : O , ₂HC , ¹RHC , and C ( RL ) 2 ; R7a is selected from the group consisting of : ( a ) C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh . , 367 WO 2025/064848 PCT / US2024 / 0477 ( b ) C ( O ) N ( C1-3 alkyl ) ¹³R or -C ( O ) N ( H ) ¹³R , wherein : ¹bR is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 R ; and ( c ) C ( O ) ¹bR , wherein ¹¹R is 4-10 membered heterocyclyl optionally substituted with 1-3 RB , wherein Rb1 is attached to the C ( O ) via a ring nitrogen atom ; and R7b is halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) .

Embodiment 77 . CH2 or CHRL The compound of Embodiment 76 , wherein ²X is CH2 ; and ³X is Embodiment 78 . ³X is CH2 . The compound of Embodiment 76 or 77 , wherein ²X is CH2 ; and Embodiment 79 . ³X is CHRL Embodiment 80 . ²X is CH2 ; and ³X is CHMe .

Embodiment 81 .

The compound of Embodiment 76 or 77 , wherein ²X is CH2 ; and The compound of any one of Embodiments 76-77 or 79 , wherein The compound of any one of Embodiments 76-80 , wherein R7a is C ( = O ) N ( ³R ) 2 , wherein each Rf is an independently selected C1-3 alkyl ; and R is -F , -Cl , or methyl .

Embodiment 82. The compound of any one of Embodiments 76-81 , wherein R7a is C ( = O ) N ( Me ) 2 ; and R7 is -F , -C1 , or methyl .

Embodiment 83. The compound of Embodiment 12 , wherein the compound of Formula ( I - c ) is a compound of Formula ( I - c3 ) or ( I - c4 ) : NH.CN b4 ( R10 ) . E Formula ( I - c3 ) 368 b4 ( R10 ) .

NH-RCN E³R PCT / US2024 / 0477 LO Formula ( I - c4 ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is CH ; R7 is C1-3 alkyl substituted with -OH ; b4 is 0 or 1 ( e.g. , 0 ) ; R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; ¹X is CH2 ; and ²X and ³X are independently selected from the group consisting of : O , CH2 , ¹RHC , and C ( RL ) 2 .

Embodiment 84 . The compound of Embodiment 83 , wherein X2 is CH2 ; and ³X is CH2 or CHRL Embodiment 85 . ³X is CH2 . The compound of Embodiment 83 or 84 , wherein ²X is CH2 ; and Embodiment 86 . ³X is CHRL The compound of Embodiment 83 or 84 , wherein X2 is CH2 ; and Embodiment 87 . ²X is CH2 , and X3 is CHMe . The compound of any one of Embodiments 83-84 or 86 , wherein Embodiment 88 . The compound of any one of Embodiments 83-87 , wherein the -R7 -R moiety is compound is a compound of Formula ( I - c4 ) ; and the Embodiment 89. The compound of any one of Embodiments 83-88 , wherein R7 is CH2OH . 369 Embodiment 90 .

PCT / US2024 / 0477 The compound of any one of Embodiments 76-89 , wherein ²Y is -CH2- ; and ³R is optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , -C1-3 alkoxy , and -C1-3 haloalkoxy .

Embodiment 91 . The compound of any one of Embodiments 76-90 , wherein ²Y is -CH2- ; and ³R is optionally substituted with 1-2 -F .

F Embodiment 92 . F The compound of any one of Embodiments 76-91 , wherein ³R is -N ( e.g. , -N Embodiment 93 . The compound of any one of Embodiments 76-92 , wherein the E 500 , åp' N ' moiety is ' N ' Embodiment 94. The compound of Embodiment 1 or 2 , wherein the compound of Formula ( A ) or Formula ( I ) is selected from the group consisting of Compound Nos . 101 , 101a , 102 , 102a , 102b , 103 , 103a , 104 , 104a , 104b , 105 , 105a , 106 , 106a , 106b , 107 , 107a , 107b , 108 , 108a , 108b , 108c , 109 , 109a , 109b , 109c , 109d , 110 , 110a , 110b , 111 , 111a , 112 , 112a , 113 , 113a , 113b , 114 , 114a , 115 , 115a , 116 , 116a , 117 , 117a , 118 , 118a , 119 , 119a , 120 , 120a , 121 , 121a , 122 , 122a , 123 , 123a , 124 , 124a , 125 , 125a , 126 , 126a , 127 , 127a , 128 , 128a , 129 , 129a , 130 , 130a , 131 , 131a , 132 , 132a , 133 , 133a , 134 , 134a , 135 , 135a , 136 , 136a , 137 , 137a , 138 , 138a , 140 , 140a , 141 , 141a , 142 , 142a , 143 , 143a , 144 , 144a , 145 , 145a , 146 , 146a , 146b , 147 , 147a , 148 , 148a , 149 , 149a , 150 , 150a , 150b , 151 , 151a , 151b , 151c , 152 , 152a , 152b , as depicted in Table C1 , or a pharmaceutically acceptable salt thereof . 370 P08 Exemplary Embodiments Embodiment 1 . A compound of Formula ( A ) R B N Formula ( A ) PCT / US2024 / 0477 or a pharmaceutically acceptable salt thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is selected from the group consisting of : ( i ) a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; A²A b2 ( R7 ) . ( ii ) ﻭ wherein b2 is 0 , 1 , 2 , or 3 ; and A1 and A2 are independently selected from the group consisting of : N , CH , and CR7 ; ( iii ) -N ( ²R ) 2 , wherein each ²R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rc ; and ( iv ) -H ; each R7 is independently selected from the group consisting of Ra and ³R ; ⁹R Ring B is : b1 ( R10 ) H * , wherein the marks the ring carbon atom common to both Ring B and ¹✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( ¹R ) 2 , and O ; 371 WO 2025/064848 PCT / US2024 / 0477 ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 ; b1 is 0 , 1 , or 2 ; R ' is selected from the group consisting of : H , OH , eRªRN , and halo ; each R10 is independently selected from the group consisting of Ra and Rb ; each ¹R is independently selected from the group consisting of C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; or one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; ²Y is a bond or a straight - chain C1-6 alkylene optionally substituted with 1-6 RY ; each RY is independently selected from the group consisting of : halo , cyano , -OH , oxo , C1-6 alkoxy , C1-6 haloalkoxy , C1-6 alkyl , and C1-6 haloalkyl , or one pair of RY on the same or different carbon atom ( s ) are taken together with the atom ( s ) connecting them to form a C3-6 cycloalkyl ring or 4-6 membered heterocyclyl ring , each of which is optionally substituted with 1-3 independently selected C1-3 alkyl ; ³R is selected from the group consisting of : ( a ) 4-15 membered heterocyclyl optionally substituted with 1-6 substituents independently selected from the group consisting of : ªR and Rb ; and ( b ) -NRdRe ; each Ra is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; ( c ) -OH ; ( d ) oxo ; ( e ) -C1-6 alkoxy ; ( f ) -C1-6 haloalkoxy ; ( g ) -NRdRe ; ( h ) C ( = O ) C1-6 alkyl ; ( i ) C ( = O ) C1-6 haloalkyl ; 372 ( j ) C ( = O ) OH ; ( k ) C ( = O ) OC1-6 alkyl ; ( 1 ) C ( = O ) OC1-6 haloalkyl ; ( m ) C ( = O ) N ( R $ ) 2 ; ( n ) S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) S ( O ) 1-2N ( R ) 2 ; and ( q ) PCT / US2024 / 0477 wherein : C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 Rc ; each Rb is independently selected from the group consisting of : - ( Lb ) b - Rb1 and ¹bR- , bis 1 , 2 , or 3 ; each -Lb is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , C ( = O ) , and C1-3 alkylene ; and each ¹¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each R is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NRdRe , C ( = O ) C1-6 alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) OH , C ( = O ) N ( ³R ) 2 , S ( O ) 0-2 ( C1-6 alkyl ) , S ( O ) 0-2 ( C1-6 haloalkyl ) , and S ( O ) 1-2N ( ³R ) 2 , each Rd and Re is independently selected from the group consisting of : H , C ( = O ) C1-alkyl , C ( = O ) C1-6 haloalkyl , C ( = O ) OC1-6 alkyl , C ( = O ) OC1-6 haloalkyl , C ( = O ) N ( ³R ) 2 , S ( O ) 1- ( C1-6 alkyl ) , S ( O ) 1-2 ( C1-6 haloalkyl ) , S ( O ) 1-2N ( ³R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : H and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2- . 373 Embodiment 2 . compound of Formula ( I ) : PCT / US2024 / 0477 The compound of Embodiment 1 , wherein the compound is a ⁹R R b1 ( R10 ) . E ' N ' ³R Formula ( I ) or a pharmaceutically acceptable salt thereof .

Embodiment 4 . The compound of any one of Embodiments 1-3 , wherein ⁹R is NRdRe .

NH2 .

Embodiment 5 . The compound of any one of Embodiments 1-4 , wherein R ' is Embodiment 6 . or 2 ( e.g. , 1 ) . The compound of any one of Embodiments 1-5 , wherein b1 is Embodiment 7 . The compound of any one of Embodiments 1-6 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Re ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 8 . The compound of any one of Embodiments 1-6 , wherein the compound is a compound of Formula ( I - a ) : NHR b1 ( R10 ) . ' E -Spa Formula ( I - a ) ³R 374 or a pharmaceutically acceptable salt thereof , wherein : b1 is 1 or 2 .

PCT / US2024 / 0477 Embodiment 9. The compound of Embodiment 8 , wherein each R10 is independently selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 R ° ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 10 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - b ) : ⁹R b4 ( R10 ) .

RCN + 2- ' N ' Formula ( I - b ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 12 . a compound of Formula ( I - c ) : The compound of Embodiment 1 or 2 , wherein the compound is NH b4 ( R10 ) . .CN R E ³R Formula ( I - c ) or a pharmaceutically acceptable salt thereof , wherein : b4 is 0 or 1 ( e.g. , 0 ) ; and 375 WO 2025/064848 PCT / US2024 / 0477 R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 R ° ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 14. The compound of any one of Embodiments 1-13 , wherein ²X and ³X are independently selected from the group consisting of : CH2 , ³RHC , C ( ¹R ) 2 , and O.

Embodiment 16 . The compound of any one of Embodiments 1-14 , wherein ¹X is CH2 ; X2 is CH2 ; and ³X is CHRL .

Embodiment 19. The compound of any one of Embodiments 1-12 , wherein ¹X is CHRL ; ²X is O or CH2 ; and ³X is CHRL , wherein the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring . ﻭ ﻭ Embodiment 20 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - d ) : ⁹R R b1 ( R10 ) . ' E Formula ( I - d ) or a pharmaceutically acceptable salt thereof , wherein : 376 LO WO 2025/064848 PCT / US2024 / 0477 ¹✗ is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , CHRL , C ( RL ) 2 , and O ; and ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that : at least one of ¹X , ²X , and ³X is ¹RHC or C ( RL ) 2 , and no more than one of X1 , X2 , and ³X is selected from the group consisting of : O and S ( O ) 0-2 .

Embodiment 21 . CH2 ; and X3 is CHRL . The compound of Embodiment 20 , wherein X1 is CH2 ; X2 is Embodiment 22 . The compound of Embodiment 20 or 21 , wherein RL is selected from the group consisting of : CH3 , CF3 , CHF2 , and CH2F ( e.g. , CH3 ) .

Embodiment 23 . The compound of Embodiment 1 or 2 , wherein the compound is a compound of Formula ( I - e ) : ⁹R b1 ( R10 ) .

R E ` ³R 0 ; Formula ( I - e ) or a pharmaceutically acceptable salt thereof , wherein : ¹X is selected from the group consisting of a bond , S ( O ) 0-2 , CH2 , ¹RHC , C ( RL ) 2 , and ²X and ³X are independently selected from the group consisting of : CH2 , ¹RHC , C ( RL ) 2 , O , and S ( O ) 0-2 , provided that 2-3 of X1 , X2 , and ³X are independently ¹RHC or C ( RL ) 2 , wherein : ﻭ one pair of RL on the same or different ring carbon atom ( s ) are taken together with the ring atom ( s ) connecting them to form a C3-6 cycloalkyl ring ; and each additional ¹R is independently selected from the group consisting of : C1-3 alkoxy , -F , CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

CH2 ) . Embodiment 24. The compound of Embodiment 23 , wherein X2 is CH2 or O ( e.g. , 377 WO 2025/064848 PCT / US2024 / 0477 LO Embodiment 25. The compound of Embodiment 23 or 24 , wherein ¹X is CHRL ; ³X is ¹RHC ( e.g. , C ( H ) CH3 ) ; and the pair of RL are taken together with the ring atoms connecting them to form a C3-4 ( e.g. , C4 ) cycloalkyl ring .

Embodiment 26 .

NRdRe ( e.g. , NH2 ) .

Embodiment 27 .

The compound of any one of Embodiments 20-25 , wherein ⁹R is The compound of any one of Embodiments 20-26 , wherein b1 is or 2 ; and each R10 is independently selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

X NHCN b4 ( R10 ) . moiety is , wherein b4 is 0 or 1 ( e.g. , 0 ) ; and R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 R ( e.g. , C1-3 alkyl optionally substituted with 1-3 F ) .

Embodiment 29 . The compound of any one of Embodiments 1-28 , wherein ¹E is CH . ﺶﻣا CR4 . Embodiment 30 . The compound of any one of Embodiments 1-28 , wherein ¹E is Embodiment 31 . ¹E is C - F . The compound of any one of Embodiments 1-28 or 30 , wherein Embodiment 32 . The compound of any one of Embodiments 1-31 , wherein Y2 is -CH2- ; and ³R is a 4-10 membered heterocyclyl having one ring nitrogen atom and 0-additional ring heteroatom selected from the group consisting of oxygen and nitrogen , wherein the heterocyclyl is optionally substituted with 1-6 Ra . 378 WO 2025/064848 PCT / US2024 / 0477 Embodiment 33. The compound of any one of Embodiments 1-32 , wherein Y2 is -CH2- and ³R is -N optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , -C1-3 alkoxy , and -C1-3 haloalkoxy ( e.g. , ³R is 888 . optionally substituted with 1-2 -F ( e.g. , ³R is . , LO -N ﻭ -N or Embodiment 34. The compound of any one of Embodiments 1-33 , wherein ³R is F b2 ( R7 ) . ( e.g. , -N Embodiment 35. The compound of any one of Embodiments 1-34 , wherein ¹R is ' N ' N ²A wherein b2 is 0 , 1 , or 2 , and ¹A and ²A are independently selected from the group consisting of : N , CH , and CR7 .

The compound of any one of Embodiments 1-35 , wherein ¹R is Embodiment 36 . R-N R or ' R ' 379 WO 2025/064848 PCT / US2024 / 0477 The compound of any one of Embodiments 1-36 , wherein ¹R is Embodiment 37 . R7a R7a R7b LO or wherein : , R7a is selected from the group consisting of : C ( = O ) N ( ³R ) 2 , C ( O ) N ( C1-3 alkyl ) ¹¹R , - C ( O ) N ( H ) ¹¹R , ¹³R , and C ( O ) ¹³R ; and R7b is selected from the group consisting of : halo , cyano , and C1-3 alkyl optionally substituted with 1-3 Rc ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

Embodiment 38. The compound of Embodiment 37 , wherein ª7R is selected from the group consisting of : ( a ) C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh . ﻭ ( b ) C ( O ) N ( C1-3 alkyl ) ¹³R or -C ( O ) N ( H ) ¹³R , wherein : ¹bR is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 Rg ; and ( c ) C ( O ) ¹¹R , wherein Rb1 is 4-10 membered heterocyclyl optionally substituted with 1-3 Rg , wherein Rb1 is attached to the C ( O ) via a ring nitrogen atom .

Embodiment 39. The compound of any one of Embodiments 36-38 , wherein R7a is C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh Embodiment 40. The compound of any one of Embodiments 36-39 , wherein Ris halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) .

Embodiment 41. The compound of any one of Embodiments 36-40 , wherein R7b is halo ( e.g. , -Cl ) . 380 LO Embodiment 42 .

Rf Rf ' N ' PCT / US2024 / 0477 The compound of any one of Embodiments 1-39 , wherein ¹R is Rf ' N ' Rf R7b or ﻭ wherein each R is independently C1-3 alkyl optionally substituted with 1-3 Rh ; and R7b is halo or C1-3 alkyl ( e.g. , R7b is halo ( e.g. , -CI ) ) .

' N ' Embodiment 43. The compound of any one of Embodiments 1-42 , wherein ¹R is ' N ' CI ' N ' or Embodiment 44. The compound of any one of Embodiments 1-34 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R7 .

Embodiment 47. The compound of any one of Embodiments 44-46 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein each Rc present on R7 is independently selected from the group consisting of : -F , -OH , and -CN . 381 Embodiment 48 . wherein ¹R is PCT / US2024 / 0477 The compound of any one of Embodiments 1-34 or 44-46 , Embodiment 49 .

-R The compound of any one of Embodiments 1-34 or 44-46 , R wherein ¹R is ﺲﻟﺎﻣ ( e.g. , ﻡﺭﺪﻣ optionally substituted with 1-3 Rg . ) , wherein R7 is a 5 - membered heteroaryl Embodiment 50. The compound of Embodiment 49 , wherein R7 is pyrazolyl N optionally substituted with 1-2 ºR ( e.g. , R7 is optionally substituted with one ºR ) ; or N wherein R7 is oxazolyl optionally substituted with one Rg ( e.g. , R7 is substituted with one R ) . optionally or N Embodiment 51 . The compound of Embodiment 49 or 50 , wherein R7 is Embodiment 52. The compound of any one of Embodiments 1-34 or 44 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . ﺶﻣا Embodiment 53 . The compound of any one of Embodiments 1-34 , 44 , or 52 , ( R7 ) n( R7 ) nA wherein ¹R is ﻭ wherein : Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms ; n4 is 0 , 1 , or 2 ; and n5 is 0 , 1 , or 2 , provided that n4 + n5 is 0 , 1 , or 2 . 382 Embodiment 54 .

PCT / US2024 / 0477 The compound of any one of Embodiments 1-34 , 44 , or 52-53 , wherein ¹R is which is optionally substituted with 1-2 R7 .

Embodiment 55 . The compound of any one of Embodiments 1-34 , 44 , or 52-54 , wherein ¹R is Embodiment 56 . The compound of any one of Embodiments 1-34 , 44 , or 52-53 , Co each of which is optionally substituted with 1-2 R The compound of any one of Embodiments 1-34 , 44 , 52-53 , or wherein ¹R is or , Embodiment 57 . 56 , wherein ¹R is ( e.g. , or or ) . ﺢﻣﺎﻣ Co ☑ ) or ( e.g. , Embodiment 58. The compound of any one of Embodiments 1-34 , wherein ¹R is a 4 - membered heterocyclyl optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

Embodiment 59. The compound of any one of Embodiments 1-34 or 58 , wherein ¹R is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . ﺶﻣا Embodiment 60. The compound of any one of Embodiments 1-34 or 58-59 , -R' RRRwherein ¹R is ( e.g. , ) or Embodiment 61 . The compound of any one of Embodiments 58-60 , wherein each R7 is independently selected from the group consisting of : 383 WO 2025/064848 PCT / US2024 / 0477 -F . -cyano , -OH , -Rb1 , wherein the ¹bR is a 5-6 membered heteroaryl optionally substituted with 1-2 R , C1-3 alkyl optionally substituted with 1-3 F , C1-3 alkyl substituted with -OH or C1-3 alkoxy , and C ( = O ) N ( ¹R ) 2 .

Embodiment 62 . The compound of any one of Embodiments 1-34 or 58-60 , -R> -R ( e.g. , wherein ¹R is ) , wherein R7 is C1-3 alkyl substituted with -OH or C1- alkoxy ( e.g. , C1-3 alkyl substituted with -OH ) .

Embodiment 63. The compound of any one of Embodiments 1-34 , 58-60 , or 62 , OH OH wherein ¹R is ( e.g. , ) . ﺶﻣا Embodiment 64. The compound of any one of Embodiments 1-34 or 58-60 , R-R wherein ¹R is of : ﻭ wherein each R7 is independently selected from the group consisting C1-3 alkyl optionally substituted with 1-3 F ; and C1-3 alkyl substituted with -OH or C1-3 alkoxy .

Embodiment 65. The compound of any one of Embodiments 1-34 , 58-60 , or 64 , wherein ¹R is R7b R7a R☑ ( e.g. , R7b HO₂HC- ) ; and ) , wherein R7a is C1-3 alkyl substituted with -OH ( e.g. , R7b is selected from the group consisting of : C1-3 alkyl optionally substituted with 1-3 F ( e.g. , methyl ) , and C1-3 alkyl substituted with -OH or C1-3 alkoxy . 384 LO WO 2025/064848 PCT / US2024 / 0477 Embodiment 66. The compound of any one of Embodiments 1-34 , 58-60 , or 64- -OH , wherein ¹R is ( e.g. , _OH .OH ) or OH NO☑ .OH Embodiment 67. The compound of any one of Embodiments 1-34 , wherein ¹R is a 4-10 membered heterocyclyl substituted with -CN , - ( C1-3 alkylene ) -CN , or - ( C3-cycloalkylene ) -CN on a ring carbon atom , wherein the heterocyclyl is further optionally substituted with 1-3 R7 .

Embodiment 70. The compound of any one of Embodiments 1-34 or 67-69 , N N ﭺﺎﻫ wherein ¹R is -N ( ²R ) 2 .

' N ' ( e.g. , Embodiment 71 . The compound of any one of Embodiments 1-34 , wherein ¹R is Embodiment 72. The compound of Embodiment 71 , wherein each ²R is independently methyl or ethyl , each optionally substituted with 1-3 Rc , wherein each Re present on ²R is independently selected from the group consisting of : -F , cyano , -OH , -C1-6 alkoxy , and -C1-6 haloalkoxy . 385 WO 2025/064848 PCT / US2024 / 0477 Embodiment 73 . The compound of any one of Embodiments 1-34 or 71-72 , wherein ¹R is selected from the group consisting of : -N ( Me ) 2 , -N ( Et ) 2 , and N– ( Me ) Et .

Embodiment 74. The compound of any one of Embodiments 1-73 , wherein the ring carbon atom labelled with * has ( S ) -stereochemistry .

Embodiment 75 . The compound of any one of Embodiments 1-73 , wherein the ' N ' E¹E moiety is Embodiment 76. The compound of Embodiment 12 , wherein the compound of Formula ( I - c ) is a compound of Formula ( I - c1 ) or ( I - c2 ) : R7a -N NH' N ' CN b4 ( R10 ) . E* ³R Formula ( I - c1 ) R7a b4 ( R10 ) .

NHCN ﻢﻳں R7b E* ³R Formula ( I - c2 ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is CH ; b4 is 0 or 1 ( e.g. , 0 ) ; R10 is selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; ¹X is CH2 ; and 386 WO 2025/064848 PCT / US2024 / 0477 ²X and ³X are independently selected from the group consisting of : O , ₂HC , ¹RHC , and C ( RL ) 2 ; R7a is selected from the group consisting of : ( a ) C ( = O ) N ( R ) 2 , wherein each R is independently H or C1-3 alkyl optionally substituted with 1-3 Rh ; ﻭ ( b ) C ( O ) N ( C1-3 alkyl ) ¹¹R or -C ( O ) N ( H ) ¹¹R , wherein : ¹bR is C3-6 cycloalkyl or 4-membered heterocyclyl , each of which is optionally substituted with 1-3 R ; and ( c ) C ( O ) Rb1 , wherein R1 is 4-10 membered heterocyclyl optionally substituted with 1-3 Rg , wherein Rb1 is attached to the C ( O ) via a ring nitrogen atom ; and R7b is halo or C1-3 alkyl ( e.g. , -F , -Cl , or methyl ) .

Embodiment 77 . CH2 or CHRL The compound of Embodiment 76 , wherein ²X is CH2 ; and ³X is Embodiment 78 . ³X is CH2 .

Embodiment 79 . ³X is CHRL The compound of Embodiment 76 or 77 , wherein ²X is CH2 ; and The compound of Embodiment 76 or 77 , wherein ²X is CH2 ; and Embodiment 80 . X2 is CH2 ; and X3 is CHMe .

Embodiment 81 .

The compound of any one of Embodiments 76-77 or 79 , wherein The compound of any one of Embodiments 76-80 , wherein R7a is C ( = O ) N ( R ) 2 , wherein each Rf is an independently selected C1-3 alkyl ; and R7 is -F , -Cl , or methyl .

Embodiment 82. The compound of any one of Embodiments 76-81 , wherein R7a is C ( = O ) N ( Me ) 2 ; and R7 is -F , -Cl , or methyl .

Embodiment 83. The compound of Embodiment 12 , wherein the compound of Formula ( I - c ) is a compound of Formula ( I - c3 ) or ( I - c4 ) : 387 LO b4 ( R10 ) NHCN Formula ( I - c3 ) NH-RCN b4 ( R10 ) * PCT / US2024 / 0477 Formula ( I - c4 ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is CH ; R7 is C1-3 alkyl substituted with -OH ; b4 is 0 or 1 ( e.g. , 0 ) ; R10 is selected from the group consisting of : -C1 , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; ¹X is CH2 ; and , ²X and ³X are independently selected from the group consisting of : O , ₂HC , ¹RHC , and C ( RL ) 2 .

Embodiment 84 . CH2 or CHRL The compound of Embodiment 83 , wherein ²X is CH2 , and ³X is Embodiment 85 . ³X is CH2 . The compound of Embodiment 83 or 84 , wherein ²X is CH2 ; and Embodiment 86 . ³X is CHRL The compound of Embodiment 83 or 84 , wherein ²X is CH2 ; and Embodiment 87 . X2 is CH2 , and ³X is CHMe . The compound of any one of Embodiments 83-84 or 86 , wherein 388 WO 2025/064848 PCT / US2024 / 0477 Embodiment 88. The compound of any one of Embodiments 83-87 , wherein the -R7 -R compound is a compound of Formula ( I - c4 ) ; and the moiety is Embodiment 89 . The compound of any one of Embodiments 83-88 , wherein R7 is LO 5 HO₂HC . Embodiment 90 . The compound of any one of Embodiments 76-89 , wherein Y2 is -CH2- ; and ³R is -N optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , -C1-3 alkoxy , and -C1-3 haloalkoxy .

Embodiment 91. The compound of any one of Embodiments 76-90 , wherein Y2 is -CH2- ; and ³R is -N optionally substituted with 1-2 -F .

Embodiment 92 . F The compound of any one of Embodiments 76-91 , wherein ³R is -N ( e.g. , -N ) .

Embodiment 93 . The compound of any one of Embodiments 76-92 , wherein the E sod , gods ' N ' moiety is Embodiment 94. The compound of Embodiment 1 or 2 , wherein the compound of Formula ( A ) or Formula ( I ) is selected from the group consisting of Compound Nos . 101 , 101a , 102 , 102a , 102b , 103 , 103a , 104 , 104a , 104b , 105 , 105a , 106 , 106a , 106b , 107 , 107a , 107b , 108 , 108a , 108b , 108c , 109 , 109a , 109b , 109d , 110 , 110a , 110b , 111 , 111a , 112 , 112a , 113 , 113a , 113b , 114 , 114a , 115 , 115a , 116 , 116a , 117 , 117a , 118 , 118a , 119 , 119a , 120 , 120a , 389 WO 2025/064848 PCT / US2024 / 0477 LO 121 , 121a , 122 , 122a , 123 , 123a , 124 , 124a , 125 , 125a , 126 , 126a , 127 , 127a , 128 , 128a , 129 , 129a , 130 , 130a , 131 , 131a , 132 , 132a , 133 , 133a , 134 , 134a , 135 , 135a , 136 , 136a , 137 , 137a , 138 , 138a , 140 , 140a , 141 , 141a , 142 , 142a , 143 , 143a , 144 , 144a , 145 , 145a , 146 , 146a , 146b , 147 , 147a , 148 , 148a , 149 , 149a , 149b , 149c , 150 , 150a , 150b , 151 , 151a , 151b , 151c , 152 , 152a , 152b , 153 , 153a , 153b , 154 , 154a , 155 , 155a , 156 , and 156a , as depicted in Table C1 , or a pharmaceutically acceptable salt thereof .

Embodiment 95. A pharmaceutical composition comprising a compound of any one of Embodiments 1-94 , or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable excipient .

Embodiment 96. A dysregulated KRas protein non - covalently bound with a compound of any one of Embodiments 1-94 , or a pharmaceutically acceptable salt thereof .

Embodiment 97. A method for treating a KRas - associated 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 Embodiments 1-94 , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 95 .

Embodiment 98. A method for treating a KRas - associated cancer in a subject in need thereof , the method comprising ( a ) determining that the cancer in the subject has a KRas dysregulation ; and ( b ) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-94 , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 95 .

Embodiment 99. A method of treating a KRas - associated cancer in a subject , the method comprising administering to a subject identified or diagnosed as having a cancer having a KRas dysregulation a therapeutically effective amount of a compound of any one of Embodiments 1-94 or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 95 .

Embodiment 100. A method of treating a KRas - associated cancer in a subject , the method comprising : 390 LO WO 2025/064848 PCT / US2024 / 0477 ( a ) ( b ) determining that the cancer in the subject has a KRas dysregulation ; and administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-94 or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to Embodiment 95 .

Embodiment 101. The method of any one of Embodiments 97-99 , wherein the KRas - associated cancer is a mutant KRas - associated cancer .

Embodiment 102. The method of Embodiment 101 , wherein the mutant KRas- associated cancer is a KRas G12A - associated cancer , a KRas G12C - associated cancer , a KRas G12D - associated cancer , a KRas G12R - associated cancer , a KRas G12S - associated cancer , or a KRas G12V - associated cancer .

Embodiment 103. The method of Embodiment 102 , wherein the mutant KRas- associated cancer is a KRas G12D - associated cancer or a KRas G12V - associated cancer .

Embodiment 104. The method of Embodiment 102 , wherein the mutant KRas- associated cancer is a KRas G12D - associated cancer .

Embodiment 105. The method of Embodiment 102 , wherein the mutant KRas- associated cancer is a KRas G12R - associated cancer .

Embodiment 106. The method of Embodiment 102 , wherein the mutant KRas- associated cancer is a KRas G12V - associated cancer .

Embodiment 107. The method of any one of Embodiments 98 or 100 , wherein the step of determining that the cancer in the subject has a KRas dysregulation includes performing an assay to detect the KRas dysregulation ( e.g. , a KRas mutation ) in a tumor sample from the subject .

Embodiment 108. The method of Embodiment 107 , wherein detecting the KRas dysregulation includes detecting a KRAS gene having a mutation corresponding to a 391 WO 2025/064848 PCT / US2024 / 0477 substitution of glycine 12 in a KRas protein and / or a KRas protein having a substitution of glycine 12 .

Embodiment 109. The method of Embodiment 108 , wherein the substitution of glycine 12 is a substitution to alanine , cysteine , aspartic acid , arginine , serine , or valine .

Embodiment 110. The method of Embodiment 109 , wherein the substitution of glycine 12 is a substitution to aspartic acid .

Embodiment 111. The method of Embodiment 109 , wherein the substitution of glycine 12 is a substitution to arginine .

Embodiment 112. The method of Embodiment 109 , wherein the substitution of glycine 12 is a substitution to valine .

Embodiment 113. The method of any one of Embodiments 107-112 , comprising obtaining a tumor sample from the subject .

Embodiment 114. The method of Embodiment 113 , wherein the tumor sample is a biopsy sample .

Embodiment 115. The method of any one of Embodiments 107-114 , wherein the assay is selected from the group consisting of sequencing , immunohistochemistry , and enzyme - linked immunosorbent assay , and fluorescence in situ hybridization ( FISH ) .

Embodiment 116. The method of Embodiment 115 , wherein the sequencing is pyrosequencing or next generation sequencing .

Embodiment 117. The method of any one of Embodiments 107-116 , wherein the KRas - associated 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 , colorectal cancer ( e.g. , colon cancer or rectal cancer ) , endometrial cancer , esophageal cancer , kidney cancer , liver cancer , lung cancer , mucinous carcinoma , ovarian cancer , pancreatic 392 PCT / US2024 / 0477 cancer , prostate cancer , skin cancer , stomach cancer , testicular cancer , thymus cancer , thyroid cancer , urothelial cancer , uterine cancer , and a combination thereof .

Embodiment 118. The method of Embodiment 117 , wherein the KRas - associated cancer is pancreatic cancer .

Embodiment 119. The method of Embodiment 117 , wherein the KRas - associated cancer is selected from the group consisting of : a hematological cancer , brain cancer , cervical cancer , colon cancer , endometrial cancer , esophageal cancer , kidney cancer , liver cancer , lung cancer , mucinous carcinoma , pancreatic cancer , prostate cancer , rectal cancer , skin cancer , stomach cancer , thymus cancer , urothelial cancer , and uterine cancer .

, Embodiment 120. The method of Embodiment 117 , wherein the KRas - associated cancer is selected from the group consisting of : a hematological cancer , bladder cancer , bile duct 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 , rectal cancer , skin cancer , stomach cancer , testicular cancer ( e.g. , seminoma ) , thymus cancer , and uterine cancer .

Embodiment 121. The method of Embodiment 117 , wherein the KRas - associated cancer is selected from the group consisting of : bladder cancer , breast cancer , cervical cancer , colorectal cancer , endometrial cancer , esophageal or stomach cancer , leukemia , lung cancer ( e.g. , NSCLC ) , pancreatic cancer , and kidney cancer .

Embodiment 122. The method of Embodiment 117 , wherein the KRas - associated cancer is selected from the group consisting of : colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , ovarian cancer , or pancreatic cancer .

Embodiment 123. The method of any one of Embodiments 97-122 , comprising administering an additional therapy or therapeutic agent to the subject .

Embodiment 124. The method of Embodiment 123 , wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway targeted therapeutic agents , kinase - targeted therapeutics , mTORC1 inhibitors or degraders , YAP inhibitors or 393 LO WO 2025/064848 PCT / US2024 / 0477 degraders , proteasome inhibitors or degraders , HSP90 inhibitors or degraders , farnesyl 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 .

Embodiment 125. A method for a method for modulating KRas protein activity in a mammalian cell , the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-94 , or a pharmaceutically acceptable salt thereof . in vivo . Embodiment 126 . The method of Embodiment 125 , wherein the contacting occurs in vitro . Embodiment 127 . The method of Embodiment 125 , wherein the contacting occurs ex vivo . Embodiment 128 . The method of Embodiment 125 , wherein the contacting occurs Embodiment 129. The method of any one of Embodiments 125-128 , wherein the mammalian cell is a mammalian cancer cell .

Embodiment 130. The method of any one of Embodiments 125-128 , wherein the KRas protein is a mutant KRas protein .

Embodiment 131. The method of Embodiment 130 , wherein the mutant KRas protein is a mutant KRas protein selected from the group consisting of : a KRas G12A mutant protein , a KRas G12C mutant protein , a KRas G12D mutant protein , a KRas G12R mutant protein , a KRas G12S mutant protein , and a KRas G12V mutant protein . 394

Claims

1. WO 2025/0648 WHAT IS CLAIMED IS : A compound of Formula ( I - c ) : b4 ( R10 ) . NHRCN E ³R PCT / US2024 / 0477 Formula ( I - c ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is selected from the group consisting of : CH and CR4 , wherein R4 is selected from the group consisting of : -CN , halo , C1-3 alkyl , C1-3 haloalkyl , and C3-6 cycloalkyl ; ¹R is a 4-10 membered heterocyclyl optionally substituted with 1-4 R7 ; each R7 is independently selected from the group consisting of ªR and ³R ; ¹X is -CH2- ; ²X is -CH2- ; ³X is -CH2- or -¹RHC- ; b4 is 0 ; R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc : ¹R is selected from the group consisting of : -CH3 , -CF3 , -CHF2 , and F₂HC- ; ²Y is -CH2- ; ³R is -N optionally substituted with 1-2 substituents each independently selected from the group consisting of : -F , C1-3 alkoxy , and C1-3 haloalkoxy ; each ªR is independently selected from the group consisting of : ( a ) halo ; ( b ) cyano ; 395 WO 2025/064848 PCT / US2024 / 0477 ( c ) -OH ; ( d ) oxo ; ( e ) C1-6 alkoxy ; ( f ) C1-6 haloalkoxy ; ( g ) -NRdRe . ( h ) -C ( = O ) C1-6 alkyl ; ( i ) -C ( = O ) C1-6 haloalkyl ; ( j ) -C ( = O ) OH ; ( k ) -C ( = O ) OC1-6 alkyl ; ( I ) -C ( = O ) OC1-6 haloalkyl ; ( m ) -C ( = O ) N ( R ) 2 ; ( n ) -S ( O ) 0-2 ( C1-6 alkyl ) ; ( 0 ) -S ( O ) 0-2 ( C1-6 haloalkyl ) ; ( p ) -S ( O ) 1-2N ( R ) 2 ; and ( q ) C1-6 alkyl , C2-6 alkenyl , or C2-6 alkynyl , each optionally substituted with 1-6 Rc ; wherein : each ³R is independently selected from the group consisting of : - ( ³L ) ₁ - ¹bR and ¹bR , b is 1 , 2 , or 3 ; each Lb is independently selected from the group consisting of : -O- , -N ( H ) - , -N ( C1-alkyl ) - , -S ( O ) 0-2- , -C ( = O ) - , and C1-3 alkylene ; and each ¹¹R is independently selected from the group consisting of : C3-10 cycloalkyl , 4-membered heterocyclyl , C6-10 aryl , and 5-10 membered heteroaryl , each of which is optionally substituted with 1-3 Rg ; each R is independently selected from the group consisting of : halo , cyano , -OH , C1-alkoxy , C1-6 haloalkoxy , -NRdRe , -C ( = O ) C1-6 alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) OH , -C ( = O ) N ( R ) 2 , -S ( O ) 0-2 ( C1-6 alkyl ) , -S ( O ) 0-2 ( C1-haloalkyl ) , and -S ( O ) 1-2N ( ³R ) 2 ; each Rd and Re is independently selected from the group consisting of : -H , -C ( = O ) C1-alkyl , -C ( = O ) C1-6 haloalkyl , -C ( = O ) OC1-6 alkyl , -C ( = O ) OC1-6 haloalkyl , -C ( = O ) N ( ³R ) 2 , S ( O ) 1-2 ( C1-6 alkyl ) , -S ( O ) 1-2 ( C1-6 haloalkyl ) , -S ( O ) 1-2N ( R ) 2 , and C1-6 alkyl optionally substituted with 1-3 Rh ; each R is independently selected from the group consisting of : -H and C1-6 alkyl 396 WO 2025/064848 PCT / US2024 / 0477 optionally substituted with 1-3 Rh ; , each R is independently selected from the group consisting of : Rh , C1-3 alkyl , C1-haloalkyl , C3-5 cycloalkyl , and 4-5 membered heterocyclyl ; and each Rh is independently selected from the group consisting of : halo , cyano , -OH , -C1- alkoxy , -C1-6 haloalkoxy , -NH2 , -N ( H ) ( C1-3 alkyl ) , and -N ( C1-3 alkyl ) 2 .

2. The compound of claim 1 , wherein RL is -CH3 .

3. The compound of claim 1 or 2 , wherein ¹E is CH .

4. The compound of any one of claims 1-3 , wherein ³R is optionally .F BE substituted with 1-2 -F ( e.g. , ³R is or , , ) . FL

5.

6. The compound of any one of claims 1-4 , wherein ³R is ( e.g. , The compound of any one of claims 1-5 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered heterocyclyl is optionally substituted with 1-4 R

7. The compound of any one of claims 1-6 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered monocyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered monocyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

8. The compound of claim 6 or 7 , wherein ¹R is optionally substituted with 1-4 R7 at one or more ring carbon atoms . 397 LO WO 2025/064848 PCT / US2024 / 0477

9. The compound of any one of claims 6-8 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 Rc , wherein each R © present on R7 is independently selected from the group consisting of : -F , OH , and -CN .

10. The compound of any one of claims 1-9 , wherein ¹R is

11. RThe compound of any one of claims 1-9 , wherein ¹R is R ﻢﻳﺮﻣ ( e.g. ,

12. ) , wherein R7 is a 5 - membered heteroaryl optionally substituted with 1-3 Rg . The compound of claim 11 , wherein R7 is pyrazolyl optionally substituted with 1-2 R ( e.g. , R7 is H -N optionally substituted with one ºR ) ; or wherein R7 is oxazolyl optionally substituted with one ºR ( e.g. , R7 is optionally substituted with one Rg ) .

13. The compound of claim 11 or 12 , wherein R7 is or

14. The compound of any one of claims 1-6 , wherein ¹R is a 7-10 ( e.g. , 7 ) membered spirocyclic bicyclic heterocyclyl having one ring nitrogen atom , one ring oxygen atom , and no additional ring heteroatoms , wherein the 7-10 membered spirocyclic bicyclic heterocyclyl is optionally substituted with 1-4 ( e.g. , 1-2 ) R7 . 398 WO 2025/064848 PCT / US2024 / 0477 ( R7 ) n( R7 ) nA

15. The compound of any one of claims 1-6 or 14 , wherein ¹R is wherein : Ring A1 is a 4-7 membered heterocyclyl ring having one ring oxygen atom and no additional ring heteroatoms ; n4 is 0 , 1 , or 2 ; and n5 is 0 , 1 , or 2 , provided that n4 + n5 is 0 , 1 , or 2 .

16. The compound of any one of claims 1-6 or 14-15 , wherein ¹R is which is optionally substituted with 1-2 R7 .

17. The compound of any one of claims 1-6 or 14-16 , wherein ¹R is

18.

19. ﻭ # ﻭ The compound of any one of claims 1-6 or 14-15 , wherein ¹R is or each of which is optionally substituted with 1-2 R7 . The compound of any one of claims 1-6 , 14-15 , or 18 , wherein ¹R is ( e.g. , or ) or ( e.g. , or

20. The compound of any one of claims 1-6 , wherein ¹R is a 4 - membered heterocyclyl optionally substituted with 1-4 ( e.g. , 1-2 ) R7 .

21. The compound of any one of claims 1-6 or 20 , wherein ¹R is substituted with 1-4 ( e.g. , 1-2 ) R7 . optionally WO 2025/0648

22. PCT / US2024 / 0477 The compound of any one of claims 1-6 or 20-21 , wherein ¹R is -R ( e.g. , N -R ) or RR

23. The compound of any one of claims 20-22 , wherein each R7 is independently selected from the group consisting of : ³R , ( a ) -F , ( b ) cyano , ( c ) -OH , ( d ) Rb1 , wherein the ¹¹R is a 5-6 membered heteroaryl optionally substituted with 1- ( e ) C1-3 alkyl optionally substituted with 1-3 F , ( f ) C1-3 alkyl substituted with -OH or C1-3 alkoxy , and ( g ) -C ( = O ) N ( R ) 2 . -R 15

24. The compound of any one of claims 1-6 or 20-22 , wherein ¹R is ( e.g. , -R ) , wherein R7 is C1-3 alkyl substituted with -OH or C1-3 alkoxy ( e.g. , C1-3 alkyl substituted with -OH ) .

25. The compound of any one of claims 1-6 , 20-22 , or 24 , wherein ¹R is OH ( e.g. , OH ) .

26. The compound of any one of claims 1-6 or 20-22 , wherein ¹R is wherein each R7 is independently selected from the group consisting of : ( a ) C1-3 alkyl optionally substituted with 1-3 -F ; and ( b ) C1-3 alkyl substituted with -OH or C1-3 alkoxy . 4 R-Rﺵاﺮﻜﻣ ﻭ WO 2025/064848 PCT / US2024 / 0477 R7b

27. R7b The compound of any one of claims 1-6 , 20-22 , or 26 , wherein ¹R is -R7a ( e.g. , R7a 7a ) , wherein Ra is C1-3 alkyl substituted with -OH ( e.g. , HO₂HC- ) ; and R7b is selected from the group consisting of : ( a ) C1-3 alkyl optionally substituted with 1-3 -F ( e.g. , methyl ) , and ( b ) C1-3 alkyl substituted with -OH or C1-3 alkoxy .

28. The compound of any one of claims 1-6 , 20-22 , or 26-27 , wherein ¹R is Xo OH COM -OH ( e.g. , -OH ) or

29. The compound of any one of claims 1-6 , wherein ¹R is a 4-10 membered . heterocyclyl substituted with -CN , - ( C1-3 alkylene ) -CN , or - ( C3-6 cycloalkylene ) -CN on a ring carbon atom , wherein the heterocyclyl is further optionally substituted with 1-3 R7 .

30. The compound of any one of claims 1-6 or 29 , wherein ¹R is a 6-8 membered heterocyclyl substituted with -CN or - ( C1-3 alkylene ) -CN on a ring carbon atom , wherein : the heterocyclyl has one ring nitrogen atom and 0-1 ring oxygen atom ; and the heterocyclyl is further optionally substituted with 1-3 R7 .

31. The compound of claim 29 or 30 , wherein each R7 is independently selected from the group consisting of : -OH ; -CN ; -F ; and C1-3 alkyl optionally substituted with 1-3 R ¢ ( e.g. , C1-3 alkyl optionally substituted with 1-3 -F ) .

32. The compound of any one of claims 1-6 or 29-31 , wherein ¹R is ( e.g. , LO is WO 2025/064848 PCT / US2024 / 0477

33. The compound of any one of claims 1-32 , wherein the moiety ' N ' E

34. The compound of claim 1 , wherein the compound of Formula ( I - c ) is a compound of Formula ( I - c3 ) or ( I - c4 ) : NHCN b4 ( º¹R ) - ' E³R Formula ( I - c3 ) NH-RCN b4 ( R10 ) . E³R Formula ( I - c4 ) or a pharmaceutically acceptable salt thereof , wherein : ¹E is CH ; R7 is C1-3 alkyl substituted with -OH ; b4 is 0 ; 402 WO 2025/064848 PCT / US2024 / 0477 R10 is selected from the group consisting of : -Cl , -F , -CN , and C1-3 alkyl optionally substituted with 1-3 Rc ; ¹X is -CH2- ; ²X is -CH2- ; and ³X is -CH2- or -¹RHC- .

35. The compound of claim 34 , wherein ²X is -CH2- ; and ³X is -CH2- .

36. The compound of claim 34 , wherein ²X is -CH2- ; and ³X is -CHRL- .

37. The compound of claim 34 or 36 , wherein ²X is -CH2- ; and ³X is -CHMe- .

38. The compound of any one of claims 34-37 , wherein the compound is a compound of Formula ( I - c4 ) ; and the -R-R moiety is

39. The compound of any one of claims 34-38 , wherein R7 is HO₂HC- .

40. The compound of any one of claims 34-39 , wherein ²Y is -CH2- ; and ³R is FL optionally substituted with 1-2 -F .

41. ...... -N $ -N ( e.g. , The compound of any one of claims 34-40 , wherein ³R is 403 WO 2025/064848 PCT / US2024 / 0477

42. The compound of any one of claims 34-41 , wherein the moiety is E ' N ' E

43. The compound of claim 1 , wherein the compound of Formula ( I - c ) is selected from the group consisting of Compound Nos . 101 , 101a , 103 , 103a , 107 , 107a , 107b , 111 , 111a , 121 , 121a , 122 , 122a , 136 , 136a , 137 , 137a , 140 , 140a , 141 , 141a , 142 , 142a , 144 , 144a , 146 , 146a , 146b , 151 , 151a , 151b , 151c , 152 , 152a , 152b , 153 , 153a , 153b , 155 , 155a , 155b , 156 , and 156a , as depicted in Table C1 , or a pharmaceutically acceptable salt thereof .

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

45. 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 1-43 , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to claim 44 .

46. A method for treating cancer in a subject in need thereof , the method comprising ( a ) determining that the cancer in the subject has a KRas dysregulation ; and ( b ) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-43 , or a pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to claim . ﺶﻣا

47. A method of treating cancer in a subject , the method comprising administering to a subject identified or diagnosed as having a cancer having a KRas dysregulation a therapeutically effective amount of a compound of any one of claims 1-43 or a 404 WO 2025/064848 PCT / US2024 / 0477 pharmaceutically acceptable salt thereof , or a pharmaceutical composition according to claim .

48. The method of any one of claims 45-47 , wherein the KRas dysregulation is a KRas mutation .

49. The method of claim 48 , wherein the KRas mutation is a KRas G12A mutation , a KRas G12C mutation , a KRas G12D mutation , a KRas G12R mutation , a KRas G12S mutation , or a KRas G12V mutation .

50. The method of claim 49 , wherein the KRas mutation is a KRas G12C mutation , a KRas G12D mutation or a KRas G12V mutation .

51. The method of claim 46 , wherein the step of determining that the cancer in the subject has a KRas dysregulation includes performing an assay to detect the KRas dysregulation ( e.g. , a KRas mutation ) in a tumor sample from the subject .

52. The method of claim 51 , wherein detecting the KRas dysregulation includes detecting a KRAS gene having a mutation corresponding to a substitution of glycine 12 in a KRas protein and / or a KRas protein having a substitution of glycine 12 .

53. The method of claim 52 , wherein the substitution of glycine 12 is a substitution to alanine , cysteine , aspartic acid , arginine , serine , or valine .

54. The method of any one of claims 45-53 , 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 , colorectal cancer ( e.g. , colon cancer or rectal cancer ) , endometrial cancer , esophageal cancer , kidney cancer , liver cancer , lung cancer , mucinous carcinoma , ovarian cancer , pancreatic cancer , prostate cancer , skin cancer , stomach cancer , testicular cancer , thymus cancer , thyroid cancer , urothelial cancer , uterine cancer , and a combination thereof . 405 WO 2025/064848 PCT / US2024 / 0477

55. The method of claim 54 , wherein the cancer is selected from the group consisting of : colon cancer , endometrial cancer , lung cancer , pancreatic cancer , and uterine cancer . LO

56. The method of claim 54 , wherein the cancer is selected from the group consisting of : colorectal cancer , endometrial cancer , lung cancer ( e.g. , NSCLC ) , ovarian cancer , and pancreatic cancer .

57. The method of any one of claims 45-56 , comprising administering an additional therapy or therapeutic agent to the subject .

58. The method of claim 57 , wherein the additional therapy or therapeutic agent is selected from the group consisting of Ras pathway targeted therapeutic agents , kinase - targeted therapeutics , mTORC1 inhibitors or degraders , YAP inhibitors or degraders , proteasome inhibitors or degraders , HSP90 inhibitors or degraders , farnesyl 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 . 406