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WO2025064848A1 - Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques - Google Patents

Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques Download PDF

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Publication number
WO2025064848A1
WO2025064848A1 PCT/US2024/047734 US2024047734W WO2025064848A1 WO 2025064848 A1 WO2025064848 A1 WO 2025064848A1 US 2024047734 W US2024047734 W US 2024047734W WO 2025064848 A1 WO2025064848 A1 WO 2025064848A1
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Prior art keywords
kras
mutant protein
protein
compound
mutant
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Inventor
Shawn Cabral
Vincent Mascitti
Sarah J. Hill
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Treeline Biosciences, Inc
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Treeline Biosciences, Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This disclosure provides compounds of Formula (A) (e.g., Formula (I) (e.g., Formula (La), (Lb), (Lc), (Lcl), (Lc2), (Lc3), (Lc4), (Ld), or (Le))) 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)).
  • the KRas protein is a dysregulated KRas protein that has a mutation (referred to herein as a mutant KRas protein).
  • KRas activation such as KRas activation associated with a mutant KRas protein
  • a subject e.g., a human
  • compositions containing compounds of Formula (A) e.g., Formula (I) (e.g., Formula (La), (Lb), (Lc), (Lcl), (Lc2), (Lc3), (Lc4), (Ld), or (Le))) or Formula (B), or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.
  • Formula (I) e.g., Formula (La), (Lb), (Lc), (Lcl), (Lc2), (Lc3), (Lc4), (Ld), or (Le)
  • the KRAS gene is frequently dysregulated (e.g., mutated or amplified) in various human cancers.
  • Oncogenic mutations in KRas typically occur at hotspots in the protein such as at amino acids positions 12, 13, and 61.
  • 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.
  • 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.
  • GTP -bound state e.g., due to a deficiency of intrinsic GTPase activity and/or insensitivity for GTPase-activating proteins (GAPs) and consequent increased KR
  • G12X such as G12A, G12C, G12D, G12R, G12S, and G12V; position
  • G13X such as G13C, G13D, and G13V
  • Q61 referred to herein as Q61X
  • 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.
  • therapies that can specifically bind and inhibit KRas signaling in cancer cells but had long been considered to be undruggable.
  • the KRas protein is a dysregulated KRas protein that has a mutation (referred to herein as a mutant KRas protein).
  • a mutant KRas protein a dysregulated KRas protein that has a mutation.
  • 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.
  • KRas activation such as KRas activation associated with a mutant KRas protein or KRas activation associated with KRas amplification
  • a subject e.g., a human
  • compositions containing compounds of Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I- b), (I-c), (I-cl), (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.
  • Formula (I) e.g., Formula (I-a), (I- b), (I-c), (I-cl), (I-c2), (I-c3), (I-c4), (I-d), or (I-e)
  • E 1 is selected from the group consisting of: CH and CR 4 , wherein R 4 is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl;
  • R 1 is selected from the group consisting of:
  • each R 2 is independently selected from the group consisting of: - H and Ci-6 alkyl optionally substituted with 1-3 R c ;
  • each R 7 is independently selected from the group consisting of R a and R b ;
  • Ring B is: , wherein the * marks the ring carbon atom common to both Ring
  • X 1 is selected from the group consisting of a bond, S(0)o-2, CH2, CHR L , C(R L )2, and X 2 and X 3 are independently selected from the group consisting of: CH2, CHR L , C(R L )2, O, and S(O)0-2, provided that no more than one of X 1 , X 2 , and X 3 is selected from the group consisting of: O and S(O)0-2; b1 is 0, 1, or 2; R 9 is selected from the group consisting of: -H, -OH, -NR d R e , and halo; each R 10 is independently selected from the group consisting of R a and R b ; each R L is independently selected from the group consisting of C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c ; or one pair of R L on the same or different ring carbon atom(s) are taken together with the ring atom(s) connecting
  • 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.
  • 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))
  • a pharmaceutically acceptable carrier e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I- d), or
  • 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.
  • 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))
  • Formula (B) 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
  • a KRas dysregulation e.
  • 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))
  • 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 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 KR
  • 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
  • T his 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
  • KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a mutant KRas protein e.g., a resistance mutation
  • KRas inhibitors e.g., a KRas inhibitor selective for a KRas G12C mutant protein
  • This disclosure also provides compositions containing the compounds provided herein as well as methods of using and making the same.
  • Ras family genes 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)).
  • GEF guanine nucleotide exchange factors
  • KRas inhibitors are described in, for example, International Publication Nos.
  • E 1 is selected from the group consisting of: CH and CR 4 , wherein R 4 is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; R 1 is selected from the group consisting of: (i) a 4-10 membered heterocyclyl optionally substituted with 1-4 R 7 ; , wherein b2 is 0, 1, 2, or 3; and A 1 and A 2 are independently selected from the group consisting of: N, CH, and CR 7 ; (iii) -N(R 2 )2, wherein each R 2 is independently selected from the group consisting of: - H and C1-6 alkyl optionally substituted with 1-3 R c ; and (iv) -H; each R 7 is independently selected from the group consisting of R a and R b ;
  • X 1 is selected from the group consisting of a bond, S(O)0-2, CH2, CHR L , C(R L )2, and O;
  • X 2 and X 3 are independently selected from the group consisting of: CH2, CHR L , C(R L )2, O, and S(O)0-2, provided that no more than one of X 1 , X 2 , and X 3 is selected from the group consisting of: O and S(O)0-2;
  • b1 is 0, 1, or 2;
  • R 9 is selected from the group consisting of: -H, -OH, -NR d R e , and halo;
  • each R 10 is independently selected from the group consisting of R a and R b ;
  • each R L is independently selected from the group consisting of C1-3 alkoxy, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c ; or one pair of R L on the same or different ring carbon atom(s)
  • E 1 is selected from the group consisting of: CH and CR 4 , wherein R 4 is selected from the group consisting of: -CN, halo, C1-3 alkyl, C1-3 haloalkyl, and C3-6 cycloalkyl; R 1 is selected from the group consisting of: (i) a 4-10 membered heterocyclyl optionally substituted with 1-4 R 7 ; and wherein b2 is 0, 1, 2, or 3; and A 1 and A 2 are independently selected from the group consisting of: N, CH, and CR 7 ; each R 7 is independently selected from the group consisting of R a and R b ; X 1 is selected from the group consisting of a bond, S(O)0-2, CH2, CHR L , C(R L )2, and O; X 2 and X 3 are independently selected from the group consisting of: CH2, CHR L , 25 C(R L )2, O, and S(O)0-2, provided that no more than one of
  • each R 10 is independently selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • the compounds of Formula (A) are compounds of Formula (I-a): Formula (I-a) or pharmaceutically acceptable salts thereof, wherein: b1 is 1 or 2.
  • each R 10 is independently selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • b1 is 1.
  • the compounds of Formula (A) are compounds of Formula (I-b): Formula (I-b) or pharmaceutically acceptable salts thereof, wherein: b4 is 0 or 1; and R 10 is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • R 9 is -NR d R e (e.g., -NH2).
  • b4 is 0.
  • R 9 is -NR d R e (e.g., -NH2); and b4 is 0.
  • the compounds of Formula (A) are compounds of Formula (I-c): Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein: b4 is 0 or 1; and R 10 is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • b4 is 0.
  • X 1 is -CH2-.
  • X 2 and X 3 are independently selected from the group consisting of: -CH2-, -CHR L -, -C(R L )2-, and -O-.
  • each R L is independently selected from the group consisting of: -CH3, -CF3, -CHF2, and -CH2F (e.g., -CH3).
  • R L is selected from the group consisting of: - CH3, -CF3, -CHF2, and -CH2F (e.g., CH3).
  • the compounds of Formula (A) are compounds of Formula (I-e): Formula (I-e) or pharmaceutically acceptable salts thereof, wherein: X 1 is selected from the group consisting of a bond, -S(O)0-2-, -CH2-, -CHR L -, -C(R L )2- , and -O-; X 2 and X 3 are independently selected from the group consisting of: -CH2-, -CHR L -, - C(R L )2-, -O-, and -S(O)0-2-, provided that 2-3 of X 1 , X 2 , and X 3 are independently -CHR L - or -C(R L )2-, wherein: one pair of R L 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 R L is independently selected
  • X 2 is -CH2- or -O- (e.g., -CH2-).
  • X 1 is -CHR L -;
  • X 3 is -CHR L -; and the pair of R L are taken together with the ring atoms connecting them to form a C3-4 (e.g., C4) cycloalkyl ring.
  • R 9 is -NR d R e (e.g., -NH2).
  • b1 is 1 or 2; and each R 10 is independently selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • the moiety is , wherein b4 is 0 or 1; and R 10 is selected from the group consisting of: - Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • b4 is 0.
  • E 1 is CH.
  • E 1 is CR 4 .
  • E 1 can be CF.
  • Y 2 is -CH2-; and R 3 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 R a .
  • Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, C1-3 alkoxy, and C1-3 haloalkoxy.
  • R 1 is , wherein b2 is 0, 1, or 2, and A 1 and A 2 are independently selected from the group consisting of: N, CH, and CR 7 .
  • R 7b is halo or C1-3 alkyl (e.g., -F, -Cl, or methyl).
  • R 7b is halo (e.g., -Cl).
  • Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- , wherein each R f is independently C1-3 alkyl optionally substituted with 1-3 R h .
  • R 1 can .
  • R 1 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 .
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c , wherein: each R c present on R 7 is independently selected from the group consisting of: -F, -OH, and -CN.
  • R 1 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) R 7 .
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c , wherein: each R c present on R 7 is independently selected from the group consisting of: -F, -OH, and -CN.
  • Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- optionally substituted with 1-4 R 7 at one or more ring carbon atoms.
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c , wherein: each R c present on R 7 is independently selected from the group consisting of: -F, -OH, and -CN.
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c , wherein: each R c present on R 7 is independently selected from the group consisting of: -F, -OH, and -CN.
  • Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein R 7 is a 5-membered heteroaryl optionally substituted with 1-3 R g .
  • R 7 is pyrazolyl optionally substituted with 1-2 R g (e.g., R 7 is optionally substituted with one R g ); or wherein R 7 is oxazolyl optionally substituted with one R g (e.g., R 7 is optionally substituted with one R g ).
  • R 7 is pyrazolyl optionally substituted with 1-2 R g (e.g., R 7 is optionally substituted with one R g ); or wherein R 7 is oxazolyl optionally substituted with one R g (e.g., R 7 is optionally substituted with one R g ).
  • R 7 is pyrazolyl optionally substituted with 1-2 R g (e.g., R 7 is optionally substitute
  • R 1 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 7 .
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c , wherein: each R c present on R 7 is independently selected from the group consisting of: -F, -OH, and -CN.
  • R 1 is , which is optionally substituted with 1-2 R 7 .
  • R 1 can .
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c , wherein: each R c present on R 7 is independently selected from the group consisting of: -F, -OH, and -CN.
  • R 1 is a monocyclic heterocyclyl. In some embodiments, R 1 is a spirocyclic bicyclic heterocyclyl.
  • R 1 is optionally substituted with 1-4 (e.g., 1-2) R 7 .
  • R 1 is .
  • Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein R 7 is C1-3 alkyl substituted with - OH or C1-3 alkoxy (e.g., C1-3 alkyl substituted with -OH).
  • R 1 is , wherein each R 7 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.
  • Formula (A) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I- wherein R 7a is C1-3 alkyl substituted with -OH (e.g., -CH2OH); and R 7b 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.
  • Formula (I) e.g., Formula (I-a), (I-b), (I- wherein R 7a is C1-3 alkyl substituted with -OH (e.g., -CH2OH); and R 7b 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.
  • R 1 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 R 7 .
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1-3 -F).
  • R 1 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 R 7 .
  • each R 7 is independently selected from the group consisting of: -OH; -CN; -F; and C1-3 alkyl optionally substituted with 1-3 R c (e.g., C1-3 alkyl optionally substituted with 1- 3 -F).
  • R1 is -N(R2)2.
  • each R2 is independently methyl or ethyl, each optionally substituted with 1-3 R c , wherein each R c present on R 2 is independently selected from the group consisting of: -F, cyano, -OH, C1-6 alkoxy, and C1-6 haloalkoxy.
  • 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.
  • b4 is 0.
  • X 2 is -CH2-; and X 3 is -CH2-.
  • X 2 is -CH2-; and X 3 is -CHR L -.
  • X 2 is -CH2-; and X 3 is -CHMe-.
  • the compounds of Formula (I-c) are compounds of Formula (I- c3) or (I-c4): Formula (I-c4) or pharmaceutically acceptable salts thereof, wherein: E 1 is CH; R 7 is C1-3 alkyl substituted with -OH; b4 is 0 or 1 (e.g., 0); R 10 is selected from the group consisting of: -Cl, -F, -CN, and C1-3 alkyl optionally substituted with 1-3 R c ; X 1 is -CH2-; and X 2 and X 3 are independently selected from the group consisting of: -O-, -CH2-, -CHR L - , and -C(R L )2-.
  • X 2 is -CH2-; and X 3 is -CH2- or - CHR L -.
  • X 2 is -CH2-; and X 3 is -CH2-.
  • X 2 is -CH2-; and X 3 is -CHR L -.
  • X 2 is -CH2-; and X 3 is -CHMe-.
  • the moiety is .
  • R 7 is -CH2OH.
  • Y 2 is -CH2-; and R 3 is optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, C1-3 alkoxy, and C1-3 haloalkoxy.
  • Y 2 is -CH2-; and R 3 optionally substituted with 1-2 -F.
  • the moiety i in some embodiments of Formula (I-c1), (I-c2), (I-c3), or (I-c4), the moiety i .
  • 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 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-
  • each stereogenic center can independently adopt a (A) or (5) stereochemical configuration.
  • such structures also encompass mixtures of stereoisomers. For example, represents or a mixture
  • 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.
  • a stereoisomeric mixture differing at this stereogenic center is represented.
  • the structure represents a mixture of (S)-(1-methylpyrrolidin-2- yl)methanol and (R)-(1-methylpyrrolidin-2-yl)methanol.
  • the structural formula refers to a mixture of stereoisomers at these two defined stereogenic centers, wherein the configuration at each of the defined stereogenic centers can vary independently of one another.
  • the structure refers to a mixture of four stereoisomers: , , b.
  • 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 (eg at R 9 when R 9 is NH2) or OH (eg at R 7 when R 7 is -OH or C1-3 alkyl substituted with -OH) functionalities.
  • R L can be methyl, ethyl, or -CF3.
  • R L can be methyl.
  • R 2a , R 2b , R 2c , and R 2d are each -H.
  • E 1 is CH.
  • R 2a , R 2b , R 2c , and R 2d are each -H; and E 1 is CH.
  • each R 7 is independently selected from the group consisting of: (a) -F; (b) cyano; (c) -OH; (d) R b1 , wherein the R b1 is a 5-6 membered heteroaryl optionally substituted with 1-2 R g ; (e) C1-3 alkyl optionally substituted with 1-3 -F; and (f) C1-3 alkyl substituted with -OH or C1-3 alkoxy.
  • R 1 is (e.g., ), wherein R 7 is C1-3 alkyl substituted with -OH or C1-3 alkoxy (e.g., C1-3 alkyl substituted with -OH).
  • R 7a is C1-3 alkyl substituted with -OH (e.g., -CH2OH); and R 7b is selected from the group consisting of: C1-3 alkyl optionally substituted with 1-3 -F (e.g., methyl), and C 1-3 alkyl substituted with -OH or C1-3 alkoxy.
  • R 1 can In some embodiments of Formula wherein R 7 is a 5-membered heteroaryl optionally substituted with 1-3 R g .
  • R 7 is selected from the group consisting of pyrazolyl and oxazolyl, each of which is optionally substituted with 1-2 R g .
  • R 7 is pyrazolyl optionally substituted with 1-2 R g (e.g., R 7 is optionally substituted with one R g ).
  • R 7 can be .
  • R 7 is oxazolyl optionally substituted with one R g (e.g., R 7 is optionally substituted with one R g ).
  • R 7 can be .
  • Y 2 is -CH2- or -CD2- (e.g., -CH2-).
  • Y 2 is -CH 2 - or -CD 2 - (e.g., -CH 2 -); and R 3 is optionally substituted with 1-2 substituents each independently selected from the group consisting of: -F, -C1-3 alkoxy, and -C1-3 haloalkoxy.
  • Y 2 is -CH2- or -CD2- (e.g., -CH2-); and R 3 is a 9-14 (e.g., 9-12) membered heterocyclyl optionally substituted with 1-3 substituents independently selected from the group consisting of: R a , R b , and .
  • R 3 is a 9-12 membered heterocyclyl optionally substituted with 1-3 R a .
  • R 3 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.
  • R 3 can be selected from the group consisting of: , , , , In some embodiments of Formula (B), Y 2 is -CH2- or -CD2- (e.g., -CH2-); and R 3 is an 8-12 membered heterocyclyl substituted with 1-2 further optionally substituted with 1-2 independently selected R a .
  • R 3 is selected from the group In some embodiments of Formula (B), Y 2 is -CH2- or -CD2- (e.g., -CH2-); and R 3 is an 8-12 membered heterocyclyl substituted with R b and further optionally substituted with 1-2 substituents independently selected from the group consisting of: R a and . In some embodiments , , . In some embodiments of Formula (B), Y 2 is -CH2- or -CD2- (e.g., -CH2-); and R 3 is selected from the group consisting of: wherein each R a3 is an independently selected C1-3 alkyl optionally substituted with 1-3 -F.
  • R 3 can be selected from the group consisting of: , In some embodiments of Formula (B), Y 2 is -CH2- or -CD2- (e.g., -CH2-); and R 3 is , ptionally substituted with 1-3 -F.
  • R 3 can be selected from the group consisting of: , In some embodiments of Formula (B), Y 2 is a straight-chain C3-6 alkylene optionally substituted with 1-6 R Y . In some embodiments, Y 2 is selected from the group consisting of: In some embodiments of Formula (B), Y 2 is a straight-chain C3-6 alkylene optionally substituted with 1-6 R Y ; and R 3 is -NR d R e .
  • Y 2 is selected from the In some embodiments of Formula (B), Y 2 is a straight-chain C3-6 alkylene optionally substituted with 1-6 R Y ; and R 3 is a 4-8 membered heterocyclyl optionally substituted with 1- 3 substituents independently selected from the group consisting of: R a , , and .
  • Y 2 is selected from the group consisting of: , , , ; and R 3 is selected from the group consisting
  • KRas protein e.g., a dysregulated KRas protein (e.g., a mutated KRas protein)
  • 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.
  • Gly10 of the KRas protein interacts non-covalently with the R 1 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 Gly10 and an -OH group of R 1 and/or via a water mediated interaction between the -NH group of Gly10 and an -OH group of R 1 ).
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e)
  • Formula (B) e.g., via a hydrogen bond between
  • the interaction between Gly10 of the KRas protein and the R 1 group of the compound of Formula (A) facilitates the inhibition of interaction between the KRas protein and Raf-RBD.
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I- c3), (I-c4), (I-d), or (I-e)
  • Formula (B) 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))
  • Formula (B) e.g., Formula (I) (e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I- c3), (I-c4), (I-d), or
  • Arg68 of the KRas protein interacts non-covalently with the R 1 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 R 1 ).
  • Formula (I) e.g., Formula (I-a), (I-b), (I-c), (I-c1), (I-c2), (I- c3), (I-c4), (I-d), or (I-e)
  • the interaction between Arg68 of the KRas protein and the R 1 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.
  • Formula (I) e.g., Formula (I- a), (I-b), (I-c), (I-c1), (I-c2), (I-c3), (I-c4), (I-d), or (I-e)
  • alkyl refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo (e.g., -CF3, -CHF2, or -CH2F).
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • haloalkoxy refers to an -O-haloalkyl radical (e.g., -OCF3, -OCHF2, or -OCH2F).
  • alkylene refers to a divalent alkyl (e.g., -CH2-).
  • terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively.
  • 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.
  • alkynyl refers to an acyclic hydrocarbon chain that may be a straight chain or branched c ynyl 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. Alkynyl groups can either be unsubstituted or substituted with one or more substituents.
  • 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.
  • aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • cycloalkyl refers to mono-, bi-, tri-, or polycyclic saturated or partially unsaturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 15 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted.
  • saturated as used in this context means only single bonds present between constituent carbon atoms.
  • 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.
  • partially unsaturated cycloalkyl include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Cycloalkyl may include multiple fused and/or bridged rings.
  • fused/bridged cycloalkyl includes: bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[4.2.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, and the like.
  • Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom).
  • 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.
  • heteroaryl 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 and P (inclusive of oxidized forms such as: ) (e.g., N, O, and S (inclusive of oxidized forms such as: )) and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl).
  • Heteroaryl groups can either be unsubstituted or substituted with one or more substituents.
  • 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]pyrimi
  • the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
  • heterocyclyl refers to a mono-, bi-, tri-, or polycyclic saturated or partially unsaturated ring system with 3-15 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-15 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, S (inclusive of oxidized forms such as: ), and P (inclusive of oxidized forms such as: (e.g., 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 atoms
  • saturated means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and/or other substituents as defined herein.
  • 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.
  • Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butyl, 2-azabicyclo[2.1.0]pentyl, 2- azabicyclo[1.1.1]pentyl, 3-azabicyclo[3.1.0]hexyl, 5-azabicyclo[2.1.1]hexyl, 3- azabicyclo[3.2.0]heptyl, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptyl, 7- azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[4.2.0]octyl, 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]
  • rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein
  • 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
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • the compounds generically or specifically disclosed herein are intended to include all tautomeric forms.
  • a compound containing the moiety: encompasses the tautomeric form containing the moiety: .
  • 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.
  • KRas-associated disease or disorder 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).
  • 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 that results in the expression of a KRas protein that includes a deletion of at least one amino acid as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with one or more point mutations as compared to a wild type KRas protein, a mutation in a KRAS gene that results in the expression of a KRas protein with at least one inserted amino acid as compared to a wild type KRas protein, a gene duplication that results in an increased level of KRas protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of KRas protein in a cell); an alternative s
  • 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.
  • 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.
  • a KRas amplification is an amplification of the wild type KRas.
  • 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.
  • 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: 1).
  • 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: 1).
  • 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).
  • 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: 1).
  • 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: 1).
  • KRas Q61P mutant protein refers to a KRas protein including a glutamine to proline substitution at the sixty-first amino acid position (relative to SEQ ID NO: 1).
  • 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: 1).
  • a “KRas inhibitor” as used herein includes any compound exhibiting KRas protein inactivation activity (e.g., inhibiting or decreasing KRas signaling activity).
  • a KRas inhibitor inhibits both the signaling activity of a wild type KRas protein and the signaling activity of one or more mutant KRas proteins and can be termed a “pan KRas inhibitor”.
  • 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.
  • a KRas inhibitor that inhibits KRas G12R mutant protein could be termed a “KRas G12R inhibitor”.
  • 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”.
  • a “mutant KRas inhibitor” inhibits two or more mutant KRas proteins and can be termed a “pan mutant KRas inhibitor”.
  • 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.
  • 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.
  • a KRas inhibitor that inhibits a KRas G13D mutant protein could be termed a “KRas G13D inhibitor”.
  • 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.
  • a KRas inhibitor is a mutant KRas inhibitor.
  • a KRas inhibitor is an allosteric inhibitor.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas Q61X inhibitor.
  • 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
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits a KRas Q61E mutant protein.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits a KRas Q61H mutant protein.
  • 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.
  • 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 KRas G12X mutant protein, a KRas G13X mutant protein, and a KRas Q61X mutant protein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 KRas Q61K mutant protein, a KRas Q61L mutant protein, a KRas Q61P mutant protein, and a KRas Q61R mutant protein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating a bladder cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating a cervical cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating a colorectal cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating an endometrial cancer.
  • 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.
  • 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.
  • 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.
  • 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, and a KRas G12V mutant protein.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating an esophageal or stomach cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating a leukemia.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, and a KRas G12S mutant protein.
  • 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits a KRas G12D mutant protein, a KRas G12V mutant protein, or both.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating an ovarian cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Q61R mutant protein.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof are useful for treating a testicular cancer (e.g., seminoma).
  • RVEDAFYTLV REIRQYRLKK ISKEEKTPGC VKIKKCI IM 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.
  • an assay e.g., binding affinity and/or potency
  • 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
  • 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 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.
  • 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.
  • 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
  • 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)).
  • a compound can inhibit each mutant KRas protein (e.g., two or more mutant KRas proteins) with an IC50 of less than 1 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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).
  • KRas proteins e.g., wild type KRas or one or more dysregulated KRas proteins
  • 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 pM or greater than 1 pM (e.g., greater than 2 pM, greater than 5 pM, greater than 10 pM, or greater than 30 pM).
  • the compound provided herein, or a pharmaceutically acceptable salt thereof inhibits ERK phosphorylation in a cell line expressing a KRas G12D mutant protein with an IC50 of about 150 nM
  • 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.
  • 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 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.
  • 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 HP AC) 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 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).
  • a KRas G12D mutant protein e.g., AGS, ASPC1, GP2D, LS180, Panc04.
  • 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 7-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.
  • 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 HP AC ) 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).
  • a KRas G12D mutant protein e.g., AGS, ASPC1, GP2D, LS180, Panc
  • 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 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.
  • 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).
  • a KRas G12V mutant protein e.g., SW620, H727, CFPAC1, CAPAN1, CAPAN2, RKN, H441, and SW480
  • 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 n
  • 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).
  • 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 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 HP AC) 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).
  • a KRas G12D mutant protein e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC
  • IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 n
  • 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 75 nM, less than 50 nM, less than 30 nM).
  • 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.
  • 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 HP AC) 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
  • 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 HP AC) 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).
  • a KRas G12D mutant protein e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC
  • IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM
  • 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).
  • 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.
  • 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 HP AC) 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 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), wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRa
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can inhibit ERK phosphorylation in a GP2d cell line with an ICso 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 ICso 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 ICso 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).
  • nM e.g., less than 200 nM, less than 150 nM, less than 125 nM
  • the compound provided herein, or a pharmaceutically acceptable salt thereof inhibits ERK phosphorylation in a GP2d cell line with an ICso 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).
  • ICso 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).
  • 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 HP AC) 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), wherein the compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits ERK phosphorylation in the cell line expressing a KRa
  • 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 HP AC) 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).
  • a KRas G12D mutant protein e.g., AGS, ASPC1, GP2D, LS180, Panc04.03, HPAFII, Panc02.03, A427, and HP AC
  • IC50 of less than 250 nM (e.g., less than 200 nM, less than 150 nM, less than 125 nM, less than 100 nM
  • 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 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 50 nM, less than 30 nM).
  • nM e.g., less than 200 nM, less than 150 nM, less than 125 nM,
  • 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).
  • 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.
  • a direct determination method e.g., surface plasmon resonance or isothermal titration calorimetry
  • 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).
  • FRET Fluorescence Resonance Energy Transfer
  • 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.
  • binding affinities e.g., as measured by dissociation constant KD
  • a KRas protein e.g., a wild type KRas protein or a mutant KRas protein
  • binding affinities e.g., as measured by dissociation constant KD
  • a KRas protein e.g., a wild type KRas protein or a mutant KRas protein
  • GTP -bound state can be measured using methods known in the art (e.g., using SPR (e.g., using one or more methods described herein (e.g., using the methods described in Example Bl 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 Bl or 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 Bl).
  • 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.
  • 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, HP AC, 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.
  • the cell line can be AGS, A375, A427, ASPC1, H727, H441, RKN, and/or SW620.
  • 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., CELLTITERGLO® 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).
  • an appropriate reagent e.g., CELLTITERGLO® 3D
  • 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., CELLTITERGLO®), 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.
  • an appropriate reagent e.g., CELLTITERGLO®
  • cellular proliferation can be assessed using a platform for live cell imaging (e.g., an INCUCYTE® SX5 Live-Cell Analysis Instrument). See also, e.g., U.S. Publication No. US 2021/0179633, US 2021/0230142, and US 2019/0284144.
  • a platform for live cell imaging e.g., an INCUCYTE® SX5 Live-Cell Analysis Instrument. See also, e.g., U.S. Publication No. US 2021/0179633, US 2021/0230142, and US 2019/0284144.
  • the potency and/or efficacy of a compound provided herein, or a pharmaceutically acceptable salt thereof can be evaluated in an animal model, for example, a xenograft model (e.g., using an established cancer cell line such as AGS, A375, A427, ASPC1, H727, H441, RKN, and/or SW620, or a patient-derived xenograft (PDX) model).
  • a xenograft model e.g., using an established cancer cell line such as AGS, A375, A427, ASPC1, H727, H441, RKN, and/or SW620
  • PDX patient-derived xenograft
  • 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is assessed in a CDX (e.g., H727, RKN, or SW620) mouse model.
  • a CDX e.g., H727, RKN, or SW620
  • 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.
  • mice 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).
  • IACUC Institutional Animal Care and Use Committee
  • 6-8 week old BALB/c nude female mice are inoculated subcutaneously on the right flank with 5 x 10 6 H727, RKN, or SW620 tumor 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 mm 3 . 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, 10 mg/kg, 20 mg/kg, 30 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 150 mg/kg, or 200 mg/kg).
  • 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, 10 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 measurement of tumor size is conducted twice weekly with a caliper and recorded.
  • the tumor volume (mm 3 )
  • 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 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)).
  • a compound e.g., a compound provided herein, or a pharmaceutically acceptable salt thereof
  • a mutant KRas protein e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein
  • 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.
  • GMPPNP non -hydrolyzable GTP mimic
  • potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can be determined by ECso value.
  • an ECso 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, HP AC, 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
  • potency of a compound provided herein, or a pharmaceutically acceptable salt thereof, as provided herein can also be determined by ICso value.
  • a compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value.
  • an ICso 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, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D, H358, H441, H460, H727, HCT116, HKA1, HP AC, 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
  • 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.
  • ERK e.g., ERK1 and/or ERK2
  • MEK 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, HP AC, 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)).
  • a cell line e.g., A375, A
  • 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 SUREFIRE® p-ERKl/2 (Thr202/Tyr204), or an HTRF® PhosphoERK (Thr202/Tyr204) cellular kit (CisBio)).
  • a kit such as Invitrogen InstantOne ERK1/ERK2 (Phospho) [pT202/pY204]/[pT185/pY187] ELISA, MesoScale Discovery p/t ERK1/2, AlphaScreen SURE
  • 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 ERK phosphorylation protocol follows.
  • an ERK phosphorylation assay can be carried out using the AlphaLisa SUREFIRE® Ultra Multiplex Phospho/Total ERK1/2 (Thr202/Tyr204) Assay Kit.
  • a plate e.g., a white, opaquebottom 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), HP AC (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 (KR
  • 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-pM 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 IX 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.
  • the Acceptor Mix prepared in accordance with manufacturer’s protocol
  • 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 ERKl/2-phosphorylation relative to Total ERK1/2 for each individual well.
  • 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 IC50 values.
  • 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 pM (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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)
  • IC50 e.g., less than 1 pM (e.g.,
  • 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 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).
  • 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)
  • IC50 of less than 200 nM (e.g., less than 150 nM, less than 200 nM, less than 100
  • 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.
  • 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)
  • IC50 0.1 nM to 100 nM, 0.1 nM to 50 nM, 1 nM to 50 nM, or 1
  • a KRas A59G mutant protein (e.g., as a single mutant or as a double 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.
  • downstream signaling e.g., interaction with an RBD and/or the phosphorylation of a downstream kinase, such as ERK
  • 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.
  • 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'- [(P,y)-imido]triphosphate (GppNHp, sometimes also referred to as GMPPNP), when exchange is inhibited.
  • MANT protein-bound N-methylanthraniloyl
  • GppNHp guanosine-5'- [(P,y)-imido]triphosphate
  • 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.
  • Bodipy-GDP e.g., EDA-GTP-DY-647P1
  • an exchange of fluorophore-tagged GDP e.g., Bodipy-GDP
  • unlabeled GTP results in a reduced TR-FRET signal.
  • 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.
  • an exchange of GDP for labeled GTP results in an increased FRET signal.
  • a guanine nucleotide exchange factor e.g., S0S1
  • S0S1 guanine nucleotide exchange factor
  • Inhibition of SOS 1 -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 methods described in Example B2 herein)). Additional examples of in vitro assays include assays that determine inhibition of the GTPase activity of KRas protein.
  • 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).
  • GTPase activity of a KRas protein can be measured using a phosphate assay system that continuously measures phosphate release.
  • 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.
  • an enzyme-linked immunosorbent assay 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.
  • 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
  • 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 ⁇ L 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 ⁇ M 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 ⁇ L 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 HTRF 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 Graphpad Prism software.
  • 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 ⁇ M (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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).
  • 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.
  • 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).
  • RBD Ras Binding Domain
  • 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 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): 199–204, doi: 10.1002/anie.201307387; and Durrant, et al. Molecular Cancer Therapeutics 20.9 (2021): 1743-1754, doi: 10.1158/1535- 7163.MCT-21-0175.
  • streptavidin donor and anti-flag acceptor beads e.g., ALPHASCREEN® beads
  • 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 IC 50 value. See, e.g., International Publication No. WO 2021/085653.
  • a RAF kinase interaction assay can be coupled with a 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.
  • 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
  • GTP and optionally, a GEF such as SOS
  • RAF e.g., cRAF
  • acceptor beads e.g., GST-tagged acceptor beads
  • donor beads e.g., glutathione donor beads
  • ALPHASCREEN® technology any appropriate FRET pair can be used to perform homogenous time resolved fluorescence. See, e.g., U.S. Publication Nos. US 2018/0334454 and US 2021/0230142.
  • Another exemplary assay to measure the affinity of 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.
  • 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 NANOBITTM 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).
  • 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.
  • 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 NANOBRETTM 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.
  • signaling system e.g., a protein and a ligand
  • 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.
  • 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
  • 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)).
  • a compound provided herein, or a pharmaceutically acceptable salt thereof modulates the interaction between the KRas protein and one or more Raf proteins.
  • the compound inhibits the interaction between the KRas protein and Raf-RBD with an IC50 of less than 1 ⁇ M (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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 0.01 nM).
  • 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.
  • 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 ⁇ M in the absence of cyclophilin A (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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 1 nM, less than 0.1 nM, or less than 0.01 nM).
  • cyclophilin A e.g., e.g., less than 150 nM, less than 200 nM, less than 100 nM, less than 10 nM, less than 1 nM, less than 0.1 nM, or less than 0.01 nM.
  • the compounds inhibit 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 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).
  • a cell line e.g., A375, A427, A549, AGS, ASPC1, CAL62, CALU1, CAPAN1, CAPAN2, CFPAC1, GP2D,
  • 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 or MesoScale Discovery p/t ERK1/2).
  • multiple concentrations of a compound provided herein, or a pharmaceutically acceptable salt thereof can be used to construct a dose response curve.
  • 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 ⁇ M (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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)
  • an IC50 of less than 1 ⁇ M (e.g., less than 750 nM, less than 500 nM, or less than 200 nM).
  • 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).
  • 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)
  • 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
  • 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 1 nM to 20 nM.
  • 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.
  • 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
  • Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 ⁇ M, 3 ⁇ M, 1.1 ⁇ M, 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.
  • inhibitor concentrations e.g. 10 ⁇ M, 3 ⁇ M, 1.1 ⁇ M, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM
  • 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 model, a dog model, or a nonhuman primate (e.g., cynomolgus monkey) model.
  • Pharmacokinetics parameters including clearance (CL), volume of distribution (Vd), 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.
  • a reference compound e.g., a first KRas inhibitor (e.g., MRTX1133)
  • a comparator e.g., MRTX1133
  • a comparator e.g., MRTX1133
  • a comparator e.g., MRTX1133
  • 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.
  • a reference compound e.g., a first KRas inhibitor (e.g., MRTX1133)
  • a comparator See, e.g., Example VI (“Liver microsomal metabolically stability”) of International Publication No. WO 2023/284881.
  • 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.
  • 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.
  • 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
  • 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., 10% DMSO/90% hydroxypropyl methylcellulose).
  • the rats have access to food and water ad libitum.
  • Blood samples e.g., 200 ⁇ L per sample
  • the blood is sampled via jugular vein puncture, then the blood samples (e.g., with K2EDTA as anticoagulant) are temporarily put on ice and then centrifuged (e.g., at 4 °C and 4600 RPM for 5 minutes) within 30 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 can be determined (e.g., via LC/MS/MS).
  • 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 C181.7 ⁇ m (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.
  • pharmacokinetic parameters of t1/2 (hr), tmax (hr), Cmax (ng/mL), AUClast (hr*ng/mL), AUCInf (hr*ng/mL), AUCExtr (%), MRTInf (hr), AUCInf/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).
  • 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.
  • 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 IKr 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.
  • hERG inhibition potency includes SyncroPatch hERG and manual patch clamp experiments.
  • 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.
  • solutions or suspension of a compound provided herein, or a pharmaceutically acceptable salt thereof, at several concentrations (0.30 ⁇ M, 1.00 ⁇ M, 3.00 ⁇ M, 10.00 ⁇ M and 30.00 ⁇ M) 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 IKr. See, e.g., Brown, Arthur M., and David Rampe. Pharmaceutical News 7.4 (2000): 15-20; Weirich, Jörg, 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.
  • 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
  • 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
  • the positive control compound can be amitriptyline (Sigma- Aldrich), for example, in a HB-PS and 0.3% DMSO solution.
  • a positive control compound can be included in the experiment.
  • the positive control compound can be E-4031 (4 ⁇ -[[1-[2-(6- Methyl-2-pyridinyl)ethyl-4-piperidinyl]carbonyl]methanesulfonanilide, 2HCl) (Sigma- Aldrich), for example, in a HB-PS and 0.3% DMSO solution. 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 ⁇ M. 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, 2 mM CaCl2, 1 mM MgCl2, 60 mM N-Methyl-D-glucamine (NMDG), 10 mM HEPES, and 5 mM glucose, pH 7.4) are prepared and stored up to 1 month.
  • NMDG N-Methyl-D-glucamine
  • 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.
  • the cell On one side of the seal, the cell is bathed in external solution.
  • addition of 40 ⁇ L of the vehicle e.g., HB-PBS
  • 40 ⁇ L of the vehicle e.g., HB-PBS
  • a dose of a compound provided herein, or a pharmaceutically acceptable salt thereof is added (40 ⁇ L), 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.
  • quality control criteria e.g., seal quality, rundown attributes
  • Five concentrations (0.30 ⁇ M, 1.00 ⁇ M, 3.00 ⁇ M, 10.00 ⁇ M, and 30.00 ⁇ M) 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.
  • 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%.
  • a reference compound e.g., E- 4031
  • the Dose-Response curves are fit to the standard Hill equation as shown below: 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.
  • a positive control can be included in the experiment.
  • the positive control compound can be cisapride (Tocris Bioscience), for example, in a 0.3% DMSO solution.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is not a hERG inhibitor.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof inhibits hERG with an IC50 of greater than 1 ⁇ M (e.g., greater than 3 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, or 30 ⁇ M). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 10 ⁇ M (e.g., greater than 20 ⁇ M or 30 ⁇ M). In some embodiments, a compound provided herein, or a pharmaceutically acceptable salt thereof, inhibits hERG with an IC50 of greater than 30 ⁇ M.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can be assessed for its stability in hepatocytes (e.g., human hepatocytes).
  • a compound provided herein, or a pharmaceutically acceptable salt thereof is 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.
  • 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.
  • cryopreserved hepatocytes e.g., human hepatocytes
  • incubation medium e.g., Williams’ Medium E (no phenol red) containing 2 mM L-Glutamine and 25 mM HEPES
  • pre-warmed incubation medium 0.5 ⁇ 10 6 cells/mL
  • Pre-warmed cell suspension (e.g., 198 ⁇ L) 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 ⁇ L) to a set of pre-labeled 96-well plates, with one quenching plate for T0 and one plate per time point to be tested.
  • stop solution e.g., acetonitrile containing tolbutamide and labetalol as internal standards
  • 2 ⁇ L of the 100X dosing solution of the compound provided herein, or a pharmaceutically acceptable salt thereof, or 2 ⁇ L of the 100X dosing solution of a control compound is added to a well of the testing plate.
  • the plate is mixed to achieve a homogenous suspension (e.g., mixed for about 1 min), then an aliquot (e.g., 25 ⁇ L) 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 ⁇ L), followed by mixing.
  • the testing plate is incubated (e.g., at 37 °C in a 95% humidified incubator at 5% CO2 with constant shaking) to start the reactions.
  • 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.
  • the reactions are stopped by removing the corresponding MC plate from the incubator and mixing with ice-cold stop solution (e.g., 125 ⁇ L).
  • Table 2 shows floor and ceiling values for the described assay. For example, if CLint (hep) falls below 6.4 ⁇ L/min/10 6 cells, an experimental value may not be able to be accurately determined. Table 3. Cut off Value in Hepatocyte Stability Assay
  • 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).
  • 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 ⁇ M in DMSO).
  • a working solution of a control compound e.g., omeprazole
  • a control compound e.g., omeprazole
  • the reaction is stopped by the addition of stop solution (e.g., 400 ⁇ L), and the resulting solution is mixed. A portion of this mixture (e.g., 200 ⁇ L) is removed and mixed with a further addition of stop solution (e.g., 400 ⁇ L).
  • the T0 samples are prepared by adding stop solution (e.g., 400 ⁇ L), mixing, then adding the FaSSGF (e.g., 200 ⁇ L) and mixing again.
  • the T0 samples are further prepared by removing a portion of this mixture (e.g., 200 ⁇ L) and mixing with a further addition of stop solution (e.g., 400 ⁇ L).
  • the samples are centrifuged (e.g., at 4000 RPM at 4 °C for 20 min).
  • a portion of the supernatant e.g., 60 ⁇ L
  • purified water e.g. 180 ⁇ L
  • the LC- MS/MS analysis is performed using an ACQUITY UPLC BEH C181.7 ⁇ m 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).
  • a working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof is prepared (e.g. 2 ⁇ M in DMSO).
  • a working solution of a control compound e.g., chlorambucil
  • An aliquot e.g., 2 ⁇ L 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).
  • the T0 samples are prepared by adding stop solution (e.g., 400 ⁇ L), mixing, then adding the FeSSIF (e.g., 200 ⁇ L) and mixing again.
  • the T0 samples are further prepared by removing a portion of this mixture (e.g., 200 ⁇ L) and mixing with a further addition of stop solution (e.g., 400 ⁇ L).
  • the samples are centrifuged (e.g., at 4000 RPM at 4 °C for 20 min). A portion of the supernatant (e.g., 60 ⁇ L) is removed and mixed with purified water (e.g., 180 ⁇ L) for LC-MS/MS analysis.
  • Fasted state simulated intestinal fluid 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 ⁇ M in DMSO).
  • a working solution of a control compound e.g., chlorambucil
  • An aliquot (e.g., 2 ⁇ L) 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).
  • an aliquot (e.g., 198 ⁇ L) 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.
  • the reaction is stopped by the addition of stop solution (e.g., 400 ⁇ L), and the resulting solution is mixed. A portion of this mixture (e.g., 200 ⁇ L) is removed and mixed with a further addition of stop solution (e.g., 400 ⁇ L).
  • the T0 samples are prepared by adding stop solution (e.g., 400 ⁇ L), mixing, then adding the FaSSIF (e.g., 200 ⁇ L) and mixing again.
  • the T0 samples are further prepared by removing a portion of this mixture (e.g., 200 ⁇ L) and mixing with a further addition of stop solution (e.g., 400 ⁇ L).
  • the samples are centrifuged (e.g., at 4000 RPM at 4 °C for 20 min).
  • a portion of the supernatant e.g., 60 ⁇ L
  • purified water e.g. 180 ⁇ L
  • the LC-MS/MS analysis is performed using an ACQUITY UPLC HSS T31.8 ⁇ m 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.
  • 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
  • PAR0 is the peak area ratio at T0.
  • 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 (eg water or pH 3.0 citrate buffer).
  • 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.
  • 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)
  • an aqueous solution e.g., water or pH 3.0 citrate buffer
  • 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 0.2 ⁇ m syringe filter), then analyzed with HPLC (e.g., HPLC is conducted using an Agilent 1290 Infinity LC System equipped with a VWD (Variable Wavelength Detector) and an Agilent 1260 ELSD (Evaporative Light Scattering Detector).
  • HPLC e.g., HPLC is conducted using an Agilent 1290 Infinity LC System equipped with a VWD (Variable Wavelength Detector) and an Agilent 1260 ELSD (Evaporative Light Scattering
  • Flow rate range of the instrument is 0.2– 5.0 mL/min, operating pressure range is 0–1300 bar, temperature range is 5 °C above ambient to 60 °C, and wavelength range is 190–600 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 ⁇ m) to determine the dissolved concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the kinetic solubility of a compound provided herein, or a pharmaceutically acceptable salt thereof can be determined.
  • 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).
  • 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
  • the dissolved concentration of the compound provided herein, or a pharmaceutically acceptable salt thereof can be determined via liquid chromatography.
  • An exemplary protocol follows.
  • 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)).
  • the chemical stability of a compound provided herein, or a pharmaceutically acceptable salt thereof can be determined.
  • 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.
  • an acidic solution e.g., pH 1.5 or pH 5
  • 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).
  • LCMS liquid chromatography- mass spectrometry
  • NMR nuclear magnetic resonance
  • a pH 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 1N sodium hydroxide. A portion (e.g., 10 ⁇ L) 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 5 (e.g., 90 ⁇ L) in separate vials denoted for each timepoint (e.g., T0, T30m, T60m, T90m, T240m, and T3d).
  • timepoint e.g., T0, T30m, T60m, T90m, T240m, and T3d.
  • the samples are incubated at 37 °C for the desired timeframe and then immediately neutralized with 10 ⁇ L of HEPES buffer to pH of 7. The T0 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.
  • deuterium oxide (5 mL) is adjusted to the desired pH of 1.5 or 5, monitoring by pH meter, using 20% DCl 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 (T0, T90m, T240m, T5d) then an aliquot (e.g., 0.3 mL) is taken and analyzed by 1 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.
  • an aliquot e.g., 0.3 mL
  • 30 ⁇ L 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.
  • 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)).
  • 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.
  • efflux pump-expressing cells such as MDCKII cells.
  • 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 10 5 cells/cm 2 for 4-7 days for confluent cell monolayer formation.
  • 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 10 mM HEPES, pH 7.4) from a DMSO stock solution to a final concentration (e.g., of 2.00 ⁇ M (DMSO ⁇ 1%)) and applied to the apical or basolateral side of the cell monolayer.
  • transport buffer e.g., Hank’s Balanced Salt Solution (HBSS) with 10 mM HEPES, pH 7.4
  • DMSO stock solution e.g., of 2.00 ⁇ M (DMSO ⁇ 1%)
  • 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.
  • digoxin is tested at 10.0 ⁇ M from A to B direction or B to A direction, while nadolol and metoprolol are tested (e.g., at 2.00 ⁇ M) in A to B direction in duplicate.
  • the plate is incubated (e.g., for 2.5 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).
  • E fflux Ratio Papp (BA) / Papp (AB)
  • Vd 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.
  • 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 addition of lucifer yellow dye (e.g., 75 ⁇ L of a 100 ⁇ M solution in transport buffer) and transport buffer (e.g., 250 ⁇ L) in the apical and basolateral chambers, respectively.
  • lucifer yellow dye e.g., 75 ⁇ L of a 100 ⁇ M solution in transport buffer
  • transport buffer e.g. 250 ⁇ L
  • 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 ⁇ L) sample is taken from the apical side, and transport buffer (e.g., 60 ⁇ L) is added. A lucifer yellow sample (e.g., 80 ⁇ L) 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: where RFUApical 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can be assessed for formation of metabolites.
  • 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 1 metabolism, Phase 2 metabolism, or a combination thereof.
  • hepatocytes e.g., rat hepatocytes, dog hepatocytes, or human hepatocytes
  • An exemplary protocol follows.
  • a working solution of a compound provided herein, or a pharmaceutically acceptable salt thereof, is prepared (e.g. 10 ⁇ M in DMSO).
  • a working solution of a control compound (e.g., 7-ethoxycoumarin) is prepared (e.g. 30 ⁇ M 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 ⁇ 10 6 cells/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 ⁇ L, for 0 minutes or 120 minutes at 37 °C in 5% CO2/saturated humidity.
  • hepatocytes e.g., 1.0 ⁇ 10 6 cells/mL
  • HEPES e.g., 5.958 g/L
  • MeCN 800 ⁇ L
  • MeCN 800 ⁇ L
  • the supernatants are dried under N2 gas, and the residue is reconstituted (e.g., with 200 ⁇ L of 10% MeCN with 0.1% FA).
  • 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 UPLC® HSS T32.1 ⁇ 100 mm, 1.8 ⁇ m column; a UV detector with ⁇ : 190 ⁇ 500 nm; and MS with a Xevo G2 Q-TOF instrument in ESI + mode with a scanning mode of MS E ).
  • the data is then analyzed to identify and, if desired, quantify the metabolites.
  • 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))).
  • 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)
  • a dysregulated KRas protein e.g., a wild-type KRas protein and/or a mutant K
  • 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.
  • 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)
  • a dysregulated KRas protein e.g., a wild-
  • 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).
  • a KRas protein e.g., a wild-type KRas protein and/or a mutant KRas protein
  • a KRas protein e.g., a wild-type KRas protein and/or a mutant KRas protein
  • a KRas G12D mutant protein e.g., a
  • 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
  • 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, 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).
  • a KRas protein e.g., a wild-type KRas protein and/or a mutant KRas protein (e.g., a KRas G12D mutant protein,
  • 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).
  • a KRas protein e.g., a wild-type KRas protein and/or a mutant KRas protein
  • a related GTPase e.g., wild-type NRas protein, and/or wild-type HRas protein
  • 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).
  • 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,
  • 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).
  • 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
  • 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).
  • a KRas protein e.g., a wild-type KRas protein and/or a mutant KRas protein
  • a related GTPase e.g., wild-type NRas protein, and/or wild-type HRas protein
  • 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).
  • 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
  • the compounds provided herein, or pharmaceutically acceptable salts thereof can exhibit potent and selective 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))).
  • 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)).
  • 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 K
  • 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.
  • 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))
  • a dysregulated KRas protein e.g., a mutant KRas protein (e.g., a KRas G12D mutant protein, a K
  • 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).
  • a mutant KRas protein e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and/or a KRas G12V mutant protein
  • related GTPases e.g., wild-type KRas protein, wild-type NRas protein, and/or wild-type HRas protein
  • 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.
  • a mutant KRas protein e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and/or a KRas G12V mutant protein
  • 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.
  • a mutant KRas protein e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and/or a KRas G12V mutant protein
  • 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.
  • a mutant KRas protein e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, and/or a KRas G12V mutant protein
  • 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.
  • a mutant KRas protein e.ga KRas G12D mutant protein, a KRas G12R mutant protein, and/or a KRas G12V mutant protein
  • 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
  • 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 G12V mutant protein (e
  • kits for treating a cancer in a subject in need of such treatment 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.
  • the subject is treatment na ⁇ ve with respect to the cancer.
  • the subject has received one or more lines of previous therapy for the cancer.
  • methods of treating a cancer in a subject in need thereof 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.
  • the subject is treatment na ⁇ ve with respect to the cancer.
  • a subject with ovarian cancer has previously received hormone therapy (e.g., an aromatase inhibitor such as anastrozole, letrozole, or exemestane).
  • hormone therapy e.g., an aromatase inhibitor such as anastrozole, letrozole, or exemestane.
  • a subject with ovarian cancer has previously received docetaxel and carboplatin.
  • a subject with ovarian cancer has previously received carboplatin and doxorubicin (e.g., liposomal doxorubicin).
  • a subject with ovarian cancer has previously received paclitaxel, carboplatin, and bevacizumab.
  • 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.
  • a subject with pancreatic cancer has previously received FOLFIRINOX.
  • a subject with pancreatic cancer has previously received GEMOX (gemcitabine and oxaliplatin).
  • a subject with pancreatic cancer has previously received gemcitabine.
  • a subject with pancreatic cancer has previously received gemcitabine and paclitaxel (e.g., albumin-bound paclitaxel).
  • paclitaxel e.g., albumin-bound paclitaxel.
  • NALIRIFOX liposomal irinotecan, fluorouracil, leucovorin, and oxaliplatin.
  • 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.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used as a medicament for the treatment of cancer, for example, any of the cancers provided herein.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament is also provided herein. 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.
  • 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.
  • 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.
  • the subject cannot tolerate the one or more therapeutic agents or therapies previously administered for the cancer.
  • the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer.
  • the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer.
  • the subject has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer.
  • 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.
  • a method of treating a cancer in a subject in need of such treatment 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 KRas dysregulation (
  • 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.
  • a KRas-associated cancer e.g., a mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a K
  • 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 pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • a KRas-associated cancer e.g., a mutant KRas-associated cancer (e.g., a KRas G12X- associated cancer)
  • administering 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.
  • 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 G
  • 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))
  • 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
  • the cancer e.g., KRas-associated cancer (e.g., mutant KRas-associated cancer)
  • the cancer is colon cancer, endometrial cancer, lung cancer, pancreatic cancer, and uterine cancer.
  • the cancer is a colorectal cancer (e.g., a colon cancer or a rectal cancer).
  • the colorectal cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).
  • the cancer is an endometrial cancer.
  • the endometrial cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).
  • the cancer is a lung cancer (e.g., NSCLC).
  • the lung cancer e.g., NSCLC
  • has a KRas dysregulation e.g., a KRas mutation (e.g., a KRas G12X mutation) or amplification).
  • the cancer is an ovarian cancer.
  • the ovarian cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).
  • the cancer is a pancreatic cancer.
  • the pancreatic cancer has a KRas dysregulation (e.g., a KRas mutation (e.g., a KRas G12X mutation)) or amplification).
  • the cancer e.g., a KRas-associated cancer (e.g., a mutant KRas- associated cancer (e.g., a KRas G12X-associated cancer))
  • a KRas-associated cancer e.g., a mutant KRas- associated cancer (e.g., a KRas G12X-associated cancer)
  • the cancer is a hematological cancer, bile duct cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, kidney cancer, liver cancer, lung cancer, mucinous carcinoma, pancreatic cancer, prostate cancer, rectal cancer, testicular cancer (e.g., seminoma), skin cancer, stomach cancer, thymus cancer, thyroid cancer, urothelial cancer, or uterine cancer.
  • testicular cancer e.g., seminoma
  • skin cancer e.g., stomach cancer, thymus cancer, thyroid cancer, urot
  • the cancer is brain cancer, colon cancer, lung cancer, pancreatic cancer, rectal cancer, testicular cancer (e.g., seminoma), or uterine cancer.
  • the cancer is a KRas G12A-associated cancer.
  • the cancer is bladder cancer, breast cancer, cervical cancer, colon cancer, lung cancer, kidney cancer, liver cancer, or rectal cancer.
  • the cancer is a KRas G12C-associated cancer.
  • 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.
  • the cancer is a KRas G12D-associated cancer.
  • 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.
  • the cancer is a KRas G12R-associated cancer.
  • the cancer is colon cancer, lung cancer, pancreatic cancer, rectal cancer, stomach cancer, testicular cancer (e.g., seminoma), or uterine cancer.
  • the cancer is a KRas G12S-associated cancer
  • 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.
  • the cancer is a G12V- associated cancer.
  • the cancer e.g., a KRas-associated cancer (e.g., a mutant KRas- associated cancer (e.g., a KRas G13X-associated cancer))
  • a KRas-associated cancer e.g., a mutant KRas- associated cancer (e.g., a KRas G13X-associated cancer)
  • the 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.
  • the cancer e.g., a KRas-associated cancer (e.g., a mutant KRas-associated cancer (e.g., a KRas Q61X-associated cancer)
  • the cancer is bladder cancer, colon cancer, lung cancer, ovarian cancer, rectal cancer, thyroid cancer, or uterine cancer.
  • 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)
  • the cancer e.g., a KRas-associated cancer (e.g., mutant KRas- associated cancer)
  • the cancer is pancreatic cancer or metastatic pancreatic cancer.
  • the cancer e.g., a KRas-associated cancer (e.g., mutant KRas-associated cancer)
  • the pancreatic cancer is a KRas G12R-associated cancer.
  • the cancer e.g., a KRas-associated cancer (e.g., mutant KRas- associated cancer)
  • the cancer is advanced-stage lung adenocarcinoma.
  • the cancer is a solid tumor.
  • the solid tumor has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • the solid tumor has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a method of treating a solid tumor in a subject in need thereof 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.
  • a method of treating a solid tumor in a subject in need thereof 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.
  • a method of treating a solid tumor in a subject in need thereof 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.
  • a method of treating a solid tumor in a subject in need thereof 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.
  • a method of treating a solid tumor in a subject in need thereof 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.
  • a method of treating a solid tumor in a subject in need thereof 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.
  • a method of treating a solid tumor in a subject in need thereof 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 acceptable salt thereof, or a pharmaceutical composition as described herein.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • a method of treating an advanced solid tumor in a subject in need thereof 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.
  • 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.
  • classification of an advanced solid tumor can be made by the subject’s physician.
  • the cancer is a bladder cancer.
  • the bladder cancer has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the bladder cancer has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation.
  • the bladder cancer has a KRas G12D mutation or a KRas G12V mutation.
  • the bladder cancer has a KRas G12C mutation.
  • the bladder cancer has a KRas G12D mutation.
  • the bladder cancer has a KRas G12R mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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 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.
  • a method of treating a bladder cancer in a subject in need thereof 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.
  • a method of treating a bladder cancer in a subject in need thereof 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.
  • a method of treating a bladder cancer in a subject in need thereof 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.
  • a method of treating a bladder cancer in a subject in need thereof 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.
  • a method of treating a bladder cancer in a subject in need thereof 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.
  • the cancer is a cervical cancer.
  • the cervical cancer has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the cervical cancer has a KRas G12D mutation or a KRas G12V 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a method of treating a cervical cancer in a subject in need thereof 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.
  • a method of treating a cervical cancer in a subject in need thereof 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.
  • a method of treating a cervical cancer in a subject in need thereof 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.
  • the cancer is a colorectal cancer.
  • the colorectal cancer has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the colorectal cancer has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation.
  • the colorectal cancer has a KRas G12D mutation or a KRas G12V mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • a method of treating a colorectal cancer in a subject in need thereof 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.
  • the cancer is an endometrial cancer.
  • the endometrial cancer has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the endometrial cancer has a KRas G12D mutation or a KRas G12V mutation.
  • the endometrial cancer has a KRas G12A mutation.
  • the endometrial cancer has a KRas G12C mutation.
  • the endometrial cancer has a KRas G12D mutation.
  • the endometrial cancer has a KRas G12S mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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 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.
  • a method of treating an endometrial cancer in a subject in need thereof 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.
  • a method of treating an endometrial cancer in a subject in need thereof 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.
  • a method of treating an endometrial cancer in a subject in need thereof 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.
  • a method of treating an endometrial cancer in a subject in need thereof 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.
  • a method of treating an endometrial cancer in a subject in need thereof 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.
  • a method of treating an endometrial cancer in a subject in need thereof 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.
  • the cancer is an esophageal or stomach cancer.
  • the esophageal or stomach cancer has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the esophageal or stomach cancer has a KRas G12D mutation or a KRas G12V mutation.
  • the esophageal or stomach cancer has a KRas G12C mutation.
  • the esophageal or stomach cancer has a KRas G12D mutation.
  • the esophageal or stomach cancer has a KRas G12S mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a method of treating an esophageal or stomach cancer in a subject in need thereof 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.
  • a method of treating an esophageal or stomach cancer in a subject in need thereof 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.
  • a method of treating an esophageal or stomach cancer in a subject in need thereof 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.
  • a method of treating an esophageal or stomach cancer in a subject in need thereof 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.
  • a method of treating an esophageal or stomach cancer in a subject in need thereof 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.
  • the cancer is a leukemia.
  • the leukemia has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the leukemia has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation.
  • the leukemia has a KRas G12D mutation or a KRas G12V mutation.
  • the leukemia has a KRas G12A mutation.
  • 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 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • a method of treating a leukemia in a subject in need thereof 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.
  • the cancer is a melanoma.
  • the melanoma has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the melanoma has a KRas G12D mutation or a KRas G12R mutation.
  • the melanoma has a KRas G12C mutation.
  • the melanoma has a KRas G12D mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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 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.
  • a method of treating a melanoma in a subject in need thereof 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.
  • a method of treating a melanoma in a subject in need thereof 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.
  • a method of treating a melanoma in a subject in need thereof 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.
  • the cancer is a lung cancer (e.g., non-small cell lung cancer).
  • the lung cancer e.g., non-small cell lung cancer
  • has a KRas dysregulation e.g., a KRas mutation or amplification.
  • 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.
  • a KRas G12A mutation e.g., non-small cell lung cancer
  • 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.
  • the lung cancer has a KRas G12D mutation or a KRas G12V mutation.
  • the lung cancer has a KRas G12A mutation.
  • the lung cancer has a KRas G12C mutation.
  • the lung cancer has a KRas G12D mutation.
  • the lung cancer has a KRas G12S mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a lung cancer e.g., non-small cell lung cancer
  • 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.
  • a lung cancer e.g., non-small cell lung cancer
  • a method of treating a lung cancer in a subject in need thereof 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.
  • a method of treating a lung cancer in a subject in need thereof 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.
  • a method of treating a lung cancer in a subject in need thereof 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.
  • a method of treating a lung cancer in a subject in need thereof 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.
  • a method of treating a lung cancer in a subject in need thereof 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.
  • a method of treating a lung cancer in a subject in need thereof 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.
  • the cancer is a pancreatic cancer.
  • the pancreatic cancer has a KRas dysregulation (e.g., a KRas mutation or amplification).
  • 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.
  • 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.
  • the pancreatic cancer has a KRas G12D mutation, a KRas G12R mutation, or a KRas G12V mutation.
  • the pancreatic cancer has a KRas G12D mutation or a KRas G12V mutation.
  • the pancreatic cancer has a KRas G12A mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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, 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • a method of treating a pancreatic cancer in a subject in need thereof 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.
  • the cancer is a testicular cancer (e.g., seminoma).
  • the testicular cancer e.g., seminoma
  • has a KRas dysregulation e.g., a KRas mutation or amplification.
  • the testicular cancer e.g., seminoma
  • 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.
  • the testicular cancer (e.g., seminoma) cancer has a KRas G12R mutation or a KRas G12V mutation.
  • the testicular cancer (e.g., seminoma) cancer has a KRas G12A mutation.
  • the testicular cancer (e.g., seminoma) cancer has a KRas G12R mutation.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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.
  • a testicular cancer e.g., seminoma
  • 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.
  • a testicular cancer e.g., seminoma
  • testicular cancer e.g., seminoma
  • 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.
  • testicular cancer e.g., seminoma
  • 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.
  • testicular cancer e.g., seminoma
  • 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.
  • testicular cancer e.g., seminoma
  • 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 pharmaceutical composition as described herein.
  • 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.
  • 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.
  • 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.
  • the cancer is a KRas G12C-associated cancer, a KRas G12D- associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer.
  • the cancer is a KRas G12D-associated cancer, a KRas G12R- associated cancer, or a KRas G12V-associated cancer.
  • the cancer is a KRas G12C-associated cancer.
  • the cancer is a KRas G12D -associated cancer.
  • the cancer is a KRas G12R-associated cancer.
  • the cancer is a KRas G12V-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, and a KRas G12V mutation.
  • the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12V- associated cancer, or a KRas G13D-associated cancer.
  • the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, or a KRas G12V-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • a KRas G12A mutation a KRas G12C mutation, a KRas G12D mutation, a KRas G12R mutation, a KRas G12S mutation, a K
  • 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.
  • 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.
  • 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 Q6 IE-associated cancer, a KRas Q61H-associated cancer, a KRas Q61K-associated cancer, a KRas Q61L-associated cancer, a KRas Q6 IP-associated cancer, or a KRas Q61R-associated cancer.
  • 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.
  • the cancer is a KRas G12D-associated cancer, a KRas G12R- associated cancer, or a KRas G12V-associated cancer.
  • the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer.
  • the cancer is a KRas G12A-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, and a KRas G12V mutation.
  • 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.
  • 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.
  • 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.
  • the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer.
  • the cancer is a KRas G12A-associated cancer.
  • the cancer is a KRas G12C-associated cancer.
  • the cancer is a KRas G12D-associated cancer.
  • the cancer is a KRas G12S-associated cancer.
  • the cancer is a KRas G12V- associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, and a KRas G12V mutation.
  • 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.
  • the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, a KRas G12S-associated cancer, or a KRas G12V- associated cancer.
  • the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer.
  • the cancer is a KRas G12C-associated cancer.
  • the cancer is a KRas G12D-associated cancer.
  • the cancer is a KRas G12S-associated cancer.
  • the cancer is a KRas G12V-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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 Q6 IE-associated cancer, a KRas Q61H-associated cancer, a KRas Q61K- associated cancer, a KRas Q61L-associated cancer, a KRas Q6 IP-associated cancer, or a KRas Q61R-associated cancer.
  • 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.
  • the cancer is a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer.
  • the cancer is a KRas G12D- associated cancer or a KRas G12V-associated cancer.
  • the cancer is a KRas G12A-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, and a KRas G12R mutation.
  • 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.
  • the cancer is a KRas G12C-associated cancer, a KRas G12D-associated cancer, or a KRas G12R-associated cancer.
  • the cancer is a KRas G12D- associated cancer or a KRas G12R-associted cancer.
  • the cancer is a KRas G12C-associated cancer.
  • the cancer is a KRas G12D -associated cancer.
  • the cancer is a KRas G12R-associated cancer.
  • 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.
  • 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.
  • 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.
  • a lung cancer e.g., NSCLC
  • 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.
  • 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 Q61
  • 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.
  • 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.
  • 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.
  • 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.
  • the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer.
  • the cancer is a KRas G12A-associated cancer.
  • the cancer is a KRas G12C- associated cancer.
  • the cancer is a KRas G12D-associated cancer.
  • the cancer is a KRas G12S-associated cancer.
  • the cancer is a KRas G12V-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cancer is a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V- associated cancer.
  • the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer.
  • the cancer is a KRas G12A-associated cancer.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas G12V inhibitor, or both.
  • testicular cancer e.g., seminoma
  • 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.
  • 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.
  • a KRas G12A mutation e.g., seminoma
  • a KRas G12R mutation e.g., seminoma
  • 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.
  • 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.
  • 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 Q6 IP-associated cancer, or a KRas Q61R-associated cancer.
  • the cancer is a KRas G12A-associated cancer, a KRas G12R-associated cancer, a KRas G12 S -associated cancer, or a KRas G12V-associated cancer. In some aspects of this embodiment, the cancer is 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.
  • 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.
  • 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.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas G12V inhibitor, or both.
  • 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.
  • the cancer has a KRas G12C mutation or a KRas G12D mutation.
  • 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.
  • 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.
  • 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.
  • the cancer is a KRas G12C-associated cancer or a KRas G12D-associated cancer, or both.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas G12D inhibitor, or both.
  • 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.
  • the cancer has a KRas G12D mutation or a KRas G12V mutation.
  • 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.
  • 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.
  • 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.
  • the cancer is a KRas G12D-associated cancer or a KRas G12V-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas G12V inhibitor, or both.
  • 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).
  • the cancer has a KRas G12D mutation or a KRas G13D mutation.
  • 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 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.
  • 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).
  • 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.
  • the cancer is a KRas G12D- associated cancer or a KRas G13D-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas G13D inhibitor, or both.
  • 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.
  • the cancer has a KRas G12C mutation or a KRas G12V mutation.
  • 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.
  • 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.
  • 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 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.
  • the cancer is a KRas G12C-associated cancer or a KRas G12V-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas G12V inhibitor, or both.
  • 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).
  • the cancer has a KRas G12C mutation or a KRas G13D mutation.
  • 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.
  • 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).
  • 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.
  • the cancer is a KRas G12C-associated cancer or a KRas G13D-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas G13D inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12D mutation or a KRas Q61H mutation.
  • 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.
  • the cancer is bladder cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12D-associated cancer or a KRas Q61H- associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas Q61H inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, or lung cancer (e.g., NSCLC).
  • the cancer has a KRas G12V mutation or a KRas G13D mutation.
  • 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.
  • the cancer is bladder cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, or lung cancer (e.g., NSCLC).
  • 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.
  • the cancer is a KRas G12V-associated cancer or a KRas G13V- associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12V inhibitor, a KRas G13D inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12V mutation or a KRas Q61H mutation.
  • 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.
  • the cancer is bladder cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, leukemia, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12V-associated cancer or a KRas Q61H- associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12V inhibitor, a KRas Q61H inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12C mutation or a KRas Q61H mutation.
  • 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.
  • the cancer is bladder cancer, colorectal cancer, endometrial cancer, esophageal or stomach cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12C-associated cancer or a KRas Q61H- associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas Q61H inhibitor, or both.
  • 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).
  • the cancer has a KRas G12S mutation or a KRas G12V mutation.
  • 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, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein.
  • the cancer is colorectal cancer, endometrial cancer, esophageal or stomach cancer, lung cancer (e.g., NSCLC), pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12S-associated cancer or a KRas G12V-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12S inhibitor, a KRas G12V inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12A mutation or a KRas G12S mutation.
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G12S-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas G12S inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12A mutation or a KRas G12V mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G12V-associated cancer.
  • 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 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.
  • the cancer is bladder cancer, colorectal cancer, skin cancer (e.g., melanoma), pancreatic cancer, or prostate cancer.
  • 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 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.
  • the cancer is colorectal cancer, endometrial cancer, esophageal or stomach cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12D-associated cancer or a KRas G12S-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas G12S inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, ovarian cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12R mutation or a KRas G12V mutation.
  • 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.
  • the cancer is bladder cancer, colorectal cancer, ovarian cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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 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.
  • the cancer is a KRas G12R-associated cancer or a KRas G12V-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas G12V inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, esophageal or stomach cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12S mutation or a KRas Q61H mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, esophageal or stomach cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12S-associated cancer or a KRas Q61H-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12S inhibitor, a KRas Q61H inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), ovarian cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12V mutation or a KRas Q61L mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), ovarian cancer, or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12V-associated cancer or a KRas Q61L-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12V inhibitor, a KRas Q61L inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12A mutation or a KRas G12C mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G12C-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas G12C inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12A mutation or a KRas G12D mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G12D-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas G12D inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12A mutation or a KRas G13C mutation.
  • 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 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G13C-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas G13C inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12A mutation or a KRas Q61H mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas Q61H-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas Q61H inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12A mutation or a KRas Q61L mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas Q61L-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas Q61L inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, skin cancer (e.g., melanoma), or pancreatic cancer.
  • the cancer has a KRas G12C mutation or a KRas G12R mutation.
  • 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 herein.
  • the cancer is bladder cancer, colorectal cancer, skin cancer (e.g., melanoma), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12C-associated cancer or a KRas G12R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas G12R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12C mutation or a KRas G13C mutation.
  • 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.
  • the cancer is a KRas G12C-associated cancer or a KRas G13C-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas G13C inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, skin cancer (e.g., melanoma), or lung cancer (e.g., NSCLC).
  • the cancer has a KRas G12C mutation or a KRas Q61L mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, skin cancer (e.g., melanoma), or lung cancer (e.g., NSCLC).
  • 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.
  • the cancer is a KRas G12C- associated cancer or a KRas Q61L-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas Q61L inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12D mutation or a KRas G13C mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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 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.
  • the cancer is a KRas G12D-associated cancer or a KRas G13C-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas G13C inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, skin cancer (e.g., melanoma), or lung cancer (e.g., NSCLC).
  • the cancer has a KRas G12D mutation or a KRas Q61L mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, skin cancer (e.g., melanoma), or lung cancer (e.g., NSCLC).
  • 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.
  • the cancer is a KRas G12D- associated cancer or a KRas Q61L-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas Q61L inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, skin cancer (e.g., melanoma), ovarian cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12R mutation or a KRas Q61L mutation.
  • 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.
  • the cancer is colorectal cancer, skin cancer (e.g., melanoma), ovarian cancer, or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12R-associated cancer or a KRas Q61L-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas Q61L inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, skin cancer (e.g., melanoma), pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12R mutation or a KRas Q61R mutation.
  • 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.
  • the cancer is colorectal cancer, skin cancer (e.g., melanoma), pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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 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.
  • the cancer is a KRas G12R-associated cancer or a KRas Q61R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas Q61R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12S mutation or a KRas G13C mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12S-associated cancer or a KRas G13C-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable saltthereof is aKRas G12S inhibitor, aKRas G13C inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, esophageal or stomach cancer, or lung cancer (e.g., NSCLC).
  • the cancer has a KRas G12S mutation or a KRas G13D mutation.
  • 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 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.
  • the cancer is colorectal cancer, endometrial cancer, esophageal or stomach cancer, or lung cancer (e.g., NSCLC).
  • 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.
  • the cancer is a KRas G12S-associated cancer or a KRas G13D-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12S inhibitor, a KRas G13D inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12S mutation or a KRas Q61L mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12S-associated cancer or a KRas Q61L-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12S inhibitor, a KRas Q61L inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • the cancer has a KRas G12V mutation or a KRas G13C mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, lung cancer (e.g., NSCLC), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12V-associated cancer or a KRas G13C-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12V inhibitor, a KRas G13C inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, pancreatic cancer, testicular cancer (e.g., seminoma), or thyroid cancer.
  • the cancer has a KRas G12V mutation or a KRas Q61R mutation.
  • 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 herein.
  • the cancer is colorectal cancer, pancreatic cancer, testicular cancer (e.g., seminoma), or thyroid cancer.
  • 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.
  • the cancer is a KRas G12V- associated cancer or a KRas Q61R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12V inhibitor, a KRas Q61R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12A mutation or a KRas G12R mutation.
  • 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.
  • the cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G12R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas G12R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, endometrial cancer, or lung cancer (e.g., NSCLC).
  • the cancer has a KRas G12A mutation or a KRas G13D mutation.
  • 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.
  • the cancer is colorectal cancer, endometrial cancer, or lung cancer (e.g., NSCLC).
  • 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.
  • the cancer is a KRas G12A-associated cancer or a KRas G13D-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas G13D inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12A mutation or a KRas Q61R mutation.
  • 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.
  • the cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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 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.
  • the cancer is a KRas G12A-associated cancer or a KRas Q61R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12A inhibitor, a KRas Q61R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, skin cancer (e.g., melanoma), or pancreatic cancer.
  • the cancer has a KRas G12C mutation or a KRas Q61R mutation.
  • 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.
  • the cancer is colorectal cancer, skin cancer (e.g., melanoma), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12C-associated cancer or a KRas Q61R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12C inhibitor, a KRas Q61R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, skin cancer (e.g., melanoma), or pancreatic cancer.
  • the cancer has a KRas G12D mutation or a KRas Q61R mutation.
  • 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 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.
  • the cancer is colorectal cancer, skin cancer (e.g., melanoma), or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12D-associated cancer or a KRas Q61R-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12D inhibitor, a KRas Q61R inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12R mutation or a KRas G12S mutation.
  • 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.
  • the cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • 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 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.
  • the cancer is a KRas G12R-associated cancer or a KRas G12S-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas G12S inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, or skin cancer (e.g., melanoma).
  • the cancer has a KRas G12R mutation or a KRas G13D mutation.
  • 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.
  • the cancer is bladder cancer, colorectal cancer, or skin cancer (e.g., melanoma).
  • 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.
  • the cancer is a KRas G12R-associated cancer or a KRas G13D-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas G13D inhibitor, or both.
  • the KRas-associated cancer is bladder cancer, colorectal cancer, or pancreatic cancer.
  • the cancer has a KRas G12R mutation or a KRas Q61H mutation.
  • 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 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.
  • the cancer is bladder cancer, colorectal cancer, or pancreatic cancer.
  • 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.
  • the cancer is a KRas G12R-associated cancer or a KRas Q61H- associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas Q61H inhibitor, or both.
  • the KRas-associated cancer is bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer, or skin cancer (e.g., melanoma).
  • the cancer has a KRas G12R mutation or a KRas Q61K mutation.
  • 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.
  • the cancer is bile duct cancer (e.g., cholangiocarcinoma), colorectal cancer, or skin cancer (e.g., melanoma).
  • 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.
  • the cancer is a KRas G12R-associated cancer or aKRas Q61K-associated cancer.
  • the compound provided herein, or a pharmaceutically acceptable salt thereof is a KRas G12R inhibitor, a KRas Q61K inhibitor, or both.
  • the KRas-associated cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the cancer has a KRas G12S mutation or a KRas Q61R mutation.
  • 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.
  • the cancer is colorectal cancer, pancreatic cancer, or testicular cancer (e.g., seminoma).
  • the compound provided herein, or a pharmaceutically acceptable saltthereof is aKRas G12S inhibitor, aKRas 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.
  • the cancer is a KRas G12S-associated cancer or a KRas Q61R-associated cancer.
  • 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.
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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))
  • 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))
  • administering e.g., a KRas G12D-associated cancer, a KRas G12R-associated cancer, or a KRas G12V-associated cancer
  • 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))
  • a regulatory agency-approved e.g., FDA-approved test or assay for identifying a dysregulation associated with KRas
  • 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 e.g., a KRAS gene having a mutation corresponding to a mutation in a KRas protein and/or a KRas protein
  • a subject diagnosed with (or identified as having) a cancer having a KRas dysregulation e.g., a KRas mutation or amplification
  • methods for treating a subject diagnosed with (or identified as having) a cancer having a KRas dysregulation that include administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the subject that has been identified or diagnosed as having a cancer with a KRas dysregulation e.g., a KRas mutation or amplification
  • a regulatory agency-approved e.g., FDA-approved test or assay for identifying a dysregulation associated with KRas (e.g., a.
  • 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.
  • 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.
  • the test or assay is provided as a kit.
  • 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))
  • 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).
  • 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.
  • another anticancer treatment e.g., chemotherapy or a kinase inhibitor (e.g., an EGFR inhibitor)
  • a kinase inhibitor e.g., an EGFR inhibitor
  • 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
  • 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))
  • 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)
  • 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 nonlimiting examples of assays described herein.
  • 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 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 K
  • 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.
  • 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/
  • 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).
  • 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.
  • 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
  • the assay utilizes next generation sequencing, pyrosequencing, or immunohistochemistry.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • 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.
  • 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 G12A KRas G12A-associated cancer, a KRas G12D-associated cancer,
  • 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
  • a cancer having a KRas dysregulation e.g., a KRas mutation or amplification
  • an assay e.g., an in vitro assay
  • a sample e.g., a tumor sample or a blood sample
  • 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
  • a KRas dysregulation e.g., a KRAS gene having a mutation corresponding to a mutation in a KRas protein and/or a KR
  • 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.
  • a tumor sample e.g., a biopsy
  • a blood sample e.g., a sample containing circulating tumor DNA (ctDNA), circulating cell-free tumor RNA (cfRNA), and/or circulating tumor cells (CTCs)
  • ctDNA circulating tumor DNA
  • cfRNA circulating cell-free tumor RNA
  • CTCs circulating tumor cells
  • 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., phosphoERKl and/or phosphoERK2), DUSP6 (dual specificity protein phosphatase 6), and/or SPRY4 (protein sprouty homolog 4).
  • a mutant KRas protein e.g., a KRas G12A mutant protein, a KRas G12C mutant protein, a KRas G12D mutant protein, a KRas G12R
  • 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).
  • IHC immunohistochemical
  • an immunofluorescence assay e.g., RT-qPCR assay or a digital droplet PCR assay
  • a sequencing assay e.g., a next-generation sequencing (NGS) assay.
  • 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 nextgeneration sequencing assay).
  • a mutant KRas protein e.g., a KRas G12D mutant protein, a KRas G12R mutant protein, or a KRas G12V mutant protein
  • 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.
  • the biomarker of response is ERK1 and/or ERK2 (e.g., phosphoERKl and/or phosphoERK2), and the assay is an IHC assay or an immunofluorescence assay.
  • the biomarker of response is DUSP6, and the assay is a PCR assay (e.g., RT-qPCR assay or a digital droplet PCR assay).
  • 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.
  • 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.
  • a mutant KRas protein e.
  • 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.
  • a sample e.g., a tumor sample or a blood sample
  • the level e.g., the protein expression level, the mRNA expression level, and/or the ctDNA level
  • 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., phosphoERKl and/or phosphoERK2), DUSP6,
  • 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.
  • a mutant KRas protein e
  • 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., phosphoERKl and/or phosphoERK2), DUSP6, and/or SPRY4; (b) after (a), administering a therapeutically effective amount of a compound provided herein,
  • a mutant KRas protein
  • 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.
  • 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 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
  • 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).
  • 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.
  • 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 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 KR
  • 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.
  • the assay utilizes next generation sequencing, pyrosequencing, or immunohistochemistry.
  • the assay is a regulatory agency-approved assay, e.g., FDA-approved kit.
  • the assay is a liquid biopsy.
  • 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- 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).
  • a KRas-associated cancer e.g., a mutant KRas-associated cancer (e.g., a KRas G12A-associated cancer, a K
  • a KRas dysregulation e.g., a KRas mutation or amplification
  • 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).
  • 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 G
  • 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.
  • 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.
  • a regulatory agency -approved e.g., FDA-approved, kit for identifying a KRas dysregulation
  • 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.
  • a regulatory agency-approved e.g., FDA-approved, kit for identifying a KRas dysregulation
  • 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))
  • a KRas-associated cancer includes those described herein and known in the art.
  • 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).
  • 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
  • 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).
  • 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 G
  • 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))).
  • 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
  • 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)).
  • a mutant KRas-associated cancer e.g., a cancer that was previously identified a cancer having no KRas mutation (e.g., KRas wild type)
  • 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))
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the first and second inhibitors of KRas are different.
  • the first and/or second inhibitor of KRas bind in a different location than a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • a first or a second inhibitor of KRas can be a KRas G12C inhibitor.
  • 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.
  • 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.
  • 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).
  • 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
  • the method also includes administering to a subject 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)) or amplification) a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • 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 G12
  • 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.
  • 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
  • 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).
  • 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 realtime RT-PCR).
  • a KRas dysregulation e.g., a KRa
  • 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).
  • a KRas mutation e.g., a KRas G12A mutation, a KRas G12C mutation, a KRas G12D mutation, a KRa
  • the sample is tumor biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject.
  • 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- 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 subject having one
  • 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).
  • 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
  • a subject that has an increased risk of developing a cancer having a KRas dysregulation e.g., a KRas mutation or amplification
  • 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).
  • a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy).
  • 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).
  • 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 G12
  • 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.
  • 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.
  • a liquid biopsy can be used to detect circulating tumor cells (CTCs).
  • a liquid biopsy can be used to detect cell-free DNA.
  • cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells.
  • ctDNA tumor DNA
  • Analysis of ctDNA 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))).
  • 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 K
  • 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)
  • 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))
  • a compound provided herein, or a pharmaceutically acceptable salt thereof comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof.
  • the contacting is in vitro.
  • the contacting is in vivo.
  • the contacting is ex vivo.
  • 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)))
  • a KRas protein e.g., a dysregulated KRas protein (e.g., a mutant KRas protein (e.g., a KRas G12A mutant protein, a KRas G12
  • 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))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))
  • 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))).
  • KRas-associated cancer cell e.g., a mutant KRas-associated cancer cell (e.g., a
  • contacting refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system.
  • “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.
  • the cell has a KRas dysregulation.
  • the cell has a KRas mutation.
  • the cell has a KRas G12D mutation or a KRas G12V mutation.
  • the cell has a KRas G12A mutation.
  • the cell has a KRas G12C mutation.
  • the cell has a KRas G12D mutation.
  • 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.
  • a method of increasing cell death, in vitro, in vivo, or ex vivo 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.
  • a method of increasing tumor cell death in a subject comprises administering to the subject a compound provided herein, or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.
  • the cell has a KRas dysregulation.
  • the cell has a KRas mutation.
  • the cell has a KRas G12D mutation or a KRas G12V mutation.
  • 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.
  • 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 provided herein, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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 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
  • 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.
  • 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).
  • 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)
  • 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
  • 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 KR
  • 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 a KRas dysregulation
  • 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)
  • amplification e.g
  • 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).
  • 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)
  • KRas dysregulation e.g., KRas mutation (e.g.
  • Also provided herein is a method of treating a subject having a cancer, wherein the method comprises:
  • 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
  • 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 KR
  • the first anticancer agent can be a first KRas inhibitor.
  • the compounds provided herein, or pharmaceutically acceptable salts thereof can be administered in the form of pharmaceutical compositions as described herein.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can be used as a monotherapy.
  • a compound provided herein, or a pharmaceutically acceptable salt thereof can be used prior to administration of an additional therapeutic agent or additional therapy.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy.
  • a subject is KRas inhibitor naive.
  • a subject is not KRas inhibitor naive.
  • a subject has undergone prior therapy.
  • a multi-kinase inhibitor MKI
  • KRas inhibitor RAF/MEK/PI3K pathway inhibitor
  • MEK inhibitor Raf inhibitor
  • YAP inhibitor a proteasome inhibitor
  • PI3K-AKT-mT0R pathway inhibitor an ERK inhibitor
  • pan-ErbB inhibitor a MET inhibitor
  • farnesyl transferase inhibitor a FAK inhibitor, a HSP90 inhibitor, or a combination thereof.
  • 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, SOSl/Ras protein-protein interaction inhibitors, SHP2 inhibitors or degraders, PI3K-AKT- mTOR pathway inhibitors or degraders)), kinase-targeted therapeutics (e.g., MEK inhibitors or degraders, ERK inhibitors or degraders, Raf inhibitors or degraders (e.g., BRaf inhibitors or degraders), PI3K inhibitors or degraders, AKT inhibitors or degraders, mTOR inhibitors or degraders, CDK4/5 inhibitors or degraders, CDK4/6 inhibitors or degraders, MET inhibitors or degraders, FAK inhibitors or degraders, ErbB family inhibitor
  • a “degrader” as used herein is a heterobifunctional molecule that induces degradation of a target protein, the degrader including a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply an E3), these two moi eties being optionally separated by a linker.
  • ubiquitin E3 ligase sometimes referred to as an E3 ligase or simply an E3
  • 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).
  • 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.
  • 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).
  • a Ras modulator is a covalent inhibitor.
  • 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.
  • a KRas pathway modulator is a KRas-targeted therapeutic agent.
  • the Ras pathway targeted therapeutic agent is a SOS1 inhibitor or a SHP2 inhibitor.
  • Non-limiting examples of SOS1 inhibitors include MRTX-0902 and RMC-5845.
  • Non-limiting examples of SHP2 inhibitors include batoprotafib (TNO-155), vociprotafib (RMC-4630), ARRY-558, BBP-398, ENT-03, ERAS-601, ET-0038, GDC- 1971 (RLY-1971), GH-21, HS-10381, ICP-189, JAB-3068, JAB-3312, and SH-3809.
  • KRas-targeted therapeutic agents include a KRas-selective inhibitor, a Ras inhibitor, and an anti- KRas antibody.
  • the KRas inhibitor is a covalent inhibitor.
  • 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.
  • the KRas-targeted therapeutic agent is an agent that inhibits the interaction between KRas and SOS1 or SHP2.
  • an agent that inhibits the interaction between SOS1 and KRas include BI-3406, BI-1701963, and BAY 293.
  • Additional KRas-targeted therapeutic agents include those disclosed in International Publication Nos. WO 2021/104431; WO WO2021/119343; WO2021/113595; WO 2021/107160; WO 2016/161361; WO 2016/17262; WO 2020/035031; WO 2021/041671; WO 2016/077793; WO 2020/180768; WO 2021/092115; WO 2020/180770; U.S. Patent Nos. US 10,898,487; US 10,829,487; US 10,858,359; US 10,561,655; US 10,532,042; U.S.
  • Ras pathway-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors.
  • the BRAF inhibitor is dressingometinib, dabrafenib (e.g., dabrafenib mesylate, TAFINLAR®), encorafenib (BRAFTOVITM), naporafenib, sorafenib (e.g., sorafenib tosylate), vemurafenib (ZELBORAF®), ARQ 736, AZ304, BMS-908662 (XL281), C17071479-F, CHIR-265, FORE-8394, GDC-0879, GSK2118436, HLX-208, HM95573, LGX818, LXH254, PLX-3603, PLX-4720, PLX-8394, RAF265, RO5126766, RO5185426, or a combination thereof.
  • dabrafenib e.g., dabrafenib mesylate, TAFINLAR®
  • BRAFTOVITM
  • the BRAF inhibitor is medicamentometinib, 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.
  • dabrafenib e.g., dabrafenib mesylate
  • encorafenib e.g., naporafenib
  • sorafenib e.g., sorafenib tosylate
  • vemurafenib C17071479-F
  • CHIR-265 CHIR-265
  • FORE-8394 HLX-208
  • the MEK inhibitor is dressingometinib, binimetinib (MEKTOVI®, MEK162), cobimetinib (e.g., cobimetinib fumarate, COTELLIC®), mirdametinib, pimasertib, refametinib, selumetinib (e.g., selumetinib sulfate, AZD6244), trametinib (e.g., trametinib dimethyl sulfoxide, GSK-1120212 MEKINIST®), zapnometinib, hypothemycin, CH040 (PD184352), CS3006, FCN-159, MSC1936369B, NFX-179, PD0325901,
  • the MEK inhibitor is perennialometinib, 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.
  • the MEK inhibitor is a MEK-Raf protein-protein interaction stabilizer, such as NST-628 or perpetuometinib (VS6766).
  • the ERK inhibitor is 25-OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), 5-7-Oxozeaenol, 5-iodotubercidin, AEZ-131 (AEZS-131), AEZS- 136, ASN007, AZ-13767370, BL-EI-001, CC-90003, FR148083, FR-180204, FRI-20 (ON- 01060), GDC0994, GDC-0994 (RG-7482), KO-947, KO-947, LTT-462, LY-3214996, MK- 8353 (SCH900353), ONC201SCH772984, ulixertinib (BVD-523), VTX-1 le, or a combination thereof.
  • the ERK inhibitor is rineterkib, ulixertinib, or a combination thereof.
  • PI3K inhibitor is alpelisib (BYL719), apitolisib (GDC-0980), buparlisib (BKM120), copanlisib (ALIQOPATM, 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, A
  • 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, umbralis
  • the AKT inhibitor is 2-[4-(2-aminoprop-2-yl)phenyl]-3- phenylquinoxaline, 3-oxo-tirucallic acid, A-443654, A-674563, afuresertib, API-1, ARQ092, AT13148, AT7867, AZD5363, BAY 1125976, boc-Phe-vinyl ketone, CCT128930, DC120, DM-PIT-1, edelfosine, erucylphophocholine, erufosine, GSK2141795, GSK690693, H-89, ipatasertib (GDC-0068, RG7440), lactoquinomycin, miltefosine (IMPADIVO®), MK-2206, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5
  • the AKT inhibitor is afuresertib, capivasertib (AZD-5363), miransertib (e.g., miransertib mesylate), pifusertib, uprosertib, MK-2206, SM-020, or a combination thereof.
  • 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.
  • 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.
  • 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.
  • the farnesyl transferase inhibitor is lonafamib, tipifarnib, BMS- 214662, L778123, L744832, FTI-277, or a combination thereof. In some embodiments, the farnesyl transferase inhibitor is lonafamib, tipifarnib, BMS-214662, or a combination thereof.
  • 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.
  • 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
  • Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere.
  • the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof.
  • the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and combinations thereof.
  • 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.
  • the platinum complex is carboplatin, cisplatin, lobaplatin, miriplatin, oxaliplatin, or a combination thereof.
  • the microtubule inhibitor is cabazitaxel, colchicine, desoxyepothilone B, docetaxel, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, plinabulin, sabizabulin, tirbanibulin, vinblastine, vinflunine, vinorelbine, or a combination thereof.
  • the microtubule inhibitor is cabazitaxel, docetaxel, nab-paclitaxel, paclitaxel, or a combination thereof.
  • 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.
  • the hypomethylating agent is azacitidine, decitabine, or a combination thereof.
  • the chemotherapy is a platinum complex and a topoisomerase inhibitor (e.g., cisplatin and etoposide).
  • 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 (
  • the antibody-drug conjugate including the microtubule inhibitor is enfortumab vedotin (e.g., enfortumab vedotin-ejfv, or a biosimilar thereof).
  • the antibody-drug conjugate including the microtubule inhibitor is mirvetuximab soravtansine (e.g., mirvetuximab soravtansine-gynx, or a biosimilar thereof).
  • the antibody-drug conjugate including the microtubule inhibitor is trastuzumab emtansine (e.g., ado-trastuzumab emtansine, or a biosimilar thereof).
  • 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.
  • the antibodydrug conjugate including the topoisomerase inhibitor is sacituzumab govitecan (e.g., sacituzumab govitecan-hziy, or a biosimilar thereof).
  • the antibody-drug conjugate including the topoisomerase inhibitor is trastuzumab deruxtecan (e.g., famtrastuzumab deruxtecan-nxki, or a biosimilar thereof).
  • the chemotherapy includes one or more of capecitabine, carboplatin, cisplatin, docetaxel, doxorubicin (e.g., liposomal doxorubicin), fluorouracil, gemcitabine, leucovorin, mitomycin, oxaliplatin, paclitaxel (e.g., albumin-bound paclitaxel), and pemetrexed.
  • doxorubicin e.g., liposomal doxorubicin
  • fluorouracil e.g., gemcitabine, leucovorin, mitomycin, oxaliplatin, paclitaxel (e.g., albumin-bound paclitaxel), and pemetrexed.
  • 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.
  • 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.
  • the CDK4/6 inhibitor is abemaciclib, birociclib, dalpiciclib, lerociclib, milciclib, palbociclib, ribociclib (e.g., ribociclib succinate), riviciclib, roniciclib, trilaciclib (e.g., trilaciclib dihydrochloride), BPL16350, FCN-437, SPH-4336, or a combination thereof.
  • the CDK4/6 inhibitor is palbociclib or ribociclib (e.g., ribociclib succinate).
  • 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), fasciartinib, neratinib (e
  • the EGFR-targeting biologic is amivantamab (e.g., amivantamab-vmjw, or a biosimilar thereof), cetuximab (e.g., ERBITUX® (cetuximab), or a biosimilar thereof (e.g., CMAB-009, CPGJ-602, or KL-140)), cetuximab sarotalocan (AKALUX® (cetuximab sarotalocan), or a biosimilar thereof), depatuxizumab, duligotuzumab, futuximab, imgatuzumab, modotuximab, necitumumab (e.g., PORTRAZZA® (necitumumab), or a biosimilar thereof), nimotuzumab (e.g., BIOMAb EGFR® (nimotuzumab), or a biosimilar thereof), panitumumab (e.g.,
  • 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.
  • the PARP inhibitor is iniparib, niraparib, olaparib (LYNPARZA®), pamiparib (BGB-290), rucaparib, talazoparib, veliparib, 2X-121, ABT-767, BMN 673, BSI-201, CEP 9722, E7016, IMP4297, INO-lOOl, JPI-289, KU-0059436 (AZD2281), NOV1401, PF-01367338, and RBN-2397.
  • 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.
  • the PARP inhibitor is a PARP1 inhibitor.
  • the PARP1 inhibitor is saruparib (AZD5305), NMS-03305293, or a combination thereof.
  • Non-limiting examples of immunotherapy include immune checkpoint therapies.
  • immune checkpoint therapies include antibodies and/or inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, AD0RA2A, TIM-3, B7-H3, VISTA, IDO, and combinations thereof.
  • the anti-CTLA4 therapy is abatacept (e.g., ORENCIA® (abatacept), or a biosimilar thereof), botensilimab, cadonilimab, erfonrilimab, gotistobart, ipilimumab (e.g., YERVOY® (ipilimumab), or a biosimilar thereof), nurulimab, quavonlimab, tremelimumab (ticilimumab) (e.g., IMIUDO® (tremelimumab), or a biosimilar thereof), volrustomig, vudalimab, zalifrelimab, BMS-986218, PSB-205, biosimilars thereof, or a combination thereof.
  • abatacept e.g., ORENCIA® (abatacept), or a biosimilar thereof
  • botensilimab e.g., ORENCIA® (abatacept), or a
  • 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-PDl or anti-PD-Ll therapy.
  • the anti-PDl therapy is balstilimab, budigalimab, cadonilimab, camrelizumab, cemiplimab (e.g., cemiplimab-rwlc, or a biosimilar thereof), cetrelimab, dostarlimab (e.g., dostarlimab-gxly, or a biosimilar thereof), enlonstobart (SG-001), ezabenlimab, geptanolimab, ivonescimab, nivolumab (e.g., OPDIVO® (nivolumab), or a biosimilar thereof), nofazinlimab, pembrolizumab (e.g., KEYTRUDA® (pembrolizumab), or a biosimilar thereof), penpulimab, pidilizumab, pimivalimab, prolgolimab, pucotenlimab, retifan
  • the anti-PDl therapy is cemiplimab, nivolumab, or pembrolizumab. In some embodiments, the anti-PDl therapy is cemiplimab. In some embodiments, the anti-PDl therapy is nivolumab. In some embodiments, the anti-PDl therapy is pembrolizumab. In some embodiments, the anti-PDl therapy is used in combination with anti-CTLA4 therapy.
  • the anti-PD-Ll therapy is adebrelimab, atezolizumab (e.g., TECENTRIQ® (atezolizumab), or a biosimilar thereof), avelumab (e.g., BAVENCIO® (avelumab), or a biosimilar thereof), benmelstobart (APL-502), bintrafusp alfa, cosibelimab, danburstotug, durvalumab (e.g., IMFINZI® (durvalumab), or a biosimilar thereof), envafolimab (e.g., ENWEIDA® (envafolimab), or a biosimilar thereof), erfonrilimab, lesabelimab, pacmilimab, socazolimab, sugemalimab (e.g., CEJEMLY® (sugemalimab), or a biosimilar thereof), tagitanlimab, at
  • the anti-PD-Ll therapy is atezolizumab or durvalumab. In some embodiments, the anti-PD-Ll therapy is atezolizumab. In some embodiments, the anti-PD-Ll therapy is durvalumab. In some embodiments, the anti- PD-Ll therapy is used in combination with anti-CTLA4 therapy.
  • the PD-L1 inhibitor is INCB-086550 or INCB-099280.

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Abstract

La présente invention concerne des composés de formule (l-c) ou leurs sels pharmaceutiquement acceptables, qui inhibent une protéine KRas. Dans certains modes de réalisation, la protéine KRas présente une dérégulation (par exemple, la protéine KRas est mutée ou amplifiée). Ces composés sont utiles, par exemple, pour traiter une maladie, un trouble ou un état pathologique dans lesquels une activation de KRas augmentée et/ou prolongée (par exemple, excessive), par exemple, une activation de KRas associée à une protéine KRas mutante, contribue à la pathologie et/ou aux symptômes et/ou à la progression de la maladie, du trouble ou de l'état pathologique (par exemple, le cancer) chez un patient (par exemple, un être humain). La présente invention concerne également des compositions contenant des composés de formule (A) (par exemple, la formule (I) (par exemple, la formule (l-a), (i- b), (l-c), (l-d), (l-c2), (l-c3), (l-c4), (l-d), ou (l-e))) ou la formule (B), ou leurs sels pharmaceutiquement acceptables, ainsi que leurs méthodes d'utilisation et de fabrication.
PCT/US2024/047734 2023-09-21 2024-09-20 Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques Pending WO2025064848A1 (fr)

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