Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • 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

Definitions

• heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
• heteroalkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene.
• a bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.
• halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
• aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
• a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings.
• two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer of from 1 to 4.
• One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
• R 1A may be substituted with one or more first substituent groups denoted by R 1A.1
• R 2A may be substituted with one or more first substituent groups denoted by R 2A.1
• R 3A may be substituted with one or more first substituent groups denoted by R 3A.1
• R 4A may be substituted with one or more first substituent groups denoted by R 4A.1
• R 5A may be substituted with one or more first substituent groups denoted by R 5A.1 and the like up to or exceeding an R 100A may be substituted with one or more first substituent groups denoted by R 100A.1 .
• the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
• the present disclosure provides compounds, which are in a prodrug form.
• Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
• Prodrugs of the compounds described herein may be converted in vivo after administration.
• prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
• a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
• a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
• a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
• Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross’ leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,
• a Switch II Binding Pocket binding compound or Switch II Binding Pocket binding moiety binds or contacts multiple K-Ras amino acids selected from amino acids in a mutant K-Ras (e.g., K-Ras(G12S), K-Ras(G13S), or K-Ras(G12T)), related Ras (e.g., H-Ras, H-Ras(G12S), H-Ras(G13S), H-Ras(G12T), N-Ras, N-Ras(G12S), N-Ras(G13S), or N- Ras(G12T)), or homolog of K-Ras corresponding to K-Ras residues V7, V9, G10, P34, T58, G60, Q61, E62, E63, R68, Y71, M72, Y96, Q99, and I100.
• the Switch II GTPase protein serine residue is a Ras protein serine residue. In embodiments, the Switch II GTPase protein serine residue is a K-Ras serine residue. In embodiments, the Switch II GTPase protein serine residue is an H-Ras serine residue. In embodiments, the Switch II GTPase protein serine residue is an N-Ras serine residue. In embodiments, the Switch II GTPase serine residue protein is an E-Ras serine residue. In embodiments, the Switch II GTPase protein serine residue is a RASD1 serine residue. In embodiments, the Switch II GTPase protein serine residue is a Rhes serine residue.
• R 9 is hydrogen or unsubstituted C1-C4 alkyl. In embodiments, R 9 is hydrogen. In embodiments, R 9 is unsubstituted C1-C4 alkyl. In embodiments, R 9 is unsubstituted methyl. In embodiments, R 9 is unsubstituted ethyl. In embodiments, R 9 is unsubstituted propyl. In embodiments, R 9 is unsubstituted n-propyl. In embodiments, R 9 is unsubstituted isopropyl. In embodiments, R 9 is unsubstituted butyl. In embodiments, R 9 is unsubstituted n-butyl.
• L 2 is unsubstituted ethylene. In embodiments, L 2 is unsubstituted propylene. In embodiments, L 2 is unsubstituted n-propylene. In embodiments, L 2 is unsubstituted isopropylene. In embodiments, L 2 is unsubstituted butylene. In embodiments, L 2 is unsubstituted n-butylene. In embodiments, L 2 is unsubstituted isobutylene. In embodiments, L 2 is unsubstituted tert- butylene. [0327] In embodiments, L 1 is –L 101 -L 102 -L 103 -.
• R 102 when R 102 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 102 is substituted, it is substituted with at least one lower substituent group.
• R 102 is independently hydrogen or unsubstituted C 1 -C 4 alkyl. In embodiments, R 102 is independently hydrogen. In embodiments, R 102 is independently unsubstituted C1-C4 alkyl. In embodiments, R 102 is independently unsubstituted methyl. In embodiments, R 102 is independently unsubstituted ethyl. In embodiments, R 102 is independently unsubstituted propyl.
• R 20A , R 20B , R 20C , and R 20D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted alkyl
• R 20 is substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted C6-C10 aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl.
• R 20 is substituted C 3 -C 8 cycloalkyl.
• R 20 is substituted 3 to 8 membered heterocycloalkyl.
• R 20 is substituted C 6 -C 10 aryl.
• R 20 is substituted phenyl.
• R 20 is substituted 5 to 10 membered heteroaryl.
• R 7 is independently unsubstituted butoxy. In embodiments, R 7 is independently unsubstituted n-butoxy. In embodiments, R 7 is independently unsubstituted isobutoxy. In embodiments, R 7 is independently unsubstituted tert-butoxy. [0386] In embodiments, R 7 is independently a halogen, -CF 3 , -CN, -OH, -NH 2 , or unsubstituted C 1 -C 4 alkyl. In embodiments, R 7 is independently –F, -Cl, -CF 3 , -CN, -OH, -NH2, or unsubstituted methyl.
• R 8 when R 8 is substituted, it is substituted with at least one substituent group. In embodiments, when R 8 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 8 is substituted, it is substituted with at least one lower substituent group. [0390] In embodiments, R 8 is independently halogen. In embodiments, R 8 is independently –F. In embodiments, R 8 is independently –Cl. In embodiments, R 8 is independently –Br. In embodiments, R 8 is independently –I. In embodiments, R 8 is independently -CCl 3 . In embodiments, R 8 is independently -CBr 3 . In embodiments, R 8 is independently -CF 3 .
• R 1 is a monovalent form of ARS-1620. In embodiments, R 1 is a wherein R 1 does not include the substituted piperazinyl moiety. [0396] In embodiments, R 1 is a monovalent form of AMG-510. In embodiments, R 1 is a monovalent form of a compound as described in Canon, J. et al. Nature 575, 217–223 (2019), which is herein incorporated by reference in its entirety for all purposes. In embodiments, R 1 510, wherein R 1 does not include the substituted piperazinyl moiety or equivalent for compounds described in Canon, et al. [0397] In embodiments, R 1 is a monovalent form of MRTX-849.
• the compound contacts a Switch II Binding Pocket amino acid corresponding to D92 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q95 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Y96 of human H-Ras protein. In embodiments, the compound contacts a Switch II Binding Pocket amino acid corresponding to Q99 of human H-Ras protein. [0459] In embodiments, the compound contacts the Switch II Binding Pocket of human N- Ras protein.
• the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 10-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions.
• a human Ras(G12D) e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)
• the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N-Ras(G12D)) protein-GDP complex at least 20-fold stronger than the compound binds a human Ras(G12D) (e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)) protein-GTP complex under identical conditions.
• a human Ras(G12D) e.g., human K-Ras(G12D), human H-Ras(G12D), or human N- Ras(G12D)
• the compound is a compound of formula (I), (I-1), (I-1a), (I-1b), (I-1c), (I-1d), (I-1e), (I-1f), (I-2), (I-2a), (I-2b), (I-3), (I-3a), (I-3b), (I-3c), (I-4), (I-4a), (I-4b), (I-5), (I-5a), (I-5b), (I-6), (I-6a), (I-7), (I-7a), (II), (II-1), (II- 1a), (III), (III-1), (III-1a), (III-2), or (III-2a).
• the H-Ras(G13S)-associated disease is cancer (e.g., rectal carcinoma, colorectal adenocarcinoma, colorectal carcinoma, non-small cell lung carcinoma, squamous cell lung carcinoma, myelodysplastic syndrome, or acute myeloid leukemia).
• the H-Ras(G13S)-associated disease is a RASopathy (e.g., capillary malformation-AV malformation syndrome, autoimmune lymphoproliferative syndrome, cardiofaciocutaneous syndrome, hereditary gingival fibromatosis type 1, neurofibromatosis type 1, Noonan syndrome, Costello syndrome, or Legius syndrome).
• the human K-Ras protein contains a G12D mutation. In embodiments, the human K-Ras protein contains a G13D mutation.
• a K-Ras protein covalently bound to a compound described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is covalently bound to a glutamate residue of the K-Ras protein.
• the K-Ras protein is a human K-Ras protein.
• the human K-Ras protein contains a G12E mutation.
• the compound is reversibly covalently bound to an aspartate residue of the K-Ras protein.
• the K-Ras(G12E) protein (e.g., human K- Ras(G12E)) is reversibly covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
• the K-Ras(G12E) protein e.g., human K-Ras(G12E)
• the K-Ras(G12E) protein is irreversibly covalently bonded to a portion of a compound described herein.
• the H-Ras(G12S) protein covalently bonded to a compound may have the formula: , wherein O is the oxygen of an H-Ras(G12S) protein serine (e.g., corresponding to serine residue 12 of human H-Ras(G12S)), which is bonded to the remainder of the H-Ras(G12S) protein and wherein R 1 , L 1 , R 3 , and z3 are as described herein, including in embodiments.
• an H-Ras(G13S) protein e.g., human H-Ras(G13S)
• a compound e.g., compound described herein or a portion of a compound described herein
• an H-Ras(G13S) protein e.g., human H-Ras(G13S)
• a compound e.g., compound described herein or a portion of a compound described herein.
• the H-Ras(G12T) protein (e.g., human H-Ras(G12T)) is reversibly covalently bonded to a portion of a compound described herein.
• the compound described herein is bonded to a threonine residue (e.g., G12T of human H-Ras(G12T) or threonine corresponding to G12T of human H-Ras(G12T)) of the H-Ras(G12T) protein (e.g., human H-Ras(G12T)).
• an H-Ras(G12D) protein e.g., human H-Ras(G12D)
• a compound e.g., compound described herein or a portion of a compound described herein
• an H-Ras(G12D) protein e.g., human H-Ras(G12D)
• a compound e.g., compound described herein or a portion of a compound described herein.
• the remnant of the E 2 substituent is a linker selected from a bond, -S(O) 2 -, -NH-, -O-, -S-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -NHC(O)NH-, -C(O)O-, -OC(O)-, -CH2NH-, substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted (e.g., substituted with a substituent group, a size-limited substituent group, or lower substituent group) or unsubstituted heteroalkylene (e.g., 2 to 8 membered,
• the compound described herein is bonded to a serine residue (e.g., G12S of human N-Ras(G12S) or serine corresponding to G12S of human N-Ras(G12S)) of the N-Ras(G12S) protein (e.g., human N- Ras(G12S)).
• the N-Ras(G12S) protein covalently bonded to a compound described herein is the product of a reaction between the N-Ras(G12S) protein and a compound described herein.
• the N-Ras(G13S) protein (e.g., human N- Ras(G13S)) is reversibly covalently bonded to a compound (e.g., compound described herein or a portion of a compound described herein).
• the N-Ras(G13S) protein (e.g., human N-Ras(G13S)) is covalently bonded to a portion of a compound (e.g., compound described herein).
• the N-Ras(G13S) protein (e.g., human N-Ras(G13S)) is irreversibly covalently bonded to a portion of a compound described herein.
• Embodiment Q28 The compound of embodiment Q14, having the formula: [0607] Embodiment Q29. The compound of one of embodiments Q14 to Q26, wherein R 3 is independently unsubstituted C 1 -C 4 alkyl. [0608] Embodiment Q30. The compound of one of embodiments Q14 to Q26, wherein R 3 is independently unsubstituted methyl. [0609] Embodiment Q31. The compound of one of embodiments Q14 to Q26, wherein two R 3 substituents are joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl. [0610] Embodiment Q32.
• L 1 is –L 101 -L 102 -L 103 -; L 101 is connected directly to E 1 ; L 101 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 101 -, -C(O)NR 101 -, -NR 101 C(O)-, -NR 101 C(O)O-, -OC(O)NR 101 -, -NR 101 C(O)NR 101 -, -NR 101 C(NH)NR 101 -, -S(O)2-, -NR 101 S(O)2-, -S(O)2NR 101 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or
• R 1 is –L 20 -R 20 ;
• L 20 is a bond, -C(O)-, -C(O)O-, -OC(O)-, -O-, -S-, -NR 200 -, -C(O)NR 200 -, -NR 200 C(O)-, -NR 200 C(O)O-, -OC(O)NR 200 -, -NR 200 C(O)NR 200 -, -NR 200 C(NH)NR 200 -, -S(O)2-, -NR 200 S(O)2-, -S(O)2NR 200 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted
• Embodiment Q51 The compound of one of embodiments Q1 to Q12, having the formula: [0630] Embodiment Q52.
• the compound of embodiment Q51 having the formula: wherein X is O or S; Y is O, S, or NR 2 ; and R 2 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H,
• GEF guanine exchange factor
• Embodiment D47 The compound of embodiment D46, wherein R 6 is independently a halogen, -OH, unsubstituted C 1 -C 4 alkyl, substituted 2 to 6 membered heteroalkyl, or substituted 5 to 6 membered heteroaryl.
• Embodiment D48 The compound of embodiment D46, wherein R 6 is independently –F, -Cl, -OH, or unsubstituted methyl.
• Embodiment D49 The compound of embodiment D46, wherein R 6 is independently a 2 to 6 membered heteroalkyl, substituted with substituted heterocycloalkyl or unsubstituted fused heterocycloalkyl.
• Embodiment D54 The compound of one of embodiments D46 to D53, wherein z7 is 1, 2, or 3.
• Embodiment D55 The compound of one of embodiments D46 to D54, wherein R 8 is independently a halogen or unsubstituted C 1 -C 4 alkyl.
• Embodiment D98 The covalently modified K-Ras protein of embodiment D97, wherein said compound is covalently bonded to aspartate residue 12.
• Embodiment D99 An H-Ras protein covalently bound to a compound of one of embodiments D1 to D68, or a pharmaceutically acceptable salt thereof, wherein said compound is covalently bound to an aspartate residue of said H-Ras protein.
• Embodiment D100 Embodiment D100.
• Embodiment 64 The compound of embodiment 50, having the formula: R 6.1 is halogen; R 6.2 is –O-(C1-C4 alkyl), wherein the C1-C4 alkyl is substituted with a 5 to 8 membered heterocycloalkyl optionally substituted with halogen or unsubstituted C 1 -C 3 alkyl; R 7 is independently halogen, -OH, or unsubstituted C 2 alkynyl; and z7 is 1, 2, or 3. [0856] Embodiment 65.
• GEF guanine exchange factor

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