Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
• • 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
  • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/504—Pyridazines; Hydrogenated pyridazines forming part of bridged ring 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
• • 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
  • 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
  • C07D491/12—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 three hetero rings
  • C07D491/18—Bridged 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
  • C07D491/22—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 four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
  • C07D498/18—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates.
• statins bind the enzyme active site of HMG-CoA reductase, thus preventing the enzyme from engaging with its substrates.
• undruggable targets include a vast and largely untapped reservoir of medically important human proteins. Thus, there exists a great deal of interest in discovering new molecular modalities capable of modulating the function of such undruggable targets.
• Ras proteins (K-Ras, H-Ras and N-Ras) play an essential role in various human cancers and are therefore appropriate targets for anticancer therapy. Indeed, mutations in Ras proteins account for approximately 30% of ail human cancers in the United States, many of which are fatal. Dysregulation of Ras proteins by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in Ras are frequently found in human cancer.
• Ras proteins function by inhibiting both GTPase-activating protein (GAP)-dependent and intrinsic hydrolysis rates of GTP, significantly skewing the population of Ras mutant proteins to the “on” (GTP-bound) state (Ras(ON)), leading to oncogenic MAPK signaling.
• GAP GTPase-activating protein
• Ras exhibits a picomolar affinity for GTP, enabling Ras to be activated even in the presence of low concentrations of this nucleotide.
• Mutations at codons 13 (e.g., G13D) and 61 (e.g., Q61 K) of Ras are also responsible for oncogenic activity in some cancers.
• Ras inhibitors are provided herein.
• the approach described herein entails formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A).
• the inhibitors of Ras described herein induce a new binding pocket in Ras by driving formation of a high affinity tri-complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA).
• CYPA cyclophilin A
• the invention features a compound, or pharmaceutically acceptable salt thereof, of structural Formula I: wherein A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
• Wis a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
• EEDQ N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline
• X 1 is CH 2 or O; m is 1 or 2; n is 0 or 1 ;
• R 1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl
• R 2 is optionally substituted C1-C6 alkyl
• R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl.
• the invention also features a compound, or pharmaceutically acceptable salt thereof, of structural Formula III:
• W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
• EEDQ N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline
• L 1 is optionally substituted 3 to 9-membered heterocycloalkylene or optionally substituted C2-C4 heteroalkylene;
• R 4 is optionally substituted C1-C6 alkyl
• R 5 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl
• R 9 is optionally substituted C1-C3 alkyl or optionally substituted C1-C3 heteroalkyl; and each R 10 is, independently, optionally substituted C 1 -C3 alkyl.
• the invention also features a compound, or pharmaceutically acceptable salt thereof, selected from Table 1 , Table 2, Table 3, Table 4, Table 5, or Table 6.
• compositions comprising a compound of Formula I or Formula III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• pharmaceutical compositions comprising a compound of Table 1 , Table 2, Table 3, Table 4, Table 5, or Table 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
• a method is provided of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• a method of inhibiting a Ras protein in a cell comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention.
• any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention.
• the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.
• the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).
• adjacent in the context of describing adjacent atoms refers to bivalent atoms that are directly connected by a covalent bond.
• salts e.g., pharmaceutically acceptable salts
• solvates hydrates, stereoisomers (including atropisomers), and tautomers thereof.
• wild-type refers to an entity having a structure or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc) state or context. Those of ordinary skill in the art will appreciate that wild-type genes and polypeptides often exist in multiple different forms (e.g., alleles).
• Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
• Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
• one or more compounds depicted herein may exist in different tautomeric forms.
• references to such compounds encompass all such tautomeric forms.
• tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
• a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form.
• moieties with prototropic tautomeric forms are ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H-pyrazole.
• tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
• tautomeric forms result from acetal interconversion.
• structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 CI, 123 l and 125 l.
• Isotopically-labeled compounds e.g., those labeled with 3 H and 14 C
• Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements).
• one or more hydrogen atoms are replaced by 2 H or 3 H, or one or more carbon atoms are replaced by 13 C- or 14 C-enriched carbon.
• Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
• isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
• a moiety of compounds of the Formulas described herein is also contemplated, such as and . Further, deuterium substitution may also take place in compounds of the present invention at the linker position, such as
• silylation substitution is also contemplated, such as in the linker as follows:
• substituents of compounds of the present invention are disclosed in groups or in ranges. It is specifically intended that the present invention include each and every individual subcombination of the members of such groups and ranges.
• C1-C6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.
• the present invention is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.
• optionally substituted X is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g., alkyl) perse is optional.
• certain compounds of interest may contain one or more “optionally substituted” moieties.
• substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein.
• an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
• substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.
• stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
• Suitable monovalent substituents on R° may be, independently, halogen, -(CH 2 )o- 2 R ⁇ , -(haloR ⁇ ), -(CH 2 )O- 2 OH, -(CH 2 )O- 2 OR ⁇ , -(CH 2 )O- 2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), -CN, -N 3 , -(CH 2 )o- 2 C(O)R ⁇ , -(CH 2 )o- 2 C(O)OH, -(CH 2 )O- 2 C(O)OR ⁇ , -(CH 2 )O- 2 SR ⁇ , -(CH 2 )O- 2 SH, -(CH 2 )O- 2 NH 2 , -(CH 2 )O- 2 NHR ⁇ , -(CH 2 )O- 2 NR ⁇ 2 , -N O 2
• Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR * 2 ) 2-3 O-, wherein each independent occurrence of R * is selected from hydrogen, C1-C6 aliphatic which may be substituted as defined below, or an unsubstituted 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on the aliphatic group of R * include halogen, -R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -O(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 , or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1 -C 4 aliphatic, -CH 2 Ph, -O(CH 2 )o-iPh, or a 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R ⁇ , -NR ⁇ 2 , -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH 2 C(O)Rt, -S(O) 2 Rt, -S(O) 2 NRt 2 , -C(S)NRt 2 , -C(NH)NR ⁇ 2 , or -N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C1-C6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3 to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with
• Suitable substituents on an aliphatic group of R ⁇ are independently halogen, -R ⁇ , -(haloR ⁇ ), -OH, -OR ⁇ , -O(haloR ⁇ ), -CN, -C(O)OH, -C(O)OR ⁇ , -NH 2 , -NHR ⁇ , -NR ⁇ 2 , or -NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1 -C 4 aliphatic, -CH 2 Ph, -O(CH 2 )o-iPh, or a 5 to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
• acetyl refers to the group -C(O)CH3.
• alkoxy refers to a -O-C1-C20 alkyl group, wherein the alkoxy group is attached to the remainder of the compound through an oxygen atom.
• alkyl refers to a saturated, straight or branched monovalent hydrocarbon group containing from 1 to 20 (e.g., from 1 to 10 or from 1 to 6) carbons. In some embodiments, an alkyl group is unbranched (i.e., is linear); in some embodiments, an alkyl group is branched. Alkyl groups are exemplified by, but not limited to, methyl, ethyl, n- and /so-propyl, n-, sec-, iso- and tert-butyl, and neopentyl.
• alkylene represents a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like.
• C x -C y alkylene represents alkylene groups having between x and y carbons. Exemplary values for x are 1 , 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-C6, C1-C10, C2-C20,
• alkylene can be further substituted with 1 , 2, 3, or 4 substituent groups as defined herein.
• alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.
• Alkenyls include both cis and trans isomers.
• alkenylene represents a divalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds.
• alkynyl represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, and 1-propynyl.
• alkynyl sulfone represents a group comprising the structure , wherein R is any chemically feasible substituent described herein.
• amino represents -N(Rt)2, e.g., -NH2 and -N(CH3)2.
• aminoalkyl represents an alkyl moiety substituted on one or more carbon atoms with one or more amino moieties.
• amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., -CO 2 H or -SO3H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
• amino acid in its broadest sense, refers to any compound or substance that can be incorporated into a polypeptide chain, e.g., through formation of one or more peptide bonds.
• an amino acid has the general structure H2N-C(H)(R)-COOH.
• an amino acid is a naturally-occurring amino acid.
• an amino acid is a synthetic amino acid; in some embodiments, an amino acid is a D-amino acid; in some embodiments, an amino acid is an L-amino acid.
• Standard amino acid refers to any of the twenty standard L-amino acids commonly found in naturally occurring peptides.
• Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, optionally substituted hydroxylnorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
• aryl represents a monovalent monocyclic, bicyclic, or multicyclic ring system formed by carbon atoms, wherein the ring attached to the pendant group is aromatic.
• aryl groups are phenyl, naphthyl, phenanthrenyl, and anthracenyl.
• An aryl ring can be attached to its pendant group at any heteroatom or carbon ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
• Co represents a bond.
• part of the term -N(C(O)-(Co-C5 alkylene-H)- includes -N(C(O)-(Co alkylene-H)-, which is also represented by -N(C(O)-H)-.
• Carbocyclic and “carbocyclyl,” as used herein, refer to a monovalent, optionally substituted 3 to 12-membered monocyclic, bicyclic, or tricyclic ring structure, which may be bridged, fused or spirocyclic, in which all the rings are formed by carbon atoms and at least one ring is non-aromatic.
• Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl groups.
• carbocyclyl groups are cyclohexyl, cyclohexenyl, cyclooctynyl, 1 ,2-dihydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indanyl, decalinyl, and the like.
• a carbocyclic ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
• cyano represents a -CN group.
• cycloalkyl represents a monovalent saturated cyclic hydrocarbon group, which may be bridged, fused, or spirocyclic having from three to eight ring carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloheptyl.
• cycloalkenyl represents a monovalent, non-aromatic, saturated cyclic hydrocarbon group, which may be bridged, fused, or spirocyclic having from three to eight ring carbons, unless otherwise specified, and containing one or more carbon-carbon double bonds.
• stereomer means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
• enantiomer means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
• guanidinyl refers to a group having the structure: wherein each R is, independently, any any chemically feasible substituent described herein.
• guanidinoalkyl alkyl represents an alkyl moiety substituted on one or more carbon atoms with one or more guanidinyl moieties.
• haloacetyl refers to an acetyl group wherein at least one of the hydrogens has been replaced by a halogen.
• haloalkyl represents an alkyl moiety substituted on one or more carbon atoms with one or more of the same of different halogen moieties.
• halogen represents a halogen selected from bromine, chlorine, iodine, or fluorine.
• heteroalkyl refers to an “alkyl” group, as defined herein, in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom).
• a heteroatom e.g., an O, N, or S atom.
• the heteroatom may appear in the middle or at the end of the radical.
• heteroaryl represents a monovalent, monocyclic or polycyclic ring structure that contains at least one fully aromatic ring: i.e. , they contain 4n+2 pi electrons within the monocyclic or polycyclic ring system and contains at least one ring heteroatom selected from N, O, or S in that aromatic ring.
• exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11 , 1 to 10, 1 to 9, 2 to 12, 2 to 11 , 2 to 10, or 2 to 9) carbons.
• heteroaryl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heteroaromatic rings is fused to one or more, aryl or carbocyclic rings, e.g., a phenyl ring, or a cyclohexane ring.
• heteroaryl groups include, but are not limited to, pyridyl, pyrazolyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, thiazolyl, quinolinyl, tetrahydroquinolinyl, and 4-azaindolyl.
• a heteroaryl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
• the heteroaryl is substituted with 1 , 2, 3, or 4 substituents groups.
• heterocycloalkyl represents a monovalent, monocyclic, bicyclic or polycyclic ring system, which may be bridged, fused, or spirocyclic, wherein at least one ring is nonaromatic and wherein the non-aromatic ring contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
• the 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds.
• Exemplary unsubstituted heterocycloalkyl groups are of 1 to 12 (e.g., 1 to 11 , 1 to 10, 1 to 9, 2 to 12, 2 to 11 , 2 to 10, or 2 to 9) carbons.
• heterocycloalkyl also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group.
• heterocycloalkyl includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or more aromatic, carbocyclic, heteroaromatic, or heterocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, a pyridine ring, or a pyrrolidine ring.
• heterocycloalkyl groups are pyrrolidinyl, piperidinyl, 1 ,2,3,4-tetrahydroquinolinyl, decahydroquinolinyl, dihydropyrrolopyridine, and decahydronapthyridinyl.
• a heterocycloalkyl ring can be attached to its pendant group at any ring atom that results in a stable structure and any of the ring atoms can be optionally substituted unless otherwise specified.
• hydroxy represents a -OH group.
• hydroxyalkyl represents an alkyl moiety substituted on one or more carbon atoms with one or more -OH moieties.
• isomer means any tautomer, stereoisomer, atropiosmer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e. , geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
• stereoisomers such as double-bond isomers (i.e. , geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
• the chemical structures depicted herein, and therefore the compounds of the invention encompass all the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
• Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
• Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
• linker refers to a divalent organic moiety connecting a first moiety (e.g., a macrocyclic moiety) to a second moiety (e.g., a crosslinking-group).
• first moiety e.g., a macrocyclic moiety
• second moiety e.g., a crosslinking-group
• the linker results in a compound capable of achieving an IC50 of 2 uM or less in the Ras-RAF disruption assay protocol provided in the Examples below, and provided here:
• this biochemical assay is to measure the ability of test compounds to facilitate ternary complex formation between a nucleotide-loaded Ras isoform and cyclophilin A; the resulting ternary complex disrupts binding to a BRAF RBD construct, inhibiting Ras signaling through a RAF effector.
• assay buffer containing 25 mM HEPES pH 7.3, 0.002% Tween20, 0.1% BSA, 100 mM NaCI and 5 mM MgCI 2 , tagless Cyclophilin A, His6-K-Ras-GMPPNP (or other Ras variant), and GST-BRAF RBD are combined in a 384-well assay plate at final concentrations of 25 ⁇ M, 12.5 nM and 50 nM, respectively.
• Compound is present in plate wells as a 10-point 3-fold dilution series starting at a final concentration of 30 ⁇ M.
• TR-FRET signal is read on a microplate reader (Ex 320 nm, Em 665/615 nm).
• Compounds that facilitate disruption of a Ras:RAF complex are identified as those eliciting a decrease in the TR-FRET ratio relative to DMSO control wells.
• the linker comprises 20 or fewer linear atoms. In some embodiments, the linker comprises 15 or fewer linear atoms. In some embodiments, the linker comprises 10 or fewer linear atoms. In some embodiments, the linker has a molecular weight of under 500 g/mol. In some embodiments, the linker has a molecular weight of under 400 g/mol. In some embodiments, the linker has a molecular weight of under 300 g/mol. In some embodiments, the linker has a molecular weight of under 200 g/mol. In some embodiments, the linker has a molecular weight of under 100 g/mol. In some embodiments, the linker has a molecular weight of under 50 g/mol.
• a “monovalent organic moiety” is less than 500 kDa. In some embodiments, a “monovalent organic moiety” is less than 400 kDa. In some embodiments, a “monovalent organic moiety” is less than 300 kDa. In some embodiments, a “monovalent organic moiety” is less than 200 kDa. In some embodiments, a “monovalent organic moiety” is less than 100 kDa. In some embodiments, a “monovalent organic moiety” is less than 50 kDa. In some embodiments, a “monovalent organic moiety” is less than 25 kDa. In some embodiments, a “monovalent organic moiety” is less than 20 kDa.
• a “monovalent organic moiety” is less than 15 kDa. In some embodiments, a “monovalent organic moiety” is less than 10 kDa. In some embodiments, a “monovalent organic moiety” is less than 1 kDa. In some embodiments, a “monovalent organic moiety” is less than 500 g/mol. In some embodiments, a “monovalent organic moiety” ranges between 500 g/mol and 500 kDa.
• stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers or conformers of the basic molecular structure, including atropisomers. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.
• sulfonyl represents an -S(O) 2 - group.
• thiocarbonyl refers to a -C(S)- group.
• vinyl ketone refers to a group comprising a carbonyl group directly connected to a carbon-carbon double bond.
• vinyl sulfone refers to a group comprising a sulfonyl group directed connected to a carbon-carbon double bond.
• references to a particular compound may relate to a specific form of that compound. In some embodiments, reference to a particular compound may relate to that compound in any form.
• a preparation of a single stereoisomer of a compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a compound may be considered to be a different form from another salt form of the compound; a preparation containing one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form from one containing the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form.
• Ras inhibitors are provided herein.
• the approach described herein entails formation of a high affinity three-component complex, or conjugate, between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: the target protein of interest (e.g., Ras), and a widely expressed cytosolic chaperone (presenter protein) in the cell (e.g., cyclophilin A).
• the inhibitors of Ras described herein induce a new binding pocket in Ras by driving formation of a high affinity tri-complex, or conjugate, between the Ras protein and the widely expressed cytosolic chaperone, cyclophilin A (CYPA).
• CYPA cyclophilin A
• the inventors believe that one way the inhibitory effect on Ras is effected by compounds of the invention and the complexes, or conjugates, they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF, which are required for propagating the oncogenic signal.
• a compound of the present invention forms a covalent adduct with a side chain of a Ras protein (e.g., the -CH2-COOH or-CFb-COO- side chain of the aspartic acid at position 12 or 13 of a mutant Ras protein). Covalent adducts may also be formed with other side chains of Ras.
• a side chain of a Ras protein e.g., the -CH2-COOH or-CFb-COO- side chain of the aspartic acid at position 12 or 13 of a mutant Ras protein.
• Covalent adducts may also be formed with other side chains of Ras.
• non-covalent interactions may be at play: for example, van der Waals, hydrophobic, hydrophilic, and hydrogen bond interactions, and combinations thereof, may contribute to the ability of the compounds of the present invention to form complexes and act as Ras inhibitors.
• a variety of Ras proteins may be inhibited by compounds of the present invention (e.g., K-Ras, N-Ras, H-Ras, and mutants thereof at positions 12, 13 and 61 , such as G12C, G12D, G12V, G12S, G13C, G13D, and Q61L, and others described herein).
• this biochemical assay is to measure the ability of test compounds to covalently label nucleotide- loaded K-Ras isoforms.
• assay buffer containing 12.5 mM HEPES pH 7.4, 75 mM NaCI, 1 mM MgCh, 1 mM BME, 5 ⁇ M Cyclophilin A and 2 ⁇ M test compound, a 5 ⁇ M stock of GMP-PNP-loaded K-Ras (1-169) G12C is diluted 10-fold to yield a final concentration of 0.5 ⁇ M; with final sample volume being 100 ⁇ L.
• the sample is incubated at 25°C for a time period of up to 24 hours prior to quenching by the addition of 10 ⁇ L of 5% Formic Acid. Quenched samples are centrifuged at 15000 rpm for 15 minutes in a benchtop centrifuge before injecting a 10 ⁇ L aliquot onto a reverse phase C4 column and eluting into the mass spectrometer with an increasing acetonitrile gradient in the mobile phase. Analysis of raw data may be carried out using Waters MassLynx MS software, with % bound calculated from the deconvoluted protein peaks for labeled and unlabeled K-Ras.
• compounds of the present invention more potently inhibit K-Ras G12D versus other K-Ras mutants or K-Ras ⁇ . In some embodiments, compounds of the present invention more potently inhibit K-Ras G12D versus compounds known in the art. In some embodiments, compounds of the present invention cross-link K-Ras G12D to a greater degree versus other K-Ras mutants. In some embodiments, compounds of the present invention cross-link K-Ras G12D to a greater degree versus compounds known in the art.
• A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
• W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
• EEDQ N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline
• X 1 is CH 2 or O; m is 1 or 2; n is 0 or 1 ;
• R 1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl
• R 2 is optionally substituted C1-C6 alkyl
• R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl.
• W is a cross-linking group comprising an aziridine or an epoxide.
• A is optionally substituted thiazole, optionally substituted oxazole, optionally substituted morpholino, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, or optionally substituted phenyl.
• a compound of the present invention has the structure of Formula la, or a pharmaceutically acceptable salt thereof:
• a compound of the present invention has the structure of Formula 11-1 , or a pharmaceutically acceptable salt thereof:
• a compound of the present invention has the structure of Formula II-2, or a pharmaceutically acceptable salt thereof:
• R 6 , R 7 , and R 8 are each independently selected from hydrogen, optionally substituted Ci- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; or
• R 6 and R 7 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl; or
• R 6 and R 8 combine with the atoms to which they are attached to form an optionally substituted 3 to 8- membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
• a compound of the present invention has the structure of Formula II-3, or a pharmaceutically acceptable salt thereof:
• a compound of the present invention has the structure of Formula II-4, or a pharmaceutically acceptable salt thereof:
• Formula II-4 wherein X 2 is CH2 or O; and 0 is 1 or 2.
• X 2 is CH2. In some embodiments, 0 is 1 . In some embodiments, 0 is 2.
• X 2 is O. In some embodiments, 0 is 1 . In some embodiments, 0 is 2.
• R 2 is:
• R 3 is optionally substituted Ci-Ce alkyl. In some embodiments, R 3 is:
• R 3 is or optionally substituted 3 to
• R 3 is:
• A is optionally substituted 5 to 10- membered heteroarylene. In some embodiments, A is:
• A is optionally substituted phenyl.
• A is:
• A is optionally substituted 3 to 6- membered heterocycloalkylene. In some embodiments, A is selected from the following, or a stereoisomer thereof:
• m is 1. In some embodiments, n is 1 . In some embodiments, X 1 is CH2. In some embodiments, X 1 is O. In some embodiments, m is 1 , n is 1 , and X 1 is CH2. In some embodiments, m is 1 , n is 1 , and X 1 is O.
• m is 2.
• X 1 is CH2.
• n is 1 .
• n is 0.
• m is 2
• X 1 is CH2
• n is 1 .
• m is 2 and X 1 is O.
• m is 2, X 1 is O, and n is 1.
• m is 2, X 1 is O, and n is 0.
• W comprises an aziridine. In some embodiments, W comprises an optionally substituted cyclopropyl-aziridinyl moiety. In some embodiments, W is selected from the following, or a stereoisomer thereof:
• W comprises an epoxide.
• W is selected from the following, or a stereoisomer thereof: or
• a compound of the present invention is selected from Table 1 , or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is selected from Table 1 , or a pharmaceutically acceptable salt or atropisomer thereof.
• the relative stereochemistry of stereoisomers has been determined; in some instances, the absolute stereochemistry has been determined. All stereoisomers of the compounds of the foregoing table are contemplated by the present invention. In particular embodiments, an atropisomer of a compound of the foregoing table is contemplated.
• W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
• EEDQ N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline
• L 1 is optionally substituted 3 to 9-membered heterocycloalkylene or optionally substituted C2-C4 heteroalkylene;
• R 4 is optionally substituted C1-C6 alkyl
• R 5 is optionally substituted C 1 -C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl
• R 9 is optionally substituted C 1 -C3 alkyl or optionally substituted C 1 -C3 heteroalkyl
• each R 10 is, independently, optionally substituted C 1 -C3 alkyl.
• W is a cross-linking group comprising an aziridine.
• R 4 is:
• R 5 is optionally substituted C1-C6 alkyl. In some embodiments, R 5 is:
• R 5 is optionally substituted 3 to 6- membered cycloalkyl. In some embodiments, R 5 is: In some embodiments of a compound of the present invention, P is -(CO)R 9 . In some
• P is selected from:
• P is -(PO)(OH)2.
• P is -Si(R 10 )3. In some embodiments, P is selected from r: X X I i o orr X 1 I
• L 1 is 3 to 9-membered heterocycloalkylene. In some embodiments, L 1 is, or a stereoisomer thereof:
• L 1 is optionally substituted C2-C4 heteroalkylene. In some embodiments, L 1 is: In some embodiments of a compound of the present invention, W is an optionally substituted cyclopropyl-aziridinyl moiety. In some embodiments, W is, or a stereoisomer thereof: In some embodiments, W is, or a stereoisomer thereof: . In some embodiments, W is: . In some embodiments, W is: . In some embodiments, W v is, or a stereoisomer thereof: In some embodiments, W is, or a stereoisomer thereof: In some embodiments, W is, or a stereoisomer thereof: . In some embodiments, v V
• W is: In some embodiments, W is: . In some embodiments, W is, or a stereoisomer thereof: In some embodiments, W is, or a stereoisomer thereof: In some embodiments, W is: In some embodiments, W is: . In some embodiments, W is, or a stereoisomer thereof: In some embodiments, W is, or a stereoisomer thereof: . In some embodiments, W is, or a stereoisomer thereof:
• a compound of the present invention is selected from Table 3, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is selected from Table 3, or a pharmaceutically acceptable salt or atropisomer thereof.
• a compound selected from Table 4 is selected from Table 4, or a pharmaceutically acceptable salt or stereoisomer thereof.
• a compound of the present invention is selected from Table 4, or a pharmaceutically acceptable salt or atropisomer thereof.
• a compound of Table 5 is provided, or a pharmaceutically acceptable salt thereof.
• a compound of the present invention is selected from Table 5, or a pharmaceutically acceptable salt or atropisomer thereof.
• a compound of the present invention is selected from Table 6, or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, a compound of the present invention is selected from Table 6, or a pharmaceutically acceptable salt or atropisomer thereof.
• W is a cross-linking group bound to an organic moiety that is a Ras binding moiety, i.e. , RBM-W, wherein upon contact of an RBM-W compound with a Ras protein, the RBM- W binds to the Ras protein to form a conjugate.
• RBM-W Ras binding moiety
• the W moiety of an RBM-W compound may bind, e.g., cross-link, with an amino acid of the Ras protein to form the conjugate.
• the Ras binding moiety is a K-Ras binding moiety.
• the K-Ras binding moiety binds to a residue of a K-Ras Switch-ll binding pocket of the K-Ras protein.
• the Ras binding moiety is an H-Ras binding moiety that binds to a residue of an H-Ras
• the Ras binding moiety is an N-Ras binding moiety that binds to a residue of an N-Ras Switch-ll binding pocket of an N-Ras protein.
• the W of an RBM-W compound may comprise any W described herein.
• the Ras binding moiety typically has a molecular weight of under 1200 Da. See, e.g., see, e.g., Johnson et al., 292:12981-12993 (2017) for a description of Ras protein domains, incorporated herein by reference.
• a compound of the present invention is or acts as a prodrug, such as with respect to administration to a cell or to a subject in need thereof.
• compositions comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Further provided is a conjugate, or salt thereof, comprising the structure of Formula IV:
• P 1 is a monovalent organic moiety
• M has the structure of Formula V:
• A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
• X 1 is CH 2 or O; m is 1 or 2; n is 0 or 1 ;
• R 1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl
• R 2 is optionally substituted C1-C6 alkyl
• R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl.
• the monovalent organic moiety is a protein.
• the protein is a Ras protein.
• the Ras protein is K- Ras G12D or K-Ras G13D.
• the linker, L 2 is bound to the monovalent organic moiety through a bond to a carboxyl group of an amino acid residue of the monovalent organic moiety.
• the cancer may, for example, be pancreatic cancer, colorectal cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma.
• the cancer comprises a Ras mutation, such as K-Ras G12D or K-Ras G13D. Other Ras mutations are described herein.
• a method of treating a Ras protein-related disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• a method of inhibiting a Ras protein in a cell comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• the Ras protein is K-Ras G12D or K-Ras G13D. Other Ras proteins are described herein.
• the cell may be a cancer cell, such as a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, an acute myeloid leukemia cell, a multiple myeloma cell, a thyroid gland adenocarcinoma cell, a myelodysplastic syndrome cell, or a squamous cell lung carcinoma cell. Other cancer types are described herein.
• the cell may be in vivo or in vitro.
• one stereoisomer may exhibit better inhibition than another stereoisomer.
• one atropisomer may exhibit inhibition, whereas the other atropisomer may exhibit little or no inhibition.
• a method or use described herein further comprises administering an additional anti-cancer therapy.
• the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCI inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, or a combination thereof.
• the additional anticancer therapy is a SHP2 inhibitor.
• Other additional anti-cancer therapies are described herein.
• the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, or enzymatic processes.
• the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
• compounds of the present invention can be synthesized using the methods described in the Schemes below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods include but are not limited to those methods described in the Schemes below.
• compounds of this type may be prepared by the reaction of an appropriate amine (1) with a carboxylic acid containing protected amine (2) in the presence of standard amide coupling reagents to give 3, followed by deprotection of the amine to produce 4. Coupling of an aziridine carboxylate (5) in the presence of standard amide coupling reagents affords 6. If R 1 is a protecting group, deprotection affords the final compound (7).
• the compounds with which the invention is concerned are Ras inhibitors, and are useful in the treatment of cancer. Accordingly, one embodiment of the present invention provides pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, as well as methods of using the compounds of the invention to prepare such compositions.
• composition refers to a compound, such as a compound of the present invention, or a pharmaceutically acceptable salt thereof, formulated together with a pharmaceutically acceptable excipient.
• a compound is present in a pharmaceutical composition in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
• pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream
• a “pharmaceutically acceptable excipient,” as used herein, refers any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject.
• Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, d is integrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration.
• Excipients include, but are not limited to: butylated optionally substituted hydroxyltoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxylpropyl cellulose, optionally substituted hydroxylpropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid
• a composition includes at least two different pharmaceutically acceptable excipients.
• salt form e.g., a pharmaceutically acceptable salt form
• pharmaceutically acceptable salt refers to those salts of the compounds described herein that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
• Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wley-VCH, 2008.
• the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
• the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
• These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention, be prepared from inorganic or organic bases.
• the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
• Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulfuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
• Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-optionally substituted hydroxyl-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
• alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
• the term “subject” refers to any member of the animal kingdom. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient. In some embodiments, “subject” refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish, or worms. In some embodiments, a subject may be a transgenic animal, genetically-engineered animal, or a clone.
• the term “dosage form” refers to a physically discrete unit of a compound (e.g., a compound of the present invention) for administration to a subject.
• a compound e.g., a compound of the present invention
• Each unit contains a predetermined quantity of compound.
• such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e. , with a therapeutic dosing regimen).
• a dosing regimen refers to a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
• a given therapeutic compound e.g., a compound of the present invention
• has a recommended dosing regimen which may involve one or more doses.
• a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount.
• a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount.
• a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount.
• a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).
• a “therapeutic regimen” refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome.
• treatment also “treat” or “treating” refers to any administration of a substance (e.g., a compound of the present invention) that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, or reduces incidence of one or more symptoms, features, or causes of a particular disease, disorder, or condition.
• a substance e.g., a compound of the present invention
• such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder or condition, or of a subject who exhibits only early signs of the disease, disorder, or condition.
• treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder, or condition.
• treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, or condition.
• treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, or condition.
• terapéuticaally effective amount means an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, or condition.
• a therapeutically effective amount is one that reduces the incidence or severity of, or delays onset of, one or more symptoms of the disease, disorder, or condition.
• therapeutically effective amount does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment.
• a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine).
• tissue e.g., a tissue affected by the disease, disorder or condition
• fluids e.g., blood, saliva, serum, sweat, tears, urine.
• a therapeutically effective amount may be formulated or administered in a single dose.
• a therapeutically effective amount may be formulated or administered in a plurality of doses, for example, as part of a dosing regimen.
• the compounds of the invention, or a pharmaceutically acceptable salt thereof can be formulated as pharmaceutical or veterinary compositions.
• the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, or therapy are formulated in ways consonant with these parameters.
• a summary of such techniques may be found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.
• compositions can be prepared according to conventional mixing, granulating, or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of a compound of the present invention, or pharmaceutically acceptable salt thereof, by weight or volume.
• compounds, or a pharmaceutically acceptable salt thereof, described herein may be present in amounts totaling 1-95% by weight of the total weight of a composition, such as a pharmaceutical composition.
• composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa.
• parenteral e.g., intravenous, intramuscular
• rectal cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, reproductive, or oral mucosa.
• the pharmaceutical composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols.
• the compositions may be formulated according to conventional pharmaceutical practice.
• administration refers to the administration of a composition (e.g., a compound, or a preparation that includes a compound as described herein) to a subject or system.
• Administration to an animal subject may be by any appropriate route.
• administration may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, or vitreal.
• bronchial including by bronchial instillation
• Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
• Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
• a formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like.
• Compounds, or a pharmaceutically acceptable salt thereof can be administered also in liposomal compositions or as microemulsions.
• formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
• Suitable excipients include, for example, water, saline, dextrose, glycerol, and the like.
• Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.
• Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration.
• Oral administration is also suitable for compounds of the invention, or pharmaceutically acceptable salts thereof. Suitable forms include syrups, capsules, and tablets, as is understood in the art.
• Each compound, or a pharmaceutically acceptable salt thereof, as described herein, may be formulated in a variety of ways that are known in the art.
• the first and second agents of the combination therapy may be formulated together or separately.
• Other modalities of combination therapy are described herein.
• kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc.
• the kit can include optional components that aid in the administration of the unit dose to subjects, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
• the unit dose kit can contain instructions for preparation and administration of the compositions.
• the kit may be manufactured as a single use unit dose for one subject, multiple uses for a particular subject (at a constant dose or in which the individual compounds, or a pharmaceutically acceptable salt thereof, may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple subjects (“bulk packaging”).
• the kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.
• Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
• excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, optionally substituted hydroxylpropyl methylcellulose,
• Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned.
• the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.
• Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
• Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.
• Dissolution or diffusion-controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound, or a pharmaceutically acceptable salt thereof, into an appropriate matrix.
• a controlled release coating may include one or more of the coating substances mentioned above or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-optionally substituted hydroxylmethacrylate, methacrylate hydrogels, 1 ,3 butylene glycol, ethylene glycol methacrylate, or polyethylene glycols.
• the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, or halogenated fluorocarbon.
• the liquid forms in which the compounds, or a pharmaceutically acceptable salt thereof, and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
• the oral dosage of any of the compounds of the invention, or a pharmaceutically acceptable salt thereof will depend on the nature of the compound, and can readily be determined by one skilled in the art.
• a dosage may be, for example, about 0.001 mg to about 2000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day, about 100 mg to about 1500 mg per day, about 500 mg to about 1500 mg per day, about 500 mg to about 2000 mg per day, or any range derivable therein.
• the pharmaceutical composition may further comprise an additional compound having antiproliferative activity.
• compounds, or a pharmaceutically acceptable salt thereof will be formulated into suitable compositions to permit facile delivery.
• Each compound, or a pharmaceutically acceptable salt thereof, of a combination therapy may be formulated in a variety of ways that are known in the art.
• the first and second agents of the combination therapy may be formulated together or separately.
• the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents.
• the compounds and pharmaceutical compositions of the present invention can be formulated and employed in combination therapies, that is, the compounds and pharmaceutical compositions can be formulated with or administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures.
• the particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder, or they may achieve different effects (e.g., control of any adverse effects).
• Administration of each drug in a combination therapy can, independently, be one to four times daily for one day to one year, and may even be for the life of the subject. Chronic, long-term administration may be indicated.
• the invention discloses a method of treating a disease or disorder that is characterized by aberrant Ras activity due to a Ras mutant.
• the disease or disorder is a cancer.
• a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound or salt.
• the cancer is colorectal cancer, non-small cell lung cancer, small-cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small bowel cancer, ampullary cancer, germ cell cancer, cervical cancer, cancer of unknown primary origin, endometrial cancer, esophagogastric cancer, Gl neuroendocrine cancer, ovarian cancer, sex cord stromal tumor cancer, hepatobiliary cancer, or bladder cancer.
• the cancer is appendiceal, endometrial or melanoma.
• the compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods of the invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas. Other cancers include, for example:
• Cardiac for example: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, !iposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma;
• Lung for example: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchio!ar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
• Gastrointestinal for example: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);
• Genitourinary tract for example: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
• Liver for example: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
• Biliary tract for exampie: gali bladder carcinoma, ampu!lary carcinoma, cholangiocarcinoma;
• Bone for example: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant ceil tumors;
• osteogenic sarcoma osteosarcoma
• fibrosarcoma malignant fibrous histiocytoma
• chondrosarcoma chondrosarcoma
• Ewing's sarcoma malignant lymphoma
• multiple myeloma malignant giant cell tumor chordoma
• osteochronfroma osteocartilaginous
• Nervous system for exampie: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, g!iomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, neurofibromatosis type 1 , meningioma, giiorna, sarcoma); Gynecological, for example: uterus (endometrial carcinoma, uterine carcinoma, uterine corpus endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia),
• Hematologic for example: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases (e.g., myelofibrosis and myeloproliferative neoplasms), multiple myeloma, mye!odysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);
• blood myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases (e.g., myelofibrosis and myeloproliferative neoplasms), multiple myeloma, mye!odysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);
• Skin for example: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dyspiastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and
• Adrenal glands for example: neuroblastoma.
• the Ras protein is wild-type (Ras ⁇ ). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Ras ⁇ (e.g., K-Ras ⁇ , H-Ras ⁇ or N-Ras ⁇ ). In some embodiments, the Ras protein is Ras amplification (e.g., K-Ras amp ). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Ras amp (K-Ras amp , H-Ras amp or N-Ras amp ). In some embodiments, the cancer comprises a Ras mutation, such as a Ras mutation described herein. In some embodiments, a mutation is selected from:
• the cancer comprises a K-Ras mutation selected from the group consisting of G12C, G12D, G13C, G12V, G13D, G12R, G12S, Q61 H, Q61 K and Q61 L.
• the cancer comprises an N-Ras mutation selected from the group consisting of G12C, Q61 H, Q61 K, Q61 L, Q61 P and Q61 R. In some embodiments, the cancer comprises an H-Ras mutation selected from the group consisting of Q61 H and Q61 L. In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D,
• the cancer comprises at least two Ras mutations selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V.
• a compound of the present invention inhibits more than one Ras mutant.
• a compound may inhibit both K-Ras G12C and K-Ras G13C.
• a compound may inhibit both N-Ras G12C and K-Ras G12C.
• a compound may inhibit both N-Ras G12C and K-Ras G12C.
• a compound may inhibit both K-Ras G12C and K-Ras G12D. In some embodiments, a compound may inhibit both K-Ras G12V and K-Ras G12C. In some embodiments, a compound may inhibit both K-Ras G12V and K-Ras G12S.
• a compound of the present invention inhibits Ras ⁇ in addition to one or more additional Ras mutations (e.g., K, H or N- Ras m and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61 H, G12S, A146T, G13C, Q61 L, Q61 R, K117N, A146V, G12F, Q61 K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K, H or N-RasTM 7 and H-Ras Q61 R, G13R, Q61 K, G12S, Q61 L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G
• a compound of the present invention inhibits Ras amp in addition to one or more additional Ras mutations (e.g., K-, H- or N-Ras amp and K-Ras G12D, G12V, G12C, G13D, G12R, G12A, Q61 H, G12S, A146T, G13C, Q61 L, Q61 R, K117N, A146V, G12F, Q61 K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V; K-, H- or N-Ras amp and H-Ras Q61 R, G13R, Q61 K, G12S, Q61 L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61 H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12
• Ras mutations are known in the art. Such means include, but are not limited to direct sequencing, and utilization of a high-sensitivity diagnostic assay (with CE-IVD mark), e.g., as described in Domagala, et al., Pol J Pathol 3: 145-164 (2012), incorporated herein by reference in its entirety, including TheraScreen PCR; AmoyDx; PNACIamp; RealQuality; EntroGen; LightMix; StripAssay; Hybcell plexA; Devyser; Surveyor; Cobas; and TheraScreen Pyro. See, also, e.g., WO 2020/106640.
• the cancer is non-small cell lung cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C, K-Ras G12V or K-Ras G12D.
• the cancer is colorectal cancer and the Ras mutation comprises a K-Ras mutation, such as K-Ras G12C, K- Ras G12V or K-Ras G12D.
• the cancer is pancreatic cancer and the Ras mutation comprises an K-Ras mutation, such as K-Ras G12D or K-Ras G12V.
• the cancer is pancreatic cancer and the Ras mutation comprises an N-Ras mutation, such as N-Ras G12D.
• the cancer is melanoma and the Ras mutation comprises an N-Ras mutation, such as N-Ras Q61 R or N-Ras Q61 K.
• the cancer is non-small cell lung cancer and the Ras protein is K-Ras amp .
• a compound may inhibit RasTM 7 (e.g., K-, H- or N-RasTM 7 ) or Ras amp (e.g., K-, H- or N-Ras amp ) as well.
• a cancer comprises a Ras mutation and an STK11 LOF , a KEAP1 , an EPHA5 or an NF1 mutation.
• the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation.
• the cancer is non-small cell lung cancer and comprises a K-Ras G12C mutation and an STK11 LOF mutation.
• the cancer is nonsmall cell lung cancer and comprises a K-Ras G12C mutation and an STK11 LOF mutation.
• a cancer comprises a K-Ras G13C Ras mutation and an STK11 LOF , a KEAP1 , an EPHA5 or an NF1 mutation.
• the cancer is non-small cell lung cancer and comprises a K- Ras G12D mutation.
• the cancer is non-small cell lung cancer and comprises a K- Ras G12V mutation.
• the cancer is colorectal cancer and comprises a K-Ras G12C mutation.
• the cancer is pancreatic cancer and comprises a K-Ras G12D mutation.
• the cancer is pancreatic cancer and comprises a K-Ras G12V mutation.
• the cancer is endometrial cancer and comprises a K-Ras G12C mutation.
• the cancer is lung cancer, colorectal cancer, or pancreactic cancer and comprises a K-Ras G12D mutation.
• the cancer is lung cancer or pancreactic cancer and comprises a K-Ras G12D mutation.
• the cancer is lung cancer and comprises a K-Ras G12D mutation.
• the cancer is colorectal cancer and comprises a K-Ras G12D mutation.
• the cancer is gastric cancer and comprises a K-Ras G12C mutation.
• a compound may inhibit Ras ⁇ (e.g., K-, H- or N-Ras ⁇ ) or Ras am P (e.g., K-, H- or N-Ras am P) as well.
• a method of inhibiting a Ras protein in a cell comprising contacting the cell with an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• a method of inhibiting RAF-Ras binding is also provided.
• the cell may be a cancer cell.
• the cancer cell may be of any type of cancer described herein.
• the cell may be in vivo or in vitro.
• the methods of the invention may include a compound of the invention used alone or in combination with one or more additional therapies (e.g., non-drug treatments or therapeutic agents).
• additional therapies e.g., non-drug treatments or therapeutic agents
• the dosages of one or more of the additional therapies may be reduced from standard dosages when administered alone. For example, doses may be determined empirically from drug combinations and permutations or may be deduced by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)).
• a compound of the present invention may be administered before, after, or concurrently with one or more of such additional therapies.
• dosages of a compound of the invention and dosages of the one or more additional therapies e.g., non-drug treatment or therapeutic agent
• a therapeutic effect e.g., synergistic or additive therapeutic effect
• a compound of the present invention and an additional therapy such as an anti-cancer agent, may be administered together, such as in a unitary pharmaceutical composition, or separately and, when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time.
• the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence or severity of side effects of treatment).
• side-effect limiting agents e.g., agents intended to lessen the occurrence or severity of side effects of treatment.
• the compounds of the present invention can also be used in combination with a therapeutic agent that treats nausea.
• agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.
• the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy).
• the one or more additional therapies includes a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor).
• the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor).
• the one or more additional therapies includes two therapeutic agents.
• the one or more additional therapies includes three therapeutic agents.
• the one or more additional therapies includes four or more therapeutic agents.
• non-drug treatments include, but are not limited to, radiation therapy, cryotherapy, hyperthermia, surgery (e.g., surgical excision of tumor tissue), and T cell adoptive transfer (ACT) therapy.
• radiation therapy e.g., radiation therapy, cryotherapy, hyperthermia
• surgery e.g., surgical excision of tumor tissue
• T cell adoptive transfer (ACT) therapy e.g., T cell adoptive transfer
• the compounds of the invention may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the invention may be used as a neo-adjuvant therapy prior to surgery.
• Radiation therapy may be used for inhibiting abnormal cell growth or treating a hyperproiiferative disorder, such as cancer, in a subject (e.g., mammal (e.g., human)).
• a subject e.g., mammal (e.g., human)
• Techniques for administering radiation therapy are known in the art. Radiation therapy can be administered through one of several methods, or a combination of methods, including, without limitation, external-beam therapy, internal radiation therapy, implant radiation, stereotactic radiosurgery, systemic radiation therapy, radiotherapy, and permanent or temporary interstitial brachy therapy.
• brachy therapy refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near a tumor or other proliferative tissue disease site.
• Suitable radiation sources for use as a cell conditioner of the present invention include both solids and liquids.
• the radiation source can be a radionuclide, such as 1-125, 1-131 , Yb-169, lr-192 as a solid source, 1-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic rays.
• the radioactive material can also be a fluid made from any solution of radionuclide(s), e.g., a solution of 1-125 or 1-131 , or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, such as Au-198, or Y-90.
• the radionuclide(s) can be embodied in a gel or radioactive micro spheres.
• the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing or inhibiting the growth of such cells.
• this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention, which amount is effective to sensitize abnormal cells to treatment with radiation.
• the amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
• the compounds of the present invention may be used as an adjuvant therapy after radiation therapy or as a neo-adjuvant therapy prior to radiation therapy.
• the non-drug treatment is a T cell adoptive transfer (ACT) therapy.
• the T cell is an activated T cell.
• the T cell may be modified to express a chimeric antigen receptor (CAR).
• CAR modified T (CAR-T) cells can be generated by any method known in the art.
• the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject.
• T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S.
• a desirable protein e.g., a CAR
• a therapeutic agent may be a compound used in the treatment of cancer or symptoms associated therewith.
• a therapeutic agent may be a steroid.
• the one or more additional therapies includes a steroid.
• Suitable steroids may include, but are not limited to, 21- acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluoromethol
• a therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL- 2)) used in treatment of cancer or symptoms associated therewith.
• the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer.
• antibody-drug conjugates are also included.
• a therapeutic agent may be a T-cell checkpoint inhibitor.
• the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody such as a monoclonal antibody).
• the antibody may be, e.g., humanized or fully human.
• the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein.
• the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein.
• the checkpoint inhibitor is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein.
• the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 . In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-L1 . In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PD-L2 (e.g., a PD-L2/lg fusion protein).
• CTLA-4 e.g., an anti-CTLA-4 antibody or fusion a protein
• the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 .
• the checkpoint inhibitor is an inhibitor or antagonist (e.g.
• the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof.
• an inhibitor or antagonist e.g., an inhibitory antibody or small molecule inhibitor of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1 , CHK2, A2aR, B-7 family ligands, or a combination thereof.
• the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi/Regeneron), a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev.
• a PD-L1 antibody such as, e.g., avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev.
• Neurol. including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514/ MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321 , lirilumab, IPH2101 , 1-7F9, and KW-6002.
• a therapeutic agent may be an anti-TIGIT antibody, such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).
• an anti-TIGIT antibody such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).
• a therapeutic agent may be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, non-peptide small molecules, or other compound useful in the treatment of cancer or symptoms associated therewith, collectively, an “anti-cancer agent”).
• Anti-cancer agents can be, e.g., chemotherapeutics or targeted therapy agents.
• Anti-cancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
• anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel.
• the one or more additional therapies includes two or more anti-cancer agents.
• the two or more anti-cancer agents can be used in a cocktail to be administered in combination or administered separately. Suitable dosing regimens of combination anti-cancer agents are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).
• anti-cancer agents include G!eevec® (Imatinib Mesylate); Kyproiis® (carfilzornib); Veicade ⁇ (bortezomib); Casodex (bicaiutarnide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryo
• dynemicin such as dynemicin A; bisphosphonates such as clodronate; an esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, adriamycin (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubic
• anti-cancer agents include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicine, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharadin, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastics (e.g., cell-cycle nonspecific antineoplastic agents, and other antineoplastics described herein), antitumorigenic herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW2992,
• anti-cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents, antiproliferative/antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil),
• nitrogen mustards
• ZarnestraTM anti-CD138 (e.g., BT062), Torcl/2 specific kinase inhibitors (e.g., INK128), ER/UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1/2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.
• an anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analog or derivative variant of the foregoing.
• the anti-cancer agent is a HER2 inhibitor.
• HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pilitinib, CP- 654577, CP-724714, canertinib (Cl 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW2992, ARRY-334543, JNJ-26483327, and JNJ-26483327.
• an anti-cancer agent is an ALK inhibitor.
• ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011 ; CT-707; TPX-0005, and AP26113. Additional examples of ALK kinase inhibitors are described in examples 3-39 of WO05016894.
• an anti-cancer agent is an inhibitor of a member downstream of a Receptor Tyrosine Kinase (RTK)/Growth Factor Receptor (e.g., a SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971 , ERAS-601 , SH3809, PF-07284892, or BBP- 398), an SOS1 inhibitor (e.g., BI-1701963, BI-3406, SDR5, MRTX0902, RMC-5845, or BAY-293), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORCI inhibitor or mTORC2 inhibitor).
• the anti-cancer agent is JAB-3312.
• an anti-cancer agent is an additional Ras inhibitor or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras.
• an anti-cancer agent is an additional Ras inhibitor.
• the Ras inhibitor targets Ras in its active, or GTP-bound state (Ras(ON)).
• the Ras(ON) inhibitor is RMC-6291 , RMC-6236, RMC-9805 or RMC-8839.
• the Ras inhibitor is a RAS(ON) inhibitor disclosed in WO 2021091956, WO 2021091967, WO 2021091982, WO 2022060836, or WO 2020132597, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, incorporated herein by reference in their entireties.
• the Ras inhibitor targets Ras in its inactive, or GDP-bound state.
• the Ras inhibitor is, such as an inhibitor of K-Ras G12C, such as AMG 510, MRTX1257, MRTX849, JNJ- 74699157 (ARS-3248), LY3499446, or ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, ERAS- 3490, JAB-21000, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351 , RMC-6291 or GDC-6036.
• K-Ras G12C such as AMG 510, MRTX1257, MRTX849, JNJ- 74699157 (ARS-3248), LY3499446, or ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, ERAS- 3490, JAB-21000, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915,
• the Ras inhibitor is an inhibitor of K-Ras G12D, such as ERAS-4, MRTX1133, RMC-9805, or JAB-22000.
• the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000.
• the Ras inhibitor is RMC-6236.
• Ras inhibitors that may be combined with a Ras inhibitor of the present invention are provided in the following, incorporated herein by reference in their entireties: WO 2022087624, WO 2022087375, WO 2022087371 , WO 2022083616, WO 2022083569, WO 2022081655, WO 2022078414, WO 2022076917, WO 2022072783, WO 2022066805, WO 2022066646, WO 2022063297, WO 2022061251 , WO 2022056307, WO 2022052895, WO 2022047093, WO 2022042630, WO 2022040469, WO 2022037560, WO 2022031678, WO 2022028492, WO 2022028346, WO 2022026726, WO 2022026723, WO 2022015375, WO 2022002102, WO 2022002018, WO 202125
• a therapeutic agent that may be combined with a compound of the present invention is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK inhibitor”).
• MAPK inhibitors include, but are not limited to, one or more MAPK inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784.
• the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901 ; CH5126766; MAP855; AZD6244; refametinib (RDEA 119/BAY 86-9766); GDC-0973/XL581 ; AZD8330 (ARRY-424704/ARRY-704); RO5126766 (Roche, described in PLoS One.
• the MAPK inhibitor may be PLX8394, LXH254, GDC-5573, or LY3009120.
• an anti-cancer agent is a disrupter or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathways.
• the PI3K/AKT inhibitor may include, but is not limited to, one or more PI3K/AKT inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758-1784.
• the PI3K/AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226; XL765/SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.
• an anti-cancer agent is a PD-1 or PD-L1 antagonist.
• additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immune therapies.
• a therapeutic agent may be a pan-RTK inhibitor, such as afatinib.
• IGF-1R inhibitors include linsitinib, or a pharmaceutically acceptable salt thereof.
• EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide orsiRNA.
• Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab.
• Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand.
• Non-limiting examples of antibody-based EGFR inhibitors include those described in Modjtahedi et al., Br. J.
• the EGFR inhibitor can be monoclonal antibody Mab E7.6.3 (Yang, 1999 supra), or Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having the binding specificity thereof.
• Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, e.g., Yan et al., Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development, BioTechniques 2005, 39(4):565-8; and Paez et al., EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy, Science 2004, 304(5676):1497- 500.
• the EGFR inhibitor is osimertinib (Tagrisso®).
• small molecule EGFR inhibitors include any of the EGFR inhibitors described in the following patent publications, and all pharmaceutically acceptable salts of such EGFR inhibitors: EP 0520722; EP 0566226; WO96/33980; U.S. Pat. No.
• an EGFR inhibitor is an ERBB inhibitor.
• the ERBB family contains HER1 (EGFR, ERBB1), HER2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).
• MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®).
• a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V.
• the MEK mutation is a Class II MEK1 mutation selected from DE51-058; AF53-Q58;
• PI3K inhibitors include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO06/044453; 4-[2-(1H-lndazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2- d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09/036082 and WO09/055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1- yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06/122806); (S)-l- (4
• PI3K inhibitors include demethoxyviridin, perifosine, CAL101 , PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.
• AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); Akt-1-1 ,2 (inhibits Akl and 2) (Barnett et al., Biochem. J. 2005, 385(Pt. 2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91 :1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05/011700); indole-3-carbinol and derivatives thereof (e.g., U.S. Pat.
• mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1/mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1 ; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94/09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO98/02441 and WO01/14387, e.g.
• AP23464 and AP23841 40-(2- hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolyt)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)- dihydrorapanycin; derivatives disclosed in WO05/005434; derivatives disclosed in U.S. Patent Nos.
• the mTOR inhibitor is a bisteric inhibitor (see, e.g.,
• WO2018204416 WO2019212990 and WO2019212991), such as as RMC-5552, having the structure
• BRAF inhibitors that may be used in combination with compounds of the invention include, for example, vemurafenib, dabrafenib, and encorafenib.
• a BRAF may comprise a Class 3 BRAF mutation.
• the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581 I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.
• MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845.
• the myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL- 2) protein family.
• BCL-1 B-cell lymphoma-2
• Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT-263.
• the additional therapeutic agent is a SHP2 inhibitor.
• SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration.
• SHP2 has two N- terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail.
• the two SH2 domains control the subcellular localization and functional regulation of SHP2.
• the molecule exists in an inactive, self-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors acting through receptor tyrosine kinases (RTKs) leads to exposure of the catalytic site resulting in enzymatic activation of SHP2.
• RTKs receptor tyrosine kinases
• SHP2 is involved in signaling through the RAS-mitogen-activated protein kinase (MAPK), the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.
• MAPK RAS-mitogen-activated protein kinase
• JAK-STAT the JAK-STAT
• phosphoinositol 3-kinase-AKT the phosphoinositol 3-kinase-AKT pathways.
• Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental diseases, such as Noonan Syndrome and Leopard Syndrome, as well as human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. Some of these mutations destabilize the auto-inhibited conformation of SHP2 and promote autoactivation or enhanced growth factor driven activation of SHP2.
• SHP2 therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases including cancer.
• a SHP2 inhibitor e.g., RMC-4550 or SHP099
• a RAS pathway inhibitor e.g., a MEK inhibitor
• combination therapy involving a SHP2 inhibitor with a RAS pathway inhibitor could be a general strategy for preventing tumor resistance in a wide range of malignancies.
• Non-limiting examples of such SHP2 inhibitors that are known in the art, include those found in the following publications: Chen et al. Mol Pharmacol.
• a SHP2 inhibitor binds in the active site.
• a SHP2 inhibitor is a mixed-type irreversible inhibitor.
• a SHP2 inhibitor binds an allosteric site e.g., a non-covalent allosteric inhibitor.
• a SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets the cysteine residue (C333) that lies outside the phosphatase’s active site.
• a SHP2 inhibitor is a reversible inhibitor.
• a SHP2 inhibitor is an irreversible inhibitor.
• the SHP2 inhibitor is SHP099.
• the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630. In some embodiments, the SHP2 inhibitor is JAB- 3068. In some embodiments, the SHP2 inhibitor is JAB-3312. In some embodiments, the SHP2 inhibitor is RLY-1971. In some embodiments, the SHP2 inhibitor is ERAS-601. In some embodiments, the SHP2 inhibitor is BBP-398.
• the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a HER2 inhibitor, a SHP2 inhibitor, a CDK4/6 inhibitor, an mTOR inhibitor, a SOS1 inhibitor, and a PD-L1 inhibitor.
• the additional therapeutic agent is selected from the group consisting of a MEK inhibitor, a SHP2 inhibitor, and a PD-L1 inhibitor. See, e.g., Hallin et al., Cancer Discovery, DOI: 10.1158/2159-8290 (October 28, 2019) and Canon et al., Nature, 575:217 (2019).
• a Ras inhibitor of the present invention is used in combination with a MEK inhibitor and a SOS1 inhibitor.
• a Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and a SOS1 inhibitor. In some embodiments, a Ras inhibitor of the present invention is used in combination with a PD-L1 inhibitor and a SHP2 inhibitor. In some embodiments, a Ras inhibitor of the present invention is used in combination with a MEK inhibitor and a SHP2 inhibitor. In some embodiments, the cancer is colorectal cancer and the treatment comprises administration of a Ras inhibitor of the present invention in combination with a second or third therapeutic agent.
• Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.
• Immune therapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T-cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1 , anti-PD-L1 , anti-CTLA4, anti-LAGI, and anti-OX40 agents).
• IMDs immunomodulatory imides
• GITR agonists e.g., CAR-T cells
• bispecific antibodies e.g., BiTEs
• anti-PD-1 anti-PD-L1
• anti-CTLA4 anti-LAGI
• anti-OX40 agents include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T-cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1 , anti-PD-L1
• Immunomodulatory agents are a class of immunomodulatory drugs (drugs that adjust immune responses) containing an imide group.
• the IMiD class includes thalidomide and its analogues (lenalidomide, pomalidomide, and apremilast).
• anti-PD-1 antibodies and methods for their use are described by Goldberg et al.,
• GITR agonists include, but are not limited to, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, a GITR fusion protein described in U.S. Pat. No. 6,111 ,090, ,
• Anti-angiogenic agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof.
• An anti-angiogenic agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth.
• the one or more additional therapies include an anti-angiogenic agent.
• Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix- metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors.
• Non-limiting examples of anti- angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab.
• Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib.
• MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP- 1. More preferred, are those that selectively inhibit MMP-2 or AMP-9 relative to the other matrix- metalloproteinases (i.e., MAP-1 , MMP-3, MMP-4, MMP-5, MMP-6, MMP- 7, MMP- 8, MMP-10, MMP-11 , MMP-12, and MMP-13).
• MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830.
• anti-angiogenic agents include KDR (kinase domain receptor) inhibitory agents (e.g., antibodies and antigen binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents (e.g., antibodies or antigen binding regions that specifically bind VEGF (e.g., bevacizumab), or soluble VEGF receptors or a ligand binding region thereof) such as VEGF-TRAPTM, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g.,
• anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003/0162712; US6,413,932), anti-TWEAK agents (e.g., specifically binding antibodies or antigen binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM distintegrin domain to antagonize the binding of integrin to its ligands (US 2002/0042368), specifically binding anti-eph receptor or anti-ephrin antibodies or antigen binding regions (U.S. Patent Nos.
• anti-PDGF-BB antagonists e.g., specifically binding antibodies or antigen binding regions
• antibodies or antigen binding regions specifically binding to PDGF-BB ligands
• PDGFR kinase inhibitory agents e.g., antibodies or antigen binding regions that specifically bind thereto
• Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US5892112); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA);
• BC 1 Genoa Institute of Cancer Research, Italy
• rBPI 21 and BPI-derived antiangiogenic XOMA, USA
• PI 88 Progen, Australia
• cilengitide Merck KGaA, German; Kunststoff Technical University, Germany, Scripps Clinic and Research Foundation, USA
• AVE 8062 Ajinomoto, Japan
• AS 1404 Cancer Research Laboratory, New Zealand
• SG 292 (Telios, USA); Endostatin (Boston Childrens Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171 , (AstraZeneca, UK); vatalanib (pINN), (Novartis,
• agents e.g., antibodies, antigen binding regions, or soluble receptors
• HGF hepatocyte growth factor
• Scatter Factor hepatocyte growth factor
• Another example of a therapeutic agent that may be used in combination with compounds of the invention is an autophagy inhibitor.
• Autophagy inhibitors include, but are not limited to chloroquine, 3- methyladenine, hydroxychloroquine (PlaquenilTM), bafilomycin A1 , 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1 , analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine.
• antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used.
• the one or more additional therapies include an autophagy inhibitor.
• anti-neoplastic agent Another example of a therapeutic agent that may be used in combination with compounds of the invention is an anti-neoplastic agent.
• the one or more additional therapies include an anti-neoplastic agent.
• anti-neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin dif
• therapeutic agents include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS- 936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271 ; IMP321 ; BMS-663513; PF- 05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224
• the compounds described herein can be used in combination with the agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of the invention will be co-administered with other therapies as described herein.
• the compounds described herein may be administered with the second agent simultaneously or separately.
• This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the invention and any of the therapies described herein can be simultaneously administered, wherein both the agents are present in separate formulations.
• a compound of the present invention can be administered and followed by any of the therapies described herein, or vice versa.
• a compound of the invention and any of the therapies described herein are administered a few minutes apart, or a few hours apart, or a few days apart.
• the first therapy e.g., a compound of the invention
• one or more additional therapies are administered simultaneously or sequentially, in either order.
• the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21 or 1-30 days before or after the one or more additional therapies.
• kits including (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, and (b) a package insert with instructions to perform any of the methods described herein.
• the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent), and (c) a package insert with instructions to perform any of the methods described herein.
• kits may comprise two separate pharmaceutical compositions: a compound of the present invention, and one or more additional therapies.
• the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags.
• the kit may comprise directions for the use of the separate components.
• the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.
• A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
• W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
• EEDQ N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline
• X 1 is CH 2 or O; m is 1 or 2; n is 0 or 1 ;
• R 1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl
• R 2 is optionally substituted C1-C6 alkyl
• R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl.
• R 6 , R 7 , and R 8 are each independently selected from hydrogen, optionally substituted Ci- C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; or
• R 6 and R 7 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl; or
• R 6 and R 8 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
• o 1 or 2. 7. The compound of embodiment 6, or pharmaceutically acceptable salt thereof, wherein X 2 is
• W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
• EEDQ N-ethoxycarbonyl-2-ethoxy- 1 ,2-dihydroquinoline
• L 1 is optionally substituted 3 to 9-membered heterocycloalkylene or optionally substituted C2-C4 heteroalkylene;
• R 4 is optionally substituted C1-C6 alkyl
• R 5 is optionally substituted C 1 -C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl
• R 9 is optionally substituted C 1 -C3 alkyl or optionally substituted C 1 -C3 heteroalkyl
• each R 10 is, independently, optionally substituted C 1 -C3 alkyl.
• a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 56 and a pharmaceutically acceptable excipient.
• P 1 is a monovalent organic moiety
• M has the structure of Formula V:
• A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
• X 1 is CH 2 or O; m is 1 or 2; n is 0 or 1 ;
• R 1 is hydrogen or optionally substituted 3 to 10-membered heterocycloalkyl
• R 2 is optionally substituted C1-C6 alkyl
• R 3 is optionally substituted C1-C6 alkyl or optionally substituted 3 to 6-membered cycloalkyl.
• a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 56 or a pharmaceutical composition of embodiment 57.
• a method of treating a Ras protein-related disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 - 56 or a pharmaceutical composition of embodiment 57.
• a method of inhibiting a Ras protein in a cell comprising contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any one of embodiments 1 to 56 or a pharmaceutical composition of embodiment 57.
• the cancer cell is a pancreatic cancer cell, a nonsmall cell lung cancer cell, a colorectal cancer cell, or an endometrial cell.
• the additional anticancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCI inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, or a combination thereof.
• Step 2 Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropan-
• Step 3 Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H- indole
• Step 6 Synthesis of 2-[(1 S)-1-methoxyethyl]-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl) pyridine
• Step 7 Synthesis of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-2-[2-[(1 S)-1- methoxyethyl]pyridin-3-yl]-1 H-indole
• Step 8 Synthesis of 5-bromo-3-[3-[(tert-butyldiphenylsilyl)oxy]-2,2-dimethylpropyl]-1-ethyl-2-[2- [(1 S)-1 -methoxyethyl]pyridin-3-yl]indole
• Step 9 Synthesis of 3-(5-bromo-1-ethyl-2-[2-[(1 S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-2,2- dimethylpropan-1-ol
• Step 2 Synthesis of 3-(5-bromo-2-[2-[(1 S)-1-methoxyethyl]pyridin-3-yl]-1H-indol-3-yl)-2,2- dimethylpropanoic acid and ethyl (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2- dimethylpropanoate
• Step 3 Synthesis of ethyl 3-(5-bromo-1-ethyl-2-[2-[(1 S)-1-methoxyethyl]pyridin-3-yl]indol-3-yl)-
• Step 4 Synthesis of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2- dimethylpropan-1-ol
• Step 2 Synthesis of (S)-methyl 2-(tert-butoxycarbonylamino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-(triisopropylsilyloxy)phenyl)-propanoate
• Step 3 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoic acid
• Step 4 Synthesis of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoyl)hexahydropyridazine-3-carboxylate
• NMM 1. g, 405 mmol
• Step 1 Synthesis of methyl (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[1-ethyl-3-(3- hydroxy-2,2-dimethylpropyl)-2-[2-[(1 S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl]-5- [(triisopro pylsilyl)oxy]phenyl]propanoyl]-1 ,2-diazinane-3-carboxylate
• Step 2 Synthesis of (3S)-1-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-[1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-[2-[(1 S)-1-methoxyethyl]pyridin-3-yl]indol-5-yl]-5- [(triisopro pylsilyl)oxy]phenyl]propanoyl]-1 ,2-diazinane-3-carboxylic acid
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-2 5 -((triisopropylsilyl)oxy)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)- pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 1 Synthesis of methyl (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate
• (2S)-3-(3-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propanoic acid 100 g, 290 mmol
• NaHCOs 48.8 g, 581 .1 mmol
• Mel 61 .9 g, 435.8 mmol
• Step 2 Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)propanoate
• Step 3 Synthesis of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoate
• Step 4 Synthesis of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5- yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate
• Step 5 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2-dimethylpropyl)-2- iodo-1 H-indol-5-yl)phenyl)propanoic acid
• Step 6 Synthesis of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2- dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 7 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2- dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 8 Synthesis of tert-butyl ((6 3 S,4S)-1 2 -iodo-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 9 Synthesis of tert-butyl ((6 3 S,4S)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)- benzenacycloundecaphane-4-yl)carbamate
• Step 10 Synthesis of tert-butyl ((6 3 S,4S)-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-
• Step 11 ⁇ Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)- benzenacycloundecaphane-4-yl)carbamate
• Step 12 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)- benzenacycloundecaphane-5,7-dione
• Step 2 Synthesis of methyl (2S)-3-[3-bromo-5-(fluoromethyl)phenyl]-2-[(tert- butoxycarbonyl)amino]propanoate
• Step 3 Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5-(fluoromethyl)phenyl)propanoate
• Step 4 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5-(fluoromethyl)phenyl)propanoic acid
• Step 5 Synthesis of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5- (fluoromethyl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 6 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5- (fluoromethyl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 7 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-2 5 -(fluoromethyl)-1 2 -(2-((S)-1- methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola- 6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 8 Synthesis of (2S)-N-((6 3 S,4S)-1 1 -ethyl-2 5 -(fluoromethyl)-1 2 -(2-((S)-1-methoxyethyl)pyridin- 3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina- 2(1 ,3)-benzenacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide
• Step 2 Synthesis of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoate
• a mixture of methyl (2S)-3-[3-bromo-5-(difluoromethyl)phenyl]-2-[(tert-butoxycarbonyl)amino] propanoate (90.0 g, 220.459 mmol), (S)-3-(1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-5-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,
• Step 3 Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-ethyl-3-(3- hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoic acid
• Step 4 Synthesis of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1- ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5- yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 5 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5- yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 6 Synthesis of tert-butyl ((6 3 S,4S)-2 5 -(difluoromethyl)-1 1 -ethyl-1 2 -(2-((S)-1- methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola- 6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 7 Synthesis of (6 3 S,4S)-4-amino-2 5 -(difluoromethyl)-1 1 -ethyl-1 2 -(2-((S)-1- methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)- pyridazina-2(1 ,3)-benzenacycloundecaphane-5,7-dione
• Step 2 Synthesis of methyl (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 3 Synthesis of (S)-3-(1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-indol-3-yl)-2,2-dimethylpropan-1 -ol
• 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2- dimethylpropan-1-ol (60 g, 134.7 mmol) in toluene (500 mL) at room temperature was added bis(pinacolato)diboron (51.31 g, 202.1 mmol), Pd(dppf)Cl2 (9.86 g, 13.48 mmol) and KOAc (26.44 g,
• Step 4 Synthesis of methyl (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2- yl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 5 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2- yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 6 Synthesis of tert-butyl ((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1 (5,3)-indola-6(1 ,3)- pyridazinacycloundecaphane-4-yl)carbamate
• Step 2 Synthesis of methyl 2-(bis(tert-butoxycarbonyl)amino)acrylate
• Step 3 Synthesis of methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(5-bromo-3,6-dihydropyridin- 1 (2H)-yl)propanoate
• Step 4 Synthesis of 3-(5-bromo-3,6-dihydropyridin-1 ( 2H)-y ⁇ )-2-((tert - butoxycarbonyl)amino)propanoic acid
• Step 5 Synthesis of methyl (3S)-1-(3-(5-bromo-3,6-dihydropyridin-1(2H)-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 6 Synthesis of methyl (3S)-1-(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)- yl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 7 Synthesis of (3S)-1-(2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6-dihydropyridin-1(2H)- yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 8 Synthesis of tert-butyl ((6 3 S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-5,7-dioxo-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -decahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina- 2(5,1)-pyridinacycloundecaphane-4-yl)carbamate
• Step 9 Synthesis of (6 3 S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10- dimethyl-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -decahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(5,1)- pyridinacycloundecaphane-5,7-dione
• Step 2 Synthesis of afford tert-butyl (S,Z)-2-(2-(((benzyloxy)carbonyl)amino)-3-methoxy-3- oxoprop-1 -en-1 -yl)morpholine-4-carboxylate
• Step 4 Synthesis of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-morpholin-2-yl)propanoate
• Step 5 Synthesis of (S)-5-bromo-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2- (2-(1 -methoxyethyl)pyridin-3-yl)-1 H-indole
• Step 6 Synthesis of methyl (2S)-2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3-[(2S)-4-(3- ⁇ 3-[(tert- butyldimethylsilyl)oxy]-2,2-dimethylpropyl ⁇ -1-ethyl-2- ⁇ 2-[(1 S)-1-methoxyethyl]pyridin-3-yl ⁇ indol-5- yl)morpholin-2-yl]propanoate
• Step 7 Synthesis of (2S)-2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3-[(2S)-4-(3- ⁇ 3-[(tert- butyldimethylsilyl)oxy]-2,2-dimethylpropyl ⁇ -1-ethyl-2- ⁇ 2-[(1 S)-1-methoxyethyl]pyridin-3-yl ⁇ indol-5- yl)morpholin-2-yl]propanoic acid
• Step 8 Synthesis of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(3-(3-((tert- butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5- yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 9 Synthesis of methyl (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(1-ethyl-3-(3- hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2- yl)propanoyl)hexahydropyridazine-3-carboxylate
• Step 10 Synthesis of (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(1-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)morpholin-2- yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 11 Synthesis of afford benzyl ((2 2 S,6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-morpholina-1 (5,3)-indola-6(1 ,3)- pyridazinacycloundecaphane-4-yl)carbamate
• Step 12 Synthesis of (2 2 S,6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)pyridin-3-yl)- 10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-morpholina-1 (5,3)-indola-6(1 ,3)- pyridazinacycloundecaphane-5,7-dione
• Step 2 Synthesis of benzyl (S)-4-(6-(1 -methoxyethyl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-
• Step 3 Synthesis of benzyl (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate
• Step 4 Synthesis of benzyl (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-1 -ethyl-1 H-indol-2-yl)-6-(1 -methoxyethyl)pyridin-3-yl)piperazine-1 -carboxylate
• Step 5 Synthesis of benzyl (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol- 2-yl)-6-(1 -methoxyethyl)pyridin-3-yl)piperazine-1 -carboxylate
• Step 6 Synthesis of benzyl (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1- carboxylate
• Step 7 Synthesis of methyl (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 8 Synthesis of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 9 Synthesis of benzyl 4-(5-((6 3 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-1 1 -ethyl-10,10- dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1 (5,3)-indola-6(1 ,3)- pyridazinacycloundecaphane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylate
• Step 10 Synthesis of tert-butyl ((6 3 S,4S,Z)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(piperazin-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1 (5,3)- indola-6(1 ,3)-pyridazinacycloundecaphane-4-yl)carbamate
• Step 11 Synthesis of tert-butyl ((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(4- methylpiperazin-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)- thiazola-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-4-yl)carbamate
• Step 2 Synthesis of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1 -ethyl-1 H-indol-2-yl)-6-(1- methoxyethyl)pyridin-3-yl)boronic acid
• Step 3 Synthesis of (S)-3-(5-bromo-1-ethyl-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3- yl)-2,2-dimethylpropyl acetate
• Step 4 Synthesis of 3-(5-bromo-1-ethyl-2-(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1 H)-yl)- 2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate
• Step 5 Synthesis of 3-(1-ethyl-2-(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1 H)-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2- dimethylpropyl acetate
• Step 6 Synthesis of methyl (S)-1-((S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2- yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 8 Synthesis of tert-butyl ((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1- c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-4-yl)carbamate To a stirred solution of (S)
• Step 9 Synthesis of (6 3 S,4S,Z)-4-amino-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin- 8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)- thiazola-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-5,7-dione
• Step 1 Synthesis of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1 H-indol-3-yl)-2,2-dimethylpropyl acetate
• Step 2 Synthesis of 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2- a]pyrazin-2-yl)pyridin-3-yl)-5-(4, 4, 5, 5-tetra methyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2- dimethylpropyl acetate
• Step 4 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1 H- indol-5-yl)thiazol-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 5 Synthesis of tert-butyl ((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro- 2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa- 2(4,2)-thiazola-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-4-yl)carbamate
• Step 6 Synthesis of (6 3 S,4S,Z)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)- thiazola-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-5,7-dione
• Step 2 Synthesis of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-(2,2,2-trifluoroethyl)-1H- indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid
• Step 3 Synthesis of (S)-3-(5-bromo-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 H-indol-3-yl)-2,2-dimethylpropyl acetate
• (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-(2,2,2-trifluoroethyl)- 1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (51.2 g, 87.487 mmol) and sodium chloro[(4- methylbenzene)sulfonyl]azanide (197 g, 699.896 mmol) in THF (258 mL) was added Nal (104.91 g, 699.896 mmol) in T
• Step 4 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)- 1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 5 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)- 1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 6 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2- dimethylpropyl)-1-(2,2,2-trifluoroethyl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid Into a 100 mL 3-necked round-bottom flask were added methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2- dimethylpropyl)-2-(5-((S)-hexahydropyrazino[2,1-c]
• Step 7 synthesis of tert-butyl ((6 3 S,4S)-12-(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-
• Step 8 Synthesis of (6 3 S,4S)-4-amino-1 2 -(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2- ((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-1 1 -(2,2,2-trifluoroethyl)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H- 8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-5,7-dione
• Step 2 Synthesis of (S)-3-(5-bromo-2-(5-iodo-2-(1-methoxyethyl)pyridin-3-yl)-1 -(2,2,2- trifluoroethyl)-1 H-indol-3-yl)-2,2-dimethylpropyl acetate
• Step 3 Synthesis of 3-(5-bromo-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2- a]pyrazin-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate
• Step 4 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-(2-((S)-1- methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indol- 5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 5 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1- (2,2,2-trifluoroethyl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 6 Synthesis of tert-butyl ((6 3 S,4S)-12-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate To a stirred mixture of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(3-(3-hydroxy-2,2- dimethylpropyl
• Step 1 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 2 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2- dimethylpropyl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin- 8(1 H)-yl)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-11 H- 8- oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 4 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin- 8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)- indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-5,7-dione Into a 100 mL round-bottom flask were added tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(5-((S)- hexahydropyrazino[2,1-c]
• Step 1 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1- methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-5-yl)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 2 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1H- indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)phenyl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa- 1 (5,3)- indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 4 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola- 6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-5,7-dione
• Step 1 Synthesis of 3-(5-bromo-1-ethyl-2-(5-((R)-hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)-2-((S)- 1 -methoxyethyl)pyridin-3-yl)-1 H-indol-3-yl)-2,2-dimethylpropyl acetate
• Step 2 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((R)- hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)-2- ((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 4 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(5-((R)-hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)- yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa- 1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate
• Step 5 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(5-((R)-hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)- yl)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)- indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-5,7-dione
• Step 1 Synthesis of methyl (S)-1-((S)-3-((S)-1-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2- ((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-5-yl)piperidin-3- yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 2 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-4-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1H- indol-5-yl)morpholin-2-yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 3 Synthesis of tert-butyl ((2 2 S,6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro- 2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa- 2(4,2)-morpholina-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-4-yl)carbamate
• Step 4 Synthesis of (2 2 S,6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro- 2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)- morpholina-1 (5,3)-indola-6(1 ,3)-pyridazinacycloundecaphane-5,7-dione
• Step 1 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5- (fluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-16-(fluoromethyl)-1 2 -(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)- benzenacycloundecaphane-4-yl)carbamate
• Step 4 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-2 5 -(fluoromethyl)-1 2 -(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl- 6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane- 5,7-dione
• Step 1 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((R)- hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5- (difluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 2 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-ethyl-2- (5-((R)-hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2- dimethylpropyl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-25-(difluoromethyl)-1 1 -ethyl-1 2 -(5-((R)- hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane- 4-yl)carbamate
• Step 4 Synthesis of (6 3 S,4S)-4-amino-25-(difluoromethyl)-1 1 -ethyl-1 2 -(5-((R)- hexahydropyrrolo[1 ,2-a]pyrazin-2(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl- 6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane- 5,7-dione
• Step 1 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-5- (difluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 2 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-ethyl-2- (5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-2 5 -(difluoromethyl)-1 1 -ethyl-1 2 -(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)- benzenacycloundecaphane-4-yl)carbamate
• Step 4 Synthesis of (6 3 S,4S)-4-amino-2 5 -(difluoromethyl)-1 1 -ethyl-1 2 -(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl- 6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane- 5,7-dione
• the reaction mixture was stirred for 1 h at 0 °C.
• the mixture was then concentrated under reduced pressure and adjusted to pH 8 by the addition of sat. aq. NaHCOs at 0 °C and extracted with 100 mL of (10% MeOH/DCM).
• the combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (500 mg, crude) as a solid, which was used in the next step directly without further purification.
• Step 1 Synthesis of methyl (S)-1-((S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1- methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-5-yl)-5- (difluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate To a stirred solution of 3-(5-bromo-1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl
• Step 2 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2- yl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 3 Synthesis of tert-butyl ((6 3 S,4S)-2 5 -(difluoromethyl)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5- ((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - hexahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-4-yl)carbamate To a solution of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(difluoromethyl)-5-(1-
• Step 4 Synthesis of (6 3 S,4S)-4-amino-2 5 -(difluoromethyl)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5- ((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H- 8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(1 ,3)-benzenacycloundecaphane-5,7-dione
• Step 1 Synthesis of 3-(1-ethyl-2-(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1 H)-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2- dimethylpropyl acetate
• Step 2 Synthesis of methyl (S)-1-((S)-3-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)-3,6- dihydropyridin-1 (2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate
• Step 3 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-2-(5-((S)- hexahydropyrazino[2,1-c][1 ,4]oxazin-8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2- dimethylpropyl)-1H-indol-5-yl)-3,6-dihydropyridin-1 (2H)-yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 4 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin- 8(1 H)-yl)-2-((S)-1 -methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 - decahydro-1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(5,1)-pyridinacycloundecaphane-4-yl)carbamate
• Step 5 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-12-(5-((S)-hexahydropyrazino[2,1-c][1 ,4]oxazin- 8(1H)-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -decahydro-1 1 H-8- oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(5,1)-pyridinacycloundecaphane-5,7-dione
• the resulting mixture was stirred for 1 h at 0 °C.
• the mixture was basified to pH 8 with sat. aq. NaHCO3.
• the resulting mixture was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na 2 SCO 4 . After filtration, the filtrate was concentrated under reduced pressure to afford the crude product (720 mg, 83% yield) as a solid, which was used in the next step directly without further purification.
• Step 1 Synthesis of 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2- a]pyrazin-2-yl)pyridin-3-yl)-5-(4, 4, 5, 5-tetra methyl-1 ,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2- dimethylpropyl acetate
• Step 2 Synthesis of methyl (S)-1-((S)-3-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1- methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1H-indol-5-yl)-3,6- dihydropyridin-1 (2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate To a stirred solution of 3-(1-ethyl-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2- a]pyrazin-2-yl) pyridin-3-yl
• Step 3 Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(5-(1-ethyl-3-(3-hydroxy-2,2- dimethylpropyl)-2-(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H-pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-1 H- indol-5-yl)-3,6-dihydropyridin-1 (2H)-yl)propanoyl)hexahydropyridazine-3-carboxylic acid
• Step 4 Synthesis of tert-butyl ((6 3 S,4S)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -decahydro- 1 1 H-8-oxa-1 (5,3)-indola-6(1 ,3)-pyridazina-2(5,1)-pyridinacycloundecaphane-4-yl)carbamate
• Step 5 Synthesis of (6 3 S,4S)-4-amino-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-((R)-octahydro-2H- pyrido[1 ,2-a]pyrazin-2-yl)pyridin-3-yl)-10,10-dimethyl-2 1 ,2 2 ,2 3 ,2 6 ,6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -decahydro-1 1 H- 8-oxa- 1 (5,3)-indola-6(1 ,3)-pyridazina-2(5,1)-pyridinacycloundecaphane-5,7-dione
• Step 1 Synthesis of (S)-5-bromo-3-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-2-(5-(4- cyclopropylpiperazin-1-yl)-2-(1-methoxyethyl)pyridin-3-yl)-1 -ethyl-1 H-indole
• Step 2 Synthesis of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((S)-4-(3-(3-((tert- butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-2-(5-(4-cyclopropylpiperazin-1-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1 -ethyl-1 H-indol-5-yl)morpholin-2-yl)propanoate

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