[go: up one dir, main page]

WO2023215256A1 - Inhibiteurs de sos1 et leurs utilisations - Google Patents

Inhibiteurs de sos1 et leurs utilisations Download PDF

Info

Publication number
WO2023215256A1
WO2023215256A1 PCT/US2023/020638 US2023020638W WO2023215256A1 WO 2023215256 A1 WO2023215256 A1 WO 2023215256A1 US 2023020638 W US2023020638 W US 2023020638W WO 2023215256 A1 WO2023215256 A1 WO 2023215256A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
methoxy
pyrimidin
pharmaceutically acceptable
prodrug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/020638
Other languages
English (en)
Inventor
Andreas BUCKL
Severin THOMPSON
John E. Knox
Adrian L. Gill
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Revolution Medicines Inc
Original Assignee
Revolution Medicines Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Revolution Medicines Inc filed Critical Revolution Medicines Inc
Publication of WO2023215256A1 publication Critical patent/WO2023215256A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • RAS-family proteins including KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey murine sarcoma virus oncogene) and any mutants thereof are small GTPases that exist in cells in either GTP-bound or GDP-bound states (McCormick et al., J. Mol. Med. (Berl), 2016, 94(3):253-8; Nimnual et al., Sci. STKE., 2002, 2002(145):pl36).
  • the RAS-family proteins have a weak intrinsic GTPase activity and slow nucleotide exchange rates (Hunter et al., Mol. Cancer Res., 2015, 13(9): 1325-35). Binding of GTPase activating proteins (GAPs) such as NF1 increases the GTPase activity of RAS-family proteins.
  • GAPs GTPase activating proteins
  • NF1 NF1
  • GEFs guanine nucleotide exchange factors
  • RAS- family proteins When in the GTP-bound state, RAS- family proteins are active and engage effector proteins including RAF and phosphoinositide 3-kinase (PI3K) to promote the RAF/mitogen or extracellular signal- regulated kinases (MEK/ERK).
  • PI3K phosphoinositide 3-kinase
  • MEK/ERK extracellular signal- regulated kinases
  • SOS1 is critically involved in the activation of RAS-family protein signaling in cancer via mechanisms other than mutations in RAS-family proteins.
  • SOS1 interacts with the adaptor protein Grb2 and the resulting SOSl/Grb2 complex binds to activated/phosphorylated Receptor Tyrosine Kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56).
  • activated/phosphorylated Receptor Tyrosine Kinases e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1 R, INSR, ALK, ROS, Tr
  • SOS1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR), B cell Receptor (BCR) and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75).
  • TCR T cell Receptor
  • BCR B cell Receptor
  • monocyte colony-stimulating factor receptor Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75.
  • SOS 1 -activation of RAS-family proteins can also be mediated by the interaction of SOSl/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myelogenous leukemia (Kardinal et al., 2001, Blood, 98:1773-81; Sini et al., Nat. Cell Biol., 2004, 6(3):268-74). Furthermore, alterations in SOS1 have been implicated in cancer.
  • SOS1 mutations are found in embryonal rhabdomyosarcomas, Sertoli cell testis tumors, granular cell tumors of the skin (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3):242-52) and lung adenocarcinoma (Cancer Genome Atlas Research Network., Nature, 2014, 511 (751 l):543-50). Meanwhile over-expression of S0S1 has been described in bladder cancer (Watanabe et al., IUBMB Life, 2000, 49(4):317-20) and prostate cancer (Timofeeva et al., Int. J. Oncol., 2009; 35(4):751-60).
  • hereditary S0S1 mutations are implicated in the pathogenesis of RASopathies like e.g., Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC) and hereditary gingival fibromatosis type 1 (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56).
  • S0S1 is also a GEF for the activation of the GTPases RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1): 125-36).
  • RAC1 Ras-related C3 botulinum toxin substrate 1
  • RAC1 Ras-related C3 botulinum toxin substrate 1
  • RAC1 Ras-related C3 botulinum toxin substrate 1
  • SOS1 inhibitor compounds are be expected to consequently inhibit signaling in cells downstream of RAS-family proteins (e.g., ERK phosphorylation).
  • SOS1 inhibitor compounds are be expected to deliver anti- cancer efficacy (e.g., inhibition of proliferation, survival, metastasis, etc.).
  • S0S1 inhibitor compound High potency towards inhibition of SOSl :RAS-family protein binding (nanomolar level IC50 values) and ERK phosphorylation in cells (nanomolar level IC50 values) are desirable characteristics for a S0S1 inhibitor compound. Furthermore, a desirable characteristic of a S0S1 inhibitor compound would be the selective inhibition of S0S1 over S0S2. This conclusion is based on the viable phenotype of S0S1 knockout mice and lethality of S0S1/S0S2 double knockout mice, as described above.
  • NCT04111458 A Study to Test Different Doses of BI 1701963 [a S0S1 inhibitor] Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation)”) and NCT04975256 (“Adagrasib in Combination With BI 1701963 [a S0S1 inhibitor] in Patients With Cancer (KRYSTAL 14)”).
  • the present disclosure relates to compounds capable of inhibiting the activity of S0S1.
  • the present disclosure further provides a process for the preparation of compounds, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SOS1.
  • One aspect of the present disclosure relates to compounds having a structure of Formula (I): or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein.
  • R 1 is selected from the group consisting of optionally substituted 6- membered aryl and optionally substituted 5-6 membered heteroaryl.
  • R 2 is selected from the group consisting of H and optionally substituted C 1- 6 alkyl.
  • R 3 is - OR 3a , and further wherein R 3a is optionally substituted C 1-3 alkyl.
  • Each R 4b is independently H, C 1-6 alkyl.
  • Each R 4c is independently H or C 1-6 alkyl.
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the present disclosure relates to a method of inhibiting S0S1 in a subject, comprising administering to the subject: a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method of inhibiting the interaction of S0S1 and a RAS-family protein in a cell or inhibiting the interaction of S0S1 and RAC1 in a cell, comprising administering to the cell: a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of S0S1 and a RAS-family protein or by inhibition of the interaction of S0S1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of: a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of: a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • the present disclosure also provides compounds that are useful in inhibiting S0S1, in vivo or in vitro.
  • 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).
  • an optionally substituted group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different.
  • an optionally substituted group has 1 substituent.
  • an optionally substituted group has 2 substituents.
  • an optionally substituted group has 3 substituents.
  • an optionally substituted group has 4 substituents.
  • an optionally substituted group has 5 substituents.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • optionally substituted means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups.
  • 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.
  • saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2 -methyl-1-propyl, 2-methyl-2- propyl, 2-methyl-1-butyl, 3 -methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2- m ethyl-1-pentyl, 3 -methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and the like, and longer alkyl groups, such as heptyl, and oc
  • alkyl group can be unsubstituted or substituted. Alkyl groups containing three or more carbon atoms may be straight or branched. As used herein, “lower alkyl” means an alkyl having from 1 to 6 carbon atoms.
  • 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.
  • alkenyl means an aliphatic hydrocarbon group containing a carbon — carbon double bond and which may be straight or branched having about 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) in the chain. Certain alkenyl groups have 2 to about 4 carbon atoms in the chain. Alkenyls include both cis and trans isomers. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n- butenyl, and i-butenyl.
  • a C2-C6 alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.
  • alkynyl means an aliphatic hydrocarbon group containing a carbon — carbon triple bond and which may be straight or branched having about 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) in the chain. Certain alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain.
  • alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3- methylbutynyl, and n-pentynyl.
  • a C2-C6 alkynyl group is an alkynyl group containing between 2 and 6 carbon atoms.
  • halo or halogen means a fluoro, chloro, bromo, or iodo group.
  • haloalkyl refers to an alkyl group substituted with at least one halogen atom. Non-limiting examples include monofluoro alkyl, difluoro alkyl, trifluoro alkyl, -CH 2 F, -CHF 2 , and CF 3 .
  • hydroxy represents a -OH group.
  • a carbon atom i.e., a carbonyl group
  • annular atoms refers to the total number of ring atoms present in the system. “Annular atoms” therefore does not include the atoms present in a substituent attached to the ring. Thus, the number of “annular atoms” includes all atoms present in a fused ring. For example, a 2-indolyl ring, , is considered a 5-membered heteroaryl, but is also a heteroaryl containing 9 annular atoms. In another example, pyridine is considered a 6-membered heteroaryl, and is a heteroaryl containing 6 annular atoms.
  • Cycloalkyl refers to a single saturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C 3 -C 20 cycloalkyl), for example from 3 to 15 annular atoms, for example, from 3 to 12 annular atoms.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contains a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated.
  • Cycloalkyl includes ring systems where the cycloalkyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkyl ring containing the point of attachment.
  • cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl 2-(2,3-dihydro-lH-indene) and 9-fluorenyl
  • cycloalkyl rings can be further characterized by the number of annular atoms.
  • a cyclohexyl ring is a C 6 cycloalkyl ring with 6 annular atoms
  • 2-(2, 3 -dihydro- IH-indene) is a C 5 cycloalkyl ring with 9 annular atoms.
  • 9-fluorenyl is a C 5 cycloalkyl ring with 13 annular atoms
  • 2- adamantyl is a C 6 cycloalkyl with 10 annular atoms.
  • cycloalkenyl may refer to a partially saturated, monocyclic, fused or spiro polycyclic, all carbon ring having from 3 to 18 carbon atoms per ring and contains at least one double bond.
  • Cycloalkenyl includes ring systems where the cycloalkenyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a cycloalkenyl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbons in the cycloalkenyl ring containing the point of attachment. Cycloalkenyl rings can be further characterized by the number of annular atoms. Examples of cycloalkenyl include 1 -cyclohex- 1-enyl and cyclopent- 1-enyl.
  • aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group has 5 to 20 annular carbon atoms, 5 to 14 annular carbon atoms, or 5 to 12 annular carbon atoms.
  • Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl).
  • Aryl includes ring systems where the aryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, and wherein the point of attachment is on an aryl ring, and, in such instances, the number of carbon atoms recited continues to designate the number of carbon atoms in the aryl ring containing the point of attachment.
  • aryl groups include phenyl and 5-(2,3-dihydro-lH-indene): .
  • aryl rings can be further characterized by the number of annular atoms. For example, phenyl is a C 6 aryl with 6 annular atoms, while 5-(2,3-dihydro-lH-indene) is a C 6 aryl with 9 annular atoms.
  • Heterocyclyl refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system (including fused and spiro polycyclic) that has at least one heteroatom in the ring (at least one annular heteroatom selected from oxygen, nitrogen, phosphorus, and sulfur). Unless otherwise specified, a heterocyclyl group has from 5 to about 20 annular atoms, for example from 5 to 15 annular atoms, for example from 5 to 10 annular atoms.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus, and sulfur in the ring.
  • the term also includes single saturated or partially unsaturated rings (e.g., 5, 6, 7, 8, 9, or 10- membered rings) having from about 4 to 9 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus, and sulfur in the ring.
  • Heterocyclyl includes ring systems where the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a heterocyclic ring, and, in such instances, the number of ring members recited continues to designate the number of annular atoms in the heterocyclic ring containing the point of attachment. Heterocyclic rings can be further characterized by the number of annular atoms.
  • heterocyclic groups include piperidinyl (6-membered heterocycle with 6 annular atoms), azepanyl (7-membered heterocycle with 7 annular atoms), and 3-chromanyl (6-membered heterocycle with 10 annular atoms) and benzofuran (9-membered heterocycle with 9 annular atoms)
  • heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such aromatic ring.
  • the term includes single heteroaryl rings of from about 1 to 10 annular carbon atoms and about 1-5 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
  • the sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • Heteroaryl includes ring systems where the heteroaryl ring, as defined above, is fused with one or more cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups, wherein the point of attachment is on a heteroaryl ring, and, in such instances, the number of ring members continues to designate the number of ring members in the heteroaryl ring containing the point of attachment.
  • Heteroaryl rings can be further characterized by the number of annular atoms. For example, pyridine is a 6-membered heteroaryl having 6 annular atoms.
  • 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 disclosure 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 C1, 123 I and 125 I.
  • 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 disclosure described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable salts include, e.g., water-soluble and water- insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylre
  • carrier encompasses excipients and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • 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, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • Excipients include, but are not limited to: butylated optionally substituted hydroxyltoluene (BEIT), 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.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.
  • a prodrug is a drug which is inactive in the body, but is transformed in the body typically either during absorption or after absorption from the gastrointestinal tract into the active compound.
  • the conversion of the prodrug into the active compound in the body may be done chemically or biologically (i.e., using an enzyme).
  • solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the present disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • tautomers refers to a set of compounds that have the same number and type of atoms, but differ in bond connectivity and are in equilibrium with one another.
  • a “tautomer” is a single member of this set of compounds. Typically, a single tautomer is drawn but it is understood that this single structure is meant to represent all possible tautomers that might exist. Examples include enol-ketone tautomerism. When a ketone is drawn it is understood that both the enol and ketone forms are part of the present disclosure.
  • the term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical or chemical properties.
  • the structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
  • 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 the compounds herein may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • the chemical structures depicted herein, and therefore the compounds of the disclosure 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 disclosure 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.
  • stereoisomers refers to the set of compounds which have the same number and type of atoms and share the same bond connectivity between those atoms, but differ in three dimensional structure.
  • stereoisomer refers to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer.
  • enantiomers refers to a pair of stereoisomers which are non- superimposable mirror images of one another.
  • enantiomer refers to a single member of this pair of stereoisomers.
  • racemic refers to a 1 : 1 mixture of a pair of enantiomers.
  • diastereomers refers to the set of stereoisomers which cannot be made superimposable by rotation around single bonds. For example, cis- and trans- double bonds, endo- and exo- substitution on bicyclic ring systems, and compounds containing multiple stereogenic centers with different relative configurations are considered to be diastereomers.
  • diastereomer refers to any member of this set of compounds. In some examples presented, the synthetic route may produce a single diastereomer or a mixture of diastereomers.
  • an “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • a “therapeutic agent” is any substance, e.g., a compound or composition, capable of treating a disease or disorder.
  • therapeutic agents that are useful in connection with the present disclosure include RAS inhibitors and cancer chemotherapeutics. Many such therapeutic agents are known in the art and are disclosed herein.
  • 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.
  • a “therapeutic regimen” refers to a dosing regimen whose administration across a relevant population is correlated with a desired or beneficial therapeutic outcome.
  • treatment refers to any administration of a substance (e.g., a compound of the present disclosure) 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 disclosure
  • 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. In some embodiments, 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.
  • prevent refers to keeping a disease or disorder from afflicting the subject. Preventing includes prophylactic treatment. For instance, preventing can include administering to the subject a compound disclosed herein before a subject is afflicted with a disease and the administration will keep the subject from being afflicted with the disease.
  • inhibiting includes any measurable or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity (e.g., SOSl :Ras-family protein binding activity) compared to normal.
  • reduction of activity e.g., SOSl :Ras-family protein binding activity
  • administer refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject’s body.
  • 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
  • the term “dosage form” refers to a physically discrete unit of a compound (e.g., a compound of the present disclosure) for administration to a subject.
  • a compound e.g., a compound of the present disclosure
  • 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).
  • the term “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 disclosure
  • has a recommended dosing regimen which may involve one or more doses.
  • a dosing regimen includes 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 includes 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 includes 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 includes 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).
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • a monotherapy refers to a method of treatment comprising administering to a subject a single therapeutic agent, optionally as a pharmaceutical composition.
  • a monotherapy may comprise administration of a pharmaceutical composition comprising a therapeutic agent and one or more pharmaceutically acceptable carrier, excipient, diluent, and/or surfactant.
  • the therapeutic agent may be administered in an effective amount.
  • the therapeutic agent may be administered in a therapeutically effective amount.
  • a combination therapy refers to a method of treatment comprising administering to a subject at least two therapeutic agents, optionally as one or more pharmaceutical compositions.
  • a combination therapy may comprise administration of a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carrier, excipient, diluent, and/or surfactant.
  • a combination therapy may comprise administration of two or more pharmaceutical compositions, each composition comprising one or more therapeutic agent and one or more pharmaceutically acceptable carrier, excipient, diluent, and/or surfactant.
  • at least one of the therapeutic agents is a S0S1 inhibitor.
  • at least one of the therapeutic agents is a RAS inhibitor.
  • the two agents may optionally be administered simultaneously (as a single or as separate compositions) or sequentially (as separate compositions).
  • the therapeutic agents may be administered in an effective amount.
  • the therapeutic agent may be administered in a therapeutically effective amount.
  • the effective amount of one or more of the therapeutic agents may be lower when used in a combination therapy than the therapeutic amount of the same therapeutic agent when it is used as a monotherapy, e.g., due an additive or synergistic effect of combining the two or more therapeutics.
  • SOS refers to SOS genes, which are known in the art to include RAS guanine nucleotide exchange factor proteins that are activated by receptor tyrosine kinases to promote GTP loading of RAS and signaling.
  • SOS includes all SOS homologs that promotes the exchange of Ras-bound GDP by GTP.
  • SOS refers specifically to "son of sevenless homolog 1" (“S0S1"). S0S1 is critically involved in the activation of RAS-family protein signaling in cancer via mechanisms other than mutations in RAS-family proteins.
  • S0S1 interacts with the adaptor protein Grb2 and the resulting SOSl/Grb2 complex binds to activated/phosphorylated Receptor Tyrosine Kinases (e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56).
  • activated/phosphorylated Receptor Tyrosine Kinases e.g., EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1 R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL
  • S0S1 is also recruited to other phosphorylated cell surface receptors such as the T cell Receptor (TCR), B cell Receptor (BCR) and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75).
  • TCR T cell Receptor
  • BCR B cell Receptor
  • monocyte colony-stimulating factor receptor Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75.
  • SOS 1 -activation of RAS-family proteins can also be mediated by the interaction of SOSl/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myelogenous leukemia (Kardinal et al., 2001, Blood, 98: 1773-81; Sini et al., Nat. Cell Biol., 2004, 6(3):268-74).
  • S0S1 is also a GEF for the activation of the GTPases RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1): 125-36).
  • RAC1 like RAS-family proteins, is implicated in the pathogenesis of a variety of human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12(10): 1925-34). Son of sevenless 2 (S0S2), a homolog of S0S1 in mammalian cells, also acts as a GEF for the activation of RAS-family proteins (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56; Buday et al., Biochim. Biophys. Acta., 2008, 1786(2): 178-87). Published data from mouse knockout models suggests a redundant role for S0S1 and S0S2 in homeostasis in the adult mouse.
  • SOS SOSl/RAS-family protein driven cancers
  • SOSl/RAS-family protein pathologies SOSl/RAS-family protein pathologies
  • SOS 1 -mediated activation of RAS-family proteins SOS 1 -mediated activation of RAS-family proteins to the GTP-bound form.
  • S0S1 inhibitor compounds are be expected to consequently inhibit signaling in cells downstream of RAS-family proteins (e.g., ERK phosphorylation).
  • S0S1 inhibitor compounds are be expected to deliver anti-cancer efficacy (e.g., inhibition of proliferation, survival, metastasis, etc.).
  • High potency towards inhibition of S0S1 :RAS-family protein binding (nanomolar level IC50 values) and ERK phosphorylation in cells (nanomolar level IC50 values) are desirable characteristics for a S0S1 inhibitor compound.
  • a desirable characteristic of a S0S1 inhibitor compound would be the selective inhibition of S0S1 over S0S2. This conclusion is based on the viable phenotype of S0S1 knockout mice and lethality of S0S1/S0S2 double knockout mice, as described above.
  • a “S0S1 inhibitor” refers to any agent, (e.g., a small molecule (e.g., less than 750 Da)) capable of inhibiting S0S1.
  • S0S1 inhibitors can include selective S0S1 inhibitors and inhibitors that also inhibit other proteins.
  • S0S1 inhibitors may also inhibit S0S2, with a selectivity ratio less than 10- fold for inhibition of S0S1 relative to S0S2.
  • S0S1 inhibitors will selectively inhibit S0S1, with a selectivity ratio greater of at least about 10-fold, such as greater than at least about 30-fold, for inhibition of S0S1 relative to S0S2.
  • the present disclosure relates to compounds having a structure of Formula (I): or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Ri is optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl.
  • Ri is selected from the group consisting of optionally substituted 6-membered aryl and optionally substituted 5-6 membered heteroaryl.
  • Ri is of the following structure and the associated compound is of Formula (II) or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • R 2 , R 3 , and R 4 are as defined herein.
  • R 5 , R 6 , R 7 , R 8, and R 9 are independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, 4-8 membered cycloalkenyl, C 2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OH, halogen, -NO 2 , -CN, - NR 11 R 12 , -SR 10 , -S(O) 2 NR 11 R 12 , -S(O) 2 R 10 , -NR 10 S(O) 2 NR 11 R 12 , -NR 10 S(O) 2 NR 11 R 12 , -NR 10 S(O) 2 R 11 , - S(O)NR 11 R 12 , -S(O)R 10 , -NR 10 S(O)NR 11 R 12 , -NR 10 S(O)R 11 , -C(O)R 10 , -CO 2 R 10 , 6
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, halogen, and -NH 2 , wherein each C 1-6 alkyl is optionally substituted with halogen.
  • R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from H, C 1-6 alkyl, halogen, and -NH 2 , wherein each C 1-6 alkyl is optionally substituted with halogen.
  • Rw, R 11 , and R 12 are at each occurrence independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, 4-8 membered cycloalkenyl, C 2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, -OR 13 , -SR 13 , halogen, -NR 13 R 14 , -NO 2 , and - CN.
  • R 13 and R 14 are at each occurrence independently selected from H, D, C 1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C 2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C 1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C 2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with -OH, -SH, -NH 2 , -NO 2 , or -CN.
  • one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl, wherein the alkyl is optionally substituted with halogen.
  • one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl, wherein the alkyl is optionally substituted with halogen or -OH.
  • one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl, and one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl optionally substituted with halogen.
  • one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is halogen, and one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl optionally substituted with halogen.
  • one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is -NH 2 .
  • one of R 5 , R 6 , R 7 , R 8 , and R 9 is -NH 2 ; and one of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl optionally substituted with halogen.
  • one or more of R 5 , R 6 , R 7 , R 8 , and R 9 is selected from among -CHF 2 , -CF 3 , -NH 2 , -F, and substituted aryl.
  • one of R 5 , R 6 , R 7 , R 8 , and R 9 is -CHF2 and one of R 5 , R 6 , R 7 , R 8 , and R 9 is -F.
  • one of R 5 , R 6 , R 7 , R 8 , and R 9 is -CF3 and one of R 5 , R 6 , R 7 , R 8 , and R 9 is - NH 2 .
  • Ri is optionally substituted 6-membered aryl.
  • Ri is N-(1] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094] n-[0094]
  • R 2 is H or optionally substituted C 1-6 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is optionally substituted C 1-3 alkyl, wherein the optional substituent is one or more halogens, or one or more fluoro. In some embodiments, R 2 is -CH 3 .
  • R 3 is -OR 3a , wherein R 3a is optionally substituted C 1-3 alkyl. In some embodiments, R 3a is C 1-3 alkyl. In some embodiments, R 3 is -OCH 3 .
  • R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl.
  • optionally substituted C 1-6 alkyl is optionally substituted C 1-3 alkyl or optionally substituted Ci alkyl.
  • optionally substituted C 1-6 haloalkyl is optionally substituted C 1-3 haloalkyl or optionally substituted Ci haloalkyl.
  • r is 1, 2, or 3.
  • each R 4b is independently H or C 1-6 alkyl. In some embodiments, each R 4b is independently H or C 1-3 alkyl. In some embodiments, each R 4b is independently H or -CH 3 .
  • each R 4a is independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or -CN; each R 4b is independently H or C 1-6 alkyl; and each R 4c is independently H or C 1-6 alkyl.
  • R 4 is selected from the group consisting of optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyridinyl, optionally substituted dihydrothiopyranyl, and optionally substituted tetrahydrothiopyranyl .
  • R 4 is selected from
  • the present disclosure provides a compound, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, selected from the group consisting of compounds of Table A: Table A.
  • the compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the examples given below.
  • the compounds of any of the formulae described herein may be prepared by methods known in the art of organic synthesis as set forth in part by the examples described below. Reference is also made to synthetic descriptions in WO 2020/180768, WO 2020/180770, and WO 2021/092115.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of any formula disclosed herein.
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds of the present disclosure may be suitable for treating diseases characterized by excessive or abnormal cell proliferation such as cancer.
  • cancers/tumors/carcinomas of the head and neck e.g., tumors/carcinomas/cancers of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity (including lip, gum, alveolar ridge, retromolar trigone, floor of mouth, tongue, hard palate, buccal mucosa), oropharynx (including base of tongue, tonsil, tonsillar pilar, soft palate, tonsillar fossa, pharyngeal wall), middle ear, larynx (including supraglottis, glottis, subglottis, vocal cords), hypopharynx, salivary glands (including minor salivary glands); intraocular cancers (e.g., uveal melanoma), and orbital and adnexal cancers; cancers/tumors/carcinomas of the head and neck: e.g., tumors/carcinomas/cancers of the nasal cavity, par
  • All cancers/tumors/carcinomas mentioned above which are characterized by their specific location/origin in the body are meant to include both the primary tumors and the metastatic tumors derived therefrom.
  • epithelial cancers e.g., squamous cell carcinoma (SCC) (carcinoma in situ, superficially invasive, verrucous carcinoma, pseudosarcoma, anaplastic, transitional cell, lymphoepithelial), adenocarcinoma (AC) (well-differentiated, mucinous, papillary, pleomorphic giant cell, ductal, small cell, signet-ring cell, spindle cell, clear cell, oat cell, colloid, adenosquamous, mucoepidermoid, adenoid cystic), mucinous cystadenocarcinoma, acinar cell carcinoma, large cell carcinoma, small cell carcinoma, neuroendocrine tumors (small cell carcinoma, paraganglioma, carcinoid); oncocytic carcinoma; and nonepithilial and mesenchymal cancer
  • the compounds of the present disclosure may be used in therapeutic regimens in the context of first line, second line, or any further line treatments.
  • the compounds of the disclosure may be used for the prevention, short- term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or surgery or other compounds.
  • the above also includes the use of the compounds of the present disclosure in various methods of treating the above diseases by administering a therapeutically effective dose to a patient in need thereof, as well as the use of these compounds for the manufacture of medicaments for the treatment of such diseases, as well as pharmaceutical compositions including such compounds of the disclosure, as well as the preparation or manufacture of medicaments including such compounds of the disclosure, and the like.
  • One aspect of the present disclosure relates to a method of inhibiting S0S1 in a subject in need thereof, the method comprising administering to the subject a S0S1 inhibitor of the present disclosure or a pharmaceutical composition comprising a S0S1 inhibitor of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to a method of treating or preventing a disease that is effected or characterized by modification (including inhibition) of the interaction of S0S1 and a RAS-family protein or RAC1 in a subject in need thereof.
  • the method comprises administering to a subject or patient in need of treatment for diseases or disorders associated with S0S1 modulation an effective amount of a compound or a pharmaceutical composition disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • a method is provided of inhibiting the interaction of S0S1 and a RAS-family protein in a cell or inhibiting the interaction of S0S1 and RAC1 in a cell, the method comprising administering to the cell a compound or a pharmaceutical composition disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • a method is provided of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound or a pharmaceutical composition disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the disease can be, but is not limited to, cancer.
  • the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, JMML (juvenile myelomonocytic leukemia), acute lymphoblastic leukemia/lymphoma, lymphomas, tumors of the central and peripheral nervous system, epithelial and nonepithelial tumors and mesenchymal tumor, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and
  • the disease can be, but is not limited to, cancer.
  • the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas.
  • the cancer comprises a Ras MUT mutation or a NF1 L0F mutati on .
  • the disease can be, but is not limited to, a RASopathy.
  • the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation- Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, and Hereditary gingival fibromatosis.
  • Another aspect of the present disclosure is directed to a method of inhibiting S0S1.
  • the method involves administering to a patient in need thereof an effective amount of a compound or a pharmaceutical composition disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the present disclosure relates to compounds and pharmaceutical compositions thereof capable of modulating the activity of (e.g., inhibiting) S0S1.
  • the present disclosure also relates to the therapeutic use of such compounds or pharmaceutical compositions comprising such compounds, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the disclosed compounds and pharmaceutical compositions can be administered in effective amounts to treat or prevent a disorder or prevent the development thereof in subjects.
  • Another aspect of the present disclosure relates to a compound of any formula, or a pharmaceutical composition thereof, disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, for use in treating or preventing a disease that is affected by modification of the interaction of S0S1 and a RAS-family protein or RAC1.
  • Another aspect of the present disclosure relates to a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, for use in treating or preventing a disease that is characterized by inhibition of the interaction of S0S1 with a RAS-family protein or the interaction of S0S1 with RAC1.
  • Another aspect of the present disclosure relates to a compound of any formula, or a pharmaceutical composition thereof, disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, for use in treating or preventing a disease, wherein the treating or preventing is effected or characterized by inhibition of the interaction of S0S1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RA.
  • Another aspect of the present disclosure relates to a compound of any formula, or a pharmaceutical composition thereof, disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, for use inhibiting the binding of hSOSl to H- or N- or K-RAS including their clinically known mutations and which inhibits the nucleotide exchange reaction catalyzed by hSOSl in the presence of a concentration of 20 pM or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 pM or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder.
  • Another aspect of the present disclosure relates to a compound of any formula, or a pharmaceutical composition thereof, disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, for the manufacture of a medicament for use inhibiting the binding of hSOSl specifically to K- RAS G12C protein or another Ras mutant, as described herein, and which inhibits the nucleotide exchange reaction catalyzed by hSOSl in the presence of a concentration of 20 pM or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 pM or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder.
  • hSOSl specifically to K- RAS G12C protein or another Ras mutant
  • the present disclosure relates to the use of a compound of any formula, or a pharmaceutical composition thereof, disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, in the manufacture of a medicament for treating or preventing a disease.
  • Administration of the disclosed compounds and pharmaceutical composition thereof can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.
  • the disclosed compounds and pharmaceutical compositions thereof can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or polyethylene glycol; for tablets also; c)
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc.
  • the disclosed compound or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.
  • the disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described for instance in U.S. Pat. No. 5,262,564, the contents of which are hereby incorporated by reference.
  • Disclosed compounds or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled.
  • the disclosed compounds or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • the disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a polymer e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • Another aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further include an excipient, diluent, or surfactant.
  • 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 the disclosed compound by weight or volume.
  • the dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, or, in a range of from one amount to another amount in the list of doses.
  • the compositions are in the form of a tablet that can be scored.
  • T he methods of the present disclosure may include a compound of the disclosure used alone or in combination with one or more 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 disclosure may be administered before, after, or concurrently with one or more of such additional therapies.
  • dosages of a compound of the disclosure 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 disclosure 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 disclosure 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. In some embodiments, the one or more additional therapies includes four or more therapeutic agents. [0149] In this Combination Therapy section, all references are incorporated by reference for the agents described, whether explicitly stated as such or not.
  • 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 disclosure may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the disclosure may be used as a neo-adjuvant therapy prior to surgery.
  • Radiation therapy may be used for inhibiting abnormal cell growth or treating a hyperproliferative 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.
  • radioactive isotopes e.g., At-21 1, I- 131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu.
  • Suitable radiation sources for use as a cell conditioner include both solids and liquids.
  • the radiation source can be a radionuclide, such as 1-125, I- 131, Yb-169, Ir-192 as a solid source, I-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 I- 125 or I-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 disclosure can render abnormal cells more sensitive to treatment with radiation for purposes of killing or inhibiting the growth of such cells. Accordingly, this disclosure 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 disclosure, 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. In some embodiments, the compounds of the present disclosure 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 disclosure, 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 compound of the present disclosure may be combined with a second, third, or fourth therapeutic agent, or more.
  • a compound of the present disclosure may be combined with one or more therapeutic agents along with one or more non-drug therapies.
  • a therapeutic agent may be a steroid. Steroids are known in the art. Accordingly, in some embodiments, the one or more additional therapies includes a steroid.
  • Suitable steroids may include, but are not limited to, 21 -acetoxy pregnenolone, 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, fluoromethoIone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenoli
  • 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.
  • cytokine e.g., interferon or an interleukin such as IL-2
  • 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 e.g., cytokine (e.g., interferon or an interleukin such as IL-2)
  • the biologic is an immunoglobulin- based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an F
  • 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).
  • 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., an inhibitory antibody or small molecule inhibitor) of PD-L1.
  • 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/Ig fusion protein).
  • 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, LAG3, 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, LAG3, 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/ MED 10680, BMS936559, MED14736, 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, AB 154, MTIG7192A or OMP-313M32 (etigilimab).
  • anti-TIGIT antibodies are known in the art.
  • 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. Such agents are known in the art.
  • 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 Gleevec® (Imatinib Mesylate), Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); 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 antibiotic 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, deoxydoxorubicin, epi
  • 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, BIBW 2992
  • 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 chloram
  • nitrogen mustards e.g
  • 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 are known in the art.
  • Non-limiting examples of 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 (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.
  • monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®)
  • an anti-cancer agent is an ALK inhibitor.
  • ALK inhibitors are known in the art. Non-limiting examples of 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 W005016894.
  • 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), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof), an S0S1 inhibitor (e.g., B 1-1701963, BI-3406, SDR5, BAY-293, MRTX-0902, or RMC-5845, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof), a Raf inhibitor, a MEK inhibitor
  • RTK Receptor Ty
  • an anti-cancer agent is a Ras inhibitor or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras. Such agents are known in the art.
  • an anti-cancer agent is a Ras inhibitor.
  • the Ras inhibitor targets Ras in its active, or GTP-bound state.
  • 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, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-3312, JAB- 21822, JAB-21000, IBI351, ERAS-3490, RMC-6291, BI 1823911, D-1553, D3S-001, HBI-2438, HS-10370, MK-1084, YL-15293 or GDC-6036.
  • K-Ras G12C such as AMG 510, MRTX1257, MRTX849, JNJ-74699157, LY3499446, ARS-1620, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-3312, JAB- 21822, JAB-21000, IBI351, ERAS-3490,
  • the Ras inhibitor is an inhibitor of K-Ras G12D, such as MRTX1133, JAB-22000, MRTX282, ERAS-4, HRS-4642, BI-2852, ASP3082, TH-Z827, TH-7835 and KD-8.
  • the Ras inhibitor is a K-Ras G12V inhibitor, such as JAB-23000.
  • the Ras inhibitor is JAB-23400.
  • the Ras inhibitor is RMC-6236.
  • the Ras inhibitor is selected from a Ras(ON) inhibitor (that is, Ras in its GTP-bound state) disclosed in the following, incorporated herein by reference in their entireties, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof: WO 2022/235870, WO 2022/235864, WO 2022/060836, WO 2021091982, WO 2021091967, WO 2021091956, and WO 2020132597.
  • Ras inhibitors are known in the art, such as in the following, incorporated herein by reference in their entireties: WO 2023287896, WO
  • the cancer comprises a SHP2 mutation (see, e.g., WO 2022/060583).
  • a cancer comprises a NF1 LOF mutation.
  • the cancer comprises a Ras MUT mutation and a compound of the present disclosure is administered to, e.g., a patient in need thereof, in combination with an additional therapeutic agent, e.g., a MEK inhibitor, such as a MEK inhibitor described herein.
  • an additional therapeutic agent e.g., a MEK inhibitor, such as a MEK inhibitor described herein.
  • the cancer is colorectal cancer and a compound of the present disclosure is administered to, e.g., a patient in need thereof, in combination with an additional therapeutic agent, such as a topoisomerase I inhibitor (e.g., irinotecan).
  • an additional therapeutic agent such as a topoisomerase I inhibitor (e.g., irinotecan).
  • the cancer is non-small cell lung cancer and a compound of the present disclosure is administered to, e.g., a patient in need thereof, in combination with an additional therapeutic agent, e.g., a MEK inhibitor, such as a MEK inhibitor described herein (e.g., trametinib).
  • the cancer is non-small cell lung cancer or colorectal cancer
  • a compound of the present disclosure is administered to, e.g., a patient in need thereof, in combination with a Ras inhibitor, such as a Ras inhibitor described herein (e.g., AMG 510, MRTX1257, LY349946, MRTX849, ARS-3248 (JNJ- 74699157), MRTX1133, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291, RMC-6236, RMC-9805, RMC-8839, GDC-6036, ERAS-3490, ERAS-4, JAB- 22000, JAB-23000, or ARS-1620).
  • a Ras inhibitor such as a Ras inhibitor described herein (e.g., AMG 510, MRTX1257, LY349946, MRTX849, ARS-3248 (JNJ- 74699157), MRT
  • a therapeutic agent that may be combined with a compound of the present disclosure 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. Such agents are known in the art.
  • 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.
  • additional therapeutic agents include FGFR inhibitors, PARP inhibitors, BET inhibitors, PRMT5i inhibitors, MAT2A inhibitors, VEGF inhibitors, and HD AC inhibitors.
  • a therapeutic agent may be a pan-RTK inhibitor, such as afatinib.
  • IGF-1R inhibitors are known in the art and include linsitinib, or a pharmaceutically acceptable salt thereof.
  • EGFR inhibitors are known in the art and include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide or siRNA.
  • 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), HER.2 (NEU, ERBB2), HER3 (ERBB3), and HER (ERBB4).
  • MEK inhibitors are known in the art and 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 AE51-Q58; AF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.
  • PI3K inhibitors are known in the art and include, but are not limited to, wortmannin; 17-hydroxywortmannin analogs described in WO06/044453; 4-[2-(lH- Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l-yl]methyl]thieno[3,2-d]pyrimidin-4- yl]morpholine (also known as pictilisib or GDC-0941 and described in W009/036082 and W009/055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5- c]quinolin-l-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in W006/122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl
  • 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 are known in the art and 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.
  • mTOR inhibitors include, but are not limited to, ATP-competitive mTORCl/mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-l-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; W094/09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO98/02441 and WOOl/14387, e.g.
  • ATP-competitive mTORCl/mTORC2 inhibitors e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-l-benzopyran-4-one derivatives; and rapa
  • AP23464 and AP23841 40-(2-hydroxyethyl)rapamycin; 40- [3 -hydroxy (hy droxymethyl)m ethylpropanoate] - rapamycin (also known as CC1779); 40-epi-(tetrazolyt)-rapamycin (also called ABT578); 32-deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin; derivatives disclosed in W005/005434; derivatives disclosed in U.S. Patent Nos.
  • the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990 and WO2019212991), such as
  • RMC-5552 having the structure:
  • BRAF inhibitors that may be used in combination with compounds of the disclosure are known in the art and 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; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E.
  • MCL-1 inhibitors are known in the art and 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
  • the additional therapeutic agent is a SHP2 inhibitor.
  • SHP2 inhibitors are known in the art.
  • SHP2 is a non-receptor 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 kin
  • 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
  • Non-limiting examples of such SHP2 inhibitors include: Chen et al. Mol Pharmacol. 2006, 70, 562; Sarver et al., J. Med. Chem. 2017, 62, 1793; Xie et al., J. Med. Chem.
  • 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 RMC-4550. In some embodiments, the SHP2 inhibitor is ERAS-601. In some embodiments, the SHP2 inhibitor is BBP-398. In some embodiments, the SHP2 inhibitor is TNO155, having the structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. In some embodiments, the SHP2 inhibitor is RMC-4630, having the structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the SHP2 inhibitor is JAB-3068, having the structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the SHP2 inhibitor is JAB-3312.
  • the SHP2 inhibitor is the following compound: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the SHP2 inhibitor is RLY-1971, having the structure: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • 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, 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 is used in combination with a MEK inhibitor and a S0S1 inhibitor of the present disclosure.
  • a Ras inhibitor is used in combination with a PD-L1 inhibitor and a S0S1 inhibitor of the present disclosure.
  • Proteasome inhibitors are known in the art and 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-Ll, anti-CTLA4, anti-LAGl, and anti-OX40 agents).
  • IMDs immunomodulatory imides
  • GITR agonists e.g., CAR-T cells
  • bispecific antibodies e.g., BiTEs
  • 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).
  • Exemplary anti-PD-1 antibodies and methods for their use are described by Goldberg et al., Blood 2007, 110(1): 186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6): 1757-1761; and WO06/121168 Al), as well as described elsewhere herein.
  • FGFR inhibitors are known in the art, such as pemigatinib and erdafitinib, including FGFR2 inhibitors and FGFR4 inhibitors. See, e.g., Cancers (Basel), 2021 Jun; 13(12) 2968.
  • BET inhibitors are known in the art, such as romidepsin, panobinostat and belinostat. See, e.g., British J. Cancer 124: 1478 (2021).
  • PRMT5i inhibitors are known in the art, such as PF-0693999, PJ-68 and MRTX1719. See, e.g., Biomed. Pharmacotherapy 144: 112252 (2021).
  • MAT2A inhibitors are known in the art, such as AG-270 and IDE397. See, e.g., Exp Opin Ther Patents (2022) DOI: 10.1080/13543776.2022.2119127.
  • 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, U.S. Pat. No. 8,586,023, W02010/003118, and WO201 1/090754; or an anti-GITR antibody described, e.g., in U.S. Pat. No. 7,025,962, EP 1947183, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, U.S. Pat. No.
  • an anti-angiogenic agent is an anti-angiogenic agent.
  • Anti -angiogenic agents are known in the art and 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-metalloproteinase 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), VEGF inhibitors, 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 domain receptor
  • 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,
  • agents that specifically bind and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as Scatter Factor), and antibodies or antigen binding regions that specifically bind its receptor, c-Met.
  • HGF hepatocyte growth factor
  • c-Met antibodies or antigen binding regions that specifically bind its receptor, c-Met.
  • Autophagy inhibitors are known in the art and 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 disclosure is an anti -neoplastic agent, which are known in the art.
  • 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), dacli
  • Additional examples of 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
  • an additional compound used in combination therapy with a compound of the present disclosure is selected from the group consisting of a CDK4/6 inhibitor (e.g., abemaciclib, palbociclib, or ribociclib), a KRAS:GDP G12C inhibitor (e.g., AMG 510, MRTX1257, MRTX849) or other mutant Ras:GDP inhibitor, a KRAS:GTP G12C inhibitor or other mutant Ras:GTP inhibitor (e.g., a Ras inhibitor described in WO 2020/132597, WO 2021/091956, WO 2021/091982, WO 2021/091967, WO 2022/060836; RMC-6291, RMC-6236, RMC-9805 or RMC-8839), a MEK inhibitor (e.g., refametinib, selumetinib, trametinib, or cobimetinib), a SHP2 inhibitor (e.
  • a S0S1 inhibitor may be used in combination with a Ras inhibitor, a SHP2 inhibitor, or a MEK inhibitor.
  • a combination therapy includes a S0S1 inhibitor, a RAS inhibitor and a MEK inhibitor.
  • an additional compound used in combination therapy with a compound of the present disclosure is selected from the group consisting of ABT-737, AT-7519, carfilzomib, cobimetinib, danusertib, dasatinib, doxorubicin, GSK- 343, JQ1, MLN-7243, NVP-ADW742, paclitaxel, palbociclib and volasertib.
  • an additional compound used in combination therapy with a compound of the present disclosure is selected from the group consisting of neratinib, acetinib and reversine.
  • 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 disclosure 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 disclosure 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 disclosure can be administered and followed by any of the therapies described herein, or vice versa.
  • a compound of the disclosure and any of the therapies described herein are administered a few minutes apart, or a few hours apart, or a few days apart.
  • a combination therapeutic regimen employs two therapeutic agents, one compound of the present disclosure and a second selected from the therapeutic agents described herein. In some embodiments, a combination therapeutic regimen employs three therapeutic agents, one compound of the present disclosure and two selected from the therapeutic agents described herein. In some embodiments, a combination therapeutic regimen employs four or more therapeutic agents, one compound of the present disclosure and three selected from the therapeutic agents described herein.
  • the first therapy e.g., a compound of the disclosure
  • 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 disclosure) 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 disclosure) 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 disclosure, 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.
  • Embodiment 1 is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein:
  • R 1 is selected from the group consisting of optionally substituted 6-membered aryl and optionally substituted 5-6 membered heteroaryl;
  • R 2 is selected from the group consisting of H and optionally substituted C 1-6 alkyl
  • Embodiment 2 is a compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 1 is optionally substituted 6-membered aryl.
  • Embodiment 3 is a compound of embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 1 is
  • Embodiment 4 is a compound of embodiment 1, having the structure of
  • Embodiment 5 is a compound of any one of embodiments 1 through 4, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 2 is H.
  • Embodiment 6 is a compound of any one of embodiments 1 through 4, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 2 is optionally substituted C 1-3 alkyl, wherein the optional substituent is one or more fluoro.
  • Embodiment 7 is a compound of any one of embodiments 1 through 4, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 2 is -CEE.
  • Embodiment 8 is a compound of any one of embodiments 1 through 7, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 3 is -OR 3a , and further wherein R 3a is C 1-3 alkyl.
  • Embodiment 9 is a compound of any one of embodiments 1 through 7, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 3 is -OCH 3 .
  • Embodiment 10 is a compound of any one of embodiments 1 through 9, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 4 is optionally substituted 3-14 membered heterocyclyl.
  • Embodiment 12 is a compound of any one of embodiments 1 through 9, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 4 is selected from the group consisting of optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyridinyl, optionally substituted dihydrothiopyranyl, and optionally substituted tetrahydrothiopyranyl.
  • Embodiment 13 is a compound of any one of embodiments 1 through 9, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, wherein R 4 is selected from the group consisting of
  • Embodiment 14 is a compound of Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, selected from the group consisting of: N-[(1R )-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-8-methoxy-6-(1-methyl-4- piperidyl)pyrido[3,4-d]pyrimidin-4-amine; N-[(1R )-1- [3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-8-methoxy-6-(4- methylpiperazin-1-yl)pyrido[3,4-J]pyrimidin-4-amine; N-[(1R )-1- [3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-8-methoxy-6-(l-methyl-3,6- di
  • Embodiment 15 is a pharmaceutical composition comprising a compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 16 is a method of inhibiting S0S1 in a subject, comprising administering to the subject: a compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of embodiment 15, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Embodiment 17 is a method of inhibiting the interaction of S0S1 and a RAS-family protein in a cell or inhibiting the interaction of S0S1 and RAC1 in a cell, comprising administering to the cell: a compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of embodiment 15, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Embodiment 18 is a method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of S0S1 and a RAS-family protein or by inhibition of the interaction of S0S1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of: a compound of any of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of embodiment 15, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Embodiment 19 is a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of: a compound of any of embodiments 1-14, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof; or a pharmaceutical composition of embodiment 15, or a pharmaceutically acceptable salt, solvate, isomer, stereoisomer, prodrug, or tautomer thereof.
  • Embodiment 20 is a method of embodiment 18 or embodiment 19, wherein the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcomas.
  • the disease or cancer is selected from the group consisting of pancreatic cancer, lung cancer, colorectal cancer, hematological cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid
  • Embodiment 21 is a method of embodiment 19 or embodiment 20, wherein the cancer comprises a Ras MUT or an NF1 LOF mutation.
  • Embodiment 22 is a method of embodiment 18, wherein the disease is a RASopathy.
  • Embodiment 23 is a method of embodiment 22, wherein the RASopathy is selected from the group consisting of Neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facio-Cutaneous Syndrome (CFC), Legius Syndrome, and Hereditary gingival fibromatosis.
  • NF1 Neurofibromatosis type 1
  • NS Noonan Syndrome
  • NML Noonan Syndrome with Multiple Lentigines
  • CM-AVM Capillary Malformation-Arteriovenous Malformation Syndrome
  • CS Costello Syndrome
  • CFC Cardio-Facio-Cutaneous Syndrome
  • Legius Syndrome and Hereditary gingival fibromatosis.
  • Step 1 To a mixture of N-[(1R )-1- [3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6- (1,1 -di oxo-3, 6-dihydro-2H -thiopyran-4-yl)-8-m ethoxy -pyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.21 mmol) in MeOH (10 mL) was added 10% Pd on carbon (10 mg). The mixture was stirred under an atmosphere of H2 (50 psi) at rt for 2 h, then filtered and the filtrate was concentrated under reduced pressure.
  • H2 50 psi
  • Tetrahydrothiopyran-4-one (272 mg, 2.34 mmol) was added, and the mixture was stirred at -78°C for 2 h, then diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered.
  • a sealed tube containing a mixture of methyl 3-amino-2,6-dibromo- pyridine-4-carboxylate (1.0 g, 3.2 mmol), MeCN (10 mL) and MeSCLH (2.0 mL, 28.1 mmol) was heated to 120°C and stirred for 12 h.
  • the mixture was adjusted to pH ⁇ 7 by addition of aqueous NaOH, then filtered and the filtrate was concentrated under reduced pressure to give 6,8-dibromo-2-methyl-pyrido[3,4-J]pyrimidin-4-ol (450 mg, 44% yield) as a solid.
  • Step 2 To a mixture of 6,8-dibromo-2-methyl-pyrido[3,4-J]pyrimidin-4- (200 mg, 0.63 mmol) in 1,4-dioxane (2 mL) was added CH 3 ONa, 30% purity (339 mg, 1.88 mmol). The mixture was heated to 100°C and stirred for 12 h, then concentrated under reduced pressure. The residue was triturated with petroleum ether (5 mL) then filtered, and the filtrate was concentrated under reduced pressure to give 6-bromo-8-methoxy-2-methyl- pyrido[3,4-d ]pyrimidin-4-ol (169 mg) as a solid.
  • Step 1 To a mixture of 6-bromo-N-[(1R )-1- [3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-8-methoxy-pyrido[3,4-d]pyrimidin-4-amine (2.5 g, 5.85 mmol) and 2-(3,6- dihydro-2H -thiopyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (3.97 g, 17.56 mmol) in 1,4-dioxane (75 mL) and H 2 O (15 mL) under an atmosphere of N 2 was added Cs 2 C O 3 (5.72 g, 17.56 mmol) and Pd(dppf)C12 (856 mg, 1.17 mmol). The mixture was heated to 100°C and stirred for 2 h, then quenched by addition H2O (100 mL) and extracted with
  • Step 1 To a mixture of 6-bromo-N-[(1R )-1- [3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-8-methoxy-pyrido[3,4-d]pyrimidin-4-amine (1.0 g, 2.3 mmol) and 2-(3,6- dihydro- 2H -thiopyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.59 g, 7.0 mmol) in 1,4-di oxane (10 mL) and H2O (2 mL) under an atmosphere of N2 was added Pd(dppf)C1 2 (343 mg, 0.47 mmol) and Cs 2 CO 3 (2.29 g, 7.0 mmol).
  • the purpose of this assay is to measure the ability of test compounds to inhibit S0S1 function in cells.
  • S0S1 activates RAS proteins by catalyzing the conversion of RAS GDP to RAS GTP in response to receptor tyrosine kinase activation.
  • Activation of RAS induces a sequence of cellular signaling events that results in increased phosphorylation of ERK at Threonine 202 and Tyrosine 204 (pERK).
  • pERK Threonine 202 and Tyrosine 204
  • the procedure described below measures the level of cellular pERK in response to test compounds in PC- 9 cells (EGFR Exl9Del).
  • PC-9 cells were grown and maintained using media and procedures recommended by the ATCC. On the day prior to compound addition, cells were plated in 384-well cell culture plates (40 pL/well) and grown overnight in a 37°C, 5% CO2 incubator. Test compounds were prepared in 10, 3 -fold dilutions in DMSO, with a top concentration of 10 mM. On the day of the assay, 40 nL of test compound was added to each well of cell culture plate using an Echo550 liquid handler (LabCyte). Concentrations of test compound were tested in duplicate with highest test concentration being 10 pM. After compound addition, cells were incubated for 1 hour at 37°C, 5% CO2. Following incubation, culture medium was removed and cells were washed once with phosphate buffered saline.
  • Cellular pERK level was determined using the AlphaLISA SureFire Ultra p-ERKl/2 Assay Kit (PerkinElmer). Cells were lysed in 25 pL lysis buffer, with shaking at 600 RPM at room temperature for 15 minutes. Lysate (10 pL) was transferred to a 384- well Opti-plate (PerkinElmer) and 5 pL acceptor mix was added. The plate was centrifuged at 1000 RPM for 1 minute, and incubated in the dark for 2 hours. Following this incubation, 5 pL of donor mix was added, the plate was sealed and centrifuged at 1000 RPM for 1 minute, and the mixture was incubated for 2 hours at room temperature.
  • Mode of Action Assay Inhibition of SOS1 Nucleotide Exchange Activity [0341] The purpose of this assay was to characterize the inhibitory activity of compounds on S0S1 nucleotide exchange of KRAS. Data was reported as IC 50 values based on the TR-FRET signal.
  • concentration series of test compounds were generated spanning 100 pM to 1.7 nM over eleven 3-fold serial dilutions in a 384- well assay plate at a volume of 20 pL.
  • the purified tagless catalytic domain of S0S1 was first diluted in assay buffer at a concentration of 100 nM, and then 20 ⁇ L of the S0S1 containing solution was directly dispensed into compound plates.
  • the SOSl/compound mixture was incubated at room temperature with constant mixing on an orbital shaker for 20 minutes to allow the reaction to reach equilibrium.
  • a KRAS mixture was prepared by diluting 66.7 nM avi-tagged KRAS (residue 1 - 169), 3.33 nM Streptavidin-Tb and 333 nM EDA-GTP-DY-647P1 in assay buffer. This mixture was prepared immediately before addition to the SOSl/compound mixture to prevent intrinsic nucleotide exchange. Then 5 pL of the pre-incubated SOSl/compound mixture and 7.5 ⁇ L of the KRAS mixture were added sequentially in a 384-well low volume black round bottom plate and incubated at room temperature with constant shaking for 30 minutes.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des modulateurs de SOS1 et leur utilisation dans le traitement d'une maladie. L'invention concerne également des compositions pharmaceutiques les comprenant.
PCT/US2023/020638 2022-05-03 2023-05-02 Inhibiteurs de sos1 et leurs utilisations Ceased WO2023215256A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263364083P 2022-05-03 2022-05-03
US63/364,083 2022-05-03

Publications (1)

Publication Number Publication Date
WO2023215256A1 true WO2023215256A1 (fr) 2023-11-09

Family

ID=88646905

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/020638 Ceased WO2023215256A1 (fr) 2022-05-03 2023-05-02 Inhibiteurs de sos1 et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2023215256A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019122129A1 (fr) * 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
US20210139517A1 (en) * 2019-11-08 2021-05-13 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019122129A1 (fr) * 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
US20210139517A1 (en) * 2019-11-08 2021-05-13 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE ANONYMOUS : "CHEMBL3219712", XP093108837, retrieved from PUBCHEM *
DATABASE PUBCHEM SUBSTANCE ANONYMOUS : "SCHEMBL12619526", XP093108840, retrieved from PUBCHEM *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

Similar Documents

Publication Publication Date Title
US12258366B2 (en) Bicyclic heteroaryl compounds and uses thereof
US11993597B2 (en) Inhibitors of KRAS G12C and methods of using the same
AU2020232242A1 (en) Bicyclic heteroaryl compounds and uses thereof
WO2022146698A1 (fr) Inhibiteurs de sos1 et leurs utilisations
WO2020180770A1 (fr) Composés hétérocyclyle bicycliques et leurs utilisations
AU2019278998A1 (en) KRAS G12C inhibitors and methods of using the same
AU2020383535A1 (en) Improved synthesis of KRAS G12C inhibitor compound
EP4058453A1 (fr) Synthèse améliorée de composé inhibiteur de kras g12c
TW202448897A (zh) Ｒａｓ抑制劑之結晶形式、含有其之組合物及其使用方法
WO2022240947A1 (fr) Utilisation d'inhibiteurs de sos1 avec des inhibiteurs de mtor pour traiter des cancers
US20240051956A1 (en) Sos1 inhibitors and uses thereof
WO2023215256A1 (fr) Inhibiteurs de sos1 et leurs utilisations
WO2023215257A2 (fr) Inhibiteurs de sos1 et leurs utilisations
WO2025137507A1 (fr) Inhibiteurs de sos1 et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23799900

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23799900

Country of ref document: EP

Kind code of ref document: A1