WO2022146698A1 - Sos1 inhibitors and uses thereof - Google Patents

Sos1 inhibitors and uses thereof Download PDF

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Publication number
WO2022146698A1
WO2022146698A1 PCT/US2021/063685 US2021063685W WO2022146698A1 WO 2022146698 A1 WO2022146698 A1 WO 2022146698A1 US 2021063685 W US2021063685 W US 2021063685W WO 2022146698 A1 WO2022146698 A1 WO 2022146698A1
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membered
alkyl
formula
pharmaceutically acceptable
prodrug
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PCT/US2021/063685
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French (fr)
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Andreas BUCKL
Severin THOMPSON
Adrian L. Gill
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Revolution Medicines, Inc.
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Priority to JP2023539813A priority Critical patent/JP2024503280A/en
Priority to CN202180094497.6A priority patent/CN116916914A/en
Priority to EP21916206.2A priority patent/EP4271374A1/en
Publication of WO2022146698A1 publication Critical patent/WO2022146698A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

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 SOS1/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
  • 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.
  • SOS1-activation of RAS-family proteins can also be mediated by the interaction of SOS1/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 (7511):543-50). Meanwhile over-expression of SOS1 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 SOS1 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).
  • SOS1 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).
  • SOS2 Son of Sevenless 2
  • SOS1 a homolog of SOS1 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).
  • SOS2 Son of Sevenless 2
  • SOS1/RAS-family protein driven cancers or other SOS1/RAS-family protein pathologies
  • SOS1/RAS-family protein pathologies or normal cells and tissues.
  • 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.).
  • High potency towards inhibition of SOS1:RAS-family protein binding (nanomolar level IC50 values) and ERK phosphorylation in cells (nanomolar level IC50 values) are desirable characteristics for a SOS1 inhibitor compound.
  • a desirable characteristic of a SOS1 inhibitor compound would be the selective inhibition of SOS1 over SOS2. This conclusion is based on the viable phenotype of SOS1 knockout mice and lethality of SOS1/SOS2 double knockout mice, as described above.
  • the present disclosure relates to compounds capable of inhibiting the activity of SOS1.
  • 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), Formula (II), or Formula (III):
  • X 1 is NH or S
  • X 2 is CH or N
  • X 3 is CH or N
  • X 4 is CR 3 or N
  • X 5 is CH or N
  • X6 is CH or N
  • R 1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl
  • R2 is selected from the group consisting of H, -NH-C 1-6 alkyl, and –NH2
  • R 3 is selected from the group consisting of H, -O-C 1-6 alkyl, and -O-C 1-6 heteroalkyl
  • L 4 is a bond or O
  • R 4 is selected from the group consisting of H, C 1-6 alkyl, 3-14 membered cycloalkyl, 3
  • R5, R6, R7, R8, and R9 are independently selected from the group consisting of 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)2NR 11 R 12 , –S(O)2R 10 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2R 11 R 11 , –NR 10 S(O)2R 11
  • Another aspect of the present disclosure relates to compounds of Formula (Ib), (IIb), or (IIIb): , or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X6, R2, L4, and R 4 are as defined in Formula (I), (II), or (III); R5, R6, and R7 are independently selected from the group consisting of H, D, C 1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 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
  • R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of 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 , –
  • Another aspect of the present disclosure relates to compounds of Formula (II-1): , or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R 1 and R 4 are as defined in Formula (II).
  • Another aspect of the present disclosure relates to compounds of Formula (III-1) or (III-2): or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R 1 , R 2 , and R 4 are as defined in Formula (III).
  • One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject a SOS1 inhibitor of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to methods of treating or preventing a disease that is effected by or characterized by inhibition of the interaction of SOS1 and a RAS-family protein and/or RAC1 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, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to methods of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to methods 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, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure relates to methods of inhibiting SOS1.
  • the method comprises administering to a patient in need thereof, an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof.
  • Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can further comprise an excipient, diluent, or surfactant.
  • the pharmaceutical composition can be effective for treating or preventing a disease associated with SOS1 modulation in a subject in need thereof.
  • the pharmaceutical composition can be effective for treating or preventing a cancer in a subject in need thereof.
  • Another aspect of the present disclosure relates to a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, for use in treating or preventing a disease associated with SOS1 modulation.
  • Another aspect of the present disclosure relates to a compound of the present disclosure, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, for use in treating or preventing a disease cancer.
  • Another aspect of the present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, in the manufacture of a medicament for treating or preventing a disease associated with SOS1 modulation.
  • Another aspect of the present disclosure relates to the use of a compound of the present disclosure, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, in the manufacture of a medicament for treating or preventing cancer.
  • the present disclosure also provides compounds that are useful in inhibiting SOS1.
  • 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 may mean a straight chain or branched saturated chain having from 1 to 10 carbon atoms.
  • Representative 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- methyl-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 octyl and the like.
  • 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. [0037] As used herein, the term “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). The heteroatom may appear in the middle or at the end of the radical.
  • a heteroatom e.g., an O, N, or S atom
  • alkenyl means an aliphatic hydrocarbon group containing a carbon—carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl 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 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 about 6 carbon atoms 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. Exemplary 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.
  • 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.
  • 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., C3-C20 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.
  • Examples of cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl ( ), 2-(2,3-dihydro-1H-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-1H-indene) is a C5 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-1H-indene): .
  • aryl rings can be further characterized by the number of 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).
  • 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.
  • rings e.g., 5, 6, 7, 8, 9, or 10- membered rings
  • 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 examples 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) .
  • 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.
  • 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.
  • pyridine is a 6-membered heteroaryl having 6 annular atoms.
  • the disclosure also includes pharmaceutical 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.
  • 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, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium, mal
  • 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.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 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.
  • substitution with heavier isotopes such as deuterium 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. Preparations of isotopically labelled compounds are known to those of skill in the art.
  • isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • 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.
  • 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.
  • the term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/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 the compounds herein may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • 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.
  • 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.
  • 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.
  • treating refers to improving at least one symptom of the subject’s disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
  • prevent or “preventing” with regard to a subject 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.
  • the terms “inhibiting” and “reducing,” or any variation of these terms includes any measurable or complete inhibition to achieve a desired result.
  • disorder 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., SOS1:Ras-family protein binding activity) compared to normal.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a disclosed compound or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer 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.
  • 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.
  • the present disclosure relates to compounds having a structure of Formula (I), Formula (II), or Formula (III): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein: X 1 is NH or S; X 2 is CH or N; X 3 is CH or N; X 4 is CR3 or N; X 5 is CH or N; X 6 is CH or N; R1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, -NH-C 1-6 alkyl, and –NH2; R3 is selected from the group consisting of H, -O-C 1-6 alkyl
  • R1 is optionally substituted 6-membered aryl.
  • the 6-membered aryl has the following structure: wherein R 5 , R 6 , R 7 , R 8 , and R 9 are as defined below in connection with Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3).
  • R1 is optionally substituted 5-6 membered heteroaryl.
  • R 1 is a 6-membered heteroaryl having any of the following structures: (IIIc-3).
  • R1 is the optionally substituted 5-6 membered heteroaryl.
  • R1 is a 5-membered heteroaryl having the following structure: wherein R 5 , R 6 , and R 7 are as defined below in connection with Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3).
  • the present disclosure relates to compounds having the structure selected from the group consisting of Formula (Ia), Formula (IIa), and Formula (IIIa): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 2 , L 4 , and R 4 are as defined in Formulas (I), (II), or (III); R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of 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
  • R5, R6, and R7 are independently selected from the group consisting of H, D, C 1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 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)2R 10 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)(O)2NR 11 R 12 , –NR 10 S(O)2NR
  • the present disclosure relates to compounds having the structure selected from the group consisting of Formula (Ic-1), Formula (Ic-2), Formula (Ic-3), Formula (IIc-1), Formula (IIc-2), Formula (IIc-3), Formula (IIIc-1), Formula (IIIc- 2), and Formula (IIIc-3):
  • R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of 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)2NR 11 R 12 , –S(O)2R 10 , –NR 10 S(O)2NR
  • the present disclosure relates to compounds having the structure of Formula (Ic-1), Formula (Ic-2), Formula (IIc-1), Formula (IIc-2), Formula (IIIc-1), or Formula (IIIc-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl, wherein the alkyl is optionally substituted with halogen. In one embodiment, the alkyl is substituted with halogen.
  • the alkyl is substituted with halogen.
  • the alkyl is substituted with halogen.
  • the alkyl is substituted with halogen.
  • the alkyl is substituted with halogen.
  • the alkyl is substituted with halogen.
  • any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9 forms a 3-14 membered fused ring.
  • any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9 forms a 3-8 membered fused ring.
  • any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9 forms a 4-8 membered fused ring.
  • any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9 forms a 4-membered fused ring or a 5-membered fused ring.
  • the fused ring is a 3-8 membered heterocyclyl or a 3-8 membered cycloalkyl. In some embodiments, the fused ring is a 4-8 membered heterocyclyl or a 4-8 membered cycloalkyl. In some embodiments, the fused ring is a 4-membered heterocyclyl or a 5-membered heterocyclyl. In some embodiments, the fused ring is a 4-membered cycloalkyl or a 5-membered cycloalkyl.
  • the fused ring is optionally substituted with halogen.
  • the fused ring is optionally substituted with halogen.
  • one or more of R 5 , R 6 , R 7 , R 8 , and R 9 is selected from among –CF 3 , -CHF 2 , –NH 2 , –F, and –CF 2 CH 2 OH.
  • one of R5, R6, R7, R8, and R9 is –CF3 and one of R5, R6, R7, R8, and R9 is –NH2.
  • one of R5, R6, R7, R8, and R9 is –F and one of R 5 , R 6 , R 7 , R 8 , and R 9 is –CF 2 CH 2 OH.
  • R5 is selected from among: ,
  • R1 is selected from among: .
  • R1 is selected from among: .
  • R1 is selected from among: , [0086] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is selected from among: , [0086] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R 1 is selected from among: .
  • the present disclosure relates to compounds having the structure selected from the group consisting of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), and Formula (Ic-3) or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • X 1 is NH
  • X 2 is CH
  • X 3 is CH
  • X 4 is N
  • X 5 is CH.
  • X 1 is NH
  • X 2 is N
  • X 3 is CH
  • X 4 is N
  • X 5 is CH.
  • X 1 is NH
  • X 2 is N
  • X 3 is CH
  • X 4 is CR 3
  • X 5 is CH.
  • X 1 is S
  • X 2 is CH
  • X 3 is CH
  • X 4 is CR 3
  • X 5 is CH.
  • X 1 is NH
  • X 2 is N
  • X 3 is N
  • X 4 is CR3
  • X 5 is CH.
  • X 1 is NH
  • X 2 is CH
  • X 3 is N
  • X 4 is CR3
  • X 5 is CH.
  • X 1 is NH
  • X 2 is CH
  • X 3 is CH
  • X 4 is CR3
  • X 5 is N.
  • X 1 is NH
  • X 2 is CH
  • X 3 is CH
  • X 4 is CR 3
  • X 5 is CH.
  • R 3 is H. In some embodiments, R 3 is –O-C 1-3 alkyl. In some embodiments, R 3 is – O-CH 3 . In some embodiments, R 3 is –O-C 1-3 heteroalkyl. In some embodiments, R 3 is H or –O-CH3.
  • L 4 is a bond. In some embodiments, L4 is O.
  • the present disclosure relates to compounds having the structure selected from the group consisting of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), and Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • X 1 is NH and X 4 is CH.
  • R3 is H.
  • R 3 is –O-C 1-3 alkyl. In some embodiments, R 3 is –O-CH 3 . In some embodiments, R3 is –O-C1-3 heteroalkyl. In some embodiments, R3 is H or –O-CH3.
  • the present disclosure relates to compounds having the structure selected from the group consisting of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), and Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • X 5 is CH and X6 is N.
  • X 5 is CH and X6 is CH.
  • R2 is H.
  • R2 is NH2.
  • R 2 is –NH-CH 3.
  • the compound has the structure selected from the group consisting of:
  • the compound has the structure of Formula (II-1): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 1 , R 3 , L 4 , and R 4 are as defined in Formula (I).
  • the compound has the structure of Formula (II-1): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 1 and R 4 are as defined in Formula (II).
  • the compound has the structure of Formula (III-1) or Formula (III-2): or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1, R2, and R 4 are as defined in Formula (III).
  • R 4 is selected from the group consisting of H, C 1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
  • R 4 is selected from the group consisting of H, C 1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl;
  • R 4a is H, C 1-6 alkyl, C 1-6 haloalkyl, –C(O)R 4b , –C(O)NR 4b R 4 c, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with
  • R 4 is 3-14 membered heterocyclyl.
  • R 4 is a substituted 3-14 membered heterocyclyl.
  • R 4 is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl.
  • the heterocyclyl substituent is oxetanyl.
  • R 4 is 3-14 membered heterocyclyl substituted with C 1-6 alkyl.
  • R 4 is 3-14 membered heterocyclyl substituted with –CH3.
  • R 4 is 3-14 membered heterocyclyl substituted with –CH2–, i.e., the substituent is a methylene bridge bridging 2 carbon atoms in the heterocyclyl ring.
  • R 4 is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl.
  • the cycloalkyl substituent is cyclopropyl.
  • the C 1-6 alkyl is –CH3.
  • R 4 is 3-14 membered heterocyclyl substituted with –C(O)
  • R 4a is C 1-6 alkyl. In one embodiment, R 4a is –CH3. [0120] In some embodiments, of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R 4 is a heterocyclyl selected from among: [0121] In some embodiments, R 4 is a heterocyclyl selected from among: . [0122] In some embodiments,
  • R 4 is a heterocyclyl selected from among: [0124] In some embodiments, R 4 is a heterocyclyl selected from among: [0125] In some embodiments, R 4 is a heterocyclyl selected from among:
  • R 4 is a heterocyclyl selected from among:
  • R 4 is a heterocyclyl selected from among: . [0128] In some embodiments, R 4 is a heterocyclyl selected from among: [0129] In some embodiments, R 4 is a heterocyclyl selected from among: [0130] In some embodiments, R 4 is a heterocyclyl selected from among: [0131] In some embodiments, R 4 is a heterocyclyl selected from among: [0132] In some embodiments, R 4 is a heterocyclyl selected from among: [0134] In some embodiments, R 4 is a heterocyclyl selected from among: [0135] In some embodiments, R 4 is selected from among: .
  • R 4 is selected from among: , [0137] In some embodiments, R 4 is 3-14 membered cycloalkyl. In some embodiments, R 4 is substituted 3-14 membered cycloalkyl. [0138] In some embodiments, R 4 is selected from among:
  • R 4 is 6-10 membered aryl. In some embodiments, R 4 is substituted 6-10 membered aryl. In some embodiments, R 4 is phenyl. In some embodiments, R 4 is phenyl substituted with one or two group selected from among –OCH 3 and –CN. [0140] In some embodiments, R 4 is 5-10 membered heteroaryl. In some embodiments, R 4 is substituted 5-10 membered heteroaryl.
  • R 4 is selected from among 1H-pyrrole, thiazole, pyridine, pyridazine, pyrimidine, each of which is optionally substituted with a group selected from among –F, –OCH3, and – OCH2CH2OH. [0141] In some embodiments, R 4 is selected from among: [0142] 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 schemes 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 following synthetic schemes and examples. In the schemes described below, it is well understood that 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).
  • 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). Preparation of Compounds [0146]
  • the compounds described in this disclosure may be synthesized from commercially available starting materials using known organic, inorganic, and/or enzymatic processes. [0147]
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • phenylethyl 1H-indazole-7- carboxamide or analogous halogenated heterocyclic ring can then be used for cross coupling reactions with appropriately substituted, amines, amides, alkyls, olefins, aromatics, or heteroaromatics. Additional deprotection and/or functionalization steps can be required to produce the final compound.
  • final compounds with an oxygen substituent in position 5 can be prepared through an SNAr reaction between an alcohol and methyl 5-fluoro-1H- indole-7-carboxylate or an analogous appropriately substituted halogenated heterocycle, as outlined in Scheme 2.
  • Scheme 2 [0151] A general synthesis of substituted 1H-pyrrolo[3,2-b]pyridine-7- carboxamides or analogous heterocycles is outlined in Scheme 3.
  • Scheme 3 [0152] 3-amino-6-bromopyridine or an analogous appropriately substituted halogenated heterocyclic ring can undergo cross coupling reactions with appropriately substituted, amines, amides, alkyls, olefins, aromatics, or heteroaromatics.
  • the resulting intermediate can then be used in a cross-coupling reaction with an appropriate terminal alkyne.
  • the resulting 2-alkynylpyridin-3-amine can then undergo an intramolecular hydroamination in the presence of a Cu catalyst.
  • the resulting 7-chloro-1H-pyrrolo[3,2- b]pyridine or analogous appropriately halogenated heterocycle can then be coupled to appropriately substituted benzyl amine in the presence of carbon monoxide a palladium catalyst. Additional deprotection and/or functionalization steps can be required to produce the final compound.
  • the appropriately substituted benzyl amine building block can be prepared as outlined in Scheme 4.
  • aryl or heteroaryl bromides can be transformed into the corresponding acetyl arene or heteroarene by metal halogen exchange followed by the addition of an acetylating reagent.
  • the ketone functionality can then be stereoselectively transformed into the desired chiral benzylamine using Ellman’s reagent.
  • Scheme 4 [0154] Due to their biological properties the compounds of the present disclosure, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms 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;
  • intraocular cancers e.g., uveal melanoma
  • orbital and adnexal cancers e.g
  • 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.
  • All cancers/tumors/carcinomas mentioned above may be further differentiated by their histopathological classification: - 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, acina
  • 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 invention may be used for the prevention, short- term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy and/or surgery and/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 invention, as well as the preparation and/or manufacture of medicaments including such compounds of the invention, and the like.
  • One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject a SOS1 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 SOS1 and a RAS-family protein and/or RAC1 in a subject in need thereof.
  • the method involves administering to a subject or patient in need of treatment for diseases or disorders associated with SOS1 modulation an effective amount of a compound of any formula 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 SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of any formula 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 of any formula 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 sarcomas.
  • pancreatic cancer lung cancer, colorectal cancer, hematological
  • the cancer is colorectal cancer or pancreatic cancer.
  • 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 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.
  • NF1 Neurofibromatosis type 1
  • NS Noonan Syndrome
  • NSML 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.
  • Another aspect of the present disclosure is directed to a method of inhibiting SOS1.
  • the method involves administering to a patient in need thereof an effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • a compound of any formula disclosed herein or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the present disclosure relates to compositions capable of modulating the activity of (e.g., inhibiting) SOS1.
  • the present disclosure also relates to the therapeutic use of such compounds or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • the disclosed compound can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.
  • 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 affected by modification of the interaction of SOS1 and a RAS-family protein and/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 SOS1 with a RAS-family protein or the interaction of SOS1 with 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, wherein the treating or preventing is effected or characterized by inhibition of the interaction of SOS1 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, for use inhibiting the binding of hSOS1 to H- or N- or K-RAS including their clinically known mutations and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 ⁇ or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 ⁇ 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 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 hSOS1 specifically to K-RAS G12C protein or another Ras mutant, as described herein, and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 ⁇ or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 ⁇ or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder.
  • the present disclosure relates to the use of a compound of any formula 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 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.
  • the disclosed compounds or pharmaceutical compositions 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 and/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 and/or polyethylene glycol; for tablets also
  • 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.
  • disclosed compounds are not covalently bound to 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 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.
  • 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.
  • Effective dosage amounts of the disclosed compounds or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, when used for the indicated effects range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat 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.
  • Combination Therapy [0188]
  • the methods of the 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).
  • Combination therapy may, for example, combine two therapies or may combine three therapies (e.g., a triple therapy of three therapeutic agents), or more.
  • the dosages of one or more of the additional therapies e.g., non-drug treatments or therapeutic agents
  • 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 invention and dosages of the one or more additional therapies provide a therapeutic effect (e.g., synergistic or additive therapeutic effect).
  • a compound of the present invention and an additional therapy such as an anti-cancer agent, may be administered together, such as in a unitary pharmaceutical composition, or separately and, when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time.
  • the additional therapy is the administration of side- effect limiting agents (e.g., agents intended to lessen the occurrence or severity of side effects of treatment.
  • the compounds of the present disclosure can also be used in combination with a therapeutic agent that treats nausea.
  • 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).
  • a therapeutic agent e.g., a compound or biologic that is an anti-angiogenic agent, signal transduction inhibitor, antiproliferative agent, glycolysis inhibitor, or autophagy inhibitor.
  • the one or more additional therapies includes two therapeutic agents.
  • the one or more additional therapies includes three therapeutic agents.
  • the one or more additional therapies includes four or more therapeutic agents.
  • Non-drug therapies [0192] Examples of 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.
  • the compounds of the disclosure may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the invention may be used as a neo-adjuvant therapy prior to surgery.
  • Radiation therapy may be used for inhibiting abnormal cell growth or treating a hyperproliferative disorder, such as cancer, in 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.
  • the term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, 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 of the present invention include both solids and liquids.
  • the radiation source can be a radionuclide, such as I-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 invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention, which amount is effective to sensitize abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
  • the compounds of the present invention may be used as an adjuvant therapy after radiation therapy or as a neo-adjuvant therapy prior to radiation therapy.
  • the non-drug treatment is a T cell adoptive transfer (ACT) therapy.
  • the T cell is an activated T cell.
  • the T cell may be modified to express a chimeric antigen receptor (CAR).
  • CAR modified T (CAR-T) cells can be generated by any method known in the art.
  • the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject.
  • T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S.
  • a desirable protein e.g., a CAR
  • a therapeutic agent may be a compound used in the treatment of cancer or symptoms associated therewith.
  • a therapeutic agent may be a steroid.
  • the one or more additional therapies includes a steroid.
  • Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide,
  • a therapeutic agent may be a biologic (e.g., cytokine (e.g., interferon or an interleukin such as IL-2)) used in treatment of cancer or symptoms associated therewith.
  • the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer.
  • antibody-drug conjugates are also included.
  • a therapeutic agent may be a 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 PDL-1.
  • the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL-2 (e.g., a PDL-2/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.
  • a therapeutic agent may be an agent that treats cancer or symptoms associated therewith (e.g., a cytotoxic agent, non-peptide small molecules, or other compound useful in the treatment of cancer or symptoms associated therewith, collectively, an “anti-cancer agent”).
  • Anti-cancer agents can be, e.g., chemotherapeutics or targeted therapy agents.
  • Anti-cancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-Asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressant, adrenocorticosteroides, progestins, estrogens, antiestrogen, androgens, antiandrogen, and gonadotropin-releasing hormone analog.
  • anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel.
  • the one or more additional therapies includes two or more anti-cancer agents.
  • the two or more anti-cancer agents can be used in a cocktail to be administered in combination or administered separately. Suitable dosing regimens of combination anti-cancer agents are known in the art and described in, for example, Saltz et al., Proc. Am. Soc. Clin. Oncol.18:233a (1999), and Douillard et al., Lancet 355(9209):1041-1047 (2000).
  • anti-cancer agents include 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.
  • an anti-cancer agent is an ALK inhibitor.
  • 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 WO05016894.
  • an anti-cancer agent is an inhibitor of a member downstream of a Receptor Tyrosine Kinase (RTK)/Growth Factor Receptor (e.g., a SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971, JAB- 3312, BBP-398, ERAS-601, SH3809, PF-07284892, ICP-189), another SOS1 inhibitor (e.g., BI-1701963), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor).
  • RTK Receptor Tyrosine Kinase
  • Growth Factor Receptor e.g., a SHP2 inhibitor (e.g., SHP099, TNO155, RMC
  • the anti-cancer agent is JAB-3312.
  • an anti-cancer agent is a Ras inhibitor (e.g., AMG 510, MRTX 1 257, LY349946, MRTX849, ARS-3248 (JNJ-74699157), MRTX 1 133, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291, RMC-6236, GDC-6036, MRTX 1 133, JAB-22000, JAB-23000, or ARS-1620, or other Ras inhibitor described herein, such as a 5 Ras inhibitor described in WO 2020/132597, WO 2021/091956, WO 2021/091982, WO 2021/091967), or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras.
  • Ras inhibitor e.g., AMG 510, MRTX 1 257, LY349946, MRTX849,
  • the Ras protein is wild-type. Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a 10 patient having a cancer comprising a Ras WT (e.g., K-Ras WT , H-Ras WT or N-Ras WT ). In some embodiments, the Ras protein is Ras amplification (e.g., K-Ras amp ). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Ras amp (K-Ras amp , H-Ras amp or N-Ras amp ).
  • a Ras WT e.g., K-Ras WT , H-Ras WT or N-Ras WT
  • the Ras protein is Ras amplification (e.g., K-Ras amp ).
  • a compound of the present invention is employed in a method of treating a patient having a cancer comprising a
  • the cancer comprises a Ras mutation (Ras MUT ).
  • a mutation is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, 20 G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G
  • the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group 30 consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. [0211] In some embodiments, a cancer comprises an NF1 LOF mutation.
  • the cancer comprises a Ras MUT and a compound of the present invention 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 invention 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).
  • the cancer is non-small cell lung cancer and a compound of the present invention 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).
  • 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 invention 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, MRTX 1 257, LY349946, MRTX849, ARS-3248 (JNJ-74699157), MRTX 1 133, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291, RMC-6236, GDC-6036, MRTX 1 133, JAB-22000, JAB-23000, or ARS-1620).
  • a Ras inhibitor such as a Ras inhibitor described herein (e.g., AMG 510, MRTX 1 257, LY349946, MRTX849, ARS-3248 (JNJ-74699157), MRTX 1 133, ARS-853, BPI-421286,
  • a therapeutic agent that may be combined with a compound of the present invention is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK inhibitor”).
  • MAPK inhibitors include, but are not limited to, one or more MAPK inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784.
  • the MAPK inhibitor may be selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS 5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA 119/BAY 86-9766); GDC-0973/XL581; AZD8330 (ARRY- 424704/ARRY-704); RO5126766 (Roche, described in PLoS One.2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res.2011 Mar 1;17(5):989- 1000).
  • an anti-cancer agent is a disrupter or inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathways.
  • the PI3K/AKT inhibitor may include, but is not limited to, one or more PI3K/AKT inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784.
  • the PI3K/AKT inhibitor may be selected from one or more of NVP-BEZ235; BGT226; XL765/SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.
  • an anti-cancer agent is a PD-1 or PD-L1 antagonist.
  • additional therapeutic agents include 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.
  • IGF-1R inhibitors include linsitinib, or a pharmaceutically acceptable salt thereof.
  • EGFR inhibitors include, but are not limited to, small molecule antagonists, antibody inhibitors, or specific antisense nucleotide 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. Cancer 1993, 67:247- 253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin.
  • 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®).
  • 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.
  • EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625.
  • an EGFR inhibitor is osimertinib.
  • MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®).
  • a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V.
  • the MEK mutation is a Class II MEK1 mutation selected from ⁇ E51-Q58; ⁇ F53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.
  • PI3K inhibitors include, but are not limited to, wortmannin; 17- hydroxywortmannin analogs described in WO06/044453; 4-[2-(1H-Indazol-4-yl)-6-[[4- (methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09/036082 and WO09/055730); 2- methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1- yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06/122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morph
  • PI3K inhibitors include demethoxyviridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI 00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS- 136.
  • AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem.
  • mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1/mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94/09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO98/02441 and WO01/14387, e.g., AP23464 and AP23841; 40-(2- hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazoly
  • the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO 2 018204416, WO 2 019212990 and WO 2 019212991), such as RMC-5552.
  • BRAF inhibitors that may be used in combination with compounds of the invention include, for example, vemurafenib, dabrafenib, and encorafenib.
  • a BRAF may comprise a Class 3 BRAF mutation.
  • the Class 3 BRAF mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E.
  • MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845.
  • the myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT- 263.
  • the additional therapeutic agent is a SHP2 inhibitor.
  • SHP2 is a 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 kinases
  • SHP2 is involved in signaling through the RAS-mitogen-activated protein kinase (MAPK), the JAK-STAT or the phosphoinositol 3-kinase-AKT pathways.
  • MAPK RAS-mitogen-activated protein kinase
  • JAK-STAT JAK-STAT
  • phosphoinositol 3-kinase-AKT phosphoinositol 3-kinase-AKT pathways.
  • Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human developmental diseases, such as Noonan Syndrome and Leopard Syndrome, as well as human cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. Some of these mutations destabilize the auto-inhibited conformation of SHP2 and promote autoactivation or enhanced growth factor driven activation of SHP2.
  • SHP2 therefore, represents a highly attractive target for the development of novel therapies for the treatment of various diseases including cancer.
  • a SHP2 inhibitor e.g., RMC-4550 or SHP099
  • a RAS pathway inhibitor e.g., a MEK inhibitor
  • combination therapy involving a SHP2 inhibitor with a RAS pathway inhibitor could be a general strategy for preventing tumor resistance in a wide range of malignancies, and may form the basis of a triple combination inhibitor with a SOS1 inhibitor.
  • Non-limiting examples of such SHP2 inhibitors that are known in the art, include: Chen et al.
  • a SHP2 inhibitor binds in the active site.
  • a SHP2 inhibitor is a mixed-type irreversible inhibitor.
  • a SHP2 inhibitor binds an allosteric site e.g., a non-covalent allosteric inhibitor.
  • a SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets the cysteine residue (C333) that lies outside the phosphatase’s active site.
  • a SHP2 inhibitor is a reversible inhibitor.
  • a SHP2 inhibitor is an irreversible inhibitor.
  • the SHP2 inhibitor is SHP099.
  • the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630. In some embodiments, the SHP2 inhibitor is JAB-3068. [0229] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.
  • Immune therapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T-cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTEs), and anti-PD-1, anti-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX 4 0 agents).
  • 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).
  • 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.
  • Anti-angiogenic agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof.
  • An anti-angiogenic agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth.
  • the one or more additional therapies include an anti-angiogenic agent.
  • Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors.
  • Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab.
  • Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib.
  • WO96/33172 examples include WO96/27583, WO98/07697, WO98/03516, WO98/34918, WO98/34915, WO98/33768, WO98/30566, WO90/05719, WO99/52910, WO99/52889, WO99/29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, and U.S. Patent Nos.5,863,949 and 5,861,510.
  • 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, or soluble VEGF receptors or a ligand binding region thereof) such as VEGF-TRAPTM, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen binding regions),
  • 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.
  • anti-PDGF-BB antagonists e.g., specifically binding antibodies or antigen binding regions
  • PDGFR kinase inhibitory agents e.g., antibodies or antigen binding regions that specifically bind thereto.
  • Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US5892112); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA);
  • agents e.g., antibodies, antigen binding regions, or soluble receptors
  • HGF hepatocyte growth factor
  • Scatter Factor hepatocyte growth factor
  • Another example of a therapeutic agent that may be used in combination with compounds of the disclosure is an autophagy inhibitor.
  • Autophagy inhibitors include, but are not limited to chloroquine, 3-methyladenine, hydroxychloroquine (PlaquenilTM), bafilomycin A1, 5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins which inhibit protein phosphatases of type 2A or type 1, analogues of cAMP, and drugs which elevate cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine.
  • antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used.
  • the one or more additional therapies include an autophagy inhibitor.
  • Another example of a therapeutic agent that may be used in combination with compounds of the disclosure is an anti-neoplastic agent.
  • the one or more additional therapies include an anti-neoplastic agent.
  • Non-limiting examples of anti-neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine
  • 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-OX 4 0 (Providence Health Services); huMAbOX 4 0L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C
  • 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, MRTX 1 257, 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; RMC-6291, or RMC-6236), a MEK inhibitor (e.g., refametinib, selumetinib, trametinib, or cobimetinib), a SHP2 inhibitor (e.g., TNO155, RMC-4630), an ERK inhibitor, and
  • a SOS1 inhibitor may be used in combination with a Ras inhibitor, a SHP2 inhibitor, or a MEK inhibitor.
  • a combination therapy includes a SOS1 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 invention 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.
  • a compound of the invention and any of the therapies described herein can be simultaneously administered, wherein both the agents are present in separate formulations.
  • a compound of the present disclosure can be administered and followed by any of the therapies described herein, or vice versa.
  • a compound of the invention and any of the therapies described herein are administered a few minutes apart, or a few hours apart, or a few days apart.
  • a combination therapeutic regimen employs two therapeutic agents, one compound of the present invention and a second selected from the therapeutic agents described herein.
  • a combination therapeutic regimen employs three therapeutic agents, one compound of the present invention and two selected from the therapeutic agents described herein.
  • a combination therapeutic regimen employs four or more therapeutic agents, one compound of the present invention and three selected from the therapeutic agents described herein.
  • the first therapy e.g., a compound of the invention
  • one or more additional therapies are administered simultaneously or sequentially, in either order.
  • the first therapeutic agent may be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to, 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to hours 16, up to 17 hours, up 18 hours, up to 19 hours up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7, 1-14, 1-21 or 1-30 days before or after the one or more additional therapies.
  • kits including (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, and (b) a package insert with instructions to perform any of the methods described herein.
  • the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent), and (c) a package insert with instructions to perform any of the methods described herein.
  • additional therapies e.g., non-drug treatment or therapeutic agent
  • the invention further relates to combining separate pharmaceutical compositions in kit form.
  • the kit may comprise two separate pharmaceutical compositions: a compound of the present invention, and one or more additional therapies.
  • the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags.
  • the kit may comprise directions for the use of the separate components.
  • the kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional. [0248] In this Combination Therapy section, all references are incorporated by reference for the agents described, whether explicitly stated as such or not.
  • Embodiment 1 is a compound having a structure of Formula (I), Formula or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein: X 1 is NH or S; X 2 is CH or N; X 3 is CH or N; X 4 is CR 3 or N; X 5 is CH or N; X6 is CH or N; R 1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, -NH-C 1-6 alkyl, and –NH2; R 3 is selected from the group consisting of H, -O-C 1-6 alky
  • Embodiment 2 is a compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 is optionally substituted 6-membered aryl.
  • Embodiment 3 is a compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 is optionally substituted 5-6 membered heteroaryl.
  • Embodiment 4 is a compound according to Embodiment 1, having the structure selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 2 , L 4 , and R 4 are as defined in Embodiment 1; R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C 1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 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(
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R 2 , L 4 , and R 4 are as defined in Embodiment 1;
  • R5, R6, and R7 are independently selected from the group consisting of 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)2R 10 , –NR 10 S(O)2NR 11 R 12 , –NR 10 S(O)2R 11 , —NR 10 S(O)2R 11 , —NR 10 S(O)2R 11 , —NR 10 S(O)2R 11
  • X 1 , X 2 , X 3 , X 4 , X 5 , X6, R2, L4, and R 4 are as defined in Embodiment 1;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are independently selected from the group consisting of H, D, C 1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 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)
  • Embodiment 7 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl substituted with halogen.
  • Embodiment 8 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is C 1-6 alkyl substituted with halogen and –OH.
  • Embodiment 9 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is halogen, and one to three of R 5 , R 6 , R 7 , R 8 , and R 9 is C 1-6 alkyl substituted with halogen.
  • Embodiment 10 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is –NH2.
  • Embodiment 11 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one of R5, R6, R7, R8, and R9 is –NH2; and one of R5, R6, R7, R8, and R 9 is C 1-6 alkyl substituted with halogen.
  • Embodiment 12 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9 forms a 3-14 membered fused ring, wherein the fused ring is substituted with halogen.
  • a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof wherein any two adjacent R 5 , R 6 , R 7 , R 8 , and R 9 forms a 3-14 membered fused ring, wherein the fused ring is substituted with halogen.
  • Embodiment 13 is a compound according to any one of Embodiments 1- 12, having the structure of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , L4, and R 4 are as defined in Embodiment 1.
  • Embodiment 14 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH, X 2 is CH, X 3 is CH, X 4 is N, and X 5 is CH.
  • Embodiment 15 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH, X 2 is N, X 3 is CH, X 4 is N, and X 5 is CH.
  • Embodiment 16 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH, X 2 is N, X 3 is CH, X 4 is CR3, and X 5 is CH.
  • Embodiment 17 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is S, X 2 is CH, X 3 is CH, X 4 is CR3, and X 5 is CH.
  • Embodiment 18 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH, X 2 is N, X 3 is N, X 4 is CR3, and X 5 is CH.
  • Embodiment 19 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof wherein X 1 is NH, X 2 is CH, X 3 is N, X 4 is CR3, and X 5 is CH.
  • Embodiment 20 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH, X 2 is CH, X 3 is CH, X 4 is CR3, and X 5 is N.
  • Embodiment 21 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH, X 2 is CH, X 3 is CH, X 4 is CR 3 , and X 5 is CH.
  • Embodiment 22 is a compound according to any one of Embodiments 16- 21or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 3 is H or –O-CH 3 .
  • Embodiment 23 is a compound according to any one of Embodiments 13- 22, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein L 4 is a bond.
  • Embodiment 24 is a compound according to any one of Embodiments 1- 12, having the structure of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), or Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 , X 4 , and R 4 are as defined in Embodiment 1.
  • Embodiment 25 is a compound according to Embodiment 24, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 1 is NH and X 4 is CH.
  • Embodiment 26 is a compound according to any one of Embodiments 1- 12, having the structure of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 5 , X6, R2, and R 4 are as defined in Embodiment 1.
  • Embodiment 27 is a compound according to Embodiment 26, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 5 is CH and X 6 is N.
  • Embodiment 28 is a compound according to Embodiment 26, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X 5 is CH and X 6 is CH.
  • Embodiment 29 is a compound according to any one of Embodiments 26- 28, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R2 is H.
  • Embodiment 30 is a compound according to any one of Embodiments 26- 28, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R2 is NH2.
  • Embodiment 31 is a compound according to any one of Embodiments 26- 28, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R2 is –NH-CH3.
  • Embodiment 32 is a compound according to Embodiment 1, having the structure selected from the group consisting of:
  • Embodiment 33 is a compound according to Embodiment 1, having the structure of Formula (II-1): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 , R 3 , L 4 , and R 4 are as defined in Embodiment 1.
  • Embodiment 33 is a compound according to Embodiment 1, having the structure of Formula (II-1): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 and R 4 are as defined in Embodiment 1.
  • Embodiment 34 is a compound according to Embodiment 1, having the structure of Formula (III-1) or (III-2): , or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1, R2, and R 4 are as defined in Embodiment 1.
  • Embodiment 36 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4 is 3-14 membered heterocyclyl.
  • Embodiment 37 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4 is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl.
  • Embodiment 38 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4 is 3-14 membered heterocyclyl substituted with C 1-6 alkyl.
  • Embodiment 39 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4 is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl.
  • Embodiment 41 is a compound according to Embodiment 40, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein the 3-14 membered heterocyclyl is further substituted with C 1-6 alkyl.
  • Embodiment 42 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4 is 3-14 membered heterocyclyl substituted with –C(O)R 4a .
  • Embodiment 43 is a compound according to Embodiment 42, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4a is C 1-6 alkyl.
  • Embodiment 44 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R 4 is selected from the group consisting of: point of attachment to the compound.
  • Embodiment 45 is a compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, selected from the group consisting of:
  • Embodiment 46 is a pharmaceutical composition comprising a compound of any one of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • Embodiment 47 is a method of inhibiting SOS1 in a subject, comprising administering to the subject a compound of any one of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • Embodiment 48 is a method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of any one of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • Embodiment 49 is a method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of a compound of any of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • Embodiment 50 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 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof.
  • Embodiment 51 is a method according to Embodiment 49 or 50, 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, endometri
  • Embodiment 52 is a method according to Embodiment 49, wherein the disease is a RASopathy.
  • Embodiment 53 is a method according to Embodiment 52, 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.
  • Embodiment 54 is a method according to Embodiment 50 or 51, wherein the cancer comprises a Ras MUT or an NF1 LOF mutation.
  • EXAMPLES [0304] The disclosure is further illustrated by the following examples and synthesis examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.
  • Example 2 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide
  • Step 1 [0307] To a solution of 7-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.16 mmol) in MeOH (2.5 mL) were added Pd(dppf)Cl2•CH2Cl2 (52.9 mg, 64.8 ⁇ mol) and Et3N (2.5 mL, 18 mmol) under N2.
  • Step 2 [0308] To a solution of methyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylate (350 mg, 1.66 mmol) in THF (2 mL) and MeOH (2 mL) was added LiOH•H 2 O (209 mg, 4.99 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The pH was adjusted to ⁇ 7 by the addition of 1 N aqueous HCl, and the mixture was then extracted with EtOAc, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 5- chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (310 mg, 95% yield).
  • Step 4 [0310] To a mixture of 5-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (450 mg, 1.22 mmol) and tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (416 mg, 1.35 mmol) in DME (7 mL) and H 2 O (2 mL) were added Pd(PPh 3 ) 4 (141 mg, 122 ⁇ mol) and Na 2 CO 3 (259 mg, 2.45 mmol) at 20 °C under N 2 .
  • Pd(PPh 3 ) 4 141 mg, 122 ⁇ mol
  • Na 2 CO 3 (259 mg, 2.45 mmol
  • Step 5 A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-pyrrolo[2,3-c]pyridin-5-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (250 mg, 486 ⁇ mol) in HCl (4 M in EtOAc, 121 ⁇ L, 484 ⁇ mol) was stirred at 25 °C for 1 hour.
  • Step 1 [0312] To a solution of 5-bromo-1H-indazole-7-carboxylic acid (100 mg, 415 ⁇ mol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (94.2 mg, 498 ⁇ mol) in THF (1 mL) were added DIEA (217 ⁇ L, 1.24 mmol) and T 3 P (50% purity, 396 mg, 622 ⁇ mol). The reaction mixture was purged with N2 and stirred at 25 °C for 3 hours under N2. The mixture was then quenched with H2O, extracted with ethyl acetate, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 2 [0313] To a mixture of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (60 mg, 1456 ⁇ mol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (54.0 mg, 175 ⁇ mol) in dioxane (1 mL) and H2O (0.2 mL) were added Pd(PPh3)2Cl2 (0.22 mg, 15 ⁇ mol) and Na2CO3 (30.9 mg, 291 ⁇ mol) at 25 °C under N2.
  • Example 4 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6- (1,2,3,6-tetrahydropyridin-4-yl)-3H-benzimidazole-4-carboxamide
  • Step 1 [0315] To a solution of 6-bromo-3H-benzimidazole-4-carboxylic acid (430 mg, 1.78 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine•HCl (483 mg, 2.14 mmol) in THF (4 mL) were added DIEA (1.55 mL, 8.92 mmol) and T 3 P (50% purity, 1.70 g, 2.68 mmol) at 25 °C.
  • Step 2 To a solution of 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-3H-benzimidazole-4-carboxamide (180 mg, 437 ⁇ mol) in dioxane (1.5 mL) and H 2 O (0.3 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (176 mg, 568 ⁇ mol), Na2CO3 (92.6 mg, 873 ⁇ mol), and Pd(PPh3)4 (252 mg, 218 ⁇ mol) at 25 °C under N2.
  • Step 2 [0319] To a solution of tert-butyl 4-(5-amino-4,6-dichloro-2-pyridyl)-3,6- dihydro-2H-pyridine-1-carboxylate (5.00 g, 14.5 mmol) in Et 3 N (100 mL) were added Pd(PPh3)2Cl2 (510 mg, 726 ⁇ mol) and CuI (138 mg, 726 ⁇ mol) at 0 °C under an atmosphere of N 2 . Ethynyl(trimethyl)silane (3.02 mL, 21.8 mmol) was then added at 0 °C and the reaction mixture was stirred at 80 °C for 4 hours.
  • Pd(PPh3)2Cl2 510 mg, 726 ⁇ mol
  • CuI 138 mg, 726 ⁇ mol
  • Step 3 [0320] To a solution of tert-butyl 4-[5-amino-4-chloro-6-(2- trimethylsilylethynyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.70 g, 6.65 mmol) in DMF (270 mL) was added CuI (253 mg, 1.33 mmol) under an atmosphere of N 2 . The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was quenched by the addition of water (400 mL) then was extracted with EtOAc, treated with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • Step 4 To a solution of tert-butyl 4-(7-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (50.0 mg, 150 ⁇ mol) in dioxane (1 mL) was added (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethanamine (85.0 mg, 449 ⁇ mol), Mo(CO) 6 (39.5 mg, 150 ⁇ mol), TEA (52.1 ⁇ L, 374 ⁇ mol) and Pd(dppf)Cl2 (11.0 mg, 15.0 ⁇ mol) under an atmosphere of N2.
  • reaction mixture was stirred at 120 °C in a microwave reactor for 4 hours.
  • the mixture was diluted in H 2 O and extracted with DCM.
  • the combined organic extracts were treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to get a tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2- fluoro-phenyl]ethyl]carbamoyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate (100 mg, crude).
  • Example 7 Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indazole-7-carboxamide
  • Step 1 [0325] To a solution of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-1H-indazole-7-carboxamide (70.0 mg, 151 ⁇ mol) and Pd/C (50.0 g, 10% purity, 50% wet) in MeOH (3.5 mL) and THF (3.5 mL) was stirred at rt for 4 hours under H2 (30 psi).
  • Step 1 [0327] To a solution of 5-bromo-1H-indazole-7-carboxylic acid (400 mg, 1.66 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine HCl (449 mg, 1.99 mmol) in THF (4 mL) were added DIEA (1.45 mL, 8.30 mmol) and T3P (1.48 mL, 2.49 mmol) at rt. The mixture was stirred at rt for 2 hours.
  • Step 2 [0328] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (300 mg, 728 ⁇ mol) in dioxane (3 mL) and H 2 O (0.6 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (293 mg, 946 ⁇ mol), Na 2 CO 3 (154 mg, 1.46 mmol), and Pd(PPh3)4 (421 mg, 364 ⁇ mol) at rt under N2.
  • Step 3 A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 194 ⁇ mol) in HCl (4 M in EtOAc, 1 mL) was stirred at rt for 2 hours. To the reaction was added water and the aqueous phase was extracted with ethyl acetate.
  • Step 4 [0330] To a solution of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide HCl (80.0 mg, 177 ⁇ mol) in THF (1 mL) were added TEA (123 ⁇ L, 887 ⁇ mol) and acetyl chloride (15.2 ⁇ L, 213 ⁇ mol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. To the reaction was added water and the aqueous phase was extracted with ethyl acetate.
  • Example 10 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5- (piperazin-1-yl)-1H-indazole-7-carboxamide
  • Step 1 [0331] To a mixture of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (300 mg, 728 ⁇ mol) and tert-butyl piperazine-1- carboxylate (324 mg, 1.74 mmol) in dioxane (6 mL) were added tert-BuONa (210 mg, 2.18 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-ditert-butyl-[2- (2,4,6-triisopropylphenyl)phenyl]pho
  • Step 2 [0332] A mixture of tert-butyl-4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]piperazine-1-carboxylate (30 mg, 58.0 ⁇ mol) HCl (4 M in EtOAc, 0.5 mL) was stirred at rt for 1 hour.
  • Example 11 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5- (pyrrolidin-3-yl)-1H-indazole-7-carboxamide
  • Step 1 [0333] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (500 mg, 1.21 mmol) and tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (394 mg, 1.33 mmol) in DME (4 mL) and H 2 O (0.8 mL) were added Na 2 CO 3 (386 mg, 3.64 mmol) and Pd(PPh3)4 (280 mg, 243 ⁇ mol)
  • Step 2 [0334] To a solution of tert-butyl 3-[7-[[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-2,5-dihydropyrrole-1-carboxylate (380 mg, 759 ⁇ mol) in MeOH (4 mL) was added Pd/C (500 mg, 10% purity, 50% wet) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2 (30 psi) at 30 °C for 4 hours.
  • Step 3 A solution of tert-butyl 3-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]pyrrolidine-1-carboxylate (227 mg, 452 ⁇ mol) in HCl (4 M in EtOAc, 3 mL) was stirred at rt for 1 hour.
  • Example 12 Synthesis of 2-amino-N-[(1R)-1-[3-amino-5-(trifluoromethyl) phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzamide
  • Step 1 [0336] To a solution of methyl 5-fluoro-2-nitro-benzoate (500 mg, 2.51 mmol) in CH3CN (5 mL) were added Cs2CO3 (2.45 g, 7.53 mmol) and (3S)-tetrahydrofuran-3-ol (265.46 mg, 3.01 mmol). The mixture was stirred at 100 °C for 1 hour.
  • Step 2 [0337] To a solution of methyl 2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzoate (150 mg, 561 ⁇ mol) in THF (1 mL), MeOH (0.5 mL) and H 2 O (1 mL) was added LiOH•H 2 O (47.1 mg, 1.12 mmol). The mixture was stirred at 20 °C for 3 hours.
  • Step 3 To a solution of 2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzoic acid (140 mg, 553 ⁇ mol) in THF (2 mL) was added T3P (247 ⁇ L, 829 ⁇ mol), DIEA (289 ⁇ L, 1.66 mmol) and 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline (113 mg, 553 ⁇ mol). The mixture was stirred at 20 °C for 2 hours.
  • Step 4 [0339] To a solution of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-2- nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzamide (110 mg, 250 ⁇ mol) in H2O (0.25 mL) and EtOH (0.5 mL) were added Fe (69.9 mg, 1.25 mmol) and NH 4 Cl (6.70 mg, 125 ⁇ mol). The reaction was stirred at 95 °C for 5 hours. The mixture was filtered, and the solvent was removed under reduced pressure.
  • Step 1 [0340] To a mixture of 5-bromo-2-fluoro-pyridine-3-carboxylic acid (5.00 g, 22.7 mmol) in DMF (25 mL) were added K2CO3 (6.28 g, 45.5 mmol) and CH3I (1.84 mL, 29.6 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried with Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-bromo-2-fluoro-pyridine-3-carboxylate (3.7 g, 70% yield).
  • Step 2 [0341] To a mixture of methyl 5-bromo-2-fluoro-pyridine-3-carboxylate (3.50 g, 15.0 mmol) and methylamine hydrochloride (1.51 g, 22.4 mmol) in DMF (35 mL) was added Cs2CO3 (14.6 g, 44.9 mmol). The mixture was stirred at 80 °C for 1 hour.
  • Step 3 To a mixture of methyl 5-bromo-2-(methylamino)pyridine-3-carboxylate (1.30 g, 5.30 mmol) in THF (13 mL) at 0 °C was added Boc2O (1.46 mL, 6.37 mmol), and NaHMDS (5.83 mL, 5.83 mmol). The mixture was stirred at 25 °C for 3 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure.
  • Step 4 [0343] To a mixture of methyl 5-bromo-2-[tert- butoxycarbonyl(methyl)amino]pyridine-3-carboxylate (1 g, 2.90 mmol) and bis(pinacolato)diboron (883 mg, 3.48 mmol) in dioxane (10 mL) were added KOAc (853 mg, 8.69 mmol), and Pd(dppf)Cl 2 . CH 2 Cl 2 (473 mg, 579 ⁇ mol) under nitrogen gas. The mixture was stirred at 100 °C for 2 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered and the solvent was removed under reduced pressure.
  • Step 5 To a mixture of [6-[tert-butoxycarbonyl(methyl)amino]-5- methoxycarbonyl-3-pyridyl]boronic acid (580 mg, 1.87 mmol) in MeOH (6 mL) was added UHP (704 mg, 7.48 mmol). The mixture was stirred at 25 °C for 4 hours. The reaction was diluted with sat. aq. Na2SO3, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure.
  • Step 6 To a mixture of methyl 2-[tert-butoxycarbonyl(methyl)amino]-5-hydroxy- pyridine-3-carboxylate (375 mg, 1.33 mmol) in DMF (4 mL) was added [(3R)- tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (483 mg, 1.99 mmol), and Cs2CO3 (866 mg, 2.66 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure.
  • Step 7 To a mixture of methyl 2-[tert-butoxycarbonyl(methyl)amino]-5-[(3S)- tetrahydrofuran-3-yl]oxy-pyridine-3-carboxylate (214 mg, 607 ⁇ mol) in THF (1 mL), MeOH (0.5 mL), and H2O (1 mL) was added NaOH (48.6 mg, 1.21 mmol). The mixture was stirred at 25 °C for 3 hours.
  • Step 8 [0347] To a mixture of 2-[tert-butoxycarbonyl(methyl)amino]-5-[(3S)- tetrahydrofuran-3-yl]oxy-pyridine-3-carboxylic acid (200 mg, 591 ⁇ mol) and 3-[(1R)-1- aminoethyl]-5-(trifluoromethyl)aniline (144 mg, 709 ⁇ mol) in THF (2 mL) was added DIEA (309 ⁇ L, 1.77 mmol), and T 3 P (264 ⁇ L, 887 ⁇ mol). The mixture was stirred at 25 °C for 12 hours.
  • Step 9 [0348] tert-Butyl N-[3-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]carbamoyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-2-pyridyl]-N- methyl-carbamate (130 mg, 248 ⁇ mol) was dissolved in a solution HCl in MeOH (5 mL) and the mixture was stirred at 25 °C for 2 hours.
  • Step 1 To a mixture of methyl 3-hydroxybenzoate (200 mg, 1.31 mmol) and [(3R)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate (350 mg, 1.45 mmol) in DMF (2 mL) was added Cs 2 CO 3 (514 mg, 1.58 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure to give methyl 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoate (220 mg, 75% yield).
  • Step 2 [0350] To a solution of methyl 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoate (200 mg, 900 ⁇ mol) in THF (2 mL), MeOH (0.5 mL), and H 2 O (0.5 mL) was added LiOH•H 2 O (56.7 mg, 1.35 mmol). The reaction stirred at 25 °C for 5 hours.
  • Step 3 To a solution of 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoic acid (200 mg, 961 ⁇ mol) in DCM (3 mL) was added DIEA (669 ⁇ L, 3.84 mmol) and HATU (730 mg, 1.92 mmol). The reaction was stirred at 25 °C for 30 minutes. 3-[(1R)-1-aminoethyl]-5- (trifluoromethyl)aniline (216 mg, 1.06 mmol) was then added and the mixture and stirred at 25 °C for 3 hours.
  • Example 15 Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5- [(3S)-tetrahydrofuran-3-yl]oxy-1H-indole-7-carboxamide
  • Step 1 To a solution of methyl 2-amino-5-bromo-benzoate (3.00 g, 13.0 mmol) in TFA (15 mL) was added NIS (3.02 g, 13.4 mmol). The reaction was stirred at 15 °C for 1 hour.
  • Step 2 [0353] To a solution of methyl 2-amino-5-bromo-3-iodo-benzoate (2.60 g, 7.30 mmol) in TEA (25 mL) was added Pd(dppf)Cl2 (802 mg, 1.10 mmol) and CuI (209 mg, 1.10 mmol) under nitrogen. The reaction stirred at 15 °C for 20 minutes. Ethynyl(trimethyl)silane (1.32 mL, 9.50 mmol) was then added and the reaction was stirred at 15 °C for 1 hour. The solvent was removed under reduced pressure, then the residue was dissolved in DCM, filtered through a plug of Celite ® , and washed with DCM.
  • Step 3 [0354] Methyl 2-amino-5-bromo-3-(2-trimethylsilylethynyl)benzoate (1.90 g, 5.82 mmol) was dissolved in NMP (15 mL) at 0 o C. tert-BuOK (1.44 g, 12.8 mmol) in NMP (15 mL) was then added dropwise to the mixture and the reaction was stirred at 0 °C for 1 hour. The mixture was diluted with water, extracted with MTBE, washed with brine, dried over MgSO 4 , filtered, and the solvent was removed under reduced pressure.
  • Step 4 [0355] To a solution of methyl 5-bromo-1H-indole-7-carboxylate (200 mg, 787 ⁇ mol) in dioxane (4 mL) were added Pd(dppf)Cl2 (57.6 mg, 78.7 ⁇ mol) and KOAc (309 mg, 3.15 mmol). The reaction was stirred for 20 minutes then bis(pinacolato)diboron (300 mg, 1.18 mmol) was added to the reaction. The mixture was stirred at 110 °C for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure.
  • Step 5 To a solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole-7-carboxylate (200 mg, 664 ⁇ mol) in MeOH (5 mL) were added NaOH (106 mg, 2.66 mmol) and hydroxylamine hydrochloride (138 mg, 1.99 mmol). The reaction was stirred at 20 °C for 5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography to get methyl 5-hydroxy-1H-indole-7- carboxylate (100 mg, 79% yield).
  • Step 7 To a solution of methyl 5-[(3S)-tetrahydrofuran-3-yl]oxy-1H-indole-7- carboxylate (35.0 mg, 134 ⁇ mol) in toluene (2 mL) was added 3-[(1R)-1-aminoethyl]-5- (trifluoromethyl)aniline (82.1 mg, 402 ⁇ mol) and Al(CH3)3 (2 M, 134 ⁇ L). The reaction was stirred at 100 °C for 2 hours. The mixture was diluted with water, extracted with DCM, washed with brine, dried with Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure.
  • Example 16 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6- (1,2,3,6-tetrahydropyridin-4-yl)-3H-benzotriazole-4-carboxamide
  • Step 1 A solution of methyl 2,3-diamino-5-bromo-benzoate (500 mg, 2.04 mmol) in acetic acid (7.5 mL) was stirred for 10 minutes at 25 °C. A solution of NaNO 2 (155 mg, 2.24 mmol) in H 2 O (1 mL) was then added and the reaction stirred for 30 minutes. The reaction was filtered, and the filter cake was washed with water.
  • Step 3 [0361] To a solution of 6-bromo-3H-benzotriazole-4-carboxylic acid (430 mg, 1.78 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (403 mg, 2.13 mmol) in THF (5 mL) was added T3P (3.17 mL, 5.33 mmol) and DIEA (2.48 mL, 14.21 mmol). The reaction was stirred at 25 °C for 1 hour. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4, filtered, and the solvent was removed under reduced pressure.
  • Step 4 [0362] To a solution of 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-3H-benzotriazole-4-carboxamide (200 mg, 484 ⁇ mol) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (299 mg, 968 ⁇ mol) in dioxane (2 mL) and H 2 O (0.4 mL) were added Na 2 CO 3 (102 mg, 968 ⁇ mol) and Pd(PPh3)2Cl2 (34.0 mg, 48.4 ⁇ mol) under nitrogen.
  • Step 5 A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-benzotriazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 388 ⁇ mol) in HCl (4 M in EtOAc, 2 mL) was stirred at 25 °C for 30 minutes.
  • Example 17 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(4- piperidyl)-1H-indazole-7-carboxamide
  • Step 1 [0364] To a solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 1.55 mmol) in THF (10 mL) was added Pd/C (10% purity, 800 mg, 389 ⁇ mol) under nitrogen.
  • Step 2 [0365] A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]piperidine-1-carboxylate (70.0 mg, 136 ⁇ mol) in HCl (4 M in EtOAc, 1 mL) was stirred at 25 °C for 30 minutes.
  • Step 1 To a solution of 7-bromo-4-methoxy-1H-indazole (700 mg, 3.08 mmol) in toluene (7 mL) was added acetic anhydride (487 ⁇ L, 5.19 mmol). The reaction mixture was stirred at 110 °C for 3 hours. The mixture was then concentrated under reduced pressure and the residue was diluted with H 2 O, then extracted with EtOAc. The combined organic extracts were treated with brine, dried over Na 2 SO 4 , filtered, concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1- (7-bromo-4-methoxy-indazol-1-yl) ethanone (700 mg, 84% yield).
  • Step 3 [0368] To a solution of 5,7-dibromo-4-methoxy-1H-indazole (260 mg, 850 ⁇ mol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (322 mg, 1.70 mmol) in dioxane (3 mL) were added Mo(CO)6 (89.7 mg, 340 ⁇ mol), TEA (237 ⁇ L, 1.70 mmol), and Pd(dppf)Cl 2 (62.2 mg, 85.0 ⁇ mol) under an atmosphere of N 2 . The reaction mixture was stirred at 120 °C in a microwave reactor for 5 hours. The mixture was diluted with H2O and extracted with EtOAc.
  • Step 4 To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide (40.0 mg, 90.4 ⁇ mol) in dioxane (1 mL) and H 2 O (0.2 mL) were added Cs 2 CO 3 (88.4 mg, 271 ⁇ mol), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (70.1 mg, 271 ⁇ mol), and [1,1 ⁇ -bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (13.2 mg, 18.1 ⁇ mol).
  • Step 1 [0370] To a solution of 7-bromo-5-chloro-indolin-2-one (300 mg, 1.22 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (460 mg, 2.43 mmol) in dioxane (4 mL) were added Mo(CO)6 (129 mg, 487 ⁇ mol), TEA (339 ⁇ L, 2.43 mmol) and Pd(dppf)Cl2 (89.1 mg, 122 ⁇ mol) under an atmosphere of N2. The reaction mixture was stirred at 120 °C in a microwave reactor for 1 hour.
  • Step 2 [0371] To a solution of 5-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-2-oxo-indoline-7-carboxamide (100 mg, 261 ⁇ mol) in THF (1 mL) and H 2 O (0.2 mL) were added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) (17.5 mg, 26.1 ⁇ mol), K3PO4 (111 mg, 523 ⁇ mol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (101 mg, 392 ⁇ mol).
  • Example 20 Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(4- methyl-1,1-dioxo-thian-4-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide
  • Step 1 [0372] To a solution of 6-bromo-2,4-dichloro-pyridin-3-amine (5.00 g, 20.7 mmol) and 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.14 g, 22.7 mmol) in dioxane (100 mL) and H 2 O (20 mL) were added Pd(PPh 3 ) 2 Cl 2 (1.45 g, 2.07 mmol) and Na 2 CO 3 (4.38 g, 41.3 mmol) at 25 °C under an atmosphere of N 2
  • Step 2 [0373] To a solution of 2,4-dichloro-6-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-3- amine (4.00 g, 15.3 mmol) in TEA (80 mL) were added Pd(PPh 3 ) 2 Cl 2 (538 mg, 766 ⁇ mol) and CuI (146 mg, 766 ⁇ mol) at 0 °C under an atmosphere of N 2 . Ethynyl(trimethyl)silane (3.18 mL, 23.0 mmol) was then added and the reaction mixture was stirred at 80 °C for 12 hours.
  • Step 3 To a solution of 4-chloro-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-(2- trimethylsilylethynyl)-pyridin-3-amine (1.00 g, 3.10 mmol) in DMF (10 mL) was added CuI (118 mg, 619 ⁇ mol) under an atmosphere of N2. The reaction mixture was stirred at 110 °C for 4 hours. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic extracts were treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
  • Step 4 To a solution of 7-chloro-5-(3,6-dihydro-2H-thiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine (280 mg, 1.12 mmol) in THF (3 mL) was added n-BuLi (2.5 M in hexanes, 1.03 mL) dropwise at -10 °C under an atmosphere N2. The mixture was cooled to -50 °C and Me 2 SO 4 (116 ⁇ L, 1.23 mmol) was added dropwise.
  • Step 5 To a solution of 7-chloro-5-(4-methyl-2,3-dihydrothiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine (60.0 mg, 227 ⁇ mol) in THF (2 mL) was added Pd/C (10% purity, 6.0 mg, 23 ⁇ mol) under an atmosphere of N2. The suspension was purged with H2 and the reaction mixture was stirred under H 2 (15 psi) at 25 °C for 4 hours.
  • Step 6 [0377] To a solution of 7-chloro-5-(4-methyltetrahydrothiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine (60 mg, 225 ⁇ mol) in dioxane (1 mL) were added (1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethanamine HCl salt (128 mg, 566 ⁇ mol), Mo(CO) 6 (59.4 mg, 225 ⁇ mol), TEA (188 ⁇ L, 1.35 mmol) and Pd(dppf)Cl2 (16.5 mg, 22.5 ⁇ mol) under an atmosphere N2.
  • Step 7 To a mixture of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (4-methyltetrahydrothiopyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide (20.0 mg, 44.7 ⁇ mol) in H2O (1 mL) and MeOH (3 mL) was added Oxone ® (55.0 mg, 89.4 ⁇ mol) under an atmosphere of N2. The reaction mixture was stirred at 25 °C for 1 hour.
  • avi-tagged SOS1 catalytic domain protein was immobilized to a level of approximately 6000 response units (RU) on a streptavidin-coated SPR sensor chip in assay buffer containing 0.01 M HEPES, 0.15 M NaCl and 0.05% v/v Surfactant P20.
  • concentration series of test compounds were generated spanning 5 ⁇ M to 4.9 nM over ten 2-fold dilutions. For each test compound, a separate 0 ⁇ M sample was generated for use during subsequent double reference subtraction.
  • SOS1 using Surface Plasmon Resonance (SPR) results are shown in Table C below.
  • Table C Potency assay: pERK [0383] The purpose of this assay is to measure the ability of test compounds to inhibit SOS1 function in cells. SOS1 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). The procedure described below measures the level of cellular pERK in response to test compounds in PC- 9 cells (EGFR Ex19Del).
  • 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 ⁇ L/well) and grown overnight in a 37°C, 5% CO 2 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 ⁇ M. After compound addition, cells were incubated for 1 hour at 37°C, 5% CO 2 .
  • Cellular pERK level was determined using the AlphaLISA SureFire Ultra p-ERK1/2 Assay Kit (PerkinElmer). Cells were lysed in 25 ⁇ L lysis buffer, with shaking at 600 RPM at room temperature for 15 minutes. Lysate (10 ⁇ L) was transferred to a 384- well Opti-plate (PerkinElmer) and 5 ⁇ L acceptor mix was added. The plate was centrifuged at 1000 RPM for 1 minute, and incubated in the dark for 2 hours.
  • Table D Mode of Action Assay Inhibition of SOS1 Nucleotide Exchange Activity
  • the purpose of this assay was to characterize the inhibitory activity of compounds on SOS1 nucleotide exchange of KRAS. Data was reported as IC50 values based on the TR-FRET signal.
  • concentration series of test compounds were generated spanning 100 ⁇ M to 1.7 nM over eleven 3-fold serial dilutions in a 384- well assay plate at a volume of 20 ⁇ L.
  • the purified tagless catalytic domain of SOS1 was first diluted in assay buffer at a concentration of 100 nM, and then 20 ⁇ L of the SOS1 containing solution was directly dispensed into compound plates.
  • the SOS1/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 SOS1/compound mixture to prevent intrinsic nucleotide exchange. Then 5 ⁇ L of the pre-incubated SOS1/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.

Abstract

The present disclosure is directed to modulators of SOS1 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.

Description

SOS1 INHIBITORS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Application Ser. No. 63/131,674, which was filed December 29, 2020, the disclosure of which is hereby incorporated by reference as if set forth in its entirety. FIELD OF THE DISCLOSURE [0002] The present disclosure relates to inhibitors of SOS1 useful in the treatment of diseases or disorders. Specifically, the present disclosure is concerned with compounds and compositions inhibiting SOS1, methods of treating diseases associated with SOS1, and methods of synthesizing these compounds. BACKGROUND OF THE DISCLOSURE [0003] 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. The binding of guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) promote release of GDP from RAS-family proteins, enabling GTP binding (Chardin et al., Science, 1993, 260(5112):1338-43). 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). Published data indicate a critical involvement of SOS1 in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depleting SOS1 levels decreased the proliferation rate and survival of tumor cells carrying a KRAS mutation whereas no effect was observed in KRAS wild type cell lines. The effect of loss of SOS1 could not be rescued by introduction of a catalytic site mutated SOS1, demonstrating the essential role of SOS1 GEF activity in KRAS mutant cancer cells. [0004] 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 SOS1/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). 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). This localization of SOS1 to the plasma membrane, proximal to RAS-family proteins, enables SOS1 to promote RAS-family protein activation. SOS1-activation of RAS-family proteins can also be mediated by the interaction of SOS1/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 (7511):543-50). Meanwhile over-expression of SOS1 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). In addition to cancer, hereditary SOS1 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). [0005] SOS1 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). [0006] Son of Sevenless 2 (SOS2), a homolog of SOS1 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 SOS1 and SOS2 in homeostasis in the adult mouse. Whilst germline knockout of SOS1 in mice results in lethality during mid-embryonic gestation (Qian et al., EMBO J., 2000, 19(4):642-54), systemic conditional SOS1 knockout adult mice are viable (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). SOS2 gene targeting did not result in any overt phenotype in mice (Esteban et al., Mol. Cell. Biol., 2000, 20(17):6410-3). In contrast, double SOS1 and SOS2 knockout leads to rapid lethality in adult mice (Baltanas et al., Mol. Cell. Biol., 2013, 33(22):4562-78). These published data suggest that selective targeting of individual SOS isoforms (e.g., selective SOS1 targeting) may be adequately tolerated to achieve a therapeutic index between SOS1/RAS-family protein driven cancers (or other SOS1/RAS-family protein pathologies) and normal cells and tissues. [0007] Selective pharmacological inhibition of the binding of the catalytic site of SOS1 to RAS-family proteins is expected to prevent SOS1-mediated activation of RAS- family proteins to the GTP-bound form. Such SOS1 inhibitor compounds are be expected to consequently inhibit signaling in cells downstream of RAS-family proteins (e.g., ERK phosphorylation). In cancer cells associated with dependence on RAS-family proteins (e.g., KRAS mutant cancer cell lines), SOS1 inhibitor compounds are be expected to deliver anti- cancer efficacy (e.g., inhibition of proliferation, survival, metastasis, etc.). High potency towards inhibition of SOS1:RAS-family protein binding (nanomolar level IC50 values) and ERK phosphorylation in cells (nanomolar level IC50 values) are desirable characteristics for a SOS1 inhibitor compound. Furthermore, a desirable characteristic of a SOS1 inhibitor compound would be the selective inhibition of SOS1 over SOS2. This conclusion is based on the viable phenotype of SOS1 knockout mice and lethality of SOS1/SOS2 double knockout mice, as described above. [0008] These characteristics have not been achieved in previously described SOS1 inhibitor compounds. In the last decades, the RAS family proteins-SOS1 protein interaction has gained increasing recognition. Several efforts to identify and optimize binders, which target either the effector binding site of RAS or the catalytic binding site of SOS1 (for a selected review see: Lu et al., ChemMedChem.2016, 11(8):814-21), have been made with limited success. [0009] Recently, small activating molecules have been identified, which bind to a lipophilic pocket of SOS1 in close proximity to the RAS binding site (Burns et al., Proc. Natl. Acad. Sci.2014, 111(9):3401-6). However, binding of these molecules seems to lead to increased nucleotide exchange and thereby activation of RAS instead of deactivation. [0010] In an effort to stabilize the protein-protein-interaction of RAS-family proteins with SOS1 and to prevent reloading of RAS-family proteins with GTP, several different fragments were subsequently identified (Winter et al., J. Med. Chem.2015, 58(5):2265-74). However, reversible binding of fragments to SOS1 did not translate into a measurable effect on the nucleotide exchange and only a weak effect was observed for fragments covalently bound to RAS. [0011] Also recently, studies have been conducted to combine rational design and screening platforms to identify small molecule inhibitors of SOS1 (Evelyn et al., Chem. Biol.2014, 21 (12):1618-28; Evelyn et al., J. Biol. Chem.2015, 290(20):12879-98; Zheng et al., WO 2016/077793), i.e. compounds which bind to SOS1 and inhibit protein-protein interaction with RAS-family proteins. Although compounds with a slight inhibitory effect on SOS1 have been identified, the effects on guanine nucleotide exchange and cellular signal transduction modulation (e.g., ERK phosphorylation) are weak. BRIEF DESCRIPTION OF THE DISCLOSURE [0012] The present disclosure relates to compounds capable of inhibiting the activity of SOS1. 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. [0013] One aspect of the present disclosure relates to compounds having a structure of Formula (I), Formula (II), or Formula (III):
Figure imgf000006_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein: X1 is NH or S; X2 is CH or N; X3 is CH or N; X4 is CR3 or N; X5 is CH or N; X6 is CH or N; R1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, -NH-C1-6 alkyl, and –NH2; R3 is selected from the group consisting of H, -O-C1-6 alkyl, and -O-C1-6 heteroalkyl; L4 is a bond or O; and R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with one or more C1-6 alkyl, –R4a, –OR4a, –O–C1-6 alkyl– R4a, =O, halogen, –C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –NR4bC(O)R4c, –CN, =NR4a, – NR4bR4c, –SO2R4a, 3-6 membered cycloalkyl optionally substituted with R4a, 3-7 membered heterocyclyl optionally substituted with R4a, 6-10 membered aryl optionally substituted with R4a, or 5-10 membered heteroaryl optionally substituted with R4a; wherein R4a is H, C1-6 alkyl, C1-6 haloalkyl, –C(O)R4b, –C(O)NR4bR4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with –OR4b, –CN, =N-3- 6 membered cycloalkyl, 3-7 membered heterocyclyl, –(CH2)rOCH3, or –(CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, C1-6 alkyl; and wherein each R4c is independently H or C1-6 alkyl. [0014] Another aspect of the present disclosure relates to compounds of Formula (Ia), (IIa), or (IIIa):
Figure imgf000007_0001
Figure imgf000008_0001
, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Formula (I), (II), or (III); R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0015] Another aspect of the present disclosure relates to compounds of Formula (Ib), (IIb), or (IIIb): ,
Figure imgf000009_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Formula (I), (II), or (III); R5, R6, and R7 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, –S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, – NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0016] Another aspect of the present disclosure relates to compounds of Formula :
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Formula (I), (II), or (III); R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0017] Another aspect of the present disclosure relates to compounds of Formula (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), or (I-8):
Figure imgf000013_0001
Figure imgf000014_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1, R3, L4, and R4 are as defined in Formula (I). [0018] Another aspect of the present disclosure relates to compounds of Formula (II-1):
Figure imgf000014_0002
, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1 and R4 are as defined in Formula (II). [0019] Another aspect of the present disclosure relates to compounds of Formula (III-1) or (III-2):
Figure imgf000015_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1, R2, and R4 are as defined in Formula (III). [0020] One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject a SOS1 inhibitor of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. [0021] Another aspect of the present disclosure relates to methods of treating or preventing a disease that is effected by or characterized by inhibition of the interaction of SOS1 and a RAS-family protein and/or RAC1 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, stereoisomer, prodrug, or tautomer thereof. [0022] Another aspect of the present disclosure relates to methods of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. [0023] Another aspect of the present disclosure relates to methods 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, stereoisomer, prodrug, or tautomer thereof. [0024] Another aspect of the present disclosure relates to methods of inhibiting SOS1. The method comprises administering to a patient in need thereof, an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. [0025] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can further comprise an excipient, diluent, or surfactant. The pharmaceutical composition can be effective for treating or preventing a disease associated with SOS1 modulation in a subject in need thereof. The pharmaceutical composition can be effective for treating or preventing a cancer in a subject in need thereof. [0026] Another aspect of the present disclosure relates to a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, for use in treating or preventing a disease associated with SOS1 modulation. Another aspect of the present disclosure relates to a compound of the present disclosure, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, and isomers thereof, for use in treating or preventing a disease cancer. [0027] Another aspect of the present disclosure relates to the use of a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, in the manufacture of a medicament for treating or preventing a disease associated with SOS1 modulation. Another aspect of the present disclosure relates to the use of a compound of the present disclosure, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, tautomers, or isomers thereof, in the manufacture of a medicament for treating or preventing cancer. [0028] The present disclosure also provides compounds that are useful in inhibiting SOS1. DETAILED DESCRIPTION OF THE DISCLOSURE [0029] The details of the present disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Terms [0030] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. [0031] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. The use of the term "or" is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." [0032] The symbol “ ” represents the point of attachment to the compound. [0033] As used herein, 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. In certain embodiments, 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). [0034] By "optional" or "optionally," it is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined herein. It will be understood by those ordinarily skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non- feasible, and/or inherently unstable. [0035] The term “optionally substituted” unless otherwise specified means that a 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. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment, an optionally substituted group has 2 substituents. In another embodiment, an optionally substituted group has 3 substituents. In another embodiment, an optionally substituted group has 4 substituents. In another embodiment, an optionally substituted group has 5 substituents. For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, 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. Thus the term “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. [0036] As used herein, “alkyl” may mean a straight chain or branched saturated chain having from 1 to 10 carbon atoms. Representative 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- methyl-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 octyl and the like. An 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. [0037] As used herein, the term “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). The heteroatom may appear in the middle or at the end of the radical. [0038] The term "alkenyl" means an aliphatic hydrocarbon group containing a carbon—carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Certain alkenyl 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 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. [0039] The term "alkynyl" means an aliphatic hydrocarbon group containing a carbon—carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms 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. Exemplary 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. [0040] As used herein, the term "halo" or "halogen" means a fluoro, chloro, bromo, or iodo group. [0041] The term “oxo” as used herein refers to an “=O” group. When an oxo group is bonded to a carbon atom, it can also be abbreviated herein as C(O) or as C=O. An oxo group can also be bonded to a sulfur atom (e.g., S=O and S(O)2) or at phosphorous atom (e.g., P=O, PO2, PO3, PO4, etc.). [0042] The term “imine” as used herein refers to an “=N” group. When an imine is bonded to a carbon atom, it can also be abbreviated herein as C=N. Nitrogen can also be double bonded to sulfur, e.g., S=N, which is referred to as a thioimine. [0043] The term “annular atoms” used in conjunction with terms relating to ring systems described herein (e.g., cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl) 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
Figure imgf000020_0001
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. [0044] "Cycloalkyl" refers to a single saturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-C20 cycloalkyl), for example from 3 to 15 annular atoms, for example, from 3 to 12 annular atoms. In certain embodiments, 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. Examples of cycloalkyl groups include cyclohexyl, cycloheptyl, 2-adamantyl (
Figure imgf000020_0002
), 2-(2,3-dihydro-1H-indene)
Figure imgf000020_0003
and 9-fluorenyl ( ). As noted above, cycloalkyl rings can be further characterized by the number of annular atoms. For example, a cyclohexyl ring is a C6 cycloalkyl ring with 6 annular atoms, while 2-(2,3-dihydro-1H-indene) is a C5 cycloalkyl ring with 9 annular atoms. Also, for example, 9-fluorenyl is a C5 cycloalkyl ring with 13 annular atoms and 2- adamantyl is a C6 cycloalkyl with 10 annular atoms. [0045] As used herein, the term “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. [0046] The term "aryl" as used herein 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. For example, in certain embodiments, 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. Examples of aryl groups include phenyl and 5-(2,3-dihydro-1H-indene):
Figure imgf000021_0001
. As noted above, aryl rings can be further characterized by the number of annular atoms. For example, phenyl is a C6 aryl with 6 annular atoms, while 5-(2,3-dihydro-1H-indene) is a C6 aryl with 9 annular atoms. [0047] "Heterocyclyl" as used herein 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. Thus, 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. Examples of 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)
Figure imgf000022_0001
. [0048] The term "heteroaryl" as used herein 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. Thus, 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. [0049] The disclosure also includes pharmaceutical 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. Representative “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, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy- 2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3- naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. [0050] The term “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. [0051] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I and 125I. Isotopically-labeled compounds (e.g., those labeled with 3H and 14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by 2H or 3H, or one or more carbon atoms are replaced by 13C- or 14C-enriched carbon. Positron emitting isotopes such as 15O, 13N, 11C, and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. [0052] The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound. Furthermore, as used herein 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). [0053] The term "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. [0054] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to 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. [0055] The term "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. The term "stereoisomer" refers to any member of this set of compounds. For instance, a stereoisomer may be an enantiomer or a diastereomer. [0056] The term "enantiomers" refers to a pair of stereoisomers which are non- superimposable mirror images of one another. The term "enantiomer” refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1:1 mixture of a pair of enantiomers. [0057] The term "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. The term "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. [0058] 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. [0059] The term “carrier”, as used in this disclosure, 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. [0060] The term “treating” with regard to a subject, refers to improving at least one symptom of the subject’s disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. [0061] The term “prevent” or “preventing” with regard to a subject 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. [0062] The terms “inhibiting” and “reducing,” or any variation of these terms, 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., SOS1:Ras-family protein binding activity) compared to normal. [0063] The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. [0064] The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer 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. [0065] 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. Compounds of Disclosed Formulae [0066] In some embodiments, the present disclosure relates to compounds having a structure of Formula (I), Formula (II), or Formula (III):
Figure imgf000026_0001
, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein: X1 is NH or S; X2 is CH or N; X3 is CH or N; X4 is CR3 or N; X5 is CH or N; X6 is CH or N; R1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, -NH-C1-6 alkyl, and –NH2; R3 is selected from the group consisting of H, -O-C1-6 alkyl, and -O-C1-6 heteroalkyl; L4 is a bond or O; and R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with one or more C1-6 alkyl, –R4a, –OR4a, –O–C1-6 alkyl– R4a, =O, halogen, –C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –NR4bC(O)R4c, –CN, =NR4a, – NR4bR4c, –SO2R4a, 3-6 membered cycloalkyl optionally substituted with R4a, 3-7 membered heterocyclyl optionally substituted with R4a, 6-10 membered aryl optionally substituted with R4a, or 5-10 membered heteroaryl optionally substituted with R4a; wherein R4a is H, C1-6 alkyl, C1-6 haloalkyl, –C(O)R4b, –C(O)NR4bR4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with –OR4b, – CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, –(CH2)rOCH3, or – (CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, C1-6 alkyl; and wherein each R4c is independently H or C1-6 alkyl. [0067] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is optionally substituted 6-membered aryl. In some embodiments, the 6-membered aryl has the following structure:
Figure imgf000028_0001
wherein R5, R6, R7, R8, and R9 are as defined below in connection with Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3). [0068] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is optionally substituted 5-6 membered heteroaryl. In some embodiments, R1 is a 6-membered heteroaryl having any of the following structures:
Figure imgf000028_0003
(IIIc-3). [0069] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is the optionally substituted 5-6 membered heteroaryl. In some embodiments, R1 is a 5-membered heteroaryl having the following structure:
Figure imgf000028_0002
wherein R5, R6, and R7 are as defined below in connection with Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3). [0070] In some embodiments, the present disclosure relates to compounds having the structure selected from the group consisting of Formula (Ia), Formula (IIa), and Formula (IIIa): ,
Figure imgf000029_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Formulas (I), (II), or (III); R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0071] In some embodiments, the present disclosure relates to compounds having the structure selected from the group consisting of Formula (Ib), Formula (IIb), and Formula (IIIb):
Figure imgf000031_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Formula (I), Formula (II), or Formula (III); R5, R6, and R7 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, –S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, – NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, and R7 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0072] In some embodiments, the present disclosure relates to compounds having the structure selected from the group consisting of Formula (Ic-1), Formula (Ic-2), Formula (Ic-3), Formula (IIc-1), Formula (IIc-2), Formula (IIc-3), Formula (IIIc-1), Formula (IIIc- 2), and Formula (IIIc-3):
Figure imgf000033_0001
Figure imgf000034_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Formula (I), Formula (II), or Formula (III); R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0073] In some embodiments, the present disclosure relates to compounds having the structure of Formula (Ic-1), Formula (Ic-2), Formula (IIc-1), Formula (IIc-2), Formula (IIIc-1), or Formula (IIIc-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0074] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl, wherein the alkyl is optionally substituted with halogen. In one embodiment, the alkyl is substituted with halogen. [0075] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl, wherein the alkyl is optionally substituted with halogen and/or –OH. [0076] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl, and one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl optionally substituted with halogen. [0077] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one to three of R5, R6, R7, R8, and R9 is halogen, and one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl optionally substituted with halogen. In one embodiment, the alkyl is substituted with halogen. [0078] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one to three of R5, R6, R7, R8, and R9 is –NH2. [0079] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one of R5, R6, R7, R8, and R9 is –NH2; and one of R5, R6, R7, R8, and R9 is C1-6 alkyl optionally substituted with halogen. In one embodiment, the alkyl is substituted with halogen. [0080] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, any two adjacent R5, R6, R7, R8, and R9 forms a 3-14 membered fused ring. In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, any two adjacent R5, R6, R7, R8, and R9 forms a 3-8 membered fused ring. In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), any two adjacent R5, R6, R7, R8, and R9 forms a 4-8 membered fused ring. In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, any two adjacent R5, R6, R7, R8, and R9 forms a 4-membered fused ring or a 5-membered fused ring. In some embodiments, the fused ring is a 3-8 membered heterocyclyl or a 3-8 membered cycloalkyl. In some embodiments, the fused ring is a 4-8 membered heterocyclyl or a 4-8 membered cycloalkyl. In some embodiments, the fused ring is a 4-membered heterocyclyl or a 5-membered heterocyclyl. In some embodiments, the fused ring is a 4-membered cycloalkyl or a 5-membered cycloalkyl. In some embodiments, the fused ring is optionally substituted with –OH, C1-6 alkyl, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, –S(O)2NR11R12, –S(O)2R10, – NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, – NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. In some embodiments, the fused ring is optionally substituted with halogen. [0081] In some embodiments of compounds of Formulas (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), and (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, one or more of R5, R6, R7, R8, and R9 is selected from among –CF3, -CHF2, –NH2, –F, and –CF2CH2OH. In some embodiments of compounds of Formula (Ia), (IIa), or (IIIa), one of R5, R6, R7, R8, and R9 is –CF3 and one of R5, R6, R7, R8, and R9 is –NH2. In some embodiments of compounds of (Ia), (IIa), or (IIIa), one of R5, R6, R7, R8, and R9 is –F and one of R5, R6, R7, R8, and R9 is –CF2CH2OH. In some embodiments of compounds of (Ia), (IIa), or (IIIa), one of R5, R6, R7, R8, and R9 is –F, and one of R5, R6, R7, R8, and R9 is – CHF2. [0082] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is selected from among:
Figure imgf000037_0001
,
Figure imgf000037_0002
Figure imgf000038_0001
[0083] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is selected from among:
Figure imgf000038_0002
Figure imgf000038_0003
. [0084] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is selected from among:
Figure imgf000038_0004
Figure imgf000038_0005
. [0085] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is selected from among:
Figure imgf000039_0001
,
Figure imgf000039_0002
[0086] In some embodiments of compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R1 is selected from among:
Figure imgf000039_0003
. [0087] In some embodiments, the present disclosure relates to compounds having the structure selected from the group consisting of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), and Formula (Ic-3) or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0088] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is CH, X3 is CH, X4 is N, and X5 is CH. [0089] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is N, X3 is CH, X4 is N, and X5 is CH. [0090] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is N, X3 is CH, X4 is CR3, and X5 is CH. [0091] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is S, X2 is CH, X3 is CH, X4 is CR3, and X5 is CH. [0092] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is N, X3 is N, X4 is CR3, and X5 is CH. [0093] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is CH, X3 is N, X4 is CR3, and X5 is CH. [0094] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is CH, X3 is CH, X4 is CR3, and X5 is N. [0095] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH, X2 is CH, X3 is CH, X4 is CR3, and X5 is CH. [0096] In some of the foregoing embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R3 is H. In some embodiments, R3 is –O-C1-3 alkyl. In some embodiments, R3 is – O-CH3. In some embodiments, R3 is –O-C1-3 heteroalkyl. In some embodiments, R3 is H or –O-CH3. [0097] In some embodiments of compounds of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, L4 is a bond. In some embodiments, L4 is O. [0098] In some embodiments, the present disclosure relates to compounds having the structure selected from the group consisting of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), and Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0099] In some embodiments of compounds of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), or Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X1 is NH and X4 is CH. [0100] In some embodiments of compounds of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), or Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R3 is H. In some embodiments, R3 is –O-C1-3 alkyl. In some embodiments, R3 is –O-CH3. In some embodiments, R3 is –O-C1-3 heteroalkyl. In some embodiments, R3 is H or –O-CH3. [0101] In some embodiments, the present disclosure relates to compounds having the structure selected from the group consisting of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), and Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0102] In some embodiments of compounds of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X5 is CH and X6 is N. [0103] In some embodiments of compounds of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, X5 is CH and X6 is CH. [0104] In some embodiments of compounds of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R2 is H. [0105] In some embodiments of compounds of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R2 is NH2. [0106] In some embodiments of compounds of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R2 is –NH-CH3. [0107] In some embodiments of compounds of Formula (I), the compound has the structure selected from the group consisting of:
Figure imgf000043_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1, R3, L4, and R4 are as defined in Formula (I). [0108] In some embodiments of compounds of Formula (II), the compound has the structure of Formula (II-1):
Figure imgf000044_0001
, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 and R4 are as defined in Formula (II). [0109] In some embodiments of compounds of Formula (III), the compound has the structure of Formula (III-1) or Formula (III-2):
Figure imgf000044_0002
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1, R2, and R4 are as defined in Formula (III). [0110] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3- 14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with C1-6 alkyl –OR4a, =O, halogen, – C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –CN, –NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein R4a, R4b, and R4c are as defined for Formulas (I), (II), or (III). [0111] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3- 14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with C1-6 alkyl –OR4a, =O, halogen, – C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –CN, –NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein R4a, R4b, and R4c are as defined for Formulas (I), (II), or (III). [0112] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4a is H, C1-6 alkyl, C1-6 haloalkyl, –C(O)R4b, –C(O)NR4bR4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with –OR4b, –CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, –(CH2)rOCH3, or –(CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, C1-6 alkyl; and wherein each R4c is independently H or C1-6 alkyl. [0113] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4a is H, C1-6 alkyl, C1-6 haloalkyl, –C(O)R4b, –C(O)NR4bR4c, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with –OR4b, –CN, 3-7 membered heterocyclyl, –(CH2)rOCH3, or –(CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, C1-6 alkyl; and wherein each R4c is independently H or C1-6 alkyl. [0114] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl. In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc- 2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc-3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is a substituted 3-14 membered heterocyclyl. [0115] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl. In some embodiments, the heterocyclyl substituent is oxetanyl. [0116] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with C1-6 alkyl. In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc-3), (I-1), (I-2), (I-3), (I- 4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with –CH3. In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc-3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with –CH2–, i.e., the substituent is a methylene bridge bridging 2 carbon atoms in the heterocyclyl ring. [0117] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl. In some embodiments, the cycloalkyl substituent is cyclopropyl. [0118] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with one or more =O. In some embodiments, the 3-14 membered heterocyclyl is substituted with one or more =O and is further substituted with C1-6 alkyl. In one such embodiment, the C1-6 alkyl is –CH3. [0119] In some embodiments of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is 3-14 membered heterocyclyl substituted with –C(O)R4a. In one embodiment, R4a is C1-6 alkyl. In one embodiment, R4a is –CH3. [0120] In some embodiments, of compounds of Formulas (I), (II), (III), (Ia), (IIa), (IIIa), (Ib), (IIb), (IIIb), (Ic-1), (Ic-2), (Ic-3), (IIc-1), (IIc-2), (IIc-3), (IIIc-1), (IIIc-2), (IIIc- 3), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (II-1), (III-1), or (III-2), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, R4 is a heterocyclyl selected from among:
Figure imgf000048_0001
[0121] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000048_0002
. [0122] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000048_0003
Figure imgf000049_0001
[0123] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000049_0002
[0124] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000049_0003
[0125] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000050_0001
[0126] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000050_0002
Figure imgf000051_0001
[0127] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000051_0002
. [0128] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000051_0003
[0129] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000051_0004
[0130] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000052_0001
[0131] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000052_0002
[0132] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000052_0004
[0134] In some embodiments, R4 is a heterocyclyl selected from among:
Figure imgf000052_0003
[0135] In some embodiments, R4 is selected from among:
Figure imgf000053_0001
. [0136] In some embodiments, R4 is selected from among: ,
Figure imgf000053_0002
[0137] In some embodiments, R4 is 3-14 membered cycloalkyl. In some embodiments, R4 is substituted 3-14 membered cycloalkyl. [0138] In some embodiments, R4 is selected from among:
Figure imgf000053_0003
Figure imgf000054_0001
[0139] In some embodiments, R4 is 6-10 membered aryl. In some embodiments, R4 is substituted 6-10 membered aryl. In some embodiments, R4 is phenyl. In some embodiments, R4 is phenyl substituted with one or two group selected from among –OCH3 and –CN. [0140] In some embodiments, R4 is 5-10 membered heteroaryl. In some embodiments, R4 is substituted 5-10 membered heteroaryl. In some embodiments, R4 is selected from among 1H-pyrrole, thiazole, pyridine, pyridazine, pyrimidine, each of which is optionally substituted with a group selected from among –F, –OCH3, and – OCH2CH2OH. [0141] In some embodiments, R4 is selected from among:
Figure imgf000054_0002
[0142] 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.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Methods of Synthesizing the Disclosed Compounds [0143] The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the schemes given below. [0144] 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 following synthetic schemes and examples. In the schemes described below, it is well understood that 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. [0145] Those skilled in the art will recognize if a stereocenter exists in any of the compounds of the present disclosure. Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. 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). Preparation of Compounds [0146] The compounds described in this disclosure may be synthesized from commercially available starting materials using known organic, inorganic, and/or enzymatic processes. [0147] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods include but are not limited to those methods described below. [0148] A general synthesis of substituted 1H-indazole-7-carboxamides or analogous heterocycles is outlined in Scheme 1. Scheme 1:
Figure imgf000061_0001
[0149] 5-bromo-1H-indazole-7-carboxylic acid or an analogous appropriately substituted halogenated heterocyclic ring can undergo an amide coupling with an appropriately substituted benzyl amine. The resulting phenylethyl 1H-indazole-7- carboxamide or analogous halogenated heterocyclic ring can then be used for cross coupling reactions with appropriately substituted, amines, amides, alkyls, olefins, aromatics, or heteroaromatics. Additional deprotection and/or functionalization steps can be required to produce the final compound. [0150] Alternatively, final compounds with an oxygen substituent in position 5 can be prepared through an SNAr reaction between an alcohol and methyl 5-fluoro-1H- indole-7-carboxylate or an analogous appropriately substituted halogenated heterocycle, as outlined in Scheme 2. The resulting aryl ether can then undergo an amide coupling with an appropriately substituted benzyl amine. Additional deprotection and/or functionalization steps can be required to produce the final compound. Scheme 2:
Figure imgf000062_0001
[0151] A general synthesis of substituted 1H-pyrrolo[3,2-b]pyridine-7- carboxamides or analogous heterocycles is outlined in Scheme 3. Scheme 3:
Figure imgf000062_0002
[0152] 3-amino-6-bromopyridine or an analogous appropriately substituted halogenated heterocyclic ring can undergo cross coupling reactions with appropriately substituted, amines, amides, alkyls, olefins, aromatics, or heteroaromatics. The resulting intermediate can then be used in a cross-coupling reaction with an appropriate terminal alkyne. The resulting 2-alkynylpyridin-3-amine can then undergo an intramolecular hydroamination in the presence of a Cu catalyst. The resulting 7-chloro-1H-pyrrolo[3,2- b]pyridine or analogous appropriately halogenated heterocycle can then be coupled to appropriately substituted benzyl amine in the presence of carbon monoxide a palladium catalyst. Additional deprotection and/or functionalization steps can be required to produce the final compound. [0153] The appropriately substituted benzyl amine building block can be prepared as outlined in Scheme 4. Appropriately substituted aryl or heteroaryl bromides can be transformed into the corresponding acetyl arene or heteroarene by metal halogen exchange followed by the addition of an acetylating reagent. The ketone functionality can then be stereoselectively transformed into the desired chiral benzylamine using Ellman’s reagent. Scheme 4:
Figure imgf000063_0001
[0154] Due to their biological properties the compounds of the present disclosure, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms may be suitable for treating diseases characterized by excessive or abnormal cell proliferation such as cancer. [0155] For example, the following cancers, tumors and other proliferative diseases may be treated with compounds of the present disclosure, without being restricted thereto: - 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 lung: e.g., non-small cell lung cancer (NSCLC) (squamous cell carcinoma, spindle cell carcinoma, adenocarcinoma, large cell carcinoma, clear cell carcinoma, bronchioalveolar), small cell lung cancer (SCLC) (oat cell cancer, intermediate cell cancer, combined oat cell cancer); - neoplasms of the mediastinum: e.g., neurogenic tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma), astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g., acoustic), spinal axis tumors; - cancers/tumors/carcinomas of the gastrointestinal (GI) tract: e.g., tumors/carcinomas/ cancers of the esophagus, stomach (gastric cancer), pancreas, liver and biliary tree (including hepatocellular carcinoma (HCC), e.g., childhood HCC, fibrolamellar HCC, combined HCC, spindle cell HCC, clear cell HCC, giant cell HCC, carcinosarcoma HCC, sclerosing HCC; hepatoblastoma; cholangiocarcinoma; cholangiocellular carcinoma; hepatic cystadenocarcinoma; angiosarcoma, hemangioendothelioma, leiomyosarcoma, malignant schwannoma, fibrosarcoma, Klatskin tumor), gall bladder, extrahepatic bile ducts, small intestine (including duodenum, jejunum, ileum), large intestine (including cecum, colon, rectum, anus; colorectal cancer, gastrointestinal stroma tumor (GIST)), genitourinary system (including kidney, e.g., renal pelvis, renal cell carcinoma (RCC), nephroblastoma (Wilms' tumor), hypernephroma, Grawitz tumor; ureter; urinary bladder, e.g., urachal cancer, urothelial cancer; urethra, e.g., distal, bulbomembranous, prostatic; prostate (androgen dependent, androgen independent, castration resistant, hormone independent, hormone refractory), penis); - cancers/tumors/carcinomas of the testis: e.g., seminomas, non-seminomas; - gynecologic cancers/tumors/carcinomas: e.g., tumors/carcinomas/cancers of the ovary, fallopian tube, peritoneum, cervix, vulva, vagina, uterine body (including endometrium, fundus); - cancers/tumors/carcinomas of the breast: e.g., mammary carcinoma (infiltrating ductal, colloid, lobular invasive, tubular, adenocystic, papillary, medullary, mucinous), hormone receptor positive breast cancer (estrogen receptor positive breast cancer, progesterone receptor positive breast cancer), HER2 positive breast cancer, triple negative breast cancer, Paget's disease of the breast; - cancers/tumors/carcinomas of the endocrine system: e.g., tumors/carcinomas/cancers of the endocrine glands, thyroid gland (thyroid carcinomas/tumors; papillary, follicular, anaplastic, medullary), parathyroid gland (parathyroid carcinoma/tumor), adrenal cortex (adrenal cortical carcinoma/tumors), pituitary gland (including prolactinoma, craniopharyngioma), thymus, adrenal glands, pineal gland, carotid body, islet cell tumors, paraganglion, pancreatic endocrine tumors (PET; non-functional PET, PPoma, gastrinoma, insulinoma, VIPoma, glucagonoma, somatostatinoma, GRFoma, ACTHoma), carcinoid tumors; - sarcomas of the soft tissues: e.g., fibrosarcoma, fibrous histiocytoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, lymphangiosarcoma, Kaposi’s sarcoma, glomus tumor, hemangiopericytoma, synovial sarcoma, giant cell tumor of tendon sheath, solitary fibrous tumor of pleura and peritoneum, diffuse mesothelioma, malignant peripheral nerve sheath tumor (MPNST), granular cell tumor, clear cell sarcoma, melanocytic schwannoma, plexosarcoma, neuroblastoma, ganglioneuroblastoma, neuroepithelioma, extraskeletal Ewing's sarcoma, paraganglioma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, desmoplastic small cell tumor; - sarcomas of the bone: e.g., myeloma, reticulum cell sarcoma, chondrosarcoma (including central, peripheral, clear cell, mesenchymal chondrosarcoma), osteosarcoma (including parosteal, periosteal, high-grade surface, small cell, radiation-induced osteosarcoma, Paget's sarcoma), Ewing's tumor, malignant giant cell tumor, adamantinoma, (fibrous) histiocytoma, fibrosarcoma, chordoma, small round cell sarcoma, hemangioendothelioma, hemangiopericytoma, osteochondroma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, chondroblastoma; - mesothelioma: e.g., pleural mesothelioma, peritoneal mesothelioma; - cancers of the skin: e.g., basal cell carcinoma, squamous cell carcinoma, Merkel's cell carcinoma, melanoma (including cutaneous, superficial spreading, lentigo maligna, acral lentiginous, nodular, intraocular melanoma), actinic keratosis, eyelid cancer; - neoplasms of the peripheral and central nervous system and brain: e.g., astrocytoma (cerebral, cerebellar, diffuse, fibrillary, anaplastic, pilocytic, protoplasmic, gemistocytary), glioblastoma, gliomas, oligodendrogliomas, oligoastrocytomas, ependymomas, ependymoblastomas, choroid plexus tumors, medulloblastomas, meningiomas, schwannomas, hemangioblastomas, hemangiomas, hemangiopericytomas, neuromas, ganglioneuromas, neuroblastomas, retinoblastomas, neurinomas (e.g., acoustic), spinal axis tumors, neurogenic tumors (including neurofibroma, neurilemoma, malignant schwannoma, neurosarcoma, ganglioneuroblastoma, ganglioneuroma, neuroblastoma, pheochromocytoma, paraganglioma), germ cell tumors (including seminoma, teratoma, non-seminoma), thymic tumors (including thymoma, thymolipoma, thymic carcinoma, thymic carcinoid), mesenchymal tumors (including fibroma, fibrosarcoma, lipoma, liposarcoma, myxoma, mesothelioma, leiomyoma, leiomyosarcoma, rhabdomyosarcoma, xanthogranuloma, mesenchymoma, hemangioma, hemangioendothelioma, hemangiopericytoma, lymphangioma, lymphangiopericytoma, lymphangiomyoma); - lymphomas and leukemias: e.g., B-cell non-Hodgkin lymphomas (NHL) (including small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma (LPL), mantle cell lymphoma (MCL), follicular lymphoma (FL), diffuse large cell lymphoma (DLCL), Burkitt's lymphoma (BL)), Burkitt leukemia, T-cell non-Hodgkin lymphomas (including anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL)), lymphoblastic T-cell lymphoma (T-LBL), adult T-cell lymphoma, lymphoblastic B-cell lymphoma (B-LBL), immunocytoma, chronic B-cell lymphocytic leukemia (B-CLL), chronic T-cell lymphocytic leukemia (T-CLL) B-cell small lymphocytic lymphoma (B- SLL), cutaneous T-cell lymphoma (CTLC), primary central nervous system lymphoma (PCNSL), immunoblastoma, Hodgkin's disease (HD) (including nodular lymphocyte predominance HD (NLPHD), nodular sclerosis HD (NSHD), mixed-cellularity HD (MCHD), lymphocyte-rich classic HD, lymphocyte-depleted HD (LDHD)), large granular lymphocyte leukemia (LGL), chronic myelogenous leukemia (CML), acute myelogenous/myeloid leukemia (AML), acute lymphatic/lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), chronic lymphocytic/lymphatic leukemia (CLL), prolymphocytic leukemia (PLL), hairy cell leukemia, chronic myelogenous/myeloid leukemia (CML), myeloma, plasmacytoma, multiple myeloma (MM), plasmacytoma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), JMML (juvenile myelomonocytic leukemia), acute leukemia of ambiguous lineage, myeloproliferative neoplasms, blastic plasmacytoid dendritic cell neoplasm, early T-cell precursor leukemia, natural killer cell leukemia/lymphoma, myeloid/lymphoid neoplasms with eosinophilia, myeloid sarcoma, transient abnormal myelopoiesis; and - cancers of unknown primary site (CUP). [0156] 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. [0157] All cancers/tumors/carcinomas mentioned above may be further differentiated by their histopathological classification: - 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 cancers, e.g., sarcomas (fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, hemangiosarcoma, giant cell sarcoma, lymphosarcoma, fibrous histiocytoma, liposarcoma, angiosarcoma, lymphangiosarcoma, neurofibrosarcoma), lymphoma, melanoma, germ cell tumors, hematological neoplasms, mixed and undifferentiated carcinomas. [0158] 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. [0159] The compounds of the invention may be used for the prevention, short- term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy and/or surgery and/or other compounds. [0160] Of course, 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 invention, as well as the preparation and/or manufacture of medicaments including such compounds of the invention, and the like. Additional Methods of Using the Disclosed Compounds [0161] One aspect of the present disclosure relates to a method of inhibiting SOS1 in a subject in need thereof, comprising administering to the subject a SOS1 inhibitor of the present disclosure, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0162] 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 SOS1 and a RAS-family protein and/or RAC1 in a subject in need thereof. The method involves administering to a subject or patient in need of treatment for diseases or disorders associated with SOS1 modulation an effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0163] In certain embodiments, a method is provided of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier. [0164] In certain embodiments, 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 of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0165] In certain embodiments, the disease can be, but is not limited to, cancer. In certain embodiments, 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 sarcomas. In some embodiments, the cancer is colorectal cancer or pancreatic cancer. [0166] In certain embodiments, the disease can be, but is not limited to, cancer. In certain embodiments, 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. [0167] In certain embodiments, the disease can be, but is not limited to, a RASopathy. In certain embodiments, 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. [0168] Another aspect of the present disclosure is directed to a method of inhibiting SOS1. The method involves administering to a patient in need thereof an effective amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0169] The present disclosure relates to compositions capable of modulating the activity of (e.g., inhibiting) SOS1. The present disclosure also relates to the therapeutic use of such compounds or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0170] The disclosed compound can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects. [0171] 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 affected by modification of the interaction of SOS1 and a RAS-family protein and/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 SOS1 with a RAS-family protein or the interaction of SOS1 with RAC1. [0172] 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, wherein the treating or preventing is effected or characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RA. [0173] 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 inhibiting the binding of hSOS1 to H- or N- or K-RAS including their clinically known mutations and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 μΜ or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 μΜ or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder. [0174] 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 the manufacture of a medicament for use inhibiting the binding of hSOS1 specifically to K-RAS G12C protein or another Ras mutant, as described herein, and which inhibits the nucleotide exchange reaction catalyzed by hSOS1 in the presence of a concentration of 20 μΜ or lower, but which are substantially inactive against EGFR-kinase at concentrations of 20 μΜ or lower for the preparation of a medicament for the treatment or prophylaxis of a hyperproliferative disorder. [0175] In another aspect, the present disclosure relates to the use of a compound of any formula 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. [0176] Administration of the disclosed compounds 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. [0177] Depending on the intended mode of administration, the disclosed compounds or pharmaceutical compositions 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. [0178] 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 and/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 and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl- cyclodextrin, PEG400, PEG200. [0179] Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, 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. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds. [0180] 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. [0181] 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. In some embodiments, 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. [0182] 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. Furthermore, 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. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate. [0183] 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. [0184] Another aspect of the present disclosure relates to 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. [0185] 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. [0186] 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. [0187] Effective dosage amounts of the disclosed compounds or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat 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. In one embodiment, the compositions are in the form of a tablet that can be scored. Combination Therapy [0188] The methods of the 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). Combination therapy may, for example, combine two therapies or may combine three therapies (e.g., a triple therapy of three therapeutic agents), or more. The dosages of one or more of the additional therapies (e.g., non-drug treatments or therapeutic agents) 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)). [0189] A compound of the present disclosure may be administered before, after, or concurrently with one or more of such additional therapies. When combined, dosages of a compound of the invention and dosages of the one or more additional therapies (e.g., non- drug treatment or therapeutic agent) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). A compound of the present invention and an additional therapy, such as an anti-cancer agent, may be administered together, such as in a unitary pharmaceutical composition, or separately and, when administered separately, this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time. [0190] In some embodiments, 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. For example, in some embodiments, the compounds of the present disclosure can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include: dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof. [0191] In some embodiments, the one or more additional therapies includes a non-drug treatment (e.g., surgery or radiation therapy). In some embodiments, 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). In some embodiments, 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). In other embodiments, the one or more additional therapies includes two therapeutic agents. In still other embodiments, 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. Non-drug therapies [0192] Examples of 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. [0193] In some embodiments, the compounds of the disclosure may be used as an adjuvant therapy after surgery. In some embodiments, the compounds of the invention may be used as a neo-adjuvant therapy prior to surgery. [0194] 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)). 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. The term "brachy therapy," as used herein, 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. The term is intended, without limitation, to include exposure to radioactive isotopes (e.g., At-211, 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 of the present invention include both solids and liquids. By way of non-limiting example, the radiation source can be a radionuclide, such as I-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. Moreover, the radionuclide(s) can be embodied in a gel or radioactive micro spheres. [0195] In some embodiments, 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 invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention, which amount is effective to sensitize abnormal cells to treatment with radiation. The amount of the compound in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. In some embodiments, the compounds of the present invention may be used as an adjuvant therapy after radiation therapy or as a neo-adjuvant therapy prior to radiation therapy. [0196] In some embodiments, the non-drug treatment is a T cell adoptive transfer (ACT) therapy. In some embodiments, 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. For example, the CAR-T cells can be generated by introducing a suitable expression vector encoding the CAR to a T cell. Prior to expansion and genetic modification of the T cells, a source of T cells is obtained from a subject. T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the present invention, any number of T cell lines available in the art may be used. In some embodiments, the T cell is an autologous T cell. Whether prior to or after genetic modification of the T cells to express a desirable protein (e.g., a CAR), the T cells can be activated and expanded generally using methods as described, for example, in U.S. Patents 6,352,694; 6,534,055; 6,905,680; 6,692,964; 5,858,358; 6,887,466; 6,905,681; 7,144,575; 7,067,318; 7,172,869; 7,232,566; 7,175,843; 7,572,631; 5,883,223; 6,905,874; 6,797,514; and 6,867,041. Therapeutic Agents [0197] A therapeutic agent may be a compound used in the treatment of cancer or symptoms associated therewith. [0198] For example, a therapeutic agent may be a steroid. Accordingly, in some embodiments, the one or more additional therapies includes a steroid. Suitable steroids may include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, hydrocortisone, loteprednol etabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof. [0199] Further examples of therapeutic agents that may be used in combination therapy with a compound of the present disclosure include compounds described in the following patents: U.S. Patent Nos.6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications WO01/37820, WO01/32651, WO02/68406, WO02/66470, WO02/55501, WO04/05279, WO04/07481, WO04/07458, WO04/09784, WO02/59110, WO99/45009, WO00/59509, WO99/61422, WO00/12089, and WO00/02871. [0200] 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. In some embodiments, 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. Also included are antibody-drug conjugates. [0201] A therapeutic agent may be a checkpoint inhibitor. In one embodiment, 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. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with the ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion a protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or small molecule inhibitor) of PDL-1. In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL-2 (e.g., a PDL-2/Ig fusion protein). In some embodiments, 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. In some embodiments, 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. Neurol., including, without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514/ MEDI0680, BMS936559, MEDl4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002. [0202] 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. [0203] 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. Further anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, 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). [0204] Other non-limiting examples of 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); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, such as calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)); 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, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti- metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes such as T- 2 toxin, verracurin A, roridin A and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., Taxol® (paclitaxel), Abraxane® (cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel), and Taxotere® (doxetaxel); chloranbucil; tamoxifen (Nolvadex™); raloxifene; aromatase inhibiting 4(5)-imidazoles; 4-hydroxytamoxifen; trioxifene; keoxifene; LY 117018; onapristone; toremifene (Fareston®); flutamide, nilutamide, bicalutamide, leuprolide, goserelin; chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicins; capecitabine (e.g., Xeloda®); and pharmaceutically acceptable salts of any of the above. [0205] Additional non-limiting examples of 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, biricodar, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferruginol, forodesine, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucanthone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitors, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitabine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur- uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosuquidar. [0206] Further non-limiting examples of anti-cancer agents include natural products such as vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), epidipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycins, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase which systemically metabolizes L-asparagine and deprives cells which do not have the capacity to synthesize their own asparagine), antiplatelet agents, antiproliferative/antimitotic alkylating agents such as nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethylenimines and methylmelamines (e.g., hexaamethylmelaamine and thiotepa), CDK inhibitors (e.g., a CDK 4/6 inhibitor such as ribociclib, abemaciclib, or palbociclib), seliciclib, UCN-01, P1446A-05, PD-0332991, dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), trazenes- dacarbazinine (DTIC), antiproliferative/antimitotic antimetabolites such as folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2- chlorodeoxyadenosine), aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidan, suberoyl anilide hydroamic acid, vorinostat, LBH 589, romidepsin, ACY-1215, and panobinostat), mTOR inhibitors (e.g., vistusertib, temsirolimus, everolimus, ridaforolimus, and sirolimus), KSP(Eg5) inhibitors (e.g., Array 520), DNA binding agents (e.g., Zalypsis®), PI3K inhibitors such as PI3K delta inhibitor (e.g., GS-1101 and TGR-1202), PI3K delta and gamma inhibitor (e.g., CAL-130), copanlisib, alpelisib and idelalisib; multi-kinase inhibitor (e.g., TG02 and sorafenib), hormones (e.g., estrogen) and hormone agonists such as leutinizing hormone releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide and triptorelin), BAFF-neutralizing antibody (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN 163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti- CSl (e.g., elotuzumab), HSP90 inhibitors (e.g., 17 AAG and KOS 953), P13K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra™), anti-CD138 (e.g., BT062), Torcl/2 specific kinase inhibitors (e.g., INK128), ER/UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1/2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists. [0207] In some embodiments, an anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine®, sorafenib, or any analog or derivative variant of the foregoing. [0208] In some embodiments, an anti-cancer agent is an ALK inhibitor. 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 WO05016894. [0209] In some embodiments, 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, RLY-1971, JAB- 3312, BBP-398, ERAS-601, SH3809, PF-07284892, ICP-189), another SOS1 inhibitor (e.g., BI-1701963), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., mTORC1 inhibitor or mTORC2 inhibitor). In some embodiments, the anti-cancer agent is JAB-3312. In some embodiments, an anti-cancer agent is a Ras inhibitor (e.g., AMG 510, MRTX1257, LY349946, MRTX849, ARS-3248 (JNJ-74699157), MRTX1133, ARS-853, BPI-421286, LY3537982, JDQ443, JAB-21000, RMC-6291, RMC-6236, GDC-6036, MRTX1133, JAB-22000, JAB-23000, or ARS-1620, or other Ras inhibitor described herein, such as a 5 Ras inhibitor described in WO 2020/132597, WO 2021/091956, WO 2021/091982, WO 2021/091967), or a Ras vaccine, or another therapeutic modality designed to directly or indirectly decrease the oncogenic activity of Ras. [0210] In some embodiments, the Ras protein is wild-type. Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a 10 patient having a cancer comprising a RasWT (e.g., K-RasWT, H-RasWT or N-RasWT). In some embodiments, the Ras protein is Ras amplification (e.g., K-Rasamp). Accordingly, in some embodiments, a compound of the present invention is employed in a method of treating a patient having a cancer comprising a Rasamp (K-Rasamp, H-Rasamp or N-Rasamp). In some embodiments, the cancer comprises a Ras mutation (RasMUT). In some 15 embodiments, a mutation is selected from: (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, 20 G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) the following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, 25 Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof; or a combination of any of the foregoing (e.g., both K-Ras G12C and K-Ras G13C). In some embodiments, the cancer comprises a Ras mutation selected from the group consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. In some embodiments, the cancer comprises at least two Ras mutations selected from the group 30 consisting of G12C, G13C, G12A, G12D, G13D, G12S, G13S, G12V and G13V. [0211] In some embodiments, a cancer comprises an NF1LOF mutation. In some embodiments of methods herein, the cancer comprises a RasMUT and a compound of the present invention 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. In some embodiments of methods herein, the cancer is colorectal cancer and a compound of the present invention 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). In some embodiments of methods herein, the cancer is non-small cell lung cancer and a compound of the present invention 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). In some embodiments of methods herein, the cancer is non-small cell lung cancer or colorectal cancer, and a compound of the present invention 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, GDC-6036, MRTX1133, JAB-22000, JAB-23000, or ARS-1620). [0212] In some embodiments, a therapeutic agent that may be combined with a compound of the present invention is an inhibitor of the MAP kinase (MAPK) pathway (or “MAPK inhibitor”). MAPK inhibitors include, but are not limited to, one or more MAPK inhibitor described in Cancers (Basel) 2015 Sep; 7(3): 1758–1784. For example, 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.2014 Nov 25;9(11)); and GSK1120212 (or JTP-74057, described in Clin Cancer Res.2011 Mar 1;17(5):989- 1000). [0213] In some embodiments, 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. For example, 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. [0214] In some embodiments, an anti-cancer agent is a PD-1 or PD-L1 antagonist. [0215] In some embodiments, additional therapeutic agents include 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. [0216] IGF-1R inhibitors include linsitinib, or a pharmaceutically acceptable salt thereof. [0217] EGFR inhibitors 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. Cancer 1993, 67:247- 253; Teramoto et al., Cancer 1996, 77:639-645; Goldstein et al., Clin. Cancer Res.1995, 1:1311-1318; Huang et al., 1999, Cancer Res.15:59(8):1935-40; and Yang et al., Cancer Res.1999, 59:1236-1243. 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. [0218] 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. Further non- limiting examples of 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.5,747,498; WO96/30347; EP 0787772; WO97/30034; WO97/30044; WO97/38994; WO97/49688; EP 837063; WO98/02434; WO97/38983; WO95/19774; WO95/19970; WO97/13771; WO98/02437; WO98/02438; WO97/32881; DE 19629652; WO98/33798; WO97/32880; WO97/32880; EP 682027; WO97/02266; WO97/27199; WO98/07726; WO97/34895; WO96/31510; WO98/14449; WO98/14450; WO98/14451; WO95/09847; WO97/19065; WO98/17662; U.S. Pat. No.5,789,427; U.S. Pat. No.5,650,415; U.S. Pat. No.5,656,643; WO99/35146; WO99/35132; WO99/07701; and WO92/20642. Additional non-limiting examples of small molecule EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp. Opin. Ther. Patents 1998, 8(12):1599-1625. In some embodiments, an EGFR inhibitor is osimertinib. [0219] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, a MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N. [0220] PI3K inhibitors include, but are not limited to, wortmannin; 17- hydroxywortmannin analogs described in WO06/044453; 4-[2-(1H-Indazol-4-yl)-6-[[4- (methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09/036082 and WO09/055730); 2- methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1- yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in WO06/122806); (S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2- d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08/070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyrido- [3',2':4,5]furo[3,2-d]pyrimidin-2-yl] phenol hydrochloride (available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]- 1-methylhydrazide-benzenesulfonic acid, monohydrochloride) (available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[l,2-c]quinazolin-5-yl)- nicotinamide (available from Axon Medchem); AS-252424 (5-[l-[5-(4-fluoro-2-hydroxy- phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione (available from Axon Medchem); TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido- [1,2-a]pyrirnidin-4-one (available from Axon Medchem); XL-765; and XL-147. Other 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. [0221] AKT inhibitors include, but are not limited to, Akt-1-1 (inhibits Aktl) (Barnett et al., Biochem. J.2005, 385(Pt.2): 399-408); Akt-1-1,2 (inhibits Akl and 2) (Barnett et al., Biochem. J.2005, 385(Pt.2): 399-408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer 2004, 91:1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05/011700); indole-3-carbinol and derivatives thereof (e.g., U.S. Pat. No.6,656,963; Sarkar and Li J Nutr.2004, 134(12 Suppl):3493S-3498S); perifosine (e.g., interferes with Akt membrane localization; Dasmahapatra et al. Clin. Cancer Res.2004, 10(15):5242-52); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis Expert. Opin. Investig. Drugs 2004, 13:787-97); and triciribine (TCN or API-2 or NCI identifier: NSC 154020; Yang et al., Cancer Res.2004, 64:4394-9). [0222] mTOR inhibitors include, but are not limited to, ATP-competitive mTORC1/mTORC2 inhibitors, e.g., PI-103, PP242, PP30; Torin 1; FKBP12 enhancers; 4H-1-benzopyran-4-one derivatives; and rapamycin (also known as sirolimus) and derivatives thereof, including: temsirolimus (Torisel®); everolimus (Afinitor®; WO94/09010); ridaforolimus (also known as deforolimus or AP23573); rapalogs, e.g., as disclosed in WO98/02441 and WO01/14387, e.g., AP23464 and AP23841; 40-(2- hydroxyethyl)rapamycin; 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin (also known as CC1779); 40-epi-(tetrazolyt)-rapamycin (also called ABT578); 32- deoxorapamycin; 16-pentynyloxy-32(S)-dihydrorapanycin; derivatives disclosed in WO05/005434; derivatives disclosed in U.S. Patent Nos.5,258,389, 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, and 5,256,790, and in WO94/090101, WO92/05179, WO93/111130, WO94/02136, WO94/02485, WO95/14023, WO94/02136, WO95/16691, WO96/41807, WO96/41807, and WO2018204416; and phosphorus-containing rapamycin derivatives (e.g., WO05/016252). In some embodiments, the mTOR inhibitor is a bisteric inhibitor (see, e.g., WO2018204416, WO2019212990 and WO2019212991), such as RMC-5552. [0223] BRAF inhibitors that may be used in combination with compounds of the invention include, for example, vemurafenib, dabrafenib, and encorafenib. A BRAF may comprise a Class 3 BRAF mutation. In some embodiments, 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. [0224] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. The myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Over-expression of MCL-1 has been closely related to tumor progression as well as to resistance, not only to traditional chemotherapies but also to targeted therapeutics including BCL-2 inhibitors such as ABT- 263. [0225] In some embodiments, the additional therapeutic agent is a SHP2 inhibitor. 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. [0226] SHP2 is involved in signaling through the RAS-mitogen-activated protein kinase (MAPK), the JAK-STAT or 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) in combination with a RAS pathway inhibitor (e.g., a MEK inhibitor) have been shown to inhibit the proliferation of multiple cancer cell lines in vitro (e.g., pancreas, lung, ovarian and breast cancer). Thus, combination therapy involving a SHP2 inhibitor with a RAS pathway inhibitor could be a general strategy for preventing tumor resistance in a wide range of malignancies, and may form the basis of a triple combination inhibitor with a SOS1 inhibitor. [0227] Non-limiting examples of such SHP2 inhibitors that are known in the art, include: Chen et al. Mol Pharmacol.2006, 70, 562; Sarver et al., J. Med. Chem.2017, 62, 1793; Xie et al., J. Med. Chem.2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; and PCT applications: WO2005094314; WO2007117699; WO2008124815; WO2009049098; WO2009135000; WO2010011666; WO2010121212; WO2011022440; WO2012041524; WO2014113584; WO2014176488; WO2015003094 WO2015107493; WO2015107494; WO2015107495; WO2016191328; WO2016196591; WO2016203404; WO2016203405; WO2016203406; WO2017078499; WO2017079723; WO2017100279; WO2017156397; WO2017210134; WO2017211303; WO2018013597; WO2018057884; WO2018081091; WO2018129402; WO2018130928; WO2018136264; WO2018136265; WO2018160731; WO2018172984; WO2018218133; WO2019051469; WO2019051084; WO2019067843; WO2019152454; WO2019158019; WO2019165073; WO2019167000; WO2019182960; WO2019183364; WO2019183367; WO2019213318; WO2019233810; WO2020022323; WO2020033286; WO2020033828; WO2020061101; WO2020061103; WO2020063760; WO2020072656; WO2020073945; WO2020073949; WO2020081848; US20110281942; US20160030594 and US8637684, each of which is incorporated herein by reference. [0228] In some embodiments, a SHP2 inhibitor binds in the active site. In some embodiments, a SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, a SHP2 inhibitor binds an allosteric site e.g., a non-covalent allosteric inhibitor. In some embodiments, 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. In some embodiments a SHP2 inhibitor is a reversible inhibitor. In some embodiments, a SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor is RMC-4630. In some embodiments, the SHP2 inhibitor is JAB-3068. [0229] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib. [0230] 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-PDL-1, anti-CTLA4, anti-LAGl, and anti-OX40 agents). [0231] Immunomodulatory agents (IMiDs) 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). [0232] 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 A1), as well as described elsewhere herein. [0233] 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, WO2010/003118 and WO2011/090754; 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.7,618,632, EP 1866339, and WO2011/028683, WO2013/039954, WO05/007190, WO07/133822, WO05/055808, WO99/40196, WO01/03720, WO99/20758, WO06/083289, WO05/115451, and WO2011/051726. [0234] Another example of a therapeutic agent that may be used in combination with the compounds of the invention is an anti-angiogenic agent. Anti-angiogenic agents are inclusive of, but not limited to, in vitro synthetically prepared chemical compositions, antibodies, antigen binding regions, radionuclides, and combinations and conjugates thereof. An anti-angiogenic agent can be an agonist, antagonist, allosteric modulator, toxin or, more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition), and thereby promote cell death or arrest cell growth. In some embodiments, the one or more additional therapies include an anti-angiogenic agent. [0235] Anti-angiogenic agents can be MMP-2 (matrix-metalloproteinase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase 11) inhibitors. Non-limiting examples of anti-angiogenic agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include alecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96/33172, WO96/27583, WO98/07697, WO98/03516, WO98/34918, WO98/34915, WO98/33768, WO98/30566, WO90/05719, WO99/52910, WO99/52889, WO99/29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, and U.S. Patent Nos.5,863,949 and 5,861,510. Preferred 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). Some specific examples of MMP inhibitors are AG-3340, RO 32-3555, and RS 13-0830. [0236] Further exemplary 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, or soluble VEGF receptors or a ligand binding region thereof) such as VEGF-TRAP™, and anti-VEGF receptor agents (e.g., antibodies or antigen binding regions that specifically bind thereto), EGFR inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto) such as Vectibix® (panitumumab), erlotinib (Tarceva®), anti-Angl and anti-Ang2 agents (e.g., antibodies or antigen binding regions specifically binding thereto or to their receptors, e.g., Tie2/Tek), and anti-Tie2 kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). Other 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.5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124 and patent family members thereof), and anti-PDGF-BB antagonists (e.g., specifically binding antibodies or antigen binding regions) as well as antibodies or antigen binding regions specifically binding to PDGF-BB ligands, and PDGFR kinase inhibitory agents (e.g., antibodies or antigen binding regions that specifically bind thereto). Additional anti-angiogenic agents include: SD-7784 (Pfizer, USA); cilengitide (Merck KGaA, Germany, EPO 0770622); pegaptanib octasodium, (Gilead Sciences, USA); Alphastatin, (BioActa, UK); M-PGA, (Celgene, USA, US 5712291); ilomastat, (Arriva, USA, US5892112); emaxanib, (Pfizer, USA, US 5792783); vatalanib, (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands), DACantiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Kyowa Hakko, Japan); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP 0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen-E fragment (BioActa, UK); angiogenic inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Sosei, Japan); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER- 68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Tsumura, Japan); TAN-1120 (Takeda, Japan); FR-111142 (Fujisawa, Japan, JP 02233610); platelet factor 4 (RepliGen, USA, EP 407122); vascular endothelial growth factor antagonist (Borean, Denmark); bevacizumab (pINN) (Genentech, USA); angiogenic inhibitors (SUGEN, USA); XL 784 (Exelixis, USA); XL 647 (Exelixis, USA); MAb, alpha5beta3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, USA); enzastaurin hydrochloride (Lilly, USA); CEP 7055 (Cephalon, USA and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI 21 and BPI-derived antiangiogenic (XOMA, USA); PI 88 (Progen, Australia); cilengitide (Merck KGaA, German; Munich Technical University, Germany, Scripps Clinic and Research Foundation, USA); AVE 8062 (Ajinomoto, Japan); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292, (Telios, USA); Endostatin (Boston Children’s Hospital, USA); ATN 161 (Attenuon, USA); 2-methoxyestradiol (Boston Childrens Hospital, USA); ZD 6474, (AstraZeneca, UK); ZD 6126, (Angiogene Pharmaceuticals, UK); PPI 2458, (Praecis, USA); AZD 9935, (AstraZeneca, UK); AZD 2171, (AstraZeneca, UK); vatalanib (pINN), (Novartis, Switzerland and Schering AG, Germany); tissue factor pathway inhibitors, (EntreMed, USA); pegaptanib (Pinn), (Gilead Sciences, USA); xanthorrhizol, (Yonsei University, South Korea); vaccine, gene-based, VEGF-2, (Scripps Clinic and Research Foundation, USA); SPV5.2, (Supratek, Canada); SDX 103, (University of California at San Diego, USA); PX 478, (ProlX, USA); METASTATIN, (EntreMed, USA); troponin I, (Harvard University, USA); SU 6668, (SUGEN, USA); OXI 4503, (OXiGENE, USA); o-guanidines, (Dimensional Pharmaceuticals, USA); motuporamine C, (British Columbia University, Canada); CDP 791, (Celltech Group, UK); atiprimod (pINN), (GlaxoSmithKline, UK); E 7820, (Eisai, Japan); CYC 381, (Harvard University, USA); AE 941, (Aeterna, Canada); vaccine, angiogenic, (EntreMed, USA); urokinase plasminogen activator inhibitor, (Dendreon, USA); oglufanide (pINN), (Melmotte, USA); HIF-lalfa inhibitors, (Xenova, UK); CEP 5214, (Cephalon, USA); BAY RES 2622, (Bayer, Germany); Angiocidin, (InKine, USA); A6, (Angstrom, USA); KR 31372, (Korea Research Institute of Chemical Technology, South Korea); GW 2286, (GlaxoSmithKline, UK); EHT 0101, (ExonHit, France); CP 868596, (Pfizer, USA); CP 564959, (OSI, USA); CP 547632, (Pfizer, USA); 786034, (GlaxoSmithKline, UK); KRN 633, (Kirin Brewery, Japan); drug delivery system, intraocular, 2-methoxyestradiol; anginex (Maastricht University, Netherlands, and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); tumor necrosis factor-alpha inhibitors; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518, (Abbott, USA); YH16 (Yantai Rongchang, China); S- 3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); MAb, alpha5 beta (Protein Design, USA); KDR kinase inhibitor (Celltech Group, UK, and Johnson & Johnson, USA); GFB 116 (South Florida University, USA and Yale University, USA); CS 706 (Sankyo, Japan); combretastatin A4 prodrug (Arizona State University, USA); chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA, Takeda, Japan, and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA) CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); irsogladine, (Nippon Shinyaku, Japan); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); squalamine, (Genaera, USA); RPI 4610 (Sirna, USA); heparanase inhibitors (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland, and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Taisho, Japan); VE-cadherin-2 antagonists(ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Tsumura, Japan); TumStatin (Beth Israel Hospital, USA); truncated soluble FLT 1 (vascular endothelial growth factor receptor 1) (Merck & Co, USA); Tie-2 ligands (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA). [0237] Further examples of therapeutic agents that may be used in combination with compounds of the invention include agents (e.g., antibodies, antigen binding regions, or soluble receptors) 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. [0238] Another example of a therapeutic agent that may be used in combination with compounds of the disclosure is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), 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. In addition, antisense or siRNA that inhibits expression of proteins including but not limited to ATG5 (which are implicated in autophagy), may also be used. In some embodiments, the one or more additional therapies include an autophagy inhibitor. [0239] Another example of a therapeutic agent that may be used in combination with compounds of the disclosure is an anti-neoplastic agent. In some embodiments, the one or more additional therapies include an anti-neoplastic agent. Non-limiting examples of anti-neoplastic agents include acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ancer, ancestim, arglabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa, interferon alfa, natural, interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-Nl, interferon alfa-n3, interferon alfacon-1, interferon alpha, natural, interferon beta, interferon beta-la, interferon beta-lb, interferon gamma, natural interferon gamma- la, interferon gamma-lb, interleukin-1 beta, iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin, lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesis stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburiembodiment, rhenium Re 186 etidronate, RII retinamide, rituximab, romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine, virulizin, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techni clone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine, nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma oncolysate vaccine (New York Medical College), viral melanoma cell lysates vaccine (Royal Newcastle Hospital), or valspodar. [0240] Additional examples of therapeutic agents that may be used in combination with compounds of the disclosure include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS- 663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilumumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP 224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); certolizumab pegol (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®); palivizumab (Synagis®); pertuzumab (Perjeta®); pertuzumab (Perjeta®); ranibizumab (Lucentis®); raxibacumab (Abthrax®); tocilizumab (Actemra®); tositumomab; tositumomab-i-131; tositumomab and tositumomab-i-131 (Bexxar®); ustekinumab (Stelara®); AMG 102; AMG 386; AMG 479; AMG 655; AMG 706; AMG 745; and AMG 951. [0241] In some embodiments, 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; RMC-6291, or RMC-6236), a MEK inhibitor (e.g., refametinib, selumetinib, trametinib, or cobimetinib), a SHP2 inhibitor (e.g., TNO155, RMC-4630), an ERK inhibitor, and an RTK inhibitor (e.g., an EGFR inhibitor). In some embodiments, a SOS1 inhibitor may be used in combination with a Ras inhibitor, a SHP2 inhibitor, or a MEK inhibitor. In some embodiments, a combination therapy includes a SOS1 inhibitor, a RAS inhibitor and a MEK inhibitor. [0242] In some embodiments, 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. In some embodiments, an additional compound used in combination therapy with a compound of the present invention is selected from the group consisting of neratinib, acetinib and reversine. [0243] 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. When used in combination therapy, the compounds described herein may be administered with the second agent simultaneously or separately. This administration in combination can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound described herein and any of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of the invention and any of the therapies described herein can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of the present disclosure can be administered and followed by any of the therapies described herein, or vice versa. In some embodiments of the separate administration protocol, a compound of the invention and any of the therapies described herein are administered a few minutes apart, or a few hours apart, or a few days apart. [0244] In some embodiments, a combination therapeutic regimen employs two therapeutic agents, one compound of the present invention 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 invention 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 invention and three selected from the therapeutic agents described herein. [0245] In some embodiments of any of the methods described herein, the first therapy (e.g., a compound of the invention) and 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. [0246] The disclosure also features kits including (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, and (b) a package insert with instructions to perform any of the methods described herein. In some embodiments, the kit includes (a) a pharmaceutical composition including an agent (e.g., a compound of the invention) described herein, (b) one or more additional therapies (e.g., non-drug treatment or therapeutic agent), and (c) a package insert with instructions to perform any of the methods described herein. [0247] As one aspect of the present disclosure contemplates the treatment of the disease or symptoms associated therewith with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit may comprise two separate pharmaceutical compositions: a compound of the present invention, and one or more additional therapies. The kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, 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. [0248] In this Combination Therapy section, all references are incorporated by reference for the agents described, whether explicitly stated as such or not. Exemplary Embodiments [0249] The present disclosure is further illustrated by the following non-limiting embodiments. [0250] Embodiment 1 is a compound having a structure of Formula (I), Formula
Figure imgf000100_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein: X1 is NH or S; X2 is CH or N; X3 is CH or N; X4 is CR3 or N; X5 is CH or N; X6 is CH or N; R1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, -NH-C1-6 alkyl, and –NH2; R3 is selected from the group consisting of H, -O-C1-6 alkyl, and -O-C1-6 heteroalkyl; L4 is a bond or O; and R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with one or more C1-6 alkyl, –R4a, –OR4a, –O–C1-6 alkyl– R4a, =O, halogen, –C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –NR4bC(O)R4c, –CN, =NR4a, – NR4bR4c, –SO2R4a, 3-6 membered cycloalkyl optionally substituted with R4a, 3-7 membered heterocyclyl optionally substituted with R4a, 6-10 membered aryl optionally substituted with R4a, or 5-10 membered heteroaryl optionally substituted with R4a; wherein R4a is H, C1-6 alkyl, C1-6 haloalkyl, –C(O)R4b, –C(O)NR4bR4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with –OR4b, – CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, –(CH2)rOCH3, or – (CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, C1-6 alkyl; and wherein each R4c is independently H or C1-6 alkyl. [0251] Embodiment 2 is a compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 is optionally substituted 6-membered aryl. [0252] Embodiment 3 is a compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 is optionally substituted 5-6 membered heteroaryl. [0253] Embodiment 4 is a compound according to Embodiment 1, having the structure selected from the group consisting of:
Figure imgf000102_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Embodiment 1; R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0254] Embodiment 5 is a compound according to Embodiment 1, having the structure selected from the group consisting of:
Figure imgf000103_0001
Figure imgf000104_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Embodiment 1; R5, R6, and R7 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, –S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, – NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0255] Embodiment 6 is a compound according to Embodiment 1, having the structure selected from the group consisting of:
Figure imgf000105_0001
Figure imgf000106_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in Embodiment 1; R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. [0256] Embodiment 7 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen. [0257] Embodiment 8 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen and –OH. [0258] Embodiment 9 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is halogen, and one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen. [0259] Embodiment 10 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is –NH2. [0260] Embodiment 11 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein one of R5, R6, R7, R8, and R9 is –NH2; and one of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen. [0261] Embodiment 12 is a compound according to any one of Embodiments 4-6, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein any two adjacent R5, R6, R7, R8, and R9 forms a 3-14 membered fused ring, wherein the fused ring is substituted with halogen. [0262] Embodiment 13 is a compound according to any one of Embodiments 1- 12, having the structure of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, L4, and R4 are as defined in Embodiment 1. [0263] Embodiment 14 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH, X2 is CH, X3 is CH, X4 is N, and X5 is CH. [0264] Embodiment 15 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH, X2 is N, X3 is CH, X4 is N, and X5 is CH. [0265] Embodiment 16 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH, X2 is N, X3 is CH, X4 is CR3, and X5 is CH. [0266] Embodiment 17 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is S, X2 is CH, X3 is CH, X4 is CR3, and X5 is CH. [0267] Embodiment 18 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH, X2 is N, X3 is N, X4 is CR3, and X5 is CH. [0268] Embodiment 19 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof wherein X1 is NH, X2 is CH, X3 is N, X4 is CR3, and X5 is CH. [0269] Embodiment 20 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH, X2 is CH, X3 is CH, X4 is CR3, and X5 is N. [0270] Embodiment 21 is a compound according to Embodiment 13, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH, X2 is CH, X3 is CH, X4 is CR3, and X5 is CH. [0271] Embodiment 22 is a compound according to any one of Embodiments 16- 21or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R3 is H or –O-CH3. [0272] Embodiment 23 is a compound according to any one of Embodiments 13- 22, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein L4 is a bond. [0273] Embodiment 24 is a compound according to any one of Embodiments 1- 12, having the structure of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), or Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1, X4, and R4 are as defined in Embodiment 1. [0274] Embodiment 25 is a compound according to Embodiment 24, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X1 is NH and X4 is CH. [0275] Embodiment 26 is a compound according to any one of Embodiments 1- 12, having the structure of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc-3), or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X5, X6, R2, and R4 are as defined in Embodiment 1. [0276] Embodiment 27 is a compound according to Embodiment 26, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X5 is CH and X6 is N. [0277] Embodiment 28 is a compound according to Embodiment 26, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein X5 is CH and X6 is CH. [0278] Embodiment 29 is a compound according to any one of Embodiments 26- 28, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R2 is H. [0279] Embodiment 30 is a compound according to any one of Embodiments 26- 28, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R2 is NH2. [0280] Embodiment 31 is a compound according to any one of Embodiments 26- 28, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R2 is –NH-CH3. [0281] Embodiment 32 is a compound according to Embodiment 1, having the structure selected from the group consisting of:
Figure imgf000111_0001
or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1, R3, L4, and R4 are as defined in Embodiment 1. [0282] Embodiment 33 is a compound according to Embodiment 1, having the structure of Formula (II-1):
Figure imgf000112_0001
, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1 and R4 are as defined in Embodiment 1. [0283] Embodiment 34 is a compound according to Embodiment 1, having the structure of Formula (III-1) or (III-2):
Figure imgf000112_0002
, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R1, R2, and R4 are as defined in Embodiment 1. [0284] Embodiment 35 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with C1-6 alkyl –OR4a, =O, halogen, –C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –CN, –NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl. [0285] Embodiment 36 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is 3-14 membered heterocyclyl. [0286] Embodiment 37 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is 3-14 membered heterocyclyl substituted with 3-6 membered heterocyclyl. [0287] Embodiment 38 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is 3-14 membered heterocyclyl substituted with C1-6 alkyl. [0288] Embodiment 39 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is 3-14 membered heterocyclyl substituted with 3-6 membered cycloalkyl. [0289] Embodiment 40 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is 3-14 membered heterocyclyl substituted with one or more =O. [0290] Embodiment 41 is a compound according to Embodiment 40, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein the 3-14 membered heterocyclyl is further substituted with C1-6 alkyl. [0291] Embodiment 42 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is 3-14 membered heterocyclyl substituted with –C(O)R4a. [0292] Embodiment 43 is a compound according to Embodiment 42, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4a is C1-6 alkyl. [0293] Embodiment 44 is a compound according to any one of Embodiments 1- 34, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, wherein R4 is selected from the group consisting of:
Figure imgf000114_0001
point of attachment to the compound. [0294] Embodiment 45 is a compound according to Embodiment 1, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, selected from the group consisting of:
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
. [0295] Embodiment 46 is a pharmaceutical composition comprising a compound of any one of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier. [0296] Embodiment 47 is a method of inhibiting SOS1 in a subject, comprising administering to the subject a compound of any one of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0297] Embodiment 48 is a method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of any one of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0298] Embodiment 49 is a method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of a compound of any of Embodiments 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0299] Embodiment 50 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 1-45, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof. [0300] Embodiment 51 is a method according to Embodiment 49 or 50, 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. [0301] Embodiment 52 is a method according to Embodiment 49, wherein the disease is a RASopathy. [0302] Embodiment 53 is a method according to Embodiment 52, 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. [0303] Embodiment 54 is a method according to Embodiment 50 or 51, wherein the cancer comprises a RasMUT or an NF1LOF mutation. EXAMPLES [0304] The disclosure is further illustrated by the following examples and synthesis examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims. [0305] Definitions used in the following examples and elsewhere herein are: AcCl Acetyl chloride AcOH Acetic acid Ac2O Acetic anhydride Boc tert-butoxycarbonyl Boc2O Di-tert-butyl dicarbonate cataCXium®A chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- PdG2 aminobiphenyl)]palladium(II) DCM Dichloromethane DIEA N,N-diisopropylethylamine DME Dimethylether DMF N,N-Dimethylformamide Et3N Triethylamine EtOAc Ethyl acetate HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate H2O Water HPLC High performance liquid chromatography HCl Hydrochloric acid KOAc Potassium acetate LCMS Liquid chromatography/mass spectrometry MeOH Methanol MeNH2 Methylamine Me2SO4 Dimethyl sulfate NaHMDS Sodium bis(trimethylsilyl)amide NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methyl pyrrolidone Pd/C Palladium on carbon Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) Dichloride Pd(dppf)Cl2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) rt Room temperature T3P Propylphosphonic anhydride t-BuONa Sodium tert-butoxide t-BuXPhospd-G3 [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-ditert- butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane t-BuOK Potassium tert-butoxide TEA Triethylamine TsO Tosyl TFA Trifluroacetic acid THF Tetrahydrofuran TMS Trimethylsilyl UHP Urea hydrogen peroxide Example 1: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,1- dioxo-3,6-dihydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide
Figure imgf000121_0001
[0306] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indole-7-carboxamide (100 mg, 243 µmol) in dioxane (1 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran-1,1- dioxide (81.6 mg, 316 µmol), Na2CO3 (51.6 mg, 486 µmol), H2O (0.5 mL) and Pd(PPh3)2Cl2(17.1 mg, 24.3 µmol) under N2. The reaction mixture was stirred at 100 °C for 12 hours. The mixture was then concentrated under reduced pressure and the crude material was purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-5-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (15 mg, 13% yield). LCMS (ESI): m/z: [M+H] calculated for C23H22F3N2O3S: 463.1; found 463.1; 1H NMR (400 MHz, CDCl3) δ ppm 10.19 (s, 1H), 7.76 (s, 1H), 7.55–7.51 (m, 2H), 7.35 (s, 1H), 7.32–7.30 (m, 1H), 7.24–7.22 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 54.8 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.56–6.54 (m, 1H), 5.86–5.84 (m, 1H), 5.58–5.51 (m, 1H), 3.86– 3.85 (m, 2H), 3.30–3.27 (m, 4H), 1.69 (d, J = 6.8 Hz, 3H). Example 2: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide
Figure imgf000121_0002
Step 1: [0307] To a solution of 7-bromo-5-chloro-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.16 mmol) in MeOH (2.5 mL) were added Pd(dppf)Cl2•CH2Cl2 (52.9 mg, 64.8 µmol) and Et3N (2.5 mL, 18 mmol) under N2. The suspension was degassed under vacuum and purged with CO several times. The reaction mixture was stirred under CO (50 psi) at 70 °C for 3 hours. The mixture was cooled to 25 °C, filtered, and the filtrate was concentrated under reduced pressure to give methyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylate (400 mg, 88% yield). LCMS (ESI): m/z: [M+H] calculated for C9H8ClN2O2: 211.0; found 211.0. Step 2: [0308] To a solution of methyl 5-chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylate (350 mg, 1.66 mmol) in THF (2 mL) and MeOH (2 mL) was added LiOH•H2O (209 mg, 4.99 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. The pH was adjusted to ~7 by the addition of 1 N aqueous HCl, and the mixture was then extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5- chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (310 mg, 95% yield). LCMS (ESI): m/z: [M+H] calculated for C8H6ClN2O2: 197.0; found 197.0. Step 3: [0309] To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (310 mg, 1.58 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (358 mg, 1.89 mmol) in THF (3 mL) were added DIEA (1.10 mL, 6.31 mmol) and T3P (50% purity, 1.51 g, 2.37 mmol) at 25 °C. The reactions mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 5-chloro-N- [(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-1H-pyrrolo[2,3-c]pyridine-7- carboxamide (450 mg, 78% yield). LCMS (ESI): m/z: [M+H] calculated for C17H14ClF3N3O: 368.1; found 368.1. Step 4: [0310] To a mixture of 5-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (450 mg, 1.22 mmol) and tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate (416 mg, 1.35 mmol) in DME (7 mL) and H2O (2 mL) were added Pd(PPh3)4 (141 mg, 122 µmol) and Na2CO3 (259 mg, 2.45 mmol) at 20 °C under N2. The reaction mixture was stirred at 100 °C under N2 for 10 hours. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl 4-[7-[[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]carbamoyl]-1H-pyrrolo[2,3-c]pyridin-5-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (500 mg, 79% yield).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.77 (s, 1H) 7.52–7.50 (m, 2H) 7.42–7.40 (m, 1H) 7.22–7.20 (m, 1H) 7.05 (t, J = 54.8 Hz, 1H) 6.58 (s, 1H) 6.55–6.54 (m, 1H) 5.54–5.50 (m, 1H) 4.17– 4.16 (m, 2H) 3.72–3.69 (m, 2H) 2.74–2.73 (m, 2H), 1.67 (d, J = 6.8 Hz, 3H) 1.49 (s, 9H). Step 5: [0311] A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-pyrrolo[2,3-c]pyridin-5-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (250 mg, 486 µmol) in HCl (4 M in EtOAc, 121 µL, 484 µmol) was stirred at 25 °C for 1 hour. The reaction mixture was then concentrated under reduced pressure and purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide (20 mg, 10% yield). LCMS (ESI): m/z: [M+H] calculated for C22H22F3N4O: 415.17; found 415.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H) 8.98–8.86 (m, 1H) 7.83 (s, 1H) 7.80– 7.79 (m, 1H) 7.52–7.50 (m, 1H) 7.54–7.52 (m, 1H) 7.37–7.11 (m, 2H) 6.69 (s, 1H) 6.57– 6.56 (m, 1H) 5.54–5.50 (m, 1H) 3.48–3.47 (m, 2H) 3.00–2.98 (m, 2H) 2.57–2.56 (m, 2H) 1.64 (d, J = 6.8 Hz, 3H). Example 3: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide
Figure imgf000124_0001
Step 1: [0312] To a solution of 5-bromo-1H-indazole-7-carboxylic acid (100 mg, 415 µmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (94.2 mg, 498 µmol) in THF (1 mL) were added DIEA (217 µL, 1.24 mmol) and T3P (50% purity, 396 mg, 622 µmol). The reaction mixture was purged with N2 and stirred at 25 °C for 3 hours under N2. The mixture was then quenched with H2O, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2- fluoro-phenyl]ethyl]-1H-indazole-7-carboxamide (60 mg, 35% yield). LCMS (ESI): m/z: [M+H] calculated for C17H14BrF3N3O: 412.02; found 412.0. Step 2: [0313] To a mixture of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (60 mg, 1456 µmol) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (54.0 mg, 175 µmol) in dioxane (1 mL) and H2O (0.2 mL) were added Pd(PPh3)2Cl2 (0.22 mg, 15 µmol) and Na2CO3 (30.9 mg, 291 µmol) at 25 °C under N2. The reaction mixture was stirred at 100 °C under N2 for 10 hours. The mixture was then quenched with H2O, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl-4- [7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-3,6- dihydro-2H-pyridine-1-carboxylate (50 mg, 55% yield). LCMS (ESI): m/z: [M+Na] calculated for C27H29F3N4O3Na: 537.2; found 537.3. Step 3: [0314] To a solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (30.0 mg, 58.3 µmol) in MeOH (0.5 mL) was added HCl in MeOH (4 M, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours. The mixture was then concentrated under reduced pressure and the crude residue was purified by prep-HPLC to give N-[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7- carboxamide (16 mg, 66% yield). LCMS (ESI): m/z: [M+H] calculated for C22H22F3N4O: 415.2; found 415.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br s, 1H), 9.28 (s, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz 1H), 7.38–7.11 (m, 2H), 6.38 (s, 1H), 5.50–5.38 (m, 1H), 3.80–3.72 (m, 2H), 3.18– 3.11 (m, 2H), 2.68–2.61 (m, 2H), 1.57 (d, J = 7.2 Hz, 3H). Example 4: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6- (1,2,3,6-tetrahydropyridin-4-yl)-3H-benzimidazole-4-carboxamide
Figure imgf000125_0001
Step 1: [0315] To a solution of 6-bromo-3H-benzimidazole-4-carboxylic acid (430 mg, 1.78 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine•HCl (483 mg, 2.14 mmol) in THF (4 mL) were added DIEA (1.55 mL, 8.92 mmol) and T3P (50% purity, 1.70 g, 2.68 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water, extracted with DCM, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-3H-benzimidazole-4-carboxamide (330 mg, 45% yield). LCMS (ESI): m/z: [M-H] calculated for C17H12BrF3N3O: 410.0; found 409.9. Step 2: [0316] To a solution of 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-3H-benzimidazole-4-carboxamide (180 mg, 437 µmol) in dioxane (1.5 mL) and H2O (0.3 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyridine-1-carboxylate (176 mg, 568 µmol), Na2CO3 (92.6 mg, 873 µmol), and Pd(PPh3)4 (252 mg, 218 µmol) at 25 °C under N2. The reaction mixture was stirred at 85 °C for 12 hours. The mixture was treated with water, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressured. The crude residue was purified by column chromatography to give tert-butyl 4-[7-[[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]carbamoyl]-1H-benzimidazol-5-yl]-3,6-dihydro- 2H-pyridine-1-carboxylate (80 mg, 34% yield). LCMS (ESI): m/z: [M-H] calculated for C27H28F3N4O3: 513.2; found 513.2. Step 3: [0317] A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (70.0 mg, 136 µmol) in HCl (4 M in MeOH, 2 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6- (1,2,3,6-tetrahydropyridin-4-yl)-3H-benzimidazole-4-carboxamide (12 mg, 21% yield). LCMS (ESI): m/z: [M+H] calculated for C22H22F3N4O: 415.2; found 415.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.38 (br s, 1H), 8.52 (br s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 6.8 Hz, 1H), 7.38–7.09 (m, 2H), 6.24 (s, 1H), 5.53–5.45 (m, 1H), 3.51 (s, 2H), 3.07 (t, J = 5.6 Hz, 2H), 2.52 (s, 2H), 1.59 (d, J = 7.2 Hz, 3H). Example 5: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide
Figure imgf000127_0001
Step 1: [0318] To a solution of 6-bromo-2,4-dichloro-pyridin-3-amine (4.00 g, 16.5 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-1-carboxylate (5.62 g, 18.2 mmol) in dioxane (50 mL) and H2O (15 mL) were added Pd(PPh3)2Cl2 (1.16 g, 1.65 mmol) and Na2CO3 (3.51 g, 33.1 mmol) under an atmosphere of N2. The reaction mixture was stirred at 100 °C for 3 hours. The reaction was quenched by the addition of water, then was extracted with EtOAc, treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl 4-(5-amino-4,6-dichloro-2- pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.07 g, 89% yield). LCMS (ESI): m/z: [M+H-56] calculated for C11H12Cl2N3O2: 288.0; found 288.0. Step 2: [0319] To a solution of tert-butyl 4-(5-amino-4,6-dichloro-2-pyridyl)-3,6- dihydro-2H-pyridine-1-carboxylate (5.00 g, 14.5 mmol) in Et3N (100 mL) were added Pd(PPh3)2Cl2 (510 mg, 726 µmol) and CuI (138 mg, 726 µmol) at 0 °C under an atmosphere of N2. Ethynyl(trimethyl)silane (3.02 mL, 21.8 mmol) was then added at 0 °C and the reaction mixture was stirred at 80 °C for 4 hours. The mixture was cooled and filtered through Celite®, washed with TEA, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl 4-[5-amino-4- chloro-6-(2-trimethylsilylethynyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.85 g, 48% yield). LCMS (ESI): m/z: [M+H] calculated for C20H29ClN3O2Si: 406.2; found 406.2. Step 3: [0320] To a solution of tert-butyl 4-[5-amino-4-chloro-6-(2- trimethylsilylethynyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.70 g, 6.65 mmol) in DMF (270 mL) was added CuI (253 mg, 1.33 mmol) under an atmosphere of N2. The reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was quenched by the addition of water (400 mL) then was extracted with EtOAc, treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give tert-butyl 4-(7-chloro-1H-pyrrolo[3,2- b]pyridin-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (280 mg, 13% yield). LCMS (ESI): m/z: [M+H] calculated for C17H21ClN3O2: 334.1; found 334.1. Step 4: [0321] To a solution of tert-butyl 4-(7-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (50.0 mg, 150 µmol) in dioxane (1 mL) was added (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethanamine (85.0 mg, 449 µmol), Mo(CO)6 (39.5 mg, 150 µmol), TEA (52.1 µL, 374 µmol) and Pd(dppf)Cl2 (11.0 mg, 15.0 µmol) under an atmosphere of N2. The reaction mixture was stirred at 120 °C in a microwave reactor for 4 hours. The mixture was diluted in H2O and extracted with DCM. The combined organic extracts were treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to get a tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2- fluoro-phenyl]ethyl]carbamoyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3,6-dihydro-2H-pyridine- 1-carboxylate (100 mg, crude). LCMS (ESI): m/z: [M+H] calculated for C27H30F3N4O3: 515.2; found 515.3. Step 5: [0322] tert-Butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-pyrrolo[3,2-b]pyridin-5-yl]-3,6-dihydro-2H-pyridine-1- carboxylate (100 mg, 194 µmol) was dissolved in a solution of HCl in MeOH (4 M, 4 mL) then was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)- 1H-pyrrolo[3,2-b]pyridine-7-carboxamide (6.0 mg, 7% yield). LCMS (ESI): m/z: [M+H] calculated for C22H22F3N4O: 415.2; found 415.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (br s, 1H), 9.38 (d, J = 7.2 Hz, 1H), 7.95 (s, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.53–7.45 (m, 2H), 7.37–7.10 (m, 2H), 6.71 (s, 1H), 6.56 (d, J = 1.6 Hz, 1H), 5.52–5.48 (m, 1H), 3.63–3.61 (m, 2H), 3.13–3.10 (m, 2H), 2.74–2.72 (m, 2H), 1.57 (d, J = 7.2 Hz, 3H). Example 6: Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(1,1- dioxido-3,6-dihydro-2H-thiopyran-4-yl)-1H-indazole-7-carboxamide
Figure imgf000129_0001
Step 1: [0323] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (200 mg, 485 µmol) and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan- 2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (163 mg, 631 µmol) in H2O (0.4 mL) and dioxane (2 mL) was added Na2CO3 (103 mg, 970 µmol), then Pd(PPh3)2Cl2 (34.1 mg, 48.5 µmol) was added under N2 at rt. The mixture was then stirred at 100 °C for 5 hours. The reaction was quenched with H2O (20 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3), dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give compound N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5-(1,1-dioxo-3,6-dihydro- 2H-thiopyran-4-yl)-1H-indazole-7-carboxamide (53.8 mg, 24% yield). [0324] LCMS (ESI): m/z: [M + H] calculated for C22H21F3N3O3S: 464.1; found: 464.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (s, 1H), 9.27 (d, J = 6.4 Hz, 1H), 8.18 (d, J = 1.2 Hz, 1H), 8.12 (s, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.31 - 7.37 (m, 1H), 7.16 (d, J = 54.4 Hz, 1H), 6.12 (t, J = 4.4 Hz, 1H), 5.50 (t, J = 7.2 Hz, 1H), 3.96(d, J = 2.8 Hz, 2H), 3.40 - 3.42 (m, 2H), 3.16 - 3.18 (m, 2H), 1.55 (d, J = 7.2 Hz, 3H). Example 7: Synthesis of (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-5-(1,1- dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indazole-7-carboxamide
Figure imgf000130_0001
Step 1: [0325] To a solution of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-1H-indazole-7-carboxamide (70.0 mg, 151 µmol) and Pd/C (50.0 g, 10% purity, 50% wet) in MeOH (3.5 mL) and THF (3.5 mL) was stirred at rt for 4 hours under H2 (30 psi). The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give N- [(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,1-dioxothian-4-yl)-1H-indazole-7- carboxamide (8 mg, 11% yield). LCMS (ESI): m/z: [M + H] calculated for C22H23F3N3O3S: 466.1; found: 466.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.97 (s, 1H), 9.23 (s, 1H), 8.03 (t, J = 8.8 Hz, 2H), 7.83 (s, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H), 7.10 - 7.38 (m, 2H), 5.51 (t, J = 7.2 Hz, 1H), 3.41 (d, J = 12.8 Hz, 2H), 3.08 - 3.19 (m, 3H), 2.17 - 2.32 (m, 4H), 1.57 (d, J = 6.8 Hz, 3H). Example 8: Synthesis of 5-(1-acetylpiperidin-4-yl)-N-[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]-1H-indazole-7-carboxamide
Figure imgf000131_0001
[0326] To a solution of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (4-piperidyl)-1H-indazole-7-carboxamide HCl (175 mg, 386 µmol) in THF (2 mL) were added Et3N (269 µL, 1.93 mmol) and acetyl chloride (24.8 µL, 348 µmol) at 0 °C for 30 minutes. To the reaction was added water (10 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 5-(1-acetylpiperidin-4-yl)-N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-1H- indazole-7-carboxamide (40 mg, 20% yield). LCMS (ESI): m/z: [M + H] calculated for C24H26F3N4O2: 459.2; found: 459.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.83 - 13.04 (br s, 1H), 9.14 (s, 1H), 8.00 - 8.09 (m, 2H), 7.80 (d, J = 0.8 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.49 - 7.56 (m, 1H), 7.39 - 7.06 (m, 2H), 5.51 (q, J = 6.8 Hz, 1H), 4.60 (d, J = 13.2 Hz, 1H), 3.98 (d, J = 13.6 Hz, 1H), 3.11 - 3.23 (m, 1H), 2.88 - 2.97 (m, 1H), 2.58 - 2.69 (m, 1H), 2.06 (s, 3H), 1.83 - 1.93 (m, 2H), 1.61 - 1.78 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H). Example 9: Synthesis of 5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-N-[(1R)-1-[3- (difluoromethyl)-2-fluorophenyl]ethyl]-1H-indazole-7-carboxamide
Figure imgf000132_0001
Step 1: [0327] To a solution of 5-bromo-1H-indazole-7-carboxylic acid (400 mg, 1.66 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine HCl (449 mg, 1.99 mmol) in THF (4 mL) were added DIEA (1.45 mL, 8.30 mmol) and T3P (1.48 mL, 2.49 mmol) at rt. The mixture was stirred at rt for 2 hours. Additional DIEA (578 µL, 3.32 mmol) and T3P (987 µL, 1.66 mmol) were then added to the mixture and stirred at rt for 1 hour. To the reaction was added water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was triturated with ethyl acetate at rt to give 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-1H-indazole-7- carboxamide (600 mg, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (br s, 1H), 9.27 (d, J = 6.4 Hz, 1H), 8.27 (s , 1H), 8.22 (d , J = 1.6 Hz, 1H), 8.11 (s , 1H), 7.70 (t , J = 7.2 Hz, 1H), 7.52 (t , J = 6.8 Hz, 1H), 7.08 - 7.39 (m , 2H), 5.48 (q , J = 7.2 Hz, 1H), 1.55 (d , J = 6.8 Hz, 3H). Step 2: [0328] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (300 mg, 728 µmol) in dioxane (3 mL) and H2O (0.6 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyridine-1-carboxylate (293 mg, 946 µmol), Na2CO3 (154 mg, 1.46 mmol), and Pd(PPh3)4 (421 mg, 364 µmol) at rt under N2. The reaction was stirred at 85 °C for 12 hours. To the reaction was added water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]carbamoyl]-1H- indazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 27% yield). LCMS (ESI): m/z: [M + H] calculated for C27H30F3N4O3: 515.2; found: 515.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.02 (s, 1H), 9.19 (d, J = 6.8 Hz, 1H), 8.21 (s, 1H), 8.09 (s, 1H), 7.92 - 8.02 (m, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.58 - 7.65 (m, 2H), 7.48 - 7.58 (m, 3H), 7.08 - 7.38 (m, 2H), 6.30 (s, 1H), 5.51 (q, J = 6.8 Hz, 1H), 4.04 - 4.12 (m, 2H), 3.53 - 3.66 (m, 2H), 2.59 - 2.60 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H), 1.44 (s, 9H). Step 3: [0329] A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 194 µmol) in HCl (4 M in EtOAc, 1 mL) was stirred at rt for 2 hours. To the reaction was added water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product N-[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]- 5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide HCl (80 mg) and used into the next step without further purification. LCMS (ESI): m/z: [M + H] calculated for C22H22F3N4O: 415.2; found: 415.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (d, J = 6.0 Hz, 3H), 8.32 (s, 1H), 8.15 (s, 1H), 8.02 (s, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.48 - 7.65 (m, 4H), 7.09 - 7.38 (m, 2H), 6.43 (s, 1H), 5.48 - 5.58 (m, 1H), 3.80 - 3.82 (m, 2H), 3.35 - 3.36 (m, 2H), 2.84 - 2.88 (m, 2H), 1.58 (d, J = 6.8 Hz, 3H). Step 4: [0330] To a solution of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-7-carboxamide HCl (80.0 mg, 177 µmol) in THF (1 mL) were added TEA (123 µL, 887 µmol) and acetyl chloride (15.2 µL, 213 µmol) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. To the reaction was added water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 5-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-N- [(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-1H-indazole-7-carboxamide (38.1 mg, 43% yield over 2 steps). LCMS (ESI): m/z: [M + H] calculated for C24H24F3N4O2: 457.2; found: 457.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 9.21 (d, J = 7.2 Hz, 1H), 8.22 (s, 1H), 8.05 - 8.15 (m, 1H), 7.96 (d, J = 7.2 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.49 - 7.57 (m, 1H), 7.07 - 7.40 (m, 2H), 6.33 (d, J = 8.8 Hz, 1H), 5.52 (q, J = 7.2 Hz, 1H), 4.20 (dd, J = 2.2, 17.6 Hz, 2H), 3.61 - 3.77 (m, 2H), 2.66 - 2.74 (m, 1H), 2.59 (s, 1H), 2.09 (d, J = 15.2 Hz, 3H), 1.57 (d, J = 7.2 Hz, 3H). Example 10: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5- (piperazin-1-yl)-1H-indazole-7-carboxamide
Figure imgf000134_0001
Step 1: [0331] To a mixture of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (300 mg, 728 µmol) and tert-butyl piperazine-1- carboxylate (324 mg, 1.74 mmol) in dioxane (6 mL) were added tert-BuONa (210 mg, 2.18 mmol) and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-ditert-butyl-[2- (2,4,6-triisopropylphenyl)phenyl]phosphane (57.8 mg, 72.8 µmol) at rt under N2 and stirred at 100 °C under N2 for 16 hours. The reaction mixture was quenched by the addition of water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl-4-[7-[[(1R)-1-[3-(difluoromethyl)-2- fluoro-phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]piperazine-1-carboxylate (30 mg, 8% yield). LCMS (ESI): m/z: [M + H] calculated for C26H31F3N5O3: 518.24; found: 518.3. Step 2: [0332] A mixture of tert-butyl-4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]piperazine-1-carboxylate (30 mg, 58.0 µmol) HCl (4 M in EtOAc, 0.5 mL) was stirred at rt for 1 hour. The mixture was filtered and purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- piperazin-1-yl-1H-indazole-7-carboxamide (20 mg, 82% yield). LCMS (ESI): m/z: [M + H] calculated for C21H23F3N5O: 418.19; found: 418.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.83 (br s, 1 H) 9.17 (s, 1 H) 8.28 (s, 1 H) 7.97 (s, 1 H) 7.89 (s, 1 H) 7.69 (t, J = 7.2 Hz, 1 H) 7.52 (t, J = 7.2 Hz, 1 H) 7.10 - 7.34 (m, 3 H) 5.46 - 5.53 (m, 1 H) 3.14 - 3.16 (m, 4 H) 3.01 - 3.05 (m, 4 H) 1.55 (d, J = 7.2 Hz, 3 H). Example 11: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5- (pyrrolidin-3-yl)-1H-indazole-7-carboxamide
Figure imgf000135_0001
Step 1: [0333] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-1H-indazole-7-carboxamide (500 mg, 1.21 mmol) and tert-butyl 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (394 mg, 1.33 mmol) in DME (4 mL) and H2O (0.8 mL) were added Na2CO3 (386 mg, 3.64 mmol) and Pd(PPh3)4 (280 mg, 243 µmol) under N2. The mixture was stirred at 85 °C for 2 hours under N2 atmosphere. The reaction mixture was poured into water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give tert-butyl 3-[7-[[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl] carbamoyl]-1H-indazol-5-yl]-2,5-dihydropyrrole- 1-carboxylate (385 mg, 61% yield). LCMS (ESI): m/z: [M + H] calculated for C26H28F3N4O3: 501.2; found: 501.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.11 (s, 1 H) 7.89 (s, 1 H) 7.78 (d, J = 4.4 Hz, 1 H) 7.68 - 7.72 (m, 1 H) 7.55 (t, J = 4.0 Hz, 2 H) 7.24 (d, J = 7.6 Hz, 1 H) 6.79 - 7.06 (m, 2 H) 6.21 (d, J = 16.8 Hz, 1 H) 5.57 - 5.61 (m, J = 7.2 Hz, 1 H) 4.60 (d, J = 7.6 Hz, 2 H) 4.36 (d, J = 16.8 Hz, 2 H) 1.71 (d, J = 6.8 Hz, 3 H) 1.54 (d, J = 6.8 Hz, 9 H). Step 2: [0334] To a solution of tert-butyl 3-[7-[[(1R)-1-[3-(difluoromethyl)-2- fluorophenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-2,5-dihydropyrrole-1-carboxylate (380 mg, 759 µmol) in MeOH (4 mL) was added Pd/C (500 mg, 10% purity, 50% wet) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (30 psi) at 30 °C for 4 hours. The reaction mixture was then filtered and the filtration was concentrated to give tert-butyl 3-[7-[[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]pyrrolidine-1- carboxylate (277 mg, 68% yield). LCMS (ESI): m/z: [M - 56 + H] calculated for C22H22F3N4O3: 447.1; found: 447.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.60 (br s, 1 H) 8.06 (s, 1 H) 7.79 (s, 1 H) 7.52 - 7.55 (m, 3 H) 7.22 - 7.26 (m, 1 H) 6.79 - 7.06 (m, 2 H) 5.55 - 5.62 (m, 1 H) 3.86 - 3.92 (s, 1 H) 3.63 - 3.70 (m, 1 H) 3.44 - 3.56 (m, 3 H) 2.33 - 2.35 (m, 1 H) 2.06- 2.13 (m, 1 H) 1.70 (d, J = 7.2 Hz, 3 H) 1.50 (s, 9 H). Step 3: [0335] A solution of tert-butyl 3-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]pyrrolidine-1-carboxylate (227 mg, 452 µmol) in HCl (4 M in EtOAc, 3 mL) was stirred at rt for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC to give N- [(1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethyl]-5-pyrrolidin-3-yl-1H-indazole-7- carboxamide (53.6 mg, 26% yield). LCMS (ESI): m/z: [M + H] calculated for C21H22F3N4O: 403.1; found: 403.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (br s, 1 H) 8.50 (s, 1 H) 8.24 (s, 1 H) 8.10 (s, 1 H) 7.91 (s, 1 H) 7.74 (t, J = 7.2 Hz, 1 H) 7.52 (t, J = 4.0 Hz, 1 H) 7.07 - 7.40 (m, 2 H) 5.49 - 5.56 (m, 1 H) 3.57 - 3.69 (m, 2 H) 3.44 (t, J = 8.0 Hz, 1 H) 3.23 - 3.28 (m, 2 H) 2.39 - 2.41 (m, 1 H) 2.05 - 2.12 (m, 1 H) 1.58 (d, J = 7.2 Hz, 3 H). Example 12: Synthesis of 2-amino-N-[(1R)-1-[3-amino-5-(trifluoromethyl) phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzamide
Figure imgf000137_0001
Step 1: [0336] To a solution of methyl 5-fluoro-2-nitro-benzoate (500 mg, 2.51 mmol) in CH3CN (5 mL) were added Cs2CO3 (2.45 g, 7.53 mmol) and (3S)-tetrahydrofuran-3-ol (265.46 mg, 3.01 mmol). The mixture was stirred at 100 °C for 1 hour. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 2-nitro-5-[(3S)-tetrahydrofuran-3-yl] oxy-benzoate (150 mg, 22% yield). LCMS (ESI): m/z: [M+H] calculated for C12H14NO6: 268.1; found: 268.0. 1H NMR (400 MHz, chloroform-d) δ ppm 8.08 - 8.02 (m, 1H), 7.05 - 6.98 (m, 2H), 5.03 (t, J = 2.2, 4.1 Hz, 1H), 3.97 (d, J = 4.9 Hz, 3H), 3.95 (s, 3H), 3.94 - 3.88 (m, 1H), 2.36 - 2.25 (m, 2H). Step 2: [0337] To a solution of methyl 2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzoate (150 mg, 561 µmol) in THF (1 mL), MeOH (0.5 mL) and H2O (1 mL) was added LiOH•H2O (47.1 mg, 1.12 mmol). The mixture was stirred at 20 °C for 3 hours. The reaction was diluted with water, washed with ethyl acetate, acidified to pH = 3 with HCl (2M), extracted with ethyl acetate, and the solvent was removed under reduced pressure to give 2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzoic acid (140 mg, 99% yield). LCMS (ESI): m/z: [M+H] calculated for C11H12NO6: 254.1; found: 254.0. Step 3: [0338] To a solution of 2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzoic acid (140 mg, 553 µmol) in THF (2 mL) was added T3P (247 µL, 829 µmol), DIEA (289 µL, 1.66 mmol) and 3-[(1R)-1-aminoethyl]-5-(trifluoromethyl)aniline (113 mg, 553 µmol). The mixture was stirred at 20 °C for 2 hours. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give N-[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]-2-nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzamide (130 mg, 53% yield). LCMS (ESI): m/z: [M+H] calculated for C20H21F3N3O5: 440.1; found: 440.1. Step 4: [0339] To a solution of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-2- nitro-5-[(3S)-tetrahydrofuran-3-yl]oxy-benzamide (110 mg, 250 µmol) in H2O (0.25 mL) and EtOH (0.5 mL) were added Fe (69.9 mg, 1.25 mmol) and NH4Cl (6.70 mg, 125 µmol). The reaction was stirred at 95 °C for 5 hours. The mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give 2- amino-N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]- oxy-benzamide (40 mg, 39% yield). LCMS (ESI): m/z: [M+H] calculated for C20H23F3N3O3: 410.2; found: 410.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.11 - 7.08 (br m, 1H), 6.95 - 6.86 (m, 3H), 6.83 - 6.80 (m, 1H), 6.77 - 6.73 (m, 1H), 5.16 - 5.09 (m, 1H), 4.95 (d, J = 1.5 Hz, 1H), 4.01 - 3.81 (m, 4H), 2.24 - 2.07 (m, 2H), 1.52 (d, J = 6.8 Hz, 3H). Example 13: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-2- (methylamino)-5-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine-3-carboxamide
Figure imgf000139_0001
Step 1: [0340] To a mixture of 5-bromo-2-fluoro-pyridine-3-carboxylic acid (5.00 g, 22.7 mmol) in DMF (25 mL) were added K2CO3 (6.28 g, 45.5 mmol) and CH3I (1.84 mL, 29.6 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-bromo-2-fluoro-pyridine-3-carboxylate (3.7 g, 70% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 - 8.62 (m, 1H), 8.55 (dd, J = 8.2, 2.4 Hz, 1H), 3.88 (s, 3H). Step 2: [0341] To a mixture of methyl 5-bromo-2-fluoro-pyridine-3-carboxylate (3.50 g, 15.0 mmol) and methylamine hydrochloride (1.51 g, 22.4 mmol) in DMF (35 mL) was added Cs2CO3 (14.6 g, 44.9 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-bromo-2-(methylamino)pyridine-3-carboxylate (3.3 g, 90% yield). LCMS (ESI): m/z: [M+H] calculated for C8H10BrN2O2: 245.0; found: 245.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.40 - 8.35 (m, 1H), 8.14 - 8.09 (m, 1H), 7.91 - 7.83 (m, 1H), 3.83 - 3.80 (m, 3H), 2.92 (d, J = 4.9 Hz, 3H). Step 3: [0342] To a mixture of methyl 5-bromo-2-(methylamino)pyridine-3-carboxylate (1.30 g, 5.30 mmol) in THF (13 mL) at 0 °C was added Boc2O (1.46 mL, 6.37 mmol), and NaHMDS (5.83 mL, 5.83 mmol). The mixture was stirred at 25 °C for 3 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-bromo-2-[tert-butoxycarbonyl(methyl)amino]pyridine-3- carboxylate (1.3 g, 71% yield). LCMS (ESI): m/z: [M+H] calculated for C13H18BrN2O4: 345.0; found: 345.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 - 8.70 (m, 1H), 8.28 (s, 1H), 3.85 - 3.76 (m, 3H), 3.26 (s, 3H), 1.49 - 1.26 (m, 9H). Step 4: [0343] To a mixture of methyl 5-bromo-2-[tert- butoxycarbonyl(methyl)amino]pyridine-3-carboxylate (1 g, 2.90 mmol) and bis(pinacolato)diboron (883 mg, 3.48 mmol) in dioxane (10 mL) were added KOAc (853 mg, 8.69 mmol), and Pd(dppf)Cl2 .CH2Cl2 (473 mg, 579 µmol) under nitrogen gas. The mixture was stirred at 100 °C for 2 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give [6-[tert- butoxycarbonyl(methyl)amino]-5-methoxycarbonyl-3-pyridyl]boronic acid (660 mg, 73% yield). LCMS (ESI): m/z: [M+H] calculated for C13H20BN2O6: 311.1; found: 311.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 - 8.82 (m, 1H), 8.56 - 8.39 (m, 2H), 3.80 (s, 3H), 3.33 - 3.23 (m, 3H), 1.33 (d, J = 9.5 Hz, 9H). Step 5: [0344] To a mixture of [6-[tert-butoxycarbonyl(methyl)amino]-5- methoxycarbonyl-3-pyridyl]boronic acid (580 mg, 1.87 mmol) in MeOH (6 mL) was added UHP (704 mg, 7.48 mmol). The mixture was stirred at 25 °C for 4 hours. The reaction was diluted with sat. aq. Na2SO3, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 2-[tert-butoxycarbonyl(methyl)amino]-5-hydroxy- pyridine-3-carboxylate (425 mg, 81% yield). LCMS (ESI): m/z: [M+H] calculated for C13H19N2O5: 283.1; found: 283.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 - 10.31 (m, 1H), 8.15 - 8.08 (m, 1H), 7.55 - 7.45 (m, 1H), 3.81 (m, 3H), 3.24 - 3.07 (m, 3H), 1.43 - 1.18 (m, 9H). Step 6: [0345] To a mixture of methyl 2-[tert-butoxycarbonyl(methyl)amino]-5-hydroxy- pyridine-3-carboxylate (375 mg, 1.33 mmol) in DMF (4 mL) was added [(3R)- tetrahydrofuran-3-yl]-4-methylbenzenesulfonate (483 mg, 1.99 mmol), and Cs2CO3 (866 mg, 2.66 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 2-[tert-butoxycarbonyl(methyl)amino]-5-[(3S)-tetrahydrofuran-3-yl]oxy- pyridine-3-carboxylate (384 mg, 82% yield). LCMS (ESI): m/z: [M+H] calculated for C17H25N2O6: 353.2; found: 353.2. Step 7: [0346] To a mixture of methyl 2-[tert-butoxycarbonyl(methyl)amino]-5-[(3S)- tetrahydrofuran-3-yl]oxy-pyridine-3-carboxylate (214 mg, 607 µmol) in THF (1 mL), MeOH (0.5 mL), and H2O (1 mL) was added NaOH (48.6 mg, 1.21 mmol). The mixture was stirred at 25 °C for 3 hours. The reaction was diluted with water, washed with ethyl acetate, acidified to pH = 2 with HCl (2M), extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure to give 2-[tert- butoxycarbonyl(methyl)amino]-5-[(3S)-tetrahydrofuran-3-yl]oxy-pyridine-3-carboxylic acid (170 mg, 83% yield). LCMS (ESI): m/z: [M+H] calculated for C16H23N2O6: 339.1; found: 339.2; 1H NMR (400 MHz, methanol-d4) δ ppm 8.23 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 3.1 Hz, 1H), 5.21 - 5.11 (m, 1H), 4.03 - 3.85 (m, 4H), 3.28 - 3.19 (m, 3H), 2.38 - 2.24 (m, 1H), 2.18 - 2.08 (m, 1H), 1.56 - 1.29 (m, 9H). Step 8: [0347] To a mixture of 2-[tert-butoxycarbonyl(methyl)amino]-5-[(3S)- tetrahydrofuran-3-yl]oxy-pyridine-3-carboxylic acid (200 mg, 591 µmol) and 3-[(1R)-1- aminoethyl]-5-(trifluoromethyl)aniline (144 mg, 709 µmol) in THF (2 mL) was added DIEA (309 µL, 1.77 mmol), and T3P (264 µL, 887 µmol). The mixture was stirred at 25 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give tert-butyl N-[3-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]carbamoyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-2-pyridyl]-N- methyl-carbamate (135 mg, 44% yield). LCMS (ESI): m/z: [M+H] calculated for C25H32F3N4O5: 525.2; found: 525.3. Step 9: [0348] tert-Butyl N-[3-[[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]carbamoyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-2-pyridyl]-N- methyl-carbamate (130 mg, 248 µmol) was dissolved in a solution HCl in MeOH (5 mL) and the mixture was stirred at 25 °C for 2 hours. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give N-[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]-2-(methylamino)-5-[(3S)-tetrahydrofuran-3-yl]oxy- pyridine-3-carboxamide (43.1 mg, 35% yield). LCMS (ESI): m/z: [M+H] calculated for C20H24F3N4O3: 425.2; found: 425.2; 1H NMR (400 MHz, methanol-d4) δ ppm 7.88 (d, J = 2.8 Hz, 1H), 7.64 (d, J = 2.9 Hz, 1H), 6.90 (d, J = 4.9 Hz, 2H), 6.81 (s, 1H), 5.16 - 5.07 (m, 1H), 4.95 (J = 2.1, 3.7 Hz, 1H), 4.03 - 3.83 (m, 4H), 2.90 (s, 3H), 2.26 - 2.08 (m, 2H), 1.52 (d, J = 7.1 Hz, 3H). Example 14: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-3- [(3S)-tetrahydrofuran-3-yl]oxy-benzamide
Figure imgf000143_0001
Step 1: [0349] To a mixture of methyl 3-hydroxybenzoate (200 mg, 1.31 mmol) and [(3R)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate (350 mg, 1.45 mmol) in DMF (2 mL) was added Cs2CO3 (514 mg, 1.58 mmol). The mixture was stirred at 60 °C for 12 hours. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give methyl 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoate (220 mg, 75% yield). LCMS (ESI): m/z: [M+H] calculated for C12H15O4: 223.1; found: 223.1; 1H NMR (400 MHz, chloroform-d) δ ppm 7.65 (d, J = 7.6 Hz, 1 H) 7.53 (s, 1 H) 7.35 (t, J = 8.0 Hz, 1 H) 7.07 - 7.10 (m, 1 H) 4.99 - 5.01 (m, 1 H) 3.92 - 4.03 (m, 4 H) 3.91 (s, 3H) 2.16 - 2.26 (m, 2 H). Step 2: [0350] To a solution of methyl 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoate (200 mg, 900 µmol) in THF (2 mL), MeOH (0.5 mL), and H2O (0.5 mL) was added LiOH•H2O (56.7 mg, 1.35 mmol). The reaction stirred at 25 °C for 5 hours. The solvent was removed under reduced pressure, acidified to pH = 2 with HCl (1M), extracted with ethyl acetate, washed with brine, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure to give 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoic acid (250 mg, crude). 1H NMR (400 MHz, chloroform-d) δ ppm 7.74 (d, J = 7.6 Hz, 1 H) 7.59 (s, 1 H) 7.34 - 7.45 (m, 1 H) 7.14 (dd, J = 8.4, 1.6 Hz, 1 H) 4.95 - 5.06 (m, 1 H) 3.88 - 4.08 (m, 4 H) 2.12 - 2.34 (m, 2 H). Step 3: [0351] To a solution of 3-[(3S)-tetrahydrofuran-3-yl]oxybenzoic acid (200 mg, 961 µmol) in DCM (3 mL) was added DIEA (669 µL, 3.84 mmol) and HATU (730 mg, 1.92 mmol). The reaction was stirred at 25 °C for 30 minutes. 3-[(1R)-1-aminoethyl]-5- (trifluoromethyl)aniline (216 mg, 1.06 mmol) was then added and the mixture and stirred at 25 °C for 3 hours. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give N-[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]-3-[(3S)-tetrahydrofuran-3-yl]oxy-benzamide (140 mg, 36% yield). LCMS (ESI): m/z: [M+H] calculated for C20H22F3N2O3: 395.2; found: 395.1; 1H NMR (400 MHz, chloroform-d) δ ppm 7.28 - 7.40 (m, 3 H) 7.02 (s, 2 H) 6.79 - 6.95 (m, 2 H) 6.33 (br d, J = 7.2 Hz, 1 H) 5.25 (q, J = 7.2 Hz, 1 H) 4.98 - 4.99 (m, 1 H) 3.84 - 4.05 (m, 4 H) 2.09 - 2.31 (m, 2 H) 1.58 (d, J = 7.2 Hz, 3 H). Example 15: Synthesis of N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-5- [(3S)-tetrahydrofuran-3-yl]oxy-1H-indole-7-carboxamide
Figure imgf000144_0001
Step 1: [0352] To a solution of methyl 2-amino-5-bromo-benzoate (3.00 g, 13.0 mmol) in TFA (15 mL) was added NIS (3.02 g, 13.4 mmol). The reaction was stirred at 15 °C for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give methyl 2-amino-5-bromo-3-iodo-benzoate (4.30 g, 91% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.95 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 3.88 (s, 3H). Step 2: [0353] To a solution of methyl 2-amino-5-bromo-3-iodo-benzoate (2.60 g, 7.30 mmol) in TEA (25 mL) was added Pd(dppf)Cl2 (802 mg, 1.10 mmol) and CuI (209 mg, 1.10 mmol) under nitrogen. The reaction stirred at 15 °C for 20 minutes. Ethynyl(trimethyl)silane (1.32 mL, 9.50 mmol) was then added and the reaction was stirred at 15 °C for 1 hour. The solvent was removed under reduced pressure, then the residue was dissolved in DCM, filtered through a plug of Celite®, and washed with DCM. The filtrate was washed with water and brine, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 2-amino-5-bromo-3-(2-trimethylsilylethynyl)benzoate (1.90 g, 80% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.80 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 3.77 (s, 3H), 0.16 (s, 9H). Step 3: [0354] Methyl 2-amino-5-bromo-3-(2-trimethylsilylethynyl)benzoate (1.90 g, 5.82 mmol) was dissolved in NMP (15 mL) at 0 oC. tert-BuOK (1.44 g, 12.8 mmol) in NMP (15 mL) was then added dropwise to the mixture and the reaction was stirred at 0 °C for 1 hour. The mixture was diluted with water, extracted with MTBE, washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-bromo-1H-indole-7- carboxylate (210 mg, 14% yield). LCMS (ESI): m/z: [M + H] calculated for C10H9BrNO2: 254.0; found 253.9. 1H NMR (400 MHz, methanol-d4) δ ppm 7.96 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 3.2 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 4.00 (s, 3H). Step 4: [0355] To a solution of methyl 5-bromo-1H-indole-7-carboxylate (200 mg, 787 µmol) in dioxane (4 mL) were added Pd(dppf)Cl2 (57.6 mg, 78.7 µmol) and KOAc (309 mg, 3.15 mmol). The reaction was stirred for 20 minutes then bis(pinacolato)diboron (300 mg, 1.18 mmol) was added to the reaction. The mixture was stirred at 110 °C for 3 hours. The reaction was filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate (210 mg, 89% yield). LCMS (ESI): m/z: [M + H] calculated for C16H21BNO4: 302.2; found 302.1.1H NMR (400 MHz, chloroform-d) δ ppm 9.93 (br s, 1H), 8.36 (d, J = 8.8 Hz, 2H), 7.30 - 7.32 (m, 1H), 6.62 (dd, J = 2.4, 3.2 Hz, 1H), 3.99 (s, 3H), 1.43 (s, 12H). Step 5: [0356] To a solution of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole-7-carboxylate (200 mg, 664 µmol) in MeOH (5 mL) were added NaOH (106 mg, 2.66 mmol) and hydroxylamine hydrochloride (138 mg, 1.99 mmol). The reaction was stirred at 20 °C for 5 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography to get methyl 5-hydroxy-1H-indole-7- carboxylate (100 mg, 79% yield). 1H NMR (400 MHz, methanol-d4) δ ppm 7.37 (d, J = 2.8 Hz, 1H), 7.29 (d, J = 2.8 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 3.97 (s, 3H). Step 6: [0357] To a solution of methyl 5-hydroxy-1H-indole-7-carboxylate (50.0 mg, 262 µmol) in DMF (1 mL) was added tetrahydrofuran-3-yl 4-methylbenzenesulfonate (63.4 mg, 262 µmol) and K2CO3 (108 mg, 785 µmol). The reaction was stirred at 90 °C for 5 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried with MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give methyl 5-[(3S)- tetrahydrofuran-3-yl]oxy-1H-indole-7-carboxylate (40 mg, 59% yield). LCMS (ESI): m/z: [M + H] calculated for C14H16NO4: 262.1; found: 262.0; 1H NMR (400 MHz, methanol-d4) δ ppm 7.46 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 3.2 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 5.05 (dd, J = 2.4, 5.2 Hz, 1H), 3.94 - 4.02 (m, 6H), 3.79 - 3.93 (m, 1H), 2.16 - 2.26 (m, 2H). Step 7: [0358] To a solution of methyl 5-[(3S)-tetrahydrofuran-3-yl]oxy-1H-indole-7- carboxylate (35.0 mg, 134 µmol) in toluene (2 mL) was added 3-[(1R)-1-aminoethyl]-5- (trifluoromethyl)aniline (82.1 mg, 402 µmol) and Al(CH3)3 (2 M, 134 µL). The reaction was stirred at 100 °C for 2 hours. The mixture was diluted with water, extracted with DCM, washed with brine, dried with Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give N-[(1R)-1-[3-amino-5- (trifluoromethyl)phenyl]ethyl]-5-[(3S)-tetrahydrofuran-3-yl]oxy-1H-indole-7-carboxamide (10 mg, 8 % yield). LCMS (ESI): m/z: [M + H] calculated for C22H23F3N3O3: 434.2; found 434.2; 1H NMR (400 MHz, chloroform-d) δ ppm 10.08 (br s, 1H), 7.32 (t, J = 2.8 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.86 (s, 1H), 6.83 (s, 1H), 6.48 - 6.52 (m, 2H), 5.27 - 5.30 (m, 1H), 4.98 - 5.04 (m, 1H), 3.90 - 4.10 (m, 5H), 3.84 - 3.90 (br m, 2H), 2.21 - 2.29 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H). Example 16: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6- (1,2,3,6-tetrahydropyridin-4-yl)-3H-benzotriazole-4-carboxamide
Figure imgf000147_0001
Step 1: [0359] A solution of methyl 2,3-diamino-5-bromo-benzoate (500 mg, 2.04 mmol) in acetic acid (7.5 mL) was stirred for 10 minutes at 25 °C. A solution of NaNO2 (155 mg, 2.24 mmol) in H2O (1 mL) was then added and the reaction stirred for 30 minutes. The reaction was filtered, and the filter cake was washed with water. The solid was dried under reduced pressure to give methyl 6-bromo-3H-benzotriazole-4-carboxylate (440 mg, 84% yield). LCMS (ESI): m/z: [M + H] calculated for C8H7BrN3O2: 255.96; found 255.9; 1H NMR (400 MHz, DMSO-d6) δ ppm 16.18 (br s, 1H), 8.69 (s, 1H), 8.13 (s, 1H), 3.99 (s, 3H). Step 2: [0360] To a solution of methyl 6-bromo-3H-benzotriazole-4-carboxylate (440 mg, 1.72 mmol) in THF (4 mL), MeOH (2 mL), and H2O (2 mL) was added LiOH•H2O (216.33 mg, 5.16 mmol). The reaction was stirred at 25 °C for 1 hour. The reaction was diluted with water, washed with ethyl acetate, acidified to pH = 2 using HCl (2M), filtered, and the solid was dried under reduced pressure to give 6-bromo-3H-benzotriazole-4- carboxylic acid (450 mg, crude). LCMS (ESI): m/z: [M + H] calculated for C7H5BrN3O2: 241.95; found 241.8; 1H NMR (400 MHz, DMSO-d6) δ ppm 16.10 (br s, 1H), 8.64 (s, 1H), 8.10 (s, 1H). Step 3: [0361] To a solution of 6-bromo-3H-benzotriazole-4-carboxylic acid (430 mg, 1.78 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (403 mg, 2.13 mmol) in THF (5 mL) was added T3P (3.17 mL, 5.33 mmol) and DIEA (2.48 mL, 14.21 mmol). The reaction was stirred at 25 °C for 1 hour. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]- 3H-benzotriazole-4-carboxamide (550 mg, 75% yield). LCMS (ESI): m/z: [M + H] calculated for C16H13BrF3N4O: 413.0; found 412.8; 1H NMR (400 MHz, methanol-d4) δ ppm 8.23 (d, J = 33.2 Hz, 2H), 7.51 - 7.68 (m, 2H), 7.30 - 7.32 (m, 1H), 7.02 (t, J = 54.8 Hz, 1H), 5.58 - 5.63 (m, 1H), 1.68 (d, J = 7.2 Hz, 3H). Step 4: [0362] To a solution of 6-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-3H-benzotriazole-4-carboxamide (200 mg, 484 µmol) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (299 mg, 968 µmol) in dioxane (2 mL) and H2O (0.4 mL) were added Na2CO3 (102 mg, 968 µmol) and Pd(PPh3)2Cl2 (34.0 mg, 48.4 µmol) under nitrogen. The mixture was stirred at 100 °C for 1 hour. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-benzotriazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (240 mg, crude). LCMS (ESI): m/z: [M + H] calculated for C26H29F3N5O3: 516.21; found: 516.2. Step 5: [0363] A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-benzotriazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 388 µmol) in HCl (4 M in EtOAc, 2 mL) was stirred at 25 °C for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by prep- HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-6-(1,2,3,6- tetrahydropyridin-4-yl)-3H-benzotriazole-4-carboxamide (30 mg, 18% yield). LCMS (ESI): m/z: [M + H] calculated for C21H21F3N5O: 416.2; found 416.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 - 10.41 (m, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.66 - 7.70 (m, 1H), 7.52 - 7.56 (m, 1H), 7.11 - 7.38 (m, 2H), 6.24 (s, 1H), 5.50 - 5.53 (m, 1H), 3.75 (d, J = 0.8 Hz, 1H), 3.29 - 3.31 (m, 2H), 2.72 - 2.80 (m, 2H), 1.61 (d, J = 6.8 Hz, 3H). Example 17: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(4- piperidyl)-1H-indazole-7-carboxamide
Figure imgf000149_0001
Step 1: [0364] To a solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 1.55 mmol) in THF (10 mL) was added Pd/C (10% purity, 800 mg, 389 µmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas. The reaction was stirred under hydrogen gas (30 psi) at 25 °C for 12 hours. The reaction was filtered, and the solvent was removed under reduced pressure. The residue was purified by prep-HPLC to give tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl] piperidine-1-carboxylate (175 mg, 22% yield). LCMS (ESI): m/z: [M + H] calculated for C27H32F3N4O3: 517.2; found: 517.1; 1H NMR (400 MHz, methanol-d4) δ ppm 7.95 - 8.07 (m, 2H), 7.84 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.25 - 7.32 (m, 1H), 7.01 (t, J = 54.8 Hz, 1H), 5.60 (q, J = 6.8 Hz, 1H), 4.23 - 4.31 (m, 2H), 2.85 - 2.99 (m, 3H), 1.93 (d, J = 12.0 Hz, 2H), 1.71 - 1.81 (m, 2H), 1.64 (d, J = 6.8 Hz, 3H), 1.49 (s, 9H). Step 2: [0365] A solution of tert-butyl 4-[7-[[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]carbamoyl]-1H-indazol-5-yl]piperidine-1-carboxylate (70.0 mg, 136 µmol) in HCl (4 M in EtOAc, 1 mL) was stirred at 25 °C for 30 minutes. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC to give N-[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(4-piperidyl)-1H-indazole-7-carboxamide (35 mg, 62% yield). LCMS (ESI): m/z: [M + H] calculated for C22H24F3N4O: 417.2; found: 417.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (br s, 1H), 9.22 (d, J = 6.0 Hz, 1H), 8.06 (d, J = 18.0 Hz, 2H), 7.77 (s, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H), 7.09 - 7.39 (m, 2H), 5.51 (q, J = 6.8 Hz, 1H), 3.25 - 3.26 (m, 1H), 2.83 - 2.96 (m, 4H), 1.80 - 1.99 (m, 4H), 1.56 (d, J = 6.8 Hz, 3H). Example 18: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,1- dioxo-3,6-dihydro-2H-thiopyran-4-yl)-4-methoxy-1H-indazole-7-carboxamide
Figure imgf000151_0001
Step 1: [0366] To a solution of 7-bromo-4-methoxy-1H-indazole (700 mg, 3.08 mmol) in toluene (7 mL) was added acetic anhydride (487 µL, 5.19 mmol). The reaction mixture was stirred at 110 °C for 3 hours. The mixture was then concentrated under reduced pressure and the residue was diluted with H2O, then extracted with EtOAc. The combined organic extracts were treated with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 1- (7-bromo-4-methoxy-indazol-1-yl) ethanone (700 mg, 84% yield). LCMS (ESI): m/z: [M + H] calculated for C10H10BrN2O2: 269.0; found: 269.0. Step 2: [0367] To a solution of 1-(7-bromo-4-methoxy-indazol-1-yl) ethanone (760 mg, 2.82 mmol) in THF (8 mL) was added NBS (782 mg, 4.39 mmol) at -10 °C. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was then diluted with H2O and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give 5,7-dibromo-4-methoxy-1H-indazole (330 mg, 38% yield). LCMS (ESI): m/z: [M + H] calculated for C8H7Br2N2O: 304.9; found: 304.8. Step 3: [0368] To a solution of 5,7-dibromo-4-methoxy-1H-indazole (260 mg, 850 µmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (322 mg, 1.70 mmol) in dioxane (3 mL) were added Mo(CO)6 (89.7 mg, 340 µmol), TEA (237 µL, 1.70 mmol), and Pd(dppf)Cl2 (62.2 mg, 85.0 µmol) under an atmosphere of N2. The reaction mixture was stirred at 120 °C in a microwave reactor for 5 hours. The mixture was diluted with H2O and extracted with EtOAc. The combined organic extracts were treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by prep-TLC to give 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide (50 mg, 13% yield). LCMS (ESI): m/z: [M + H] calculated for C18H16BrF3N3O2: 442.0; found: 442.0. Step 4: [0369] To a solution of 5-bromo-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-4-methoxy-1H-indazole-7-carboxamide (40.0 mg, 90.4 µmol) in dioxane (1 mL) and H2O (0.2 mL) were added Cs2CO3 (88.4 mg, 271 µmol), 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (70.1 mg, 271 µmol), and [1,1ʹ-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (13.2 mg, 18.1 µmol). The reaction mixture was stirred at 100 °C for 2 hours under N2. The mixture was then diluted with MeOH, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give N-[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-4- methoxy-1H-indazole-7-carboxamide (8.5 mg, 19% yield). LCMS (ESI): m/z: [M + H] calculated for C23H23F3N3O4S: 494.1; found: 494.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br s, 1H) 9.08 (s, 1H) 8.41 (s, 1H) 7.93 (s, 1H) 7.67 (t, J = 8.0 Hz, 1H) 7.49–7.34 (m, 1H) 7.32–7.10 (m, 1H) 5.72 (s, 1H) 5.49–5.46 (m, 1H) 4.23 (s, 3H) 3.93 (br s, 2H) 3.35 (br s, 2H) 3.02 (br s, 2H) 1.54 (d, J = 8.0 Hz, 3H). Example 19: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,1- dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-oxo-indoline-7-carboxamide
Figure imgf000153_0001
Step 1: [0370] To a solution of 7-bromo-5-chloro-indolin-2-one (300 mg, 1.22 mmol) and (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethanamine (460 mg, 2.43 mmol) in dioxane (4 mL) were added Mo(CO)6 (129 mg, 487 µmol), TEA (339 µL, 2.43 mmol) and Pd(dppf)Cl2 (89.1 mg, 122 µmol) under an atmosphere of N2. The reaction mixture was stirred at 120 °C in a microwave reactor for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give 5-chloro-N-[(1R)-1-[3-(difluoromethyl)-2- fluoro-phenyl]ethyl]-2-oxo-indoline-7-carboxamide (220 mg, 29% yield, 62% purity). LCMS (ESI): m/z: [M + H] calculated for C18H15ClF3N2O2: 383.1; found: 383.0. Step 2: [0371] To a solution of 5-chloro-N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-2-oxo-indoline-7-carboxamide (100 mg, 261 µmol) in THF (1 mL) and H2O (0.2 mL) were added chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2- aminobiphenyl)]palladium(II) (17.5 mg, 26.1 µmol), K3PO4 (111 mg, 523 µmol) and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-thiopyran 1,1-dioxide (101 mg, 392 µmol). The reaction mixture was stirred at 80 °C for 12 hours under N2. The mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(1,1-dioxo-3,6- dihydro-2H-thiopyran-4-yl)-2-oxo-indoline-7-carboxamide (4.8 mg, 3.8% yield). LCMS (ESI): m/z: [M + H] calculated for C23H22F3N2O4S: 479.1; found: 479.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (br, s, 1H) 9.10 (br, s, 1H) 7.86 (s, 1H) 7.65 (t, J = 6.4 Hz, 1H) 7.55–7.47 (m, 2H) 7.38–7.09 (m, 1H) 6.00 (s, 1H) 5.50–5.38 (m, 1H) 3.92 (s, 2H) 3.51 (s, 2H) 3.38 (s, 2H) 3.13–3.04 (m, 2H) 1.52 (d, J = 7.0 Hz, 3H). Example 20: Synthesis of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(4- methyl-1,1-dioxo-thian-4-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide
Figure imgf000154_0001
Step 1: [0372] To a solution of 6-bromo-2,4-dichloro-pyridin-3-amine (5.00 g, 20.7 mmol) and 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.14 g, 22.7 mmol) in dioxane (100 mL) and H2O (20 mL) were added Pd(PPh3)2Cl2 (1.45 g, 2.07 mmol) and Na2CO3 (4.38 g, 41.3 mmol) at 25 °C under an atmosphere of N2. The reaction mixture was stirred at 100 °C for 4 hours. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 2,4-dichloro-6-(3,6-dihydro-2H-thiopyran- 4-yl)pyridin-3-amine (4.00 g, 74% yield). LCMS (ESI): m/z: [M + H] calculated for C10H11Cl2N2S: 261.0; found: 260.9. Step 2: [0373] To a solution of 2,4-dichloro-6-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-3- amine (4.00 g, 15.3 mmol) in TEA (80 mL) were added Pd(PPh3)2Cl2 (538 mg, 766 µmol) and CuI (146 mg, 766 µmol) at 0 °C under an atmosphere of N2. Ethynyl(trimethyl)silane (3.18 mL, 23.0 mmol) was then added and the reaction mixture was stirred at 80 °C for 12 hours. The mixture was then cooled, filtered, washed with EtOAc, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 4-chloro-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-(2-trimethylsilylethynyl)pyridin-3- amine (2.90 g, 59% yield). LCMS (ESI): m/z: [M + H] calculated for C15H20ClN2SSi: 323.1; found: 322.9. Step 3: [0374] To a solution of 4-chloro-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-(2- trimethylsilylethynyl)-pyridin-3-amine (1.00 g, 3.10 mmol) in DMF (10 mL) was added CuI (118 mg, 619 µmol) under an atmosphere of N2. The reaction mixture was stirred at 110 °C for 4 hours. The reaction mixture was quenched with water and then extracted with EtOAc. The combined organic extracts were treated with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give 7-chloro-5-(3,6-dihydro-2H-thiopyran-4-yl)-1H-pyrrolo[3,2- b]pyridine (380 mg, 49% yield). LCMS (ESI): m/z: [M + H] calculated for C12H12ClN2S: 251.0; found: 250.9. Step 4: [0375] To a solution of 7-chloro-5-(3,6-dihydro-2H-thiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine (280 mg, 1.12 mmol) in THF (3 mL) was added n-BuLi (2.5 M in hexanes, 1.03 mL) dropwise at -10 °C under an atmosphere N2. The mixture was cooled to -50 °C and Me2SO4 (116 µL, 1.23 mmol) was added dropwise. The reaction mixture was stirred at -50 °C for 30 minutes, then was slowly transferred into a dilute solution of aqueous NH4OH (1.5 ml) and heptanes (1.5 ml). The reaction mixture was warmed to 25 °C and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC to give 7-chloro-5-(4-methyl-2,3- dihydrothiopyran-4-yl)-1H-pyrrolo[3,2-b]pyridine (50 mg, 17% yield) as a yellow solid. LCMS (ESI): m/z: [M + H] calculated for C13H14ClN2S: 265.0; found: 264.9. Step 5: [0376] To a solution of 7-chloro-5-(4-methyl-2,3-dihydrothiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine (60.0 mg, 227 µmol) in THF (2 mL) was added Pd/C (10% purity, 6.0 mg, 23 µmol) under an atmosphere of N2. The suspension was purged with H2 and the reaction mixture was stirred under H2 (15 psi) at 25 °C for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 7-chloro-5-(4- methyltetrahydrothiopyran-4-yl)-1H-pyrrolo[3,2-b]pyridine (60 mg, 99% yield). LCMS (ESI): m/z: [M + H] calculated for C13H16ClN2S: 267.1; found: 267.0. Step 6: [0377] To a solution of 7-chloro-5-(4-methyltetrahydrothiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine (60 mg, 225 µmol) in dioxane (1 mL) were added (1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethanamine HCl salt (128 mg, 566 µmol), Mo(CO)6 (59.4 mg, 225 µmol), TEA (188 µL, 1.35 mmol) and Pd(dppf)Cl2 (16.5 mg, 22.5 µmol) under an atmosphere N2. The reaction mixture was stirred at 120 °C in a microwave reactor for 16 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by prep-HPLC to give N-[(1R)-1-[3- (difluoromethyl)-2-fluoro-phenyl]ethyl]-5-(4-methyltetrahydrothiopyran-4-yl)-1H- pyrrolo[3,2-b]pyridine-7-carboxamide (22 mg, 22% yield). LCMS (ESI): m/z: [M + H] calculated for C23H25F3N3OS: 448.2; found: 448.1. Step 7: [0378] To a mixture of N-[(1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethyl]-5- (4-methyltetrahydrothiopyran-4-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide (20.0 mg, 44.7 µmol) in H2O (1 mL) and MeOH (3 mL) was added Oxone® (55.0 mg, 89.4 µmol) under an atmosphere of N2. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by prep-HPLC to give N-[(1R)-1-[3-(difluoromethyl)-2-fluoro- phenyl]ethyl]-5-(4-methyl-1,1-dioxo-thian-4-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide (10 mg, 58% yield). LCMS (ESI): m/z: [M + H] calculated for C23H25F3N3O3S: 480.1; found: 480.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.34 (br s, 1H), 9.28 (d, J = 7.1 Hz, 1H), 7.82 (s, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.57–7.51 (m, 2H), 7.36–7.10 (m, 2H), 6.58 (dd, J = 2.0, 3.2 Hz, 1H), 5.53–5.46 (m, 1H), 3.18–3.15 (m, 2H), 3.00–2.95 (m, 2H), 2.87–2.83 (m, 2H), 2.22–2.15 (m, 2H), 1.58 (d, J = 7.1 Hz, 3H), 1.37 (s, 3H). Additional Compounds [0379] The compounds listed in Table B were prepared using methods similar to those described above for Examples 1-20. Table B
Figure imgf000157_0001
Figure imgf000158_0001
Biological Examples Potency assay: Measurement of the binding affinity of Compounds of the Disclosure to SOS1 using Surface Plasmon Resonance (SPR) [0380] The purpose of the SPR assay was to measure the direct binding of compounds to SOS1 catalytic domain (residues 564 – 1049) immobilized on a sensor chip. Data was reported as equilibrium dissociation constant (Kd) values. [0381] Using a GE Biacore 8K SPR instrument, avi-tagged SOS1 catalytic domain protein was immobilized to a level of approximately 6000 response units (RU) on a streptavidin-coated SPR sensor chip in assay buffer containing 0.01 M HEPES, 0.15 M NaCl and 0.05% v/v Surfactant P20. In assay buffer containing 2% DMSO, concentration series of test compounds were generated spanning 5 µM to 4.9 nM over ten 2-fold dilutions. For each test compound, a separate 0 µM sample was generated for use during subsequent double reference subtraction. Serially for each test compound, individual dilution samples were flowed over the immobilized SOS1 protein at a flow rate of 50 µL/minute to monitor the association with SOS1. Dissociation of bound test compound from the SOS1 protein was immediately monitored by flowing assay buffer over the sensor surface and monitoring the decrease in binding signal back to the baseline level seen in the absence of compound. This was repeated for all compound dilutions in each series. The binding level response for each test compound concentration was noted immediately prior to the end of the association phase, and a secondary plot generated showing binding response level versus test compound concentration generated for each compound dilution series. This data was fitted to a model describing reversible equilibrium 1:1 binding between test compound and SOS1, yielding an estimate of the Kd value for the interaction. [0382] SOS1 using Surface Plasmon Resonance (SPR) results are shown in Table C below. Table C
Figure imgf000159_0001
Potency assay: pERK [0383] The purpose of this assay is to measure the ability of test compounds to inhibit SOS1 function in cells. SOS1 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). The procedure described below measures the level of cellular pERK in response to test compounds in PC- 9 cells (EGFR Ex19Del). [0384] 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 µL/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 µM. 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. [0385] Cellular pERK level was determined using the AlphaLISA SureFire Ultra p-ERK1/2 Assay Kit (PerkinElmer). Cells were lysed in 25 µL lysis buffer, with shaking at 600 RPM at room temperature for 15 minutes. Lysate (10 µL) was transferred to a 384- well Opti-plate (PerkinElmer) and 5 µL 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 µL 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. Signal was read on an Envision plate reader (PerkinElmer) using standard AlphaLISA settings. Analysis of raw data was carried out in Excel (Microsoft) and Prism (GraphPad). Signal was plotted vs. the decadal logarithm of compound concentration, and IC50 was determined by fitting a 4-parameter sigmoidal concentration response model. [0386] SOS1 pERK IC50 Assay results are shown in Table D below. Table D
Figure imgf000160_0001
Mode of Action Assay: Inhibition of SOS1 Nucleotide Exchange Activity [0387] The purpose of this assay was to characterize the inhibitory activity of compounds on SOS1 nucleotide exchange of KRAS. Data was reported as IC50 values based on the TR-FRET signal. [0388] Note – the following protocol describes a procedure for monitoring the inhibition of SOS1 nucleotide exchange activity of wild-type KRAS in response to a compound of the invention. Other KRAS mutants and RAS isoforms maybe employed. [0389] In assay buffer containing 20 mM HEPES, pH 7.5, 150 mM NaCl, 5 mM MgCl2, 0.05% Tween-20, 0.1% BSA, 1 mM DTT, concentration series of test compounds were generated spanning 100 µM to 1.7 nM over eleven 3-fold serial dilutions in a 384- well assay plate at a volume of 20 µL. The purified tagless catalytic domain of SOS1 (residues 564 - 1049) was first diluted in assay buffer at a concentration of 100 nM, and then 20 µL of the SOS1 containing solution was directly dispensed into compound plates. The SOS1/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 SOS1/compound mixture to prevent intrinsic nucleotide exchange. Then 5 µL of the pre-incubated SOS1/compound mixture and 7.5 µL 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. Time-resolved fluorescence was measured on a PerkinElmer Envision plate reader. DMSO and 10 µM of compound (i) were used as negative and positive controls, respectively.
Figure imgf000161_0001
compound (i) [0390] Three replicates were performed for each compound. Data were normalized by the following: (Positive control - Sample signal)/(Positive control – negative control)*100. The data were fit using a four-parameter logistic fit. [0391] SOS1 TR-FRET IC50 Assay results are shown in Table E below. Table E
Figure imgf000162_0001
Equivalents [0392] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

WHAT IS CLAIMED IS: 1. A compound having a structure of Formula (I), Formula (II), or Formula (III):
Figure imgf000163_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein: X1 is NH or S; X2 is CH or N; X3 is CH or N; X4 is CR3 or N; X5 is CH or N; X6 is CH or N; R1 is selected from the group consisting of optionally substituted 3-6 membered cycloalkyl, optionally substituted 3-6 membered heterocyclyl, optionally substituted 6- membered aryl, and optionally substituted 5-6 membered heteroaryl; R2 is selected from the group consisting of H, -NH-C1-6 alkyl, and –NH2; R3 is selected from the group consisting of H, -O-C1-6 alkyl, and -O-C1-6 heteroalkyl; L4 is a bond or O; and R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with one or more C1-6 alkyl, –R4a, –OR4a, –O–C1-6 alkyl– R4a, =O, halogen, –C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –NR4bC(O)R4c, –CN, =NR4a, – NR4bR4c, –SO2R4a, 3-6 membered cycloalkyl optionally substituted with R4a, 3-7 membered heterocyclyl optionally substituted with R4a, 6-10 membered aryl optionally substituted with R4a, or 5-10 membered heteroaryl optionally substituted with R4a; wherein R4a is H, C1-6 alkyl, C1-6 haloalkyl, –C(O)R4b, –C(O)NR4bR4c, =O, 3-6 membered cycloalkyl, 6-10 membered aryl optionally substituted with –OR4b, – CN, =N-3-6 membered cycloalkyl, 3-7 membered heterocyclyl, –(CH2)rOCH3, or – (CH2)rOH, wherein r is 1, 2, or 3; wherein each R4b is independently H, C1-6 alkyl; and wherein each R4c is independently H or C1-6 alkyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1 is optionally substituted 6- membered aryl. 3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1 is optionally substituted 5-6 membered heteroaryl. 4. The compound of claim 1, having the structure selected from the group consisting of:
Figure imgf000165_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6, R2, L4, and R4 are as defined in claim 1; R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl,
3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl,
4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN.
5. The compound of claim 1, having the structure selected from the group consisting of:
Figure imgf000166_0001
Figure imgf000167_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6,R2, L4, and R4 are as defined in claim 1; R5, R6, and R7 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, –S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, – NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10, 6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN. 6. The compound of claim 1, having the structure selected from the group consisting of:
Figure imgf000168_0001
Figure imgf000169_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, X6,R2, L4, and R4 are as defined in claim 1; R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, –OH, halogen, –NO2, –CN, –NR11R12, –SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, –C(O)R10, –CO2R10, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with –OH, C1-6 alkyl optionally substituted with -R10, halogen, –NO2, =O, –CN, −R10, –OR10, –NR11R12, −SR10, – S(O)2NR11R12, –S(O)2R10, –NR10S(O)2NR11R12, –NR10S(O)2R11, –S(O)NR11R12, –S(O)R10, –NR10S(O)NR11R12, –NR10S(O)R11, 3-8 membered cycloalkyl, 3-14 membered heterocyclyl optionally substituted with R10,
6-10 membered aryl, or 5-10 membered heteroaryl, or any two adjacent R5, R6, R7, R8, and R9 forms an optionally substituted 3-14 membered fused ring; R10, R11, and R12 are at each occurrence independently selected from H, D, C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, 3- 14 membered heterocyclyl, –OR13, –SR13, halogen, –NR13R14, –NO2, and –CN; and R13 and R14 are at each occurrence independently selected from H, D, C1-6 alkyl, C2- 6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl, wherein each C1-6 alkyl, C2-6 alkenyl, 4-8 membered cycloalkenyl, C2-6 alkynyl, 3-8 membered cycloalkyl, and 3-14 membered heterocyclyl are independently optionally substituted with –OH, –SH, –NH2, –NO2, or –CN.
7. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen.
8. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen and –OH.
9. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is halogen, and one to three of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen.
10. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein one to three of R5, R6, R7, R8, and R9 is –NH2.
11. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein one of R5, R6, R7, R8, and R9 is –NH2; and one of R5, R6, R7, R8, and R9 is C1-6 alkyl substituted with halogen.
12. The compound of any one of claims 4-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein any two adjacent R5, R6, R7, R8, and R9 forms a 3-14 membered fused ring, wherein the fused ring is substituted with halogen.
13. The compound of any one of claims 1-12, having the structure of Formula (I), Formula (Ia), Formula (Ib), Formula (Ic-1), Formula (Ic-2), or Formula (Ic-3), or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X2, X3, X4, X5, L4, and R4 are as defined in claim 1.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein L4 is a bond.
15. The compound of any one of claims 1-12, having the structure of Formula (II), Formula (IIa), Formula (IIb), Formula (IIc-1), Formula (IIc-2), or Formula (IIc-3), or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X1, X4, and R4 are as defined in claim 1.
16. The compound of any one of claims 1-12, having the structure of Formula (III), Formula (IIIa), Formula (IIIb), Formula (IIIc-1), Formula (IIIc-2), or Formula (IIIc- 3), or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein X5, X6, R2, and R4 are as defined in claim 1.
17. The compound of claim 1, having the structure selected from the group consisting of:
Figure imgf000172_0001
or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1, R3, L4, and R4 are as defined in claim 1.
18. The compound of claim 1, having the structure of Formula (II-1):
Figure imgf000173_0001
, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1 and R4 are as defined in claim 1.
19. The compound of claim 1, having the structure of Formula (III-1) or (III-2):
Figure imgf000173_0002
, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R1, R2, and R4 are as defined in claim 1.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, wherein R4 is selected from the group consisting of H, C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl; wherein each C1-6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl is optionally substituted with C1-6 alkyl –OR4a, =O, halogen, –C(O)R4a, –C(O)OR4a, –C(O)NR4bR4c, –CN, – NR4bR4c, 3-6 membered cycloalkyl, 3-7 membered heterocyclyl, 6-10 membered aryl, or 5- 10 membered heteroaryl.
21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, selected from the group consisting of:
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof, and a pharmaceutically acceptable carrier. 23. A method of inhibiting SOS1 in a subject, comprising administering to the subject a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. 24. A method of inhibiting the interaction of SOS1 and a RAS-family protein in a cell or inhibiting the interaction of SOS1 and RAC1 in a cell, comprising administering to the cell a compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. 25. A method of treating or preventing a disease, wherein treating or preventing the disease is characterized by inhibition of the interaction of SOS1 and a RAS-family protein or by inhibition of the interaction of SOS1 and RAC1, the method comprising administering to a subject in need thereof an effective amount of a compound of any of claims 1-21, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. 26. 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 claims 1-21, or a pharmaceutically acceptable salt, solvate, stereoisomer, prodrug, or tautomer thereof. 27. The method of claim 25 or 26, 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. 28. The method of claim 26 or 27, wherein the cancer comprises a RasMUT or an NF1LOF mutation. 29. The method of claim 25, wherein the disease is a RASopathy. 30. The method of claim 29, 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.
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