Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• Autophagy is a central cellular mechanism for elimination of damaged proteins, protein complexes, and organelles. This conserved process plays crucial roles in the cellular response to nutrient deprivation and other stresses, in addition to being required for proper cellular and tissue homeostasis during embryonic development and in defense against pathogens. Defects in autophagy pathways are associated with certain human pathologies, including infectious diseases, neurodegenerative disorders, and cancer. In spite of these highly conserved fundamental cellular functions, the molecular and biochemical details of how autophagy is initiated for different cargoes, and the coordination of steps starting from autophagosome initiation to ultimate fusion with the lysosome remain poorly understood.
• the diseases provided herein are treatable with an inhibitor specific for ULK1.
• ULK2 may compensate for loss of ULK1 function.
• the diseases provided herein require treatment with a compound that inhibits both ULK1 and ULK2.
• compounds useful as ULK inhibitors are compounds useful as ULK inhibitors. In some embodiments, the compounds are useful for the treatment of various diseases, including cancer.
• R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or halogen
• any group that is optionally substituted is optionally substituted with one or more substituent.
• any group that is substituted herein is substituted with one or more substituents.
• X 1 , X 2 , X 3 , and X 4 are each independently -O-, -NR 5 -, or –S.
• a 1 and A 2 are each independently aryl or heteroaryl.
• a 1 and A 2 are each independently 6-membered aryl or 6-membered heteroaryl.
• each R b is independently C 1 -C 6 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently optionally substituted with one or more halogen, -OH, -NH 2 , or C 1 -C 6 alkyl.
• R 2 is halogen, -CN, -NO 2 , or C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more R 20 .
• R 2 is halogen, -CN, or -CF 3.
• R 2 is Br, Cl, or -CF 3 .
• R 2 is -CF 3 .
• n is 1.
• R 4 is .
• wherein each R 40 is independently halogen, -CN, or –OH.
• a 1 is .
• a 2 is phenyl or pyridyl.
• a 2 is phenyl.
• a 2 is .
• each R 3 is independently fluorine, chlorine, bromine, -O(C 1 -C 6 alkyl), - OH, -NH 2 , or C 1 -C 6 alkyl.
• each R 3 is independently fluorine, chlorine, bromine, or –OMe.
• each R 3 is –OMe.
• m is 1 or 2. In some embodiments, m is 1.
• each R 30 is independently halogen, -CN, or –OH.
• a 2 is .
• X 1 is –O- or –NR 5 -.
• X 1 is –NH- or –N(Me)-.
• X 1 is –NH-.
• X 2 is –O- or –NR 5 -. In some embodiments, X 2 is –NH- or –N(Me)-. In some embodiments, X 2 is –NH-. In some embodiments, X 3 is –O-. In some embodiments, X 4 is –O-. In some embodiments, L is a chain of 3-8 atoms, wherein each atom in the chain is independently selected from –CR 6 R 7 - or -O-.
• a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of any one of the compounds provided herein and a pharmaceutically acceptable carrier.
• the pharmaceutical composition is formulated for intravenous or intraperitoneal injection.
• a method of treating a ULK1 or ULK2 mediated disease in a subject in need thereof comprising administering to the subject a compound or pharmaceutical composition of any one of the compounds provided herein.
• the ULK1 or ULK2 mediated disease is characterized by abnormal autophagy.
• the abnormal autophagy has been therapeutically induced.
• the disease is Tuberous Sclerosis Complex (TSC) or lymphangioleiomyomatosis (LAM).
• TSC Tuberous Sclerosis Complex
• LAM lymphangioleiomyomatosis
• the compound is co-administered with an additional therapeutic agent.
• the additional therapeutic agent is an mechanistic target of rapamycin (mTOR) inhibitor.
• the additional therapeutic agent is carboplatin.
• the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor.
• the additional therapeutic agent is trametinib.
• the additional therapeutic agent is a poly (ADP-ribose) polymerase (PARP) inhibitor.
• PARP poly (ADP-ribose) polymerase
• the additional therapeutic agent is olaparib.
• the additional therapeutic agent is a standard of care therapy.
• administering the compound degrades autophagy-related protein 13 (ATG13) in the subject.
• ATG13 autophagy-related protein 13
• the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n- pentyl).
• the alkyl is attached to the rest of the molecule by a single bond.
• the term “alkyl” and its equivalents encompass linear, branched, and/or cyclic alkyl groups.
• an “alkyl” comprises both cyclic and acyclic (linear and/or branched) alkyl components.
• an alkyl group is described as “linear,” the referenced alkyl group is not substituted with additional alkyl groups and is unbranched.
• an alkyl group is described as “saturated,” the referenced alkyl group does not contain any double or triple carbon-carbon bonds (e.g. alkene or alkyne).
• “Alkylene” or “alkylene chain” refers to a divalent alkyl group, which may be saturated or unsaturated with one or more double or triple bonds.
• Aryl refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system.
• the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) S–electron system in accordance with the Hückel theory.
• the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
• C x-y or “C x -C y ” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain.
• C x-y alkyl refers to saturated or unsaturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
• C x-y alkenyl and “C x-y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
• Cycloalkyl refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12- membered fused bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond.
• Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.
• “Halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo.
• halo is fluoro, chloro, or bromo.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like.
• the alkyl part of the haloalkyl radical is optionally substituted as described herein.
• Heteroalkyl refers to an alkyl group wherein one or more of the carbons of the alkyl group is replaced with a heteroatom.
• Heterocycloalkyl refers to a saturated or unstaturated (e.g., non-aromatic) ring with carbon atoms and at least one heteroatom (e.g., a cycloalkyl wherein one or more of the carbon groups is substituted with a heteroatom).
• exemplary heteroatoms include N, O, Si, P, B, and S atoms.
• Heterocycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered fused bicyclic rings, 6- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings.
• the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
• the heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl.
• heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thio
• Heteroaryl refers to an aromatic ring comprising carbon atoms and one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) S–electron system in accordance with the Hückel theory.
• the heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized.
• salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
• Pharmaceutically acceptable acid addition salts may be formed with inorganic acids and organic acids.
• Inorganic acids from which salts are derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
• Organic acids from which salts are derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
• Pharmaceutically acceptable base addition salts may be formed with inorganic and organic bases.
• Inorganic bases from which salts are derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
• phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
• substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substituted is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• the permissible substituents may be one or more and the same or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. In embodiments where it is unspecified whether a group is substituted or unsubstituted, it is intended that the group is unsubstituted.
• treat may include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
• “may” refers to optional alternatives to be used in the alternative or in addition to other specified components.
• Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
• Autophagy In certain instances, autophagy is a cellular response to loss of nutrients in which cells catabolize various proteins and organelles to provide building blocks and critical metabolites needed for cell survival. In some instances, autophagy plays an important homeostatic role in many tissues by removing protein aggregates and defective organelles that accumulate with cellular damage over time.
• autophagy In healthy individuals, normal autophagy is, in certain instances, an important process for balancing sources of energy at critical times in development and in response to nutrient stress. In certain instances, autophagy also plays a housekeeping role in removing misfolded or aggregated proteins, clearing damaged organelles, such as mitochondria, endoplasmic reticulum and peroxisomes, as well as eliminating intracellular pathogens. Thus, autophagy is often thought of as a survival mechanism In various instances, autophagy is either non-selective or selective in the removal of specific organelles, ribosomes and protein aggregates.
• autophagy promotes cellular senescence and cell surface antigen presentation, protects against genome instability and prevents or inhibits necrosis, giving it an important role in preventing, treating, or inhibiting diseases such as cancer, neurodegeneration, cardiomyopathy, diabetes, liver disease, autoimmune diseases and infections.
• defects in autophagy pathways are associated with a number of human pathologies, including infectious diseases, neurodegenerative disorders, and cancer.
• the role of autophagy differs in different stages of cancer development; for example, in some instances, initially, autophagy has a preventive effect against cancer, but once a tumor develops, the cancer cells, in certain instances, utilize autophagy for their own cytoprotection.
• the mutations that cause uncontrolled cell growth which results in the formation of tumors or other cancerous tissue also effectuates changes in autophagy. In some instances, these changes in the autophagic pathways in the cancer cells results in increased survivability and durability of cancer cells.
• the therapeutics rather than killing the cancer cells, the therapeutics merely have the effect of arresting cancer tissue growth, with the cancer tissue entering a cystostatic phase upon treatment. Consequently, in some instances, the cancerous tissue is not killed during treatment, the growth is simply arrested. Upon cessation of treatment, the cancerous tissue is able to resume growth, thus increasing symptoms and complications for the patient.
• the addition of a therapeutic that disrupts autophagy has the effect of converting the cytostatic response of the cancer cells to cancer cell death.
• the changes in autophagy caused by the cancer are important for the survival of the cancer cells.
• these cells rely on autophagy to properly regulate the consumption of nutrients to ensure the survival of the cells in conditions that would cause the death of a healthy cel
• methods of inhibiting autophagy in cells present, in certain instances, a method of treating cancer without the need of an additional cancer therapeutic.
• methods of inhibiting autophagy in cells present, in certain instances, a method of treating cancer without the need of an additional cancer therapeutic.
• ULK1 and/or ULK2 are important proteins in regulating autophagy in mammalian cells.
• ULK1 and/or ULK2 are activated under conditions of nutrient deprivation by several upstream signals, which is followed by the initiation of autophagy.
• the requirement for ULK1 and/or ULK2 in autophagy initiation has been studied in the context of nutrient deprivation.
• ULK1 complex combining ULK1, ATG13, FIP200 (focal adhesion kinase family interacting protein of 200 kDa), and autophagy-related protein 101 (ATG101) is one of the first protein complexes that comes in to play in the initiation and formation of autophagosomes when an autophagic response is initiated.
• ULK1 is considered to be unique as a core conserved component of the autophagy pathway which is a serine/threonine kinase, making it a particularly unique target of opportunity for the development of compounds to control autophagy.
• mice genetically engineered to completely lack ULK1 are viable without significant pathology.
• a ULK1 selective kinase inhibitor is well tolerated by normal tissues, but not by tumor cells that have become reliant on ULK1 mediated autophagy for survival.
• ULK2 takes over the functional role of ULK1 when ULK1 function has been inhibited.
• an inhibitor that is effective for both ULK1 and ULK2 is desirable to mitigate this effect.
• the present disclosure provides compounds and salts, and formulations thereof, for use in treating various diseases.
• the compounds are ULK inhibitors.
• the compounds of the present disclosure are ULK1 inhibitors.
• the compounds of the present disclosure are specific ULK1 inhibitors.
• the compounds are inhibitors of both ULK1 and ULK2.
• the present disclosure provides a compound having a structure of Formula (I):
• R 1 is hydrogen, alkyl optionally substituted with one or more R 10 , or halogen
• each R 10 is independently halogen, -CN, or –OH.
• each R 20 is independently halogen, -CN, or –OH.
• a 1 is aryl or heteroaryl.
• a 1 is phenyl or pyridyl substituted with n R 4 substituents.
• a 1 is phenyl substituted with n R 4 substituents.
• a 1 is 6-membered heteroaryl substituted with n R 4 substituents. In some embodiments, A 1 is pyridyl substituted with n R 4 substituents. In some embodiments, A 1 is . In some embodiments, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 0 or 1. In some embodiments, n is 0.
• each R 30 is independently halogen, -CN, or –OH.
• a 2 is .
• X 2 is –NH-. In some embodiments, X 2 is –O-. In some embodiments, X 2 is absent. In some embodiments, X 2 is alkylene. In some embodiments, X 3 is-S-, –O- or –NR 5 -. In some embodiments, X 3 is –O- or –NR 5 -. In some embodiments, X 3 is –O- or –NH- In some embodiments, X 3 is –O-. In some embodiments, X 3 is absent. In some embodiments, X 3 is alkylene. In some embodiments, X 4 is-S-, –O- or –NR 5 -.
• X 4 is –O- or –NR 5 -. In some embodiments, X 4 is –O- or –NH-. In some embodiments, X 4 is –O-. In some embodiments, X 4 is absent. In some embodiments, X 4 is alkylene. In some embodiments, L is a chain of 3-12 atoms. In some embodiments, L is a chain of 3-12 atoms, wherein each atom in the chain is independently selected from –CR 6 R 7 - or -O- . In some embodiments, L is a chain of 3-8 atoms, wherein each atom in the chain is independently selected from –CR 6 R 7 - or -O-.
• each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, cycloalkyl, and heterocycloalkyl, are independently optionally substituted with one or more R 60 ; or adjacent R 6 are taken together to form a double bond.
• each R 6 and R 7 is independently hydrogen, C 1 -C 6 alkyl, or cycloalkyl; or adjacent R 6 are taken together to form a double bond.
• each R 6 and R 7 is independently hydrogen or adjacent R 6 are taken together to form a double bond.
• L is selected from (substituted or unsubstituted)
• R 1 is hydrogen, halogen, or haloalkyl (e.g., -CF 3 );
• R 1 is hydrogen or halogen.
• each R 20 is independently –OH, -O(C 1 -C 6 alkyl), C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 alkyl.
• X 1 is -O-, -NR 5 -, or –S-.
• R 5 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
• each R 31 , R 32 , R 33 , R 34 , R 41 , R 42 , R 43 , and R 44 is independently hydrogen, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 alkyl.
• L is a C 3 -C 8 alkylene chain.
• m is 0, 1, or 2.
• n is 0, 1 or 2.
• the compound is a pharmaceutically acceptable salt of a compound of Formula (Ia).
• ULK1 inhibition assays were performed in a 5 uL reaction volume containing 2 ug/mL recombinant human ULK1 protein (1-649, SignalChem #U01-11G) and 80 ug/mL myelin basic protein (MBP, Sigma-Aldrich #M1891) in the presence of 25 uM ATP (Sigma-Aldrich A7699). ULK 1 inhibition was assessed after one hour. Compounds were tested in triplicate in a 16-dose IC 50 mode with 3-fold serial dilution and a starting dose of 30 uM. Staurosporine, a non-selective protein kinase inhibitor, was used in the assay as a positive control. Three separate experiments were carried out.
• IC 50 s were also measured by ULK1 NanoBRET assay according to the following protocol: Human embryonic kidney cells (HEK293T) were transfected with NanoLuc®-ULK1 Fusion Vector (Promega #NV2211) using jetPRIME transfection reagent (Polyplus Transfection #114-15). Following 24 h, cells were trypsinized and resuspended in Opti-MEM® I (1X), Reduced Serum Medium (Gibco, #11058-021). Approximately, 7,000 cells per well (in 34 ⁇ L total volume) were replated into non-binding surface 384 well plates.
• NanoBRET 20X Tracer K-5 reagent was prepared according to the manufacturer’s directions and 2 ⁇ L were added to each well of the 384 plate (assay plate).
• the assay plate was mixed on an orbital shaker for 15 seconds at 700 rpm.
• Compounds were serially diluted at 200X final concentration in 100% DMSO, then diluted to 10X final concentration in assay media (Opti-MEM® I, Reduced Serum Medium).
• 4 ⁇ L 10x test compounds were added to each well of the assay plate, followed by mixing at 700 rpm for 15 seconds.
• the assay plate was incubated for 2 h in a 37 C incubator with 5% CO2 and then equilibrated to RT for 15 min.
• the invention provides salts of any one of the compounds described herein.
• Pharmaceutically-acceptable salts include, for example, acid-addition salts and base-addition salts.
• the acid that is added to the compound to form an acid-addition salt is an organic acid or an inorganic acid.
• a base that is added to the compound to form a base-addition salt is an organic base or an inorganic base.
• a pharmaceutically- acceptable salt is a metal salt.
• metal salts arise from the addition of an inorganic base to a compound of the invention.
• the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
• the metal is an alkali metal, alkaline earth metal, transition metal, or main group metal.
• the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
• a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
• ammonium salts arise from the addition of ammonia or an organic amine to a compound of the invention.
• the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine.
• an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N- methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, an imidazole salt, or a pyrazine salt.
• the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesul
• the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms.
• the compounds and salts presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, ‘Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.
• the compounds of the present invention may be administered in various forms, including those detailed herein.
• the treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds.
• this combination therapy is sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously.
• these are administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed.
• a “pharmaceutically acceptable carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human.
• the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
• Liposomes are also a pharmaceutically acceptable carrier.
• the dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.
• a dosage unit of the compounds used in the method of the present invention may comprise a single compound or mixtures thereof with additional agents.
• the compounds are administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
• the compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection, topical application, or other methods, into or onto a site of infection, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.
• the compounds used in the method of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles.
• Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
• the compounds may be administered as components of tissue-targeted emulsions.
• the compounds used in the method of the present invention may also be coupled to soluble polymers as targetable drug carriers or as a prodrug.
• soluble polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
• the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
• a class of biodegradable polymers useful in achieving controlled release of a drug
• a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
• Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
• ULK inhibitors are used and/or useful in the treatment of cancer and/or ULK mediated disorders. Surprisingly, in certain instances, ULK inhibitors are efficacious as a monotherapy. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2. In other instances, it is also surprising that ULK inhibitors are used/useful in augmenting or improving standard of care therapies.
• a method of treating a disease or disorder with a ULK inhibitor is administered alone to treat a disease or disorder.
• the method comprises administering to a subject in need thereof a therapeutically effective amount of a ULK inhibitor.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the ULK inhibitor is administered as a monotherapy. In some embodiments, the ULK inhibitor is the sole therapeutic agent administered to the patient for the treatment of the disease or disorder. In some embodiments, the ULK inhibitor is the sole anti-cancer agent administered to the patient. In some embodiments, the ULK inhibitor is administered as a monotherapy with additional inactive ingredients as part of a pharmaceutical formulation. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• the disease or disorder treated with a ULK inhibitor as a monotherapy is cancer.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the cancer is lung cancer.
• the lung cancer is NSCLC.
• the cancer is an advanced stage NSCLC.
• the cancer comprises a tumor.
• the NSCLC comprises a tumor.
• the NSCLC is characterized by abnormal autophagy.
• the lung cancer is refractory.
• the lung cancer is refractory to treatment with carboplatin.
• the NSCLC is refractory.
• the NSCLC is refractory to treatment with carboplatin.
• the lung cancer is characterized by cytostasis.
• the cancer is breast cancer.
• the breast cancer comprises a tumor.
• the breast cancer is characterized by abnormal autophagy.
• the breast cancer is refractory.
• the breast cancer is characterized by cytostasis.
• the breast cancer is TNBC.
• the method of treatment comprises decreasing phosphorylation of ATG13 in the subject. In some embodiments, the method comprises degrading ATG13 in diseased tissue of the subject. In some embodiments, administering the ULK inhibitor degrades ATG13.
• the subject comprises a mutation in at least one of KRAS, PTEN, TSC1, TSC2, PIk3CA, P53, STK11 (a.k.a. LKB 1 ), KE AP 1 , NRF2, ALK4, GNAS, or EGFR.
• the subject comprises a mutation in at least one of SMAD4, pl6/CDKM2A, or BRCA2.
• the combination therapies of the present invention comprise a ULK inhibitor and an additional therapeutic agent.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• there is an additional therapeutic benefit when compared to treatment with the additional therapeutic agent alone.
• the combination of the ULK inhibitor and the additional therapeutic agent shut down pathways of autophagy. This allows for enhanced cell death in diseased tissue, as the diseased cells will not be able to rely on autophagic processes for survival once the pathway is shut off with a ULK inhibitor.
• the addition of a ULK inhibitor allows for successful treatment of a disease that is otherwise refractory to treatment of the additional therapeutic agent by itself. In some embodiments, the addition of the ULK inhibitor enhances the efficacy of the additional therapeutic agent. In some embodiments, the addition of the ULK inhibitor has a synergistic effect with the additional therapeutic agent. In some embodiments, the additional therapeutic agent is a standard of care therapy.
• a method of treating a disease or disorder with a ULK inhibitor and an additional therapeutic agent comprises administering to a subject in need thereof a therapeutically effective amount of a ULK inhibitor. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a ULK inhibitor and a therapeutically effective amount of an additional therapeutic agent.
• the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• the additional therapeutic agent is FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), gemcitabine, or gemcitabine/abraxane.
• the additional therapeutic agent is capeditabine, leucovorin, nab-paclitaxel, nanoliposomal irinotecan, gemcitabine/nab-paclitaxel, pembrolizumab, or cisplatin.
• the additional therapeutic agent is capeditabine, leucovorin, nab-paclitaxel, nanoliposomal irinotecan, gemcitabine/nab-paclitaxel, pembrolizumab, or cisplatin.
• the pancreatic cancer is PDAC.
• the subject with pancreatic cancer comprises a mutation in at least one of SMAD4, pl6/CDKM2A, or BRCA2.
• the cancer is pancreatic cancer and the additional therapeutic agent is a standard of care therapy.
• the cancer is breast cancer. In some embodiments, the cancer is breast cancer and the additional therapeutic agent is a standard of care therapy. In some embodiments, the cancer is breast cancer and the additional therapeutic agent is anastrozole, exemestane, letrozole, or tamoxifen. In some embodiments, the cancer is breast cancer and the additional therapeutic agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib, or talazoparib. In some embodiments, the breast cancer is triple negative breast cancer (TNBC).
• TNBC triple negative breast cancer
• the cancer is lung cancer and the additional therapeutic agent is carboplatin. In some embodiments, the cancer is lung cancer and the additional therapeutic agent is a carboplatin analog. In some embodiments, the cancer is NSCLC and the additional therapeutic agent is carboplatin. In some embodiments, the cancer is NSCLC and the additional therapeutic agent is a carboplatin analog. In some embodiments, the carboplatin analog is cisplatin or dicycloplatin. In some embodiments, the cancer is lung cancer and the additional therapeutic agent is erlotinib, gefitinib, osimertinib, or crizotinib.
• the cancer is lung cancer and the additional therapeutic agent is gemcitabine, bortexomib, trastuzumab, vinorelbine, doxorubicin, irinotecan, temsirolimus, sunitinib, nivolumab, or bevacizumab.
• the cancer is lung cancer and the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/ doce taxel/be vac izumab.
• the cancer is NSCLC and the additional therapeutic agent is gemcitabine, bortexomib, trastuzumab, vinorelbine, doxorubicin, irinotecan, temsirolimus, sunitinib, nivolumab, or bevacizumab.
• the cancer is NSCLC and the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/docetaxel/bevacizumab, everolimus/nab-paclitaxel, or tremelimumab/durvalumab.
• the subject with lung cancer comprises a mutation in KRAS, PTEN, TSC1, TSC2, PIk3CA, P53, STK11 (a k a. LKB1), KEAP1,NRF2, ALK4, GNAS or EGFR.
• the additional therapeutic agent is erlotinib, gefitinib, osimertinib, or crizotinib. In some embodiments, the additional therapeutic agent is pemetrexed, docetaxol, or pembroluzimab. In some embodiments, the additional therapeutic agent is carboplatin/gemcitabine, carboplatin/paclitaxel/cetuximua, cisplatin/pemetrexed, cisplatin/docetaxel, cisplatin/docetaxel/bevacizumab, everolimus/nab-paclitaxel, or tremelimumab/durvalumab.
• the additional therapeutic agent is anastrozole, exemestane, letrozole, or tamoxifen. In some embodiments, the additional therapeutic agent is a PARP inhibitor. In some embodiments, the PARP inhibitor is olaparib, rucaparib, niraparib, or talazoparib.
• the additional therapeutic agent is gemcitabine, everolimus, erlotinib, or sunitinib.
• the additional therapeutic agent is a nucleoside analog.
• the additional therapeutic agent is capeditabine, leucovorin, nab-paclitaxel, nanoliposomal irinotecan, gemcitabine/nab-paclitaxel, pembrolizumab, or cisplatin.
• the additional therapeutic agent is gemcitabine. In some embodiments, the additional therapeutic agent is a nucleoside analog.
• the additional therapeutic agent is an mTOR inhibitor.
• the additional therapeutic agent is rapamycin.
• mTOR inhibitor is rapamycin, sirolimus, temsirolimus, everolimus, ridaforolimus, NVPBEZ235, BGT226, XL765, GDC0980, SF1 126, PKI587, PFO4691502, GSK2126458, INK128, TORKiCC223, OSI027, AZD8055, AZD2014, and Palomid 529, metformin, or AICAR (5-amino-l-P-D-ribofuranosyl- imidazole-4- carboxamide).
• the additional therapeutic agent is a rapamycin analog.
• the disease or disorder is lymphoangiomyoleiomatosis and the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the disease or disorder is tuberous sclerosis complex and the additional therapeutic agent is an mTOR inhibitor.
• the additional therapeutic agent was previously administered to the subject without a ULK inhibitor. In some embodiments, the additional therapeutic agent induces a cytostatic response. In some embodiments, the additional therapeutic agent induces a cytostatic response when administered without a ULK inhibitor. In some embodiments, the additional therapeutic agent induces a cytostatic response in disease tissue. In some embodiments, the additional therapeutic agent induces a cytostatic response in the diseased tissue when the additional therapeutic agent was administered without a ULK inhibitor. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK 1 and ULK2.
• the subject is treated with the additional therapeutic agent prior to treatment with the ULK inhibitor.
• treatment with the additional therapeutic agent is ceased prior to administration of the ULK inhibitor.
• treatment with the additional therapeutic agent produces a cytostatic response in diseased tissue.
• the ULK inhibitor and the additional therapeutic agent are administered concomitantly. In some embodiments, the ULK inhibitor and the additional therapeutic agent are administered together at the start of treatment. In some instances, the ULK inhibitor inhibits ULK1. In some instances, the ULK inhibitor is a ULK1 specific inhibitor. In some instances, the ULK inhibitor inhibits both ULK1 and ULK2.
• the disease or disorder is characterized by abnormal autophagy. In some embodiments, the abnormal autophagy is therapeutically induced. In some embodiments, the disease or disorder is refractory. In some embodiments, the disease or disorder is refractory to treatment with an additional therapeutic agent. In embodiments, the disease or disorder is resistant to treatment with an additional therapeutic agent.
• administering a ULK inhibitor slows progression of the disease or disorder. In some embodiments, administering a ULK inhibitor slows progression of the disease or disorder when compared to administration of the additional therapeutic agent with the ULK inhibitor. In some embodiments, administering a ULK inhibitor slows progression of the disease or disorder by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%.
• administering a ULK slows the progression of the disease or disorder by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% when compared to administration of the additional therapeutic agent without the ULK inhibitor.
• progression of the disease or disorder comprises growth of a tumor.
• progression is measured by tumor growth.
• administering a ULK inhibitor arrests cancer cell growth.
• administering a ULK inhibitor reduces tumor volume.
• the ULK inhibitor inhibits ULK1.
• the ULK inhibitor is a ULK1 specific inhibitor.
• the ULK inhibitor inhibits both ULK1 and ULK2.
• the method of treatment comprises decreasing phosphorylation of ATG13 in the subject. In some embodiments, the method comprises degrading ATG13 in diseased tissue of the subject. In some embodiments, administering a ULK inhibitor causes degradation of ATG13.
• the subject comprises a mutation in at least one of KRAS, PTEN, TSC1, TSC2, PIk3CA, P53, STK11 (a.k.a. LKB 1 ), KE AP 1 , NRF2, ALK4, GNAS, or EGFR.
• the subject comprises a mutation in at least one of SMAD4, pl6/CDKM2A, or BRCA2.
• Reactions were performed in oven-dried glassware under a nitrogen atmosphere with magnetic stirring. All solvents and chemicals were purchased from commercial sources and used without further purification unless specified. Reactions conducted under microwave irradiation were performed in a CEM Discover microwave reactor using 10 mL reaction vessels. Reaction progress was monitored by reverse-phase HPLC and/or thin-layer chromatography (TLC). Chromatographic purification was carried out using pre-packed silica or C18 cartridges (from RediSep and Luknova) and eluted using an ISCO Companion system. Reverse phase purifications were conducted using water and acetonitrile or methanol doped with 0.1% formic acid.
• DIPEA or DIEA N,N-diisopropylethylamine
• EDCI.HC1 l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride eq equivalent(s)
• HOBt hydroxybenzotriazole
• RP-HPLC reverse phase-high pressure liquid chromatography rt or RT room temperature
• the crude product (tert-butyl ((allyloxy)-methoxyphenyl)carbamate) was purified by automated normal phase chromatography (Method 1a).
• the Boc amino protecting group of the substituted aniline (tert-butyl ((allyloxy)-methoxyphenyl)carbamate) was removed by treatment with a solution of hydrochloric acid in dioxane (4 M) for 1 hour at room temperature, then concentrated in vacuo.
• the corresponding hydrochloride salt was treated with aqueous sat. NaHCO 3 (10 mL) and stirred for 20 min.
• the Boc protected aniline intermediate was prepared by reaction of tert-butyl (4-hydroxy-3-methoxyphenyl)carbamate (1.300 g, 5.43 mmol), allyl bromide (0.56 mL, 6.52 mmol), and potassium carbonate (2.253 g, 16.3 mmol) in acetonitrile (30 mL) for 20 hour according to Method 1a to provide tert-butyl (4-(allyloxy)-3-methoxyphenyl)carbamate as a white solid (1.490 g, 98%).
• the title compound was prepared by reaction of the Boc protected aniline intermediate tert- butyl (4-(allyloxy)-3-methoxyphenyl)carbamate (1.490 g, 5.33 mmol) and hydrochloic acid (10 mL, 40 mmol, 4 M in dioxane) for 1 hour and processed according to Method 2b to provide the title compound as a white solid (868 mg, 91%).
• LC-MS (ESI) calcd. for C 10 H 14 NO 2 [M+H] + : 180.10; found: 180.40. 3-(Allyloxy)-4-methoxyaniline.
• the hydrochloride salt was prepared by reaction of the Boc protected aniline intermediate tert-butyl (3-(allyloxy)-4-methoxyphenyl)carbamate (3.387 g, 12.13 mmol) and hydrochloic acid (8.0 mL, 32 mmol, 4 M in dioxane) for 1 hour and processed according to Method 2b to provide the hydrochloride salt of the title compound as a brown solid (2.384 mg, 91%).
• LC-MS (ESI) calcd. for C 10 H 14 NO 2 [M+H] + : 180.10; found: 180.40.
• the methyl ester intermediate was prepared by reaction of methyl 2-amino-4-hydroxybenzoate (1.100 g, 6.58 mmol), pent-4-en-1-ol (1.0 mL, 9.87 mmol), triphenylphosphine (2.598 mg, 9.87 mmol), and DEAD (1.55 mL, 9.87 mmol) in THF (11 mL) according to Method 2a to provide methyl 2-amino-4-(pent-4-en-1-yloxy)benzoate as a yellow solid (1.302 mg, 84%).
• LC-MS (ESI) calcd. for C 13 H 18 NO 3 [M+H] + : 236.13; found: 236.45.
• the title compound was prepared by reaction of 2-((2-((4-(allyloxy)-3-methoxyphenyl)amino)-5- (trifluoromethyl)pyrimidin-4-yl)amino)-5-(but-3-en-1-yloxy)-N-methylbenzamide (73.5 mg, 135 Pmol) with catalytic Grubs I catalyst (11 mg, 14 Pmol) in dichloromethane (270 mL) for a total of 36 hours according to Method 5 to provide: (E)-1 3 -methoxy-N-methyl-3 5 -(trifluoromethyl)-6,12-dioxa- 2,4-diaza-3(2,4)-pyrimidina-1,5(1,4)-dibenzenacyclododecaphan-9-ene-5 2 -carboxamide (white solid, 16 mg, 23%), LC-MS (ESI) calcd.

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