WO2024059525A2 - Composés et procédés pour la dégradation ciblée de la kinase du lymphome anaplasique et de la ros1 kinase - Google Patents

Composés et procédés pour la dégradation ciblée de la kinase du lymphome anaplasique et de la ros1 kinase Download PDF

Info

Publication number
WO2024059525A2
WO2024059525A2 PCT/US2023/073910 US2023073910W WO2024059525A2 WO 2024059525 A2 WO2024059525 A2 WO 2024059525A2 US 2023073910 W US2023073910 W US 2023073910W WO 2024059525 A2 WO2024059525 A2 WO 2024059525A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
methyl
phenyl
piperidin
dione
Prior art date
Application number
PCT/US2023/073910
Other languages
English (en)
Other versions
WO2024059525A3 (fr
Inventor
Guangdi Wang
Xianyou PENG
Original Assignee
Endotarget, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Endotarget, Inc. filed Critical Endotarget, Inc.
Publication of WO2024059525A2 publication Critical patent/WO2024059525A2/fr
Publication of WO2024059525A3 publication Critical patent/WO2024059525A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • ALK anaplastic lymphoma kinase
  • ROS ROS proto-oncogene 1
  • ALK anaplastic lymphoma kinase
  • ROS1 ROS protooncogene 1
  • ALK fusion proteins are seen in diffuse large B-cell lymphoma (DLBCL), inflammatory myofibroblastic tumor (IMT), breast cancer, colorectal cancer, esophageal squamous cell cancer (ESCC), renal cell cancer (RCC), and non-small-cell lung cancer (NSCLC).
  • ALK is an established therapeutic target for ALK+ non-small cell lung cancer and anaplastic large cell lymphoma.
  • ROS1 is an orphan receptor tyrosine kinase encoded by the ROS1 proto-oncogene (4).
  • ROS1 Chromosomal rearrangements joining the 3’ region of ROS1 , which encodes the kinase domain, with the 5’ region of partner genes produce constitutively active ROS1 fusion kinases. These fusions drive aberrant downstream signaling and transformation and are recurrent oncogenic drivers in human cancers (4).
  • ROS1 fusions are present in 1 % to 3% of advanced non-small cell lung cancer (NSCLC), in which CD74-ROS1 is the most prevalent fusion (5).
  • NSCLC advanced non-small cell lung cancer
  • TKIs small-molecule tyrosine kinase inhibitors
  • Crizotinib is a first generation ALK and ROS1 inhibitor currently used as the standard first- line therapy for patients with advanced NSCLC who have ALK or ROS1 rearrangements [3,5], However, most ALK-positive and ROS1-positive patients relapse on crizotinib within a few years as resistance develops.
  • Second-generation ALK and ROS1 TKIs have been developed to overcome crizotinib resistance, including three US Food and Drug Administration (FDA)-approved ALK and ROS1 inhibitors ceritinib, alectinib, brigatinib, entrectinib, and lorlatinib.
  • FDA US Food and Drug Administration
  • acquired resistance to second-generation ALK TKIs given as any line of treatment, inevitably develops and is mediated by on-target and off-target mechanisms.
  • About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one-third of lorlatinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic.
  • the compound ALK mutation (for instance, G1269A + 11171S/C1 156, G1202R + L1 196M/F1 174L, and L1 196M + D1203N), which is the main cause of lorlatinib resistance, is the most clinically important major unmet need.
  • ROS1-positive NSCLC the most common mechanism of resistance to crizotinib is ROS1 G2032R, the solvent front mutation identified in 30% to 40% of patients after crizotinib or lorlatinib progression.
  • Other clinically observed ROS1 resistance mutations include S1986F, S1986Y, F2004C, F2004I, F2004V, L2026M, D2033N, and G2101A [6-10],
  • compositions and methods for modulating the anaplastic lymphoma kinase and ROS1 kinase are provided.
  • novel bifunctional compounds and compositions useful for the degradation of a target protein by recruiting the target protein to an E3 ubiquitin ligase for degradation by the endogenous cellular ubiquitin proteasome system (UPS).
  • UPS endogenous cellular ubiquitin proteasome system
  • bifunctional compounds that facilitate targeted ubiquitination and degradation of ALK and ROS1 (target protein), and/or exhibit inhibition of ALK/ROS1 activities.
  • methods of making such compounds and compositions methods of using such compounds and compositions; pharmaceutical compositions comprising such compounds and compositions; and methods of using such pharmaceutical compositions, for the treatment or amelioration of a disease condition, such as cancer, especially non-small cell lung cancer.
  • the therapeutic compositions of a compound or multiple compounds that degrade and/or inhibit the target protein in a patient or subject, such as a human or animal can be used for treating or ameliorating disease conditions/states, e.g., non-small cell lung cancer, through modulation of wild-type ALK or mutant ALK.
  • Target Protein Ligand is capable of binding to the target protein ALK and ROS1
  • the Linker is a group that is covalently bonded to the Target Protein Ligand and the Degron
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., CRBN).
  • Another aspect of the present invention is a pharmaceutical composition containing a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • a further aspect of the present invention is a method of treating a disease involving aberrant ALK signaling, of administering a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • bifunctional compounds including bifunctional compounds that link an E3 ubiquitin ligase-binding moiety to a ligand that binds the targeted proteins is also disclosed herein.
  • composition comprising a compound of Formula (I).
  • the composition is a pharmaceutical composition.
  • the pharmaceutical composition comprises at least one compound of Formula (I) and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is suitable for oral administration. In one embodiment, the pharmaceutical composition is suitable for intravenous administration. In one embodiment, the pharmaceutical composition is suitable for intramuscular administration. In one embodiment, the pharmaceutical composition is suitable for parenteral administration.
  • the target protein is ALK.
  • the target protein is ROS1 .
  • Figure 1 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compound 6 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 2 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 4 and 5 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 3 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 11 and 52 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 4 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compound 82 in H2228 NSLC cells with EML4-ALK fusion gene.
  • FIG. 5 representative results demonstrating shows the dose-dependent degradation of ALK by exemplary compounds 87 and 109 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 6 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 72 and 26 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 7 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 110 and 184 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 8 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 62 and 185 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 9 shows representative results demonstrating the dose-dependent ALK degradation by exemplary compounds 109 and 110 in Karpas-299 anaplastic large cell lymphoma cells that carries the NPM-ALK fusion gene.
  • Figure 10 shows representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 112 and 186 in H2228 NSLC cells with EML4-ALK fusion gene.
  • FIG 11 representative results demonstrating the dose-dependent degradation of ALK by exemplary compounds 188 and 189 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 12 shows representative results demonstrating the dose-dependent ALK degradation by exemplary compounds 188 and 189 in Karpas-299 anaplastic large cell lymphoma cells that carries the NPM-ALK fusion gene.
  • Figure 13 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 109 and brigatinib in Karpas-299 anaplastic large cell lymphoma cells that carries the NPM-ALK fusion gene.
  • Figure 14 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 110 and brigatinib in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 15 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 111 and brigatinib in H2228 NSLC cells with EML4-ALK fusion gene.
  • Figure 16 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 111 and brigatinib in Karpas-299 anaplastic large cell lymphoma cells that carries the NPM-ALK fusion gene.
  • Figure 17 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 109, 111 and brigatinib in BaF3 cells expressing mutant ALK (11171 N) .
  • Figure 18 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 109, 111 and 188 in BaF3 cells expressing mutant ALK (G1202R).
  • Figure 19 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 111 and 188 in BaF3 cells expressing mutant ALK (11171N/D1203N).
  • Figure 20 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compound 111 and brigatinib in BaF3 cells expressing mutant ALK (G1202R/L1196M).
  • Figure 21 shows representative results demonstrating the dose-dependent ALK and phospho-ALK degradation by exemplary compounds 164 and 169 in BaF3 cells expressing mutant ALK (G1202R/L1196M).
  • Figure 22 shows representative results demonstrating the dose-dependent degradation of ROS1 and phospho-ROS1 by exemplary compound 111 and lorlatinib in BaF3 cells expressing SLC34A2-ROS1 fusion protein.
  • Figure 23 shows representative results demonstrating the dose-dependent degradation of ROS1 and phospho-ROS1 by exemplary compound 111 and lorlatinib in BaF3 cells expressing mutant SLC34A2-ROS1 (G2032R).
  • Figure 24 shows representative results demonstrating the dose-dependent degradation of ROS1 and phospho-ROS1 by exemplary compounds 164 and 169 in BaF3 cells expressing SLC34A2-ROS1 fusion protein.
  • Figure 25 shows representative results demonstrating the dose-dependent degradation of ROS1 and phospho-ROS1 by exemplary compounds 164 and 169 in BaF3 cells expressing mutant SLC34A2-ROS1 (G2032R).
  • Figure 26 shows representative results demonstrating the pharmacokinetic profile of compound 87 in Sprague Dawley rats.
  • Figure 27 shows representative results demonstrating the pharmacokinetic profile of compound 109 in Sprague Dawley rats.
  • Figure 28 shows representative results demonstrating the in vivo efficacy of Compound 109 in H2228 xenograft tumor inhibition.
  • Figure 29 shows representative results demonstrating the in vivo efficacy of Compound 109 in Karpas-299 xenograft tumor inhibition.
  • the bifunctional compounds described below modulate target proteins, anaplastic lymphoma kinase (ALK) and by eliminating the kinase protein via ubiquitination and subsequent proteasomal degradation to block ALK signaling.
  • the bifunctional compounds comprise one ligand that binds ALK and another ligand that binds to an E3 ubiquitin ligase. The two ligands are connected via a linker.
  • the bifunctional compounds can simultaneously bind ALK (target protein) and a cereblon (CRBN) E3 ubiquitin ligase, which promotes ubiquitination of ALK and leads to degradation of ALK by the proteasome.
  • Figure 3 shows the dose-dependent degradation of ALK by exemplary compounds 11 and 52 in H2228 NSLC cells with EML4-ALK fusion gene.
  • Compounds of the present invention bind competitively and/or non-competitively to ALK, and the E3 ubiquitin ligase, cereblon (CRBN) to effect ubiquitination and subsequent degradation of the ALK protein, thereby blocking the ALK signaling pathways and inhibiting the growth of ALK dependent cells.
  • the disclosure also relates to pharmaceutical compositions comprising these ALK degrading compounds, and methods for using the same for treatment of diseases and conditions mediated by ALK, including non-small cell lung cancer.
  • the invention provides the disclosed bifunctional compounds that may be applied to targeted degradation of ALK and ROS1 and may be used to treat or prevent diseases where ALK and ROS1 are dysregulated.
  • patient refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • the patient, subject or individual is a human.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • cancer refers to any of various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites and are likely to recur after attempted removal and to cause death of the patient unless adequately treated.
  • neoplasia comprises cancer.
  • Representative cancers include, for example, squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias, including non-acute and acute leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryoc
  • a disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.
  • minimize or “reduce”, or derivatives thereof, include a complete or partial degradation of a target protein (ALK or ROS1) and/or inhibition of a specified biological effect and/or reduction of ALK or ROS1 expression at the transcript or protein level, (which is apparent from the context in which the terms “minimize” or “reduce” are used).
  • inhibitor means to suppress or block an activity or function by at least about ten percent relative to a control value.
  • the activity is suppressed or blocked by 50% compared to a control value, more preferably by 75%, and even more preferably by 95% or more.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a disease or disorder contemplated herein, the signs or symptoms of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.
  • parenteral administration of a composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
  • the compounds according to the disclosure are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material.
  • reverse phase preparative HPLC of compounds of Formula (I) which possess a sufficiently basic or acidic functionality may result in the formation of a salt, such as, in the case of a compound of Formula (I) which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the disclosure which is sufficiently acidic, an ammonium salt for example.
  • Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the disclosure may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognize which solvates or inclusion complexes are acceptable to be used in subsequent biological assays.
  • salts of the compounds according to the disclosure including all inorganic and organic salts, especially all pharmaceutically acceptable inorganic and organic salts, particularly all pharmaceutically acceptable inorganic and organic salts customarily used in pharmacy.
  • salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NH 3 or organic amines having from 1 to 16 C-atoms such as, e.g., ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, ethylendiamine, N-methylpiperindine, arginine, lysine, and guanidinium salts.
  • the salts of the disclosed compounds include pharmaceutically acceptable waterinsoluble and, particularly, water-soluble salts.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • pharmaceutically acceptable salts refer to derivatives of the compounds disclosed herein wherein the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1 ,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic,
  • salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1 -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt may be 1 :1 , or any ratio other than 1 :1 , e.g., 3:1 , 2:1 , 1 :2, or 1 :3.
  • Salts of the compounds of Formulas (I) according to the disclosure can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic
  • the acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom.
  • the salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.
  • the compounds of Formula (I) as well as their salts may contain, e.g., when isolated in crystalline form, varying amounts of solvents. Included within the scope of the disclosure are therefore all solvates and in particular all hydrates of the compounds of Formula (I) according to this disclosure as well as all solvates and in particular all hydrates of the salts of the compounds of Formula (I) according to this disclosure.
  • Solvate means solvent addition forms that contain either stoichiometric or non- stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O.
  • tautomer refers to one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH conditions. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism arises as a result of the aldehyde group ( — CHO) in a sugar chain molecule reacting with one of the hydroxy groups ( — OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine.
  • the compounds of the disclosure may, depending on their structure, exist in different stereoisomeric forms. These forms include configurational isomers or optically conformational isomers (enantiomers and/or diastereoisomers including those of atropisomers).
  • the disclosure therefore includes enantiomers, diastereoisomers as well as mixtures thereof. From those mixtures of enantiomers and/or disastereoisomers pure stereoisomeric forms can be isolated with methods known in the art, preferably methods of chromatography, especially high-performance liquid chromatography (HPLC) using achiral or chiral phase.
  • HPLC high-performance liquid chromatography
  • the disclosure further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.
  • the compounds of the disclosure may, depending on their structure, exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms have been replaced with deuterium atoms, those in which one or more nitrogen atoms have been replaced with 15 N atoms, or those in which one or more atoms of carbon, fluorine, chlorine, bromine, sulfur, or oxygen have been replaced by the stable isotope of the respective, original atoms.
  • the term “pharmaceutical composition” refers to a mixture of at least one compound of Formula (I) with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • pharmacological composition,” “therapeutic composition,” “therapeutic formulation” or “pharmaceutically acceptable formulation” can mean, but is in no way limited to, a composition or formulation that allows for the effective distribution of an agent provided by the invention, which is in a form suitable for administration to the physical location most suitable for their desired activity, e.g., systemic administration.
  • Non-limiting examples of agents suitable for formulation with the compounds of Formula (I) include: cinnamoyl, PEG, phospholipids or lipophilic moieties, phosphorothioates, P- glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet-Riant and Tillement, 1999); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, D F et al, 1999) Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Schroeder et al, 1999).
  • P- glycoprotein inhibitors such as Pluronic P85
  • a “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of pathology disease or disorder, for the purpose of diminishing or eliminating those signs or symptoms.
  • the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and/or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying ortransporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying ortransporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound of Formula (I), and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound of Formula (I), and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • halo or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., Ci. s means one to six carbon atoms) and includes straight, branched chain, or cyclic substituent groups.
  • alkyl examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkyl unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl”, “haloalkyl” and “homoalkyl”.
  • substituted alkyls include, but are not limited to, 2,2-difluoroprop
  • cycloalkyl refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • the cycloalkyl group is saturated or partially unsaturated.
  • the cycloalkyl group is fused with an aromatic ring.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.
  • Polycyclic cycloalkyls include adamantine and norbornane.
  • cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include:
  • -O-CH 2 -CH 2 -CH3, -CH 2 -CH 2 -CH 2 -OH, -CH 2 -CH 2 -NH-CH 3 , -CH 2 -S-CH 2 -CH 3 , and -CH 2 CH 2 -S( O)-CH 3 .
  • Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or -CH 2 -CH 2 -S-S-CH 3 .
  • heteroalkyl refers to “alkoxy,” “alkylamino” and “alkylthio” that are used in their conventional sense, and refers to alkyl groups linked to molecules via an oxygen atom, an amino group, a sulfur atom, respectively.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • heterocycloalkyl refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N.
  • each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the heterocycloalkyl group is fused with an aromatic ring.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
  • a heterocycle may be aromatic or non-aromatic in nature.
  • the heterocycle is a heteroaryl.
  • An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine.
  • 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam.
  • 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
  • 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine.
  • Other non-limiting examples of heterocycloalkyl groups are:
  • non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1 ,2,3,6-tetrahydropyridine, 1 ,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized TT (pi) electrons, where n is an integer.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
  • aryl groups include phenyl, anthracyl, and naphthyl.
  • heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
  • a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moieties:
  • heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,3,4-triazolyl, tetrazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,3-oxadiazolyl, 1 ,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • polycyclic heterocycles and heteroaryls examples include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1 ,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1 ,8-naphthyridinyl, 1 ,4-benzodioxanyl, coumarin, dihydrocoumarin, 1 ,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1 ,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-,
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • substituted further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two. The substituents are independently selected, and substitution may be at any chemically accessible position.
  • the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two. In yet another embodiment, the substituents are independently selected from the group consisting of Ci. 6 alkyl, -OH, Ci. 8 alkoxy, halo, amino, acetamido and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of Ci. s alkyl, Ci. 6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with straight being preferred.
  • the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
  • the substituents are independently selected from the group consisting of Ci. s alkyl, -OH, Ci. 6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of Ci- 6 alkyl, Ci- 6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.
  • an analog is meant to refer to a chemical compound or molecule made from a parent compound or molecule by one or more chemical reactions.
  • an analog can be a structure having a structure similar to that of the small molecule therapeutic agents described herein or can be based on a scaffold of a small molecule therapeutic agents described herein, but differing from it in respect to certain components or structural makeup, which may have a similar or opposite action metabolically.
  • An analog or derivative can also be a small molecule that differs in structure from the reference molecule, but retains the essential properties of the reference molecule.
  • An analog or derivative may change its interaction with certain other molecules relative to the reference molecule.
  • An analog or derivative molecule may also include a salt, an adduct, tautomer, isomer, or other variant of the reference molecule.
  • the term “potency” refers to the dose needed to produce half the maximal response (ED 5 o).
  • the term “efficacy” refers to the maximal effect (E max ) achieved within an assay.
  • the Target Protein Ligand is capable of binding to the target protein ALK or ROS1 .
  • the Target Protein Ligand is capable of binding to the target protein ALK, and is of the structure of Formula (la) or Formula (lb):
  • R 4 is -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 .
  • R 5 is F, Cl, Br, I, CH 3 , CF 3 .
  • X 1 , X 2 , X 3 , X 4 , X 5 , X s , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 are each independently CH or N.
  • A is selected from:
  • the linker is a group that is covalently bonded to the Target Protein Ligand and the Degron.
  • the linker is an optionally substituted linking moiety comprising a branched or unbranched, cyclized or uncyclized, saturated or unsaturated chain of 5 to 16 carbon atoms in length.
  • the linker is an optionally substituted linking moiety.
  • the linker comprises a branched or unbranched, cyclized or uncyclized, saturated or unsaturated chain of 5 to 16 carbon atoms in length, or any combination thereof; wherein 1 to 6 of the carbon atoms are optionally replaced with a heteroatom.
  • each occurrence of the heteroatom is independently O, N, or S.
  • the linking moiety comprises a branched or linear C 5 to C alkyl, branched or linear amino-C 5 to C alkyl, branched or linear C 5 to Ci 6 alkoxy, branched or linear thio-C 5 to Ci 6 alkyl, C 5 to Cw cycloalkyl, amino-C 5 to Cw cycloalkyl, hydroxy- C 5 to C cycloalky, thio- C 5 to C cycloalkyl, or any combination thereof; wherein 1 to 6 of the carbon atoms are optionally replaced with a heteroatom.
  • each occurrence of the heteroatom is independently O, N, or S.
  • the linker is selected from:
  • the Degron is capable of binding to a ubiquitin ligase, such as an E3 ubiquitin ligase (e.g., CRBN).
  • a ubiquitin ligase such as an E3 ubiquitin ligase (e.g., CRBN).
  • the Degron is selected from the following structures:
  • a compound, or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof is selected from the group consisting of compounds presented in Table 1 and any combination thereof.
  • the compound of the present invention or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds presented in Table 1 and any combination thereof.
  • Antiproliferation in H2228 and BaF3 cells A: IC50 ⁇ 50 nM; B: 50 nM ⁇ IC 5 o ⁇ 200 nM; C: IC 5 o > 200 nM
  • ALK degradation (ALK DC50): A: ⁇ 50 nM; B: 50-200 nM; C: > 200 nM
  • ALK degradation (ALK D max ): A: >80%; B: >60%; C > 50%; D ⁇ 50%
  • ROS1 degradation (ROS1 DC50): A: ⁇ 50 nM; B: 50-200 nM; C: > 200 nM
  • ROS1 degradation (ROS1 D max ): A: >80%; B: >60%; C > 50%; D ⁇ 50%
  • composition which comprises a compound of Formula (I), ora derivative, tautomer, stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, or solvate thereof.
  • This specification also describes, in part, a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in reducing the level or activity of a target protein (e.g., anaplastic lymphoma kinase).
  • a target protein e.g., anaplastic lymphoma kinase
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in inhibiting a target protein (e.g., an ALK or ROS1 protein).
  • a target protein e.g., an ALK or ROS1 protein.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.
  • This specification also describes, in part, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
  • This specification also describes, in part, a method for treating cancer in a warmblooded animal in need of such treatment, which comprises administering to the warm-blooded animal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the disclosure provides for a pharmaceutical composition comprising at least one compound of one of Formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the pharmaceutical compound is for use in treatment of a proliferative disease, such as a cancer, for example, breast cancer.
  • a further embodiment may provide a method of treating breast cancer comprising administering to a subject in need of treatment or amelioration a compound according to any one of the preceding paragraphs.
  • a compound as presented above is used in the preparation of a medicament for treatment of breast cancer in a patient or subject, such as a human or animal.
  • compositions of the disclosure can be in any form known to those of skill in the art, and a suitable dosage form of the compound(s) can be administered by an appropriate route.
  • the pharmaceutical compositions are in a form of a product for oral delivery, said product form being selected from a group consisting of a concentrate, dried powder, liquid, capsule, pellet, and pill.
  • the pharmaceutical compositions of the disclosure are in the form of a product for parenteral administration including intravenous, intradermal, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal and subcutaneous administration.
  • the compounds described herein may be administered as a single dose or a divided dose over a period of time.
  • compositions disclosed herein may also further comprise carriers, binders, diluents, and excipients.
  • the described carriers, diluents and excipients may include dried corn starch or lactose, the binder may include microcrystalline cellulose, gum tragacanth or gelatin, in addition, the excipients may also include a dispersing agent, a lubricant, a glidant, a sweetening agent or a flavoring agent.
  • the disclosure provides a method of modulating a kinase, comprising contacting the kinase with a bifunctional compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, or with a pharmaceutical composition disclosed herein.
  • the kinase is ALK.
  • the kinase is ROS1 .
  • the disclosed compounds can be used to slow the rate of primary tumor growth.
  • the disclosed compounds can also be used to prevent, abate, minimize, control, and/or lessen tumor metastasis in humans and animals.
  • the disclosed compounds when administered to a subject in need of treatment can be used to stop the spread of cancer cells.
  • the compounds disclosed herein can be administered as part of a combination therapy with one or more drugs or other pharmaceutical agents.
  • the decrease in metastasis and reduction in primary tumor growth afforded by the disclosed compounds allows for a more effective and efficient use of any pharmaceutical or drug therapy being used to treat the patient.
  • control of metastasis by the disclosed compound affords the subject a greater ability to concentrate the disease in one location.
  • cancers that can be treated by the disclosed methods and compositions: Acute Lymphoblastic; Acute Myeloid Leukemia; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; Appendix Cancer; Basal Cell Carcinoma; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer; Osteosarcoma and Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Childhood; Central Nervous System Embryonal Tumors; Cerebellar Astrocytoma; Cerebral Astrocytotna/Malignant Glioma; Craniopharyngioma; Ependymoblastoma; Ependymoma; Medulloblastom
  • the methods for treating a clinical indication by the ALK/ROS1 degrading compounds disclosed herein may be effectuated by administering a therapeutically effective amount of the ALK/R0S1 degrading compounds to a patient in need thereof, this therapeutically effective amount may comprise administration of the prodrug to the patient at about 1 mg/kg/day, about 2 mg/kg/day, about 3 mg/kg/day, about 4 mg/kg/day, about 5 mg/kg/day, about 10 mg/kg/day and about 20mg/kg/day.
  • amounts ranging from about 0.001 mg/kg/day to about 0.01 mg/kg/day, or about 0.01 mg/kg/day to about 0.1 mg/kg/day, or about 0.1 mg/kg/day to about 1 mg/kg/day, or about 1 mg/kg/day to about 10 mg/kg/day, or about 10 mg/kg/day to about 100 mg/kg/day are also contemplated.
  • a further object of the disclosure is a kit, comprising a composition containing at least one ALK/ROS1 degrading compound for treatment and prevention of cancer and cancer related morbidities.
  • the composition of the kit may comprise at least one carrier, at least one binder, at least one diluent, at least one excipient, at least one other therapeutic agent, or mixtures thereof.
  • the kit may be designed, developed, distributed, or sold as a unit for performing the methods of the invention and to deliver the drugs to the targeted cells for the treatment and prevention of cancer and related diseases.
  • the kits may also include instructions to customers for proper usage of the kit to treat patients exhibiting the symptoms of the desired disease, e.g., breast cancer.
  • One aspect of the disclosure is the compounds disclosed herein as well as the intermediates as used for their synthesis, and the synthetic scheme for the preparation of the disclosed final compounds and the intermediates resulted before the final compound is generated.
  • Another object of the disclosure is to provide a composition, for example a pharmaceutical composition, comprising at least one ALK/ROS1 degrader compound in an amount effective for the indication of proliferative diseases such as cancer, including but not limited to breast cancer.
  • the object of such treatment is to degrade ALK and/or inhibit ALK- dependent proliferation of a cell. In a further embodiment, said object is to inhibit ALK-induced proliferation of a cell by a mechanism selected from ALK degradation. [00155] In an embodiment, the object of such treatment is to degrade ROS1 and/or inhibit ROS1 -dependent proliferation of a cell. In a further embodiment, said object is to inhibit ROS1- induced proliferation of a cell by a mechanism selected from ROS1 degradation.
  • treating means administering to a subject a pharmaceutical composition to ameliorate, reduce or lessen the symptoms of a disease.
  • “treating” or “treat” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a compound disclosed herein, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” may also include treatment of a cell in vitro or an animal model.
  • subject or “subjects” refers to any animal, such as mammals including rodents (e.g., mice or rats), dogs, primates, lemurs or humans.
  • Treating cancer may result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as “tumor regression.”
  • tumor size is reduced by about 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by about 10% or greater; more preferably, reduced by about 20% or greater; more preferably, reduced by about 30% or greater; more preferably, reduced by about 40% or greater; even more preferably, reduced by about 50% or greater; and most preferably, reduced by greater than about 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer may result in a reduction in tumor volume.
  • tumor volume is reduced by about 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by about 10% or greater; more preferably, reduced by about 20% or greater; more preferably, reduced by about 30% or greater; more preferably, reduced by about 40% or greater; even more preferably, reduced by about 50% or greater; and most preferably, reduced by about 75% or greater.
  • Tumor volume may be measured by any reproducible means of measurement.
  • Treating cancer may result in a decrease in number of tumors.
  • tumor number is reduced by about 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by about 10% or greater; more preferably, reduced by about 20% or greater; more preferably, reduced by about 30% or greater; more preferably, reduced by about 40% or greater; even more preferably, reduced by about 50% or greater; and most preferably, reduced by greater than about 75%.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification.
  • the specified magnification is 2*, 3*, 4*, 5*, 10*, or 50*.
  • Treating cancer may result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by about 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by about 10% or greater; more preferably, reduced by about 20% or greater; more preferably, reduced by about 30% or greater; more preferably, reduced by about 40% or greater; even more preferably, reduced by about 50% or greater; and most preferably, reduced by greater than about 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.
  • Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer may result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer may result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and most preferably, by more than about 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer may result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound disclosed herein, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • the mortality rate is decreased by more than about 2%; more preferably, by more than about 5%; more preferably, by more than about 10%; and most preferably, by more than about 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.
  • Treating cancer may result in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least about 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 45%; even more preferably, reduced by at least about 50%; and most preferably, reduced by at least about 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate may be measured according to a change in tumor diameter per unit time.
  • Treating cancer may result in a decrease in tumor regrowth, for example, following attempts to remove it surgically.
  • tumor regrowth is less than about 5%; more preferably, tumor regrowth is less than about 10%; more preferably, less than about 20%; more preferably, less than about 30%; more preferably, less than about 40%; more preferably, less than about 45%; even more preferably, less than about 50%; and most preferably, less than about 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • Treating or preventing a cell proliferative disorder may result in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 45%; even more preferably, by at least about 50%; and most preferably, by at least about 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • Treating or preventing a cell proliferative disorder may result in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least about 5%; more preferably, by at least about 10%; more preferably, by at least about 20%; more preferably, by at least about 30%; more preferably, by at least about 40%; more preferably, by at least about 45%; even more preferably, by at least about 50%; and most preferably, by at least about 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells may be equivalent to the mitotic index.
  • Treating or preventing a cell proliferative disorder may result in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least about 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 45%; even more preferably, reduced by at least about 50%; and most preferably, reduced by at least about 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • the size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • Treating or preventing a cell proliferative disorder may result in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least about 5% relative to its size prior to treatment; more preferably, reduced by at least about 10%; more preferably, reduced by at least about 20%; more preferably, reduced by at least about 30%; more preferably, reduced by at least about 40%; more preferably, reduced by at least about 45%; even more preferably, reduced by at least about 50%; and most preferably, reduced by at least about 75%.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • An abnormal cellular morphology may be measured by microscopy, e.g., using an inverted tissue culture microscope.
  • An abnormal cellular morphology may take the form of nuclear pleiomorphism.
  • the chemical entities described herein can be synthesized according to one or more illustrative schemes herein and/or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from about -10 °C. to about 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 200 °C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours.
  • Isolation and purification of the chemical entities and intermediates described herein can be implemented, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.
  • Step 1 tert-butyl 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)-5-isopropoxy-2-methylphenyl)-[1,4'-bipiperidine]-1 '-carboxylate
  • Step 1 tert-butyl (2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)-5-isopropoxy-2-methylphenyl)-[1 ,4'-bipiperidin]-T-yl)ethyl)carbamate
  • Step 2 N2-(4-( -(2-aminoethyl)-[1,4'-bipiperidin]-4-yl)-2-isopropoxy-5-methylphenyl)-5- chloro-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
  • Step 3 5-((2-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)- 5-isopropoxy-2-methylphenyl)-[1 ,4'-bipiperidin]-T-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1 ,3-dione
  • Step 1 tert-butyl 3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)azetidine-1 -carboxylate
  • Step 3 tert-butyl 3-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)azetidin-1-yl)methyl)azetidine-1- carboxylate
  • Step 5 5-(3-((3-(4-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)-5-isopropoxy-2-methylphenyl)piperidin-1-yl)azetidin-1-yl)methyl)azetidin-1-yl)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione
  • Step 2 (2-((2-((4-(4-(4-(4-(2-aminoethyl)piperazin-1-yl)piperidin-1-yl)-2-methoxyphenyl)amino) -5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • tert-butyl (2-(4-(1-(4-((5-chloro-4-((2- (dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidin-4- yl)piperazin-1-yl)ethyl)carbamate (0.25 g) in 5 mL of DCM was added 1 mL of 6M HCI in IPA at rt.
  • Step 3 5-((2-(4-(1-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl) amino)-3-methoxyphenyl)piperidin-4-yl)piperazin-1-yl)ethyl)amino)-2-(2,6-dioxopiperidin- 3-yl)isoindoline-1 ,3-dione
  • Step 6 (2-((2-((4-( [1 ,4'-bipiperidin]-4-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4- yl)amino)phenyl)dimethylphosphine oxide
  • Step 7 5-(4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-3-methoxyphenyl)-[1 ,4'-b i p i pe ri d i n] -1 '-yl)methyl)piperidin-1 -yl )-2-( 2 , 6- dioxopiperidin-3-yl)isoindoline-1 , 3-dione
  • Step 4 (2-((5-chloro-2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4- yl)amino)phenyl)dimethylphosphine oxide
  • Step 5 5-(4-((4-(4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-3-methoxyphenyl)piperazin-1 -yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1 ,3-dione
  • Step 5-1 5-(3-((4-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2- yl)amino)-3-methoxyphenyl)piperazin-1 -yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1 ,3-dione [00221] To a stirred suspension of (2-((5-chloro-2-((2-methoxy-4-(piperazin-1- yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1 10 mg, 0.2 mmol), 1-(2- (2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (120
  • Step 1 tert-butyl (R)-4-(4-(6-amino-5-(1-(5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)phenyl)ethoxy) pyridin-3-yl)-1H-pyrazol-1 -yl)piperidine-1-carboxylate
  • Step 3 5-(4-((4-(4-(4-(6-amino-5-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)pyridin- 3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1 ,3-dione
  • Step 1 (R)-3-(1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2 -amine
  • Step 4 5-(4-((4-((5-(6-amino-5-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)ethoxy) pyridin-3-yl)-4-methylthiazol-2-yl)methyl)piperazin-1 -yl)methyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1, 3-dione
  • Karpas 299 cells were obtained from Sigma-Aldrich (06072604- 1VL). Cells were maintained in RPMI 1640 (Life Technologies, Grand Island, NY) supplemented with 2mM Glutamine and 20% fetal bovine serum (FBS) culture. H2228 cells were obtained from American Type Culture Collection (ATCC, Manassas, VA) and were maintained in RPMI 1640 supplemented with 10% FBS culture, cells were plated in 24-well plates at a density of 105 cells/well. Media containing various drug concentrations were added on the day following plating (day 0) and allowed to incubate for 24 hours for Western blot. Media were removed and dishes were washed with 1 x DPBS.
  • Lysates were made by adding 150 pL of complete lysis solution and scraping cells into a 1 .5 mL microcentrifuge tube. Lysates were placed on a rotisserie at 4 °C for 30 min and then spun at 4 °C at 12000 ref for 10 min. Supernatants were assayed for protein content, snap-frozen, and stored a -80 °C if not run immediately. Then 50 pg of protein was subjected to Western blot protocol. Membranes were blocked and then incubated with 1 :200 dilution of ALK antibody at 4 °C overnight followed by 1 : 10000 dilution of secondary antibody for 1 h at room temperature. They were then imaged on a LICOR infrared scanner.
  • Figures 1 , 2, 3, 4, 5, 6, 7, 8, 9 show the ALK or ROS1 degradation efficacy of compounds 4, 5, 6, 1 1 , 26, 52, 62, 72, 82, 87, 109, 110, 1 11 , 112, 164, 169, 184, 185, 186, 188, 189 in H2228, Karpas 299, or engineered BaF3 cells at various concentrations.
  • Degradation of ALK or ROS1 was expressed as an DC 5 o value and was determined for exemplary compounds in Table 2 by calculation of the concentration of compound that was required to give a 50% reduction of ALK or ROS1 expression level.
  • Antiproliferative effect of the exemplary compounds was assessed in ALK positive or ROS1 positive cancer cell models.
  • H2228 cells harboring EML4-ALK variant 3b were treated with the indicated doses of exemplary compounds for 72 h, and the IC 5 o values were determined by an MTT assay. Data are presented as the mean ⁇ SD of duplicate independent experiments.
  • BaF3 cells expressing ALK, mutant ALK, ROS1 , and mutant ROS1 were treated with the indicated doses of exemplary compounds for 72 h, and the IC50 values were determined by an MTT assay. Data are presented as the mean ⁇ SD of duplicate independent experiments.
  • PG propylene glycol
  • PG propylene glycol
  • solutol 40%HP-b-CD in DI water (20:5:75 v:v) at a single dose of 10 mg/kg.
  • blood samples were collected from the tail vein of the rats at various time points into 1.5 mL microcentrifuge tubes containing 0.1 mL of 10 % EDTA anticoagulant. Plasma was then separated from cell pellets by centrifugation in a refrigerated centrifuge at 4 °C and transferred to a separate tube. Plasma samples were frozen at
  • Plasma samples were extracted with chloroform/methanol (2:1) using traditional Folch method for lipid extraction. Methanol (1 mL) and chloroform (2 mL) were added to each plasma sample followed by addition of 5 ng trans- Tamoxifen-13C2, 15N to each sample as the internal standard. The mixtures were stored at -20 °C overnight. Next the samples were sonicated for 5 min and centrifuged with a Thermo Scientific Heraeus Megafuge16 Centrifuge. The top layer was transferred to another test tube. The bottom layer was washed with 1 mL chloroform/methanol (2:1), centrifuged, and the solvent was transferred and combined with previous washings.
  • a binary mobile phase (A: water with 0.05% formic acid, B: acetonitrile with 0.05% formic acid) was used to achieve the gradient of initial 30% B for 1 min and then to 80% B at 8 min, to 100% B at 9 min, and returned to 30% B for 4 min.
  • the flow rate was controlled at 0.6 mL/min.
  • the settings of HESI source were as follows: spray voltage (3200 volt); vaporizer temperature (365 °C); sheath gas pressure (45 psi); auxiliary gas pressure (10 psi); capillary temperature (330 °C). Nitrogen was used as the sheath gas and axillary gas. Argon was used as the collision gas.
  • Figure 26 and 27 show the pharmacokinetic profile of exemplary compounds 87 and 109 in SD rats.
  • Tumors were established by subcutaneous injection of Karpas-299, H2228, or engineered Ba/F3 cells into the right flank of about 8-week-old NOD/SCID beige female mice (Jackson Laboratory). When the average tumor volume reached about 300 mm 3 , mice were randomized to the various treatment groups and administered vehicle or exemplary compounds. The following treatments were administered in cohorts of 6 mice for each treatment: vehicle alone, 25 mg/kg brigatinib, 10 mg/kg Compound 109, or 25 mg/kg Compound 109 was administered daily via oral gavage for 3 weeks. Tumor growth was monitored every other day by calipers and tumor volume was calculated using the equation: (1/2 (length x width2)).
  • Figure 28 and Figure 29 show the efficacy of Compound 109 in inhibiting H2228 and Karpas 299 xenograft tumor growth in mice.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés de formule (I) : ou un sel, un hydrate, un solvate, un promédicament, un stéréoisomère ou un tautomère pharmaceutiquement acceptable de ceux-ci, qui agissent en tant que fractions induisant une dégradation de protéine pour une kinase de lymphome anaplasique (ALK) et ROS1. Ces composés sont utiles dans des procédés pour la dégradation ciblée de ALK et ROS1 par l'utilisation des composés bifonctionnels qui lient une fraction de liaison à l'ubiquitine ligase à un ligand qui est capable de se lier à ALK et ROS1 qui peut être utilisé dans le traitement de troubles modulés par ALK et ROS1.
PCT/US2023/073910 2022-09-12 2023-09-12 Composés et procédés pour la dégradation ciblée de la kinase du lymphome anaplasique et de la ros1 kinase WO2024059525A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263375292P 2022-09-12 2022-09-12
US63/375,292 2022-09-12

Publications (2)

Publication Number Publication Date
WO2024059525A2 true WO2024059525A2 (fr) 2024-03-21
WO2024059525A3 WO2024059525A3 (fr) 2024-04-18

Family

ID=90275799

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/073910 WO2024059525A2 (fr) 2022-09-12 2023-09-12 Composés et procédés pour la dégradation ciblée de la kinase du lymphome anaplasique et de la ros1 kinase

Country Status (1)

Country Link
WO (1) WO2024059525A2 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210283261A1 (en) * 2017-12-05 2021-09-16 Icahn School Of Medicine At Mount Sinai Compositions and Methods for Treating ALK-Mediated Cancer
KR102538307B1 (ko) * 2017-12-13 2023-05-31 상하이테크 유니버시티 Alk 단백질 분해제 및 암 치료에서의 이의 용도
CA3109686A1 (fr) * 2018-09-27 2020-04-02 Dana-Farber Cancer Institute, Inc. Agents de degradation ciblant l'alk et leurs utilisations therapeutiques
WO2020147702A1 (fr) * 2019-01-17 2020-07-23 Betta Pharmaceuticals Co., Ltd Inhibiteurs d'egfr, compositions et procédés associés
GB201915618D0 (en) * 2019-10-28 2019-12-11 Univ Oslo ALK inhibitors for treatment of ALK-negative cancer and antibody-mediated diseases

Also Published As

Publication number Publication date
WO2024059525A3 (fr) 2024-04-18

Similar Documents

Publication Publication Date Title
US20230118795A1 (en) Aryl or heteroaryl pyridone or pyrimidine derivative, preparation method and use thereof
CA2771775C (fr) Composes et compositions en tant qu'inhibiteurs de proteine kinase
CA2819410C (fr) 2h-phthalazine-1-one substitues, procedes de preparation et leurs usages medicaux
CA3120791A1 (fr) Pyrimidine et derive heterocycle pentagonal de nitrogene, leur procede de preparation et applications medicales
US9890168B2 (en) 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof
CN113544128A (zh) Kras-g12c抑制剂
AU2018222073A1 (en) O-aminoheteroaryl alkynyl-containing compound, preparation method therefor, and use thereof
ES2951427T3 (es) Macrociclo que contiene aminopirazol y pirimidina y composición farmacéutica y uso del mismo
IL259711B (en) Methods for the preparation of protein kinase inhibitors and their medical use
HUE029275T2 (en) Phthalazinone ketone derivative, method of preparation and therapeutic use
WO2011124580A1 (fr) Composés pyrazol-4-yl-hétérocyclyle-carboxamide et leurs procédés d'utilisation
EP3556761B1 (fr) Composé hétérocyclique pyrrolo-aromatique, son procédé de préparation et son utilisation médicale
BRPI0613644A2 (pt) moduladores de tieno pirimidina e tieno pirimidina cinase
EA028175B1 (ru) Производные пиразолопирролидин-4-она в качестве ингибиторов вет и их применение при лечении заболевания
US11008318B2 (en) 2-phenylimidazo[4,5-b]pyridin-7-amine derivates useful as inhibitors of mammalian tyrosine kinase ROR1 activity
TWI785474B (zh) 用作選擇性Aurora A抑制劑的新型雜環化合物
US20230137175A1 (en) Compounds and methods for the targeted degradation of bruton's tyrosine kinase
WO2022188819A1 (fr) Modulateur de protéolyse sos1, son procédé de préparation et son application
CN118055933A (zh) 选择性parp1抑制剂及其应用
WO2023279041A1 (fr) Composés indazoles
CN114437116A (zh) 杂环化合物及其制备方法、药物组合物和应用
US20230295118A1 (en) Compounds and methods for the targeted degradation of cyclin dependent kinases
CN107428762A (zh) 酞嗪酮衍生物、其制备方法及用途
WO2024059525A2 (fr) Composés et procédés pour la dégradation ciblée de la kinase du lymphome anaplasique et de la ros1 kinase
KR101854117B1 (ko) 1,6-이치환된 인돌 화합물을 함유하는 약물 내성 및 부작용이 저감된 만성골수성백혈병 치료제

Legal Events

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

Ref document number: 23866370

Country of ref document: EP

Kind code of ref document: A2