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WO2025085580A1 - Inhibiteurs de kras(g12d) - Google Patents

Inhibiteurs de kras(g12d) Download PDF

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Publication number
WO2025085580A1
WO2025085580A1 PCT/US2024/051673 US2024051673W WO2025085580A1 WO 2025085580 A1 WO2025085580 A1 WO 2025085580A1 US 2024051673 W US2024051673 W US 2024051673W WO 2025085580 A1 WO2025085580 A1 WO 2025085580A1
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compound
formula
tautomer
pharmaceutically acceptable
derivative
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Inventor
Volodymyr KYSIL
Roman TIMAKHOV
Nikolay Savchuk
Alexei Pushechnikov
Aleksei RIAKHOVSKII
Alexander Khvat
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Windermere Therapeutics Inc
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Windermere Therapeutics Inc
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    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting KRAS(G12D).
  • Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with KRAS(G12D).
  • the present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of KRAS(G12D).
  • the present disclosure also provides agents with novel mechanisms of action toward KRAS(G12D) in the treatment of various types of diseases.
  • the present invention further provides methods of treating Cancer diseases, Endocrine diseases, Genetic diseases, Neuronal diseases, Respiratory diseases, Gastrointestinal diseases, Rare diseases, Metabolic diseases, Blood diseases, Immune diseases, Reproductive diseases, Skin diseases, Bone diseases, Cardiovascular diseases, Ear diseases, Eye diseases, Fetal diseases, Mental diseases, Nephrological diseases, Liver diseases, Bone diseases, Muscle diseases, Oral diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • a compound of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the present invention further provides methods of treating a disease, disorder, or condition selected from: Lung Cancer (LNCR); Pancreatic Cancer (PNCA); Colorectal Cancer (CRC); Adenocarcinoma; Gastric Cancer (GASC); Breast Cancer (BC); Noonan Syndrome 1 (NS1); Lung Cancer Susceptibility 3 (LNCR3); Ovarian Cancer (OC); Juvenile Myelomonocytic Leukemia (JMML); Leukemia, Acute Myeloid (AML); Cardiofaciocutaneous Syndrome 1 (CFC1); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Myeloma, Multiple (MM); Leukemia, Chronic Myeloid (CML); Lynch Syndrome (HNPCC); Hepatocellular Carcinoma (HCC); Melanoma; Prostate Cancer (PC); Esophageal Cancer (ESCR); Familial Adenomatous Polyposis (FAP); Costello Syndrome (CSTLO); Skin Melanoma; Gastrointestinal Strom
  • the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure).
  • a method for preparing compounds described herein e.g., a method comprising one or more steps described in General Procedure.
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.
  • the present disclosure provides a method of preparing compounds of the present disclosure.
  • the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein. [0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
  • an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon).
  • the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein.
  • substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, – OH, –CN, –COOH, –CH 2 CN, –O-(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C1-C6) haloalkoxy, –O-(C2-C6) alkenyl, –O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, —OH, –OP(O)(OH)2, –OC(O)(C1-C6) alkyl, –C(O)(C1-C6) alkyl, —O)(C1-C6) alkyl, —O
  • substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below. [0034] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment.
  • substituents include, but are not limited to, –H, -halogen, –O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, – O-(C2-C6)alkenyl, –O-(C2-C6) alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, –OH, – OP(O)(OH)2, –OC(O)(C1-C6)alkyl, –C(O)(C1-C6) alkyl, –OC(O)O(C1-C6)alkyl, —NH2, – NH((C 1 -C 6 )alkyl), –N((C 1 -C 6 )alkyl) 2 , –S(O) 2 -(C 1 -C 6 ) alkyl, –S(O)NH(C 1 -C 6 )alkyl, and — S(
  • the substituents can themselves be optionally substituted.
  • the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring.
  • Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.
  • heteroaryl means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C.
  • a polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like.
  • fused means two rings sharing two ring atoms.
  • spiro-fused means two rings sharing one ring atom.
  • Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2- yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyri
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring.
  • a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein.
  • the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo.
  • Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-d
  • Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.
  • Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, neo-pentyl, and iso-hexyl.
  • Alkoxy refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy groups.
  • Alkenyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
  • alkenyl groups examples include ethenyl, propenyl, n- butenyl, iso-butenyl, pentenyl, or hexenyl.
  • An alkenyl group can be unsubstituted or substituted.
  • Alkenyl, as herein defined, may be straight or branched.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain.
  • alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • alkylene or “alkylenyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C 1 -C 6 alkylene. An alkylene may further be a C1-C4 alkylene.
  • Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like.
  • Cycloalkyl means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl.
  • a polycyclic cycloalkyl comprises at least one non-aromatic ring.
  • cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.
  • Heterocyclyl mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic.
  • the heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted.
  • heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted with one or more halogen.
  • haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.
  • cyano as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C ⁇ N.
  • Spirocycloalkyl or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom.
  • the ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane.
  • One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring.
  • One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P).
  • a (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • spiroheterocycloalkyl is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).
  • solvate refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH.
  • Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers).
  • the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
  • the present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2 H and 14 C).
  • Deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • salts include, e.g., water- soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2- disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.
  • An effective amount when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • treating refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound
  • salt refers to pharmaceutically acceptable salts
  • pharmaceutically acceptable salt also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • KRAS(G12D) inhibitor refer to compounds of Formula (A) and/or compositions comprising a compound of Formula(A) which inhibits KRAS(G12D).
  • the amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose.
  • therapeutic agents e.g. compounds or compositions of Formula A (and/or additional agents) described herein
  • the therapeutic agents are given at a pharmacologically effective dose.
  • a pharmacologically effective amount, pharmacologically effective dose, “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease.
  • An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease.
  • administration of therapeutic agents to a subject suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival.
  • Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
  • Compounds of the Present Disclosure [0067]
  • the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: A), wherein W, Q, G, R 1 , , , , , , , , , scribed herein.
  • W, Q, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can each be, where applicable, selected from the groups described herein, and any group described herein for any W, Q, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R , R , R and R can be combined, where applicable, with any group described herein for one or more of the remainders of W, Q, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 .
  • the compounds of Formula (A) have the structure of Formula (I): I), or a pharmaceutic , isotopic derivative, or tautomer thereof, wherein Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as described herein.
  • Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 .
  • the compounds of Formula (A) have the structure of Formula (II):
  • Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 .
  • the compounds of Formula (A) have the structure of Formula (III): I), or a pharmaceuti , , , , isotopic derivative, or tautomer thereof, wherein Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as described herein.
  • Q, G, R , R , R , R , R , R 9 , R 10 and R 11 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, G, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 .
  • the compound is of Formula (I-A): R 6 A), or a pharmaceut isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1): 1), or a pharmaceu sotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a):
  • the compound is of Formula (I-A-1-a-I): F -I), or a pharma opic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-A): A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-A-1): 1), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-A-1-a): a), or a pha derivative, or tautomer thereof. [0082] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1-a-I):
  • the compound is of Formula (I-A-1-a-I-A-1-b): b), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-I-A-1-b-I): -I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-II): II), or a pharmac topic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-II-A): A), or a pharm pic derivative, or tautomer thereof. [0087] In some embodiments, the compound is of Formula (I-A-1-a-II-A-1):
  • the compound is of Formula (I-A-1-a-II-A-1-a): a), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-II-A-1-a-I): -I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-II-A-1-b): b), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-a-II-A-1-b-I): -I), or a pha derivative, or tautomer thereof. [0092] [0093] In some embodiments, the compound is of Formula (I-A-1-b):
  • the compound is of Formula (I-A-1-b-I): -I), or a pharma opic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-I-A): F A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-I-A-1): F 1), or a phar ic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-I-A-1-a): F a), or a phar c derivative, or tautomer thereof. [0098] In some embodiments, the compound is of Formula (I-A-1-b-I-A-1-a-I):
  • the compound is of Formula (I-A-1-b-I-A-1-a-II): F II), or a ph derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-I-B): F B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-I-B-1): F 1), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-I-B-1-a): a), or a pha derivative, or tautomer thereof. [0103] In some embodiments, the compound is of Formula (I-A-1-b-II):
  • the compound is of Formula (I-A-1-b-II-A): A), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-II-A-1): F 1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-II-A-1-a): F a), or a phar ic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-II-A-1-a-I): -b-II-A-1-a-I), or a phar rug, isotopic derivative, or tautomer thereof. [0108] In some embodiments, the compound is of Formula (I-A-1-b-II-A-1-a-II):
  • the compound is of Formula (I-A-1-b-II-B): B), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-II-B-1): F 1), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-1-b-II-B-1-a): a), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (I-B): B), or a pharmaceut isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1):
  • the compound is of Formula (I-B-1-a): a), or a pharmace otopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-I): F -I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-I-A): A), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-I-A-1): 1), or a phar c derivative, or tautomer thereof. [0118] In some embodiments, the compound is of Formula (I-B-1-a-I-A-1-a):
  • the compound is of Formula (I-A-1-a-I-A-1-a-I): -I), or a ph derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-I-A-1-b): b), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-I-A-1-b-I): -I), or a ph derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-II): II), or a pharmac topic derivative, or tautomer thereof. [0123] In some embodiments, the compound is of Formula (I-B-1-a-II-A):
  • the compound is of Formula (I-B-1-a-II-A-1): 1), or a phar ic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-II-A-1-a): a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-II-A-1-a-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-a-II-A-1-b): -a-II-A-1-b), or a phar g, isotopic derivative, or tautomer thereof. [0128] In some embodiments, the compound is of Formula (I-B-1-a-II-A-1-b-I):
  • the compound is of Formula (I-B-1-b): b), or a pharmace otopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-I): F -I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-I-A): F A), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-I-A-1): 1), or a phar c derivative, or tautomer thereof. [0133] In some embodiments, the compound is of Formula (I-B-1-b-I-A-1-a):
  • the compound is of Formula (I-B-1-b-I-A-1-a-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-I-A-1-a-II): F II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-I-B): F B), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-I-B-1): F 1), or a phar c derivative, or tautomer thereof. [0138] In some embodiments, the compound is of Formula (I-B-1-b-I-B-1-a):
  • the compound is of Formula (I-B-1-b-II): II), or a pharmac topic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-II-A): -b-II-A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-II-A-1): F 1), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-II-A-1-a): F a), or a phar ic derivative, or tautomer thereof. [0143] In some embodiments, the compound is of Formula (I-B-1-b-II-A-1-a-I):
  • the compound is of Formula (I-B-1-b-II-A-1-a-II): II), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-II-B): B), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-II-B-1): F 1), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-1-b-II-B-1-a): a), or a phar c derivative, or tautomer thereof. [0148] In some embodiments, the compound is of Formula (II-A):
  • the compound is of Formula (II-A-1): 1), or a pharmace sotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-a):
  • the compound is of Formula (II-A-1-a-I): -I), or a pharma opic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-a-I-A):
  • the compound is of Formula (II-A-1-a-I-A-1): 1), or a pha c derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-a-I-A-1-a):
  • the compound is of Formula (II-A-1-a-I-A-1-a-I): ve, [0156] In some embodiments, the compound is of Formula (II-A-1-a-I-A-1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0157] In some embodiments, the compound is of Formula (II-A-1-a-I-A-1-b-I): ve, [0158] In some embodiments, the compound is of Formula (II-A-1-a-II): II), or a pharmac topic derivative, or tautomer thereof. [0159] In some embodiments, the compound is of Formula (II-A-1-a-II-A):
  • the compound is of Formula (II-A-1-a-II-A-1): 1), or a phar ic derivative, or tautomer thereof. [0161] In some embodiments, the compound is of Formula (II-A-1-a-II-A-1-a):
  • the compound is of Formula (II-A-1-a-II-A-1-a-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-a-II-A-1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-a-II-A-1-b-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b): b), or a pharmace otopic derivative, or tautomer thereof. [0166] In some embodiments, the compound is of Formula (II-A-1-b-I):
  • the compound is of Formula (II-A-1-b-I-A): A), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-I-A-1):
  • the compound is of Formula (II-A-1-b-I-A-1-a): a), or a phar derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-I-A-1-a-I):
  • the compound is of Formula (II-A-1-b-I-A-1-a-II): I), or a ph derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-I-B):
  • the compound is of Formula (II-A-1-b-I-B-1): 1), or a pha c derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-I-B-1-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-I-C): C), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-I-C-1): ve, [0177] In some embodiments, the compound is of Formula (II-A-1-b-I-C-1-a):
  • the compound is of Formula (II-A-1-b-I-C-1-a-I): I), or a ph derivative, or tautomer thereof. [0179] In some embodiments, the compound is of Formula (II-A-1-b-I-C-1-a-I-A):
  • the compound is of Formula (II-A-1-b-II): II), or a pharmac topic derivative, or tautomer thereof. [0181] In some embodiments, the compound is of Formula (II-A-1-b-II-A):
  • the compound is of Formula (II-A-1-b-II-A-1): 1), or a pharm ic derivative, or tautomer thereof. [0183] In some embodiments, the compound is of Formula (II-A-1-b-II-A-1-a):
  • the compound is of Formula (II-A-1-b-II-A-1-a-I): -I), or a phar c derivative, or tautomer thereof. [0185] In some embodiments, the compound is of Formula (II-A-1-b-II-A-1-a-II):
  • the compound is of Formula (II-A-1-b-II-B): B), or a pharm pic derivative, or tautomer thereof. [0187] In some embodiments, the compound is of Formula (II-A-1-b-II-B-1):
  • the compound is of Formula (II-A-1-b-II-B-1-a): a), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-II-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-II-C-1): 1), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1-b-II-C-1-a): a), or a phar c derivative, or tautomer thereof. [0192] In some embodiments, the compound is of Formula (II-A-1-b-II-C-1-a-I):
  • the compound is of Formula (II-A-1-b-II-C-1-a-I-A): A), or a rivative, or tautomer thereof.
  • the compound is of Formula (II-A-2):
  • the compound is of Formula (II-A-2-a): a), or a pharmace otopic derivative, or tautomer thereof. [0196] In some embodiments, the compound is of Formula (II-A-2-a-I):
  • the compound is of Formula (II-A-2-a-I-A): A), or a phar ic derivative, or tautomer thereof. [0198] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1):
  • the compound is of Formula (II-A-2-a-I-A-1-a): ve, [0200] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1-a-I):
  • the compound is of Formula (II-A-2-a-I-A-1-b): b), or a pha derivative, or tautomer thereof. [0202] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1-b-I):
  • the compound is of Formula (II-A-2-a-II): II), or a pharmac topic derivative, or tautomer thereof. [0204] In some embodiments, the compound is of Formula (II-A-2-a-II-A):
  • the compound is of Formula (II-A-2-a-II-A-1): 1), or a phar ic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-a-II-A-1-a):
  • the compound is of Formula (II-A-2-a-II-A-1-a-I): ve, [0208] In some embodiments, the compound is of Formula (II-A-2-a-II-A-1-b):
  • the compound is of Formula (II-A-2-a-II-A-1-b-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b):
  • the compound is of Formula (II-A-2-b-I): -I), or a pharma opic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-I-A):
  • the compound is of Formula (II-A-2-b-I-A-1): 1), or a phar ic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-I-A-1-a):
  • the compound is of Formula (II-A-2-b-I-A-1-a-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-I-A-1-a-II):
  • the compound is of Formula (II-A-2-b-I-B): B), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-I-B-1):
  • the compound is of Formula (II-A-2-b-I-B-1-a): a), or a ph derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-I-C):
  • the compound is of Formula (II-A-2-b-I-C-1): ve, [0222] In some embodiments, the compound is of Formula (II-A-2-b-I-C-1-a):
  • the compound is of Formula (II-A-2-b-I-C-1-a-I): -I), or a ph derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-I-C-1-a-I-A):
  • the compound is of Formula (II-A-2-b-II): II), or a pharmac topic derivative, or tautomer thereof. [0226] In some embodiments, the compound is of Formula (II-A-2-b-II-A):
  • the compound is of Formula (II-A-2-b-II-A-1): 1), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-II-A-1-a):
  • the compound is of Formula (II-A-2-b-II-A-1-a-I): -I), or a phar c derivative, or tautomer thereof. [0230] In some embodiments, the compound is of Formula (II-A-2-b-II-A-1-a-II):
  • the compound is of Formula (II-A-2-b-II-B): B), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-II-B-1):
  • the compound is of Formula (II-A-2-b-II-B-1-a): a), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-II-C):
  • the compound is of Formula (II-A-2-b-II-C-1): 1), or a pharm ic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-II-C-1-a):
  • the compound is of Formula (II-A-2-b-II-C-1-a-I): -I), or a pha derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2-b-II-C-1-a-I-A):
  • the compound is of Formula (II-B): B), or a pharmaceut isotopic derivative, or tautomer thereof. [0240] In some embodiments, the compound is of Formula (II-B-1):
  • the compound is of Formula (II-B-1-a): a), or a pharmace otopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-a-I):
  • the compound is of Formula (II-B-1-a-I-A): A), or a pharm ic derivative, or tautomer thereof. [0244] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1):
  • the compound is of Formula (II-B-1-a-I-A-1-a): ve, [0246] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-a-I-A-1-b): ve, [0248] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1-b-I): -I), or a ph derivative, or tautomer thereof. [0249] In some embodiments, the compound is of Formula (II-B-1-a-II):
  • the compound is of Formula (II-B-1-a-II-A): A), or a pharm pic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-a-II-A-1):
  • the compound is of Formula (II-B-1-a-II-A-1-a): a), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-a-II-A-1-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-a-II-A-1-b): b), or a phar c derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-a-II-A-1-b-I): -I), or a pha derivative, or tautomer thereof. [0256] In some embodiments, the compound is of Formula (II-B-1-b):
  • the compound is of Formula (II-B-1-b-I): -I), or a pharma opic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-b-I-A):
  • the compound is of Formula (II-B-1-b-I-A-1): 1), or a phar ic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1-b-I-A-1-a):
  • the compound is of Formula (II-B-l-b-I-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-I-A-l-a-II):
  • the compound is of Formula (II-B-l-b-I-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-I-B-1):
  • the compound is of Formula (II-B-l-b-I-B-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-I-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1 -b-I-C-1 ): or tautomer thereof.
  • the compound is of Formula (II-B-l-b-I-C-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1 -b-I-C-1 -a-I):
  • the compound is of Formula (II-B-l-b-I-C-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-1 -b-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-A-1):
  • the compound is of Formula (II-B-l-b-II-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-A-l-a-I):
  • the compound is of Formula (II-B-l-b-II-A-l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-B):
  • the compound is of Formula (II-B-l-b-II-B-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-B-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-C-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-C-1 -a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-C-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-l-b-II-C-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-a):
  • the compound is of Formula (II-B-2-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-a-I-A):
  • the compound is of Formula (II-B-2-a-I-A-l-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-a-II-A-l):
  • the compound is of Formula (II-B-2-a-II-A-l-a-I):
  • the compound is of Formula (II-B-2-a-II-A- l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-a-II-A-l-b-I):
  • the compound is of Formula (II-B-2-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I):
  • the compound is of Formula (II-B-2-b-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I-A-l):
  • the compound is of Formula (II-B-2-b-I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I-A-l-a-I):
  • the compound is of Formula (II-B-2-b-I-A- l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I-B):
  • the compound is of Formula (II-B-2-b-I-B-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I-B-l-a):
  • the compound is of Formula (II-B-2-b-I-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I-C-l):
  • the compound is of Formula (II-B-2-b-I-C-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-I-C-l-a-I):
  • the compound is of Formula (II-B-2-b-I-C-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
  • the compound is of Formula (II-B-2-b-II):
  • the compound is of Formula (II-B-2-b-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-A-l):
  • the compound is of Formula (II-B-2-b-II-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-A-l-a-I):
  • the compound is of Formula (II-B-2-b-II-A- l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-B):
  • the compound is of Formula (II-B-2-b-II-B-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-B-l-a):
  • the compound is of Formula (II-B-2-b-II-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-C-l):
  • the compound is of Formula (II-B-2-b-II-C-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-C-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-2-b-II-C-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A):
  • the compound is of Formula (III-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-I-A-1):
  • the compound is of Formula (III-A-l-a-I-A-l-a): or tautomer thereof.
  • the compound is of Formula (III-A-l-a-I-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-I-A-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-I-A-l-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-II):
  • the compound is of Formula (III-A-l-a-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-II-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-II-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-II-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-a-II-A-l-b):
  • the compound is of Formula (III-A-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A- 1-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A- 1-b-I- A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A- 1-b-I-A-l):
  • the compound is of Formula (III-A-l-b-I-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-I-A-l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II- A):
  • the compound is of Formula (III-A-l-b-II-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II-A-1 -a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II-A-l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II-B):
  • the compound is of Formula (III-A- 1 -b-II-B-1 ): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-A-l-b-II-B-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-1 -a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I-A-l-a): or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I-A-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-I-A-l-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-II):
  • the compound is of Formula (III-B-l-a-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-II-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-II-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-II-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-a-II-A-l-b):
  • the compound is of Formula (III-B-1 -a-II-A-1 -b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-I-A-1):
  • the compound is of Formula (III-B-l-b-I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-I-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-I-A-l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-1 -b-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-II-A):
  • the compound is of Formula (III-B-1 -b-II-A-1 ): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-1 -b-II-A-1 -a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-II-A-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-II-A-l-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-II-B):
  • the compound is of Formula (III-B-1 -b-II-B-1 ): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III-B-l-b-II-B-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (A).
  • the compound is of Formula (I).
  • the compound is of Formula (II).
  • the compound is of Formula (III).
  • the compound is of Formula (A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • W is CHR w , wherein R w and R 5 together form a double bond.
  • W is NH.
  • Q is selected from CR q and N, wherein R q is halogen.
  • Q is CR q , wherein R q is halogen.
  • Q is CF.
  • R 1 is selected from H, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.
  • R 1 is H. [0418] In some embodiments, R 1 is halogen. [0419] In some embodiments, R 1 is F. [0420] In some embodiments, R 2 is C 1 -C 6 alkyl. [0421] In some embodiments, R 2 is methyl. [0422] In some embodiments, R 3 is selected from H and C1-C6 alkyl. [0423] In some embodiments, R 3 is H. [0424] In some embodiments, R 3 is C 1 -C 6 alkyl.
  • R 4 is selected from H and C1-C6 alkyl.
  • R 4 is H.
  • R 4 is C 1 -C 6 alkyl.
  • R 5 is selected from H, C 1 -C 6 alkyl.
  • R 5 is H.
  • R 5 is C1-C6 alkyl.
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, wherein W is NH.
  • R 6 is H.
  • R 6 is F.
  • R 6 is -CHF2.
  • R 4 is H, W is CHR w , wherein R w and R 5 together form a double bond, R 6 is F.
  • R 4 is H, W is CHR w , wherein R w and R 5 together form a double bond, R 6 is F.
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, W is NH, R 6 is -CHF2.
  • R 4 is H
  • R 5 is H
  • R 6 is H.
  • R 7 is selected from -NH 2 and -SH.
  • R 7 is -NH 2 .
  • R 7 and R g together with the atoms to which they are attached and any intervening atoms, form a 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, -NH2, CN, C1-C6 alkyl, C1-C6 alkoxy.
  • R 7 and R g together with the atoms to which they are attached and any intervening atoms form a 5 membered heteroaryl comprising two nitrogen atoms, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, -NH2, CN, C1-C6 alkyl, C1-C6 alkoxy.
  • R 7 and R g together with the atoms to which they are attached and any intervening atoms form a 5 membered heteroaryl comprising two nitrogen atoms.
  • R 7 and R g together with the atoms to which they are attached and any intervening atoms form a 5 membered heteroaryl comprising S and N atoms, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, -NH2, CN, C1-C6 alkyl, C1-C6 alkoxy.
  • R 7 and R g together with the atoms to which they are attached and any intervening atoms form a 5 membered heteroaryl comprising S and N atoms, wherein the heteroaryl is optionally substituted with one -NH2.
  • R 8 is selected from H, halogen. [0452] In some embodiments, R 8 is H. [0453] In some embodiments, R 8 is halogen. [0454] In some embodiments, R 8 is F. [0455] In some embodiments, R 9 is selected from H, halogen, C1-C6 alkyl. [0456] In some embodiments, R 9 is H. [0457] In some embodiments, R 9 is halogen. [0458] In some embodiments, R 9 is F. [0459] In some embodiments, R 9 is C1-C6 alkyl. [0460] In some embodiments, R 9 is methyl.
  • R 10 is selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen.
  • R 10 is H.
  • R 10 is C 1 -C 6 alkyl.
  • R 10 is methyl.
  • R 10 is C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen.
  • R 10 is methyl, wherein the alkyl is optionally substituted with one or more halogen .
  • R 10 is -CF 3 .
  • R 9 and R 10 together with the atoms to which they are attached and any intervening atoms, form a 6 membered aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl.
  • R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a 6 membered aryl, wherein the aryl is substituted with one halogen atom and one C 2 -C 6 alkynyl group.
  • R 9 and R 10 together with the atoms to which they are attached and any intervening atoms form a substituted 6 membered ar .
  • R 11 is selected from H, halogen.
  • R 11 is H
  • R 11 is halogen.
  • R 11 is F.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof. [0476] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0477] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0478] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0479] In some embodiments, the compound is selected from the compounds described in Table 1. [0480] Table 1.
  • the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.
  • the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1.
  • Table 2 Pharmaceutical acceptable acid forming salts with the Compound of Formulas (A).
  • the compound is a salt of adipic acid and any one of the compounds described in Table 1.
  • the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.
  • the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.
  • the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.
  • the compound is a salt of citric acid and any one of the compounds described in Table 1.
  • the compound is a salt of glutamic acid and any one of the compounds described in Table 1.
  • the compound is a salt of oxalic acid and any one of the compounds described in Table 1.
  • the compound is a salt of formic acid and any one of the compounds described in Table 1.
  • the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.
  • the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is an isotopic derivative of any one of the compounds described in Table 1.
  • the isotopic derivative can be prepared using any of a variety of art-recognized techniques.
  • the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the isotopic derivative is a deuterium labeled compound.
  • the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.
  • isotopic derivative refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled.
  • an isotopic derivative of a compound of Formula (A), (I), (II), (III) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (A), (I), (II), (III).
  • the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2 H, 13 C, 14 C, 15 N, 18 O, 29 Si, 31 P, and 34 S.
  • the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2 H with regard to one or more atoms thereof).
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is a deuterium labeled compound of any one of the compounds described in Table 1.
  • the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.
  • the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.
  • the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a deuterium labeled reagent for a non- deuterium labeled reagent.
  • a compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure.
  • the compound is a 18 F labeled compound.
  • the compound is a 33 S labeled compound, a 34 S labeled compound, a 35 S labeled compound, a 36 S labeled compound, or any combination thereof. .
  • the 18 F, 33 S, 34 S, 35 S, and/or 36 S labeled compound can be prepared using any of a variety of art-recognized techniques.
  • the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a 18 F, 33 S, 34 S, 35 S, and/or 36 S labeled reagent for a non-isotope labeled reagent.
  • a compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18 F, 33 S, 34 S, 35 S, and 36 S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,, 18 F, 33 S, 34 S, 35 S, and/or 36 S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
  • the various functional groups and substituents making up the compounds of the Formula (I) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”
  • chiral center refers to a carbon atom bonded to four nonidentical substituents.
  • chiral isomer means a compound with at least one chiral center.
  • Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.”
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
  • geometric isomer means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • atropic isomers are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.
  • tautomer is 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 tautomerisation 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. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed.
  • An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory (/. ⁇ ?., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
  • the compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (,S')-stereoi somers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.
  • the present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.
  • any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable.
  • a salt for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., tri fluoroacetate).
  • the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt.
  • a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein.
  • Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethyl ammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting examples of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • 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 H2O.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.
  • bioisostere refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based.
  • carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.
  • solvated forms such as, for example, hydrated forms.
  • a suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.
  • keto-, enol-, and enolate-forms examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci -nitro.
  • keto enol enolate examples include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci -nitro.
  • a reference herein to a compound of Formula (A) that contains an amine function also includes the A-oxide.
  • a reference herein to a compound of Formula (A) that contains an amine function also includes the A-oxide.
  • one or more than one nitrogen atom may be oxidised to form an A-oxide.
  • Particular examples of A-oxides are the A-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • A-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g.
  • A-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.
  • mCPBA meta-chloroperoxybenzoic acid
  • the compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure.
  • a prodrug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the disclosure.
  • a prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.
  • the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof.
  • An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(Ci-C(, alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups
  • Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(Ci-C(, alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ⁇ -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C 1-4 alkylamine such as methylamine, a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C 1 -C 4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.
  • an amine such as ammonia
  • a C 1-4 alkylamine such as methylamine
  • a (C 1 -C 4 alkyl) 2 amine such as dimethylamine, N- ethyl-N-methylamine or
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-1-ylmethyl and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.
  • the in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).
  • the compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.
  • the compounds of Formula (A) and in particular of Formula (I), (II), (III) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999).
  • the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below.
  • Compounds of the present invention can be synthesized by following the steps outlined in General Procedures which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.
  • All reagents may be commercially available compounds itself or products of synthesis from commercially available reagents. For preparation these reagents may be used one step or multi step synthetic procedures, including but not limited procedures described herein in preparative part.
  • Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity.
  • the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.
  • high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below. [0561] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.
  • in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-fdled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • any suitable solubility enhancing agent can be used.
  • a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P- cyclodextrin, ethylated-P-cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P- cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulfated P- cyclodextrin (S-P-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenedi aminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • any suitable preservative can be used.
  • a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine
  • examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenyl
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the formulation may further comprise a wetting agent.
  • wetting agents include those selected from the group consisting of polyoxypropylenepolyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
  • a therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a KRAS(G12D) related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • a therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an KRAS(G12D) related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of present disclosure will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well- known principles of medicine.
  • the present disclosure provides a method of inhibiting of KRAS(G12D) (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • the disease or disorder is associated with KRAS(G12D). In some embodiments, the disease or disorder is a disease or disorder in which KRAS(G12D) is implicated.
  • the compounds of the invention are also useful in treating diseases associated with KRAS(G12D).
  • diseases and conditions treatable according to the methods of the invention include Lung Cancer (LNCR); Pancreatic Cancer (PNCA); Colorectal Cancer (CRC); Adenocarcinoma; Gastric Cancer (GASC); Breast Cancer (BC); Noonan Syndrome 1 (NS1); Lung Cancer Susceptibility 3 (LNCR3); Ovarian Cancer (OC); Juvenile Myelomonocytic Leukemia (JMML); Leukemia, Acute Myeloid (AML); Cardiofaciocutaneous Syndrome 1 (CFC1); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Myeloma, Multiple (MM); Leukemia, Chronic Myeloid (CML); Lynch Syndrome (HNPCC); Hepatocellular Carcinoma (HCC); Melanoma; Prostate Cancer (PC); Esophageal Cancer (ESCR); Familial Adenomatous Polyposis (FAP); Cost
  • the compounds of the invention are also useful in treating diseases associated with KRAS(G12D).
  • diseases and conditions treatable according to the methods of the invention include Lung Cancer (LNCR); Pancreatic Cancer (PNCA); Colorectal Cancer (CRC); Adenocarcinoma; Gastric Cancer (GASC); Breast Cancer (BC); Noonan Syndrome 1 (NS1); Lung Cancer Susceptibility 3 (LNCR3); Ovarian Cancer (OC); Juvenile Myelomonocytic Leukemia (JMML); Leukemia, Acute Myeloid (AML); Cardiofaciocutaneous Syndrome 1 (CFC1); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Myeloma, Multiple (MM); Leukemia, Chronic Myeloid (CML); Lynch Syndrome (HNPCC); Hepatocellular Carcinoma (HCC); Melanoma; Prostate Cancer (PC); Esophageal Cancer (ESCR); Familial Adenomatous Polyposis (FAP); Cost
  • the disease or disorder is a Lung Cancer (LNCR).
  • LNCR Lung Cancer
  • the disease or disorder is a Pancreatic Cancer (PNCA).
  • PNCA Pancreatic Cancer
  • the disease or disorder is a Colorectal Cancer (CRC).
  • CRC Colorectal Cancer
  • the present disclosure provides a method of treating or preventing a Lung Cancer (LNCR) in a subj ect in need thereof, compri sing administering to the subj ect a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • LNCR Lung Cancer
  • the present disclosure provides a method of treating a Lung Cancer (LNCR) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • LNCR Lung Cancer
  • the present disclosure provides a method of treating a Pancreatic Cancer (PNCA) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • PNCA Pancreatic Cancer
  • the present disclosure provides a method of treating or preventing a Colorectal Cancer (CRC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • CRC Colorectal Cancer
  • the present disclosure provides a method of treating a Colorectal Cancer (CRC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.
  • CRC Colorectal Cancer
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of KRAS(G12D) (e.g., in vitro or in vivo).
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Lung Cancer (LNCR) in a subject in need thereof.
  • LNCR Lung Cancer
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Pancreatic Cancer (PNCA) in a subject in need thereof.
  • PNCA Pancreatic Cancer
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a Colorectal Cancer (CRC) in a subject in need thereof.
  • CRC Colorectal Cancer
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Lung Cancer (LNCR) in a subject in need thereof.
  • LNCR Lung Cancer
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Pancreatic Cancer (PNC A) in a subject in need thereof.
  • PNC A Pancreatic Cancer
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating Colorectal Cancer (CRC) in a subject in need thereof.
  • CRC Colorectal Cancer
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of KRAS(G12D) (e.g., in vitro or in vivo).
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Lung Cancer (LNCR) in a subject in need thereof.
  • LNCR Lung Cancer
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Pancreatic Cancer (PNC A) in a subject in need thereof.
  • PNC A Pancreatic Cancer
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Colorectal Cancer (CRC) in a subject in need thereof.
  • CRC Colorectal Cancer
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Lung Cancer (LNCR) in a subject in need thereof.
  • LNCR Lung Cancer
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Pancreatic Cancer (PNCA) in a subject in need thereof.
  • PNCA Pancreatic Cancer
  • the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating Colorectal Cancer (CRC) in a subject in need thereof.
  • CRC Colorectal Cancer
  • the present disclosure provides compounds that function as inhibitors of KRAS(G12D) (e.g., in vitro or in vivo).
  • the present disclosure therefore provides a method of inhibiting of BTK in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the inhibitor of KRAS(G12D) is a compound of the present disclosure.
  • Effectiveness of compounds of the disclosure can be determined by industry- accepted assays/ disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.
  • the subject is a mammal. In some embodiments, the subject is a human.
  • the compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcut
  • Compound activity was determined using recombinant KRAS[G12D]*GDP (BPS Bioscience, Cat# 101312), recombinant SOS1 (BPS Bioscience, Cat# 101573), recombinant cRAF (BPS Bioscience, Cat# 100519), MAb Anti GST-Tb (Cisbio, Cat# 61GSTTLB) and MAb Anti 6His-d2 (Cisbio, Cat# 61HISDLB) in an in vitro TR-FRET assay. Final concentrations were 25 nM, 5 nM, 1.25 nM, 0.5 nM and 5 nM, respectively.
  • reaction was carried out in assay buffer (50 mM HEPES pH 7.5, 5 mM MgCl 2 , 0.005% Tween 20, 1 mM DTT, 0.1mg/ml BSA).
  • assay buffer 50 mM HEPES pH 7.5, 5 mM MgCl 2 , 0.005% Tween 20, 1 mM DTT, 0.1mg/ml BSA.
  • Compounds serial dilutions were prepared as 400x DMSO stock on a 384-well Diamond Well Plate (Axygen, Cat# P-384-120SQ-C-S) using the Biomek 3000 liquid handling system.
  • 3.33x MAb Anti GST-Tb + MAb Anti 6His-d2 + SOS1 mix was prepared in assay buffer and 6 ⁇ l of this mix was added into 384w white ProxiPlate Plus reaction plate wells (Corning). Plate was centrifuged for 1 min at 200 g.
  • Em1/Em2 490/520 ratio was used to calculate tracer displacement % and IC50 values.
  • Wells w/o SOS1 was used as 100% SOS1 inhibition control
  • wells w/o KRAS[G12D]*GDP was used as 100% KRAS[G12D] inhibition control
  • wells w/o GTP-BODIPY was used for blank.
  • Example B KRAS[G12D] tracer displacement TR-FRET assay.
  • Compound activity was determined using recombinant KRAS[G12D] (BPS Bioscience, Cat# 100623), MAb Anti-His Tb (Cisbio, Cat# 61HISTLB) and GTP-BODIPY (ThermoFisher, Cat# G12411) as tracer in an in vitro tracer displacement TR-FRET assay. Final concentrations were 25 nM, 0.5 nM and 80 nM, respectively. The reaction was carried out in assay buffer (50 mM HEPES pH 7.5, 5 mM MgCl 2 , 0.005% Tween 20, 1 mM DTT, 0.1 mg/ml BSA).
  • assay buffer 50 mM HEPES pH 7.5, 5 mM MgCl 2 , 0.005% Tween 20, 1 mM DTT, 0.1 mg/ml BSA).
  • Compound activity was determined using recombinant KRAS[G12D]*GDP (BPS Bioscience, Cat# 101312), recombinant SOS1 (BPS Bioscience, Cat# 101573), MAb Anti- His Tb (Cisbio, Cat# 61HISTLB) and GTP-BODIPY (ThermoFisher, Cat# G12411) as tracer in an in vitro tracer displacement TR-FRET assay. Final concentrations were 25 nM, 5 nM, 0.5 nM and 80 nM, respectively.
  • reaction was carried out in assay buffer (50 mM HEPES pH 7.5, 5 mM MgCl 2 , 0.005% Tween 20, 1 mM DTT, 0.1 mg/ml BSA).
  • assay buffer 50 mM HEPES pH 7.5, 5 mM MgCl 2 , 0.005% Tween 20, 1 mM DTT, 0.1 mg/ml BSA.
  • Compounds serial dilutions were prepared as 400x DMSO stock on a 384-well Diamond Well Plate (Axygen, Cat# P-384-120SQ-C-S) using the Biomek 3000 liquid handling system. 3.33x MAb Anti-His Tb and SOS1 mix was prepared in assay buffer and 6 ⁇ l of this mix was added into 384w white ProxiPlate Plus reaction plate wells (Corning). Plate was centrifuged for 1 min at 200 g.
  • Em1/Em2 490/520 ratio was used to calculate tracer displacement % and IC50 values.
  • Wells w/o SOS1 was used as 100% SOS1 inhibition control
  • wells w/o KRAS[G12D]*GDP was used as 100% KRAS[G12D] inhibition control
  • wells w/o GTP-BODIPY was used for blank.
  • Table C Determination of half-maximal inhibitory concentration (IC50) in KRAS[G12D]*GDP - SOS1 tracer displacement TR-FRET assay.
  • KRAS-G12D, Compound # *- compound MRTX11 ith the structure presented below:
  • Example D P 7-9 Weeks-old male C57BL/6J mice (Jihui, China) were given a single intravenous (IV), intraperitoneal (IP) or oral (PO) doses of tested compounds.
  • IV intravenous
  • IP intraperitoneal
  • PO oral
  • MRTX1133 was given IV at 1 mg/kg and PO at 10 mg/kg in 5%DMSO+5%Solutol+ 90% (20% HP- ⁇ -CD); and IP at 30 mg/kg in 10% HP- ⁇ -CD in 50 mM citrate buffer pH 5.0.
  • Compound was given IV at 2 mg/kg in aq. solution with 20% HP- ⁇ -CD, and PO at 30 mg/kg in 0.5% methylcellulose (15 cP) +0.5% Tween-80.
  • the analysis was performed using a Qtrap5500 mass spectrometer (AB Sciex) coupled with an Agilent 1290 UPLC (for MRTX1133) or Shimadzu LC-30AD (ZE98-0128).
  • the pharmacokinetic parameters (Kel, elimination rate constant; AUCINF, area under the curve (infinite time); AUClast, area under the curve (the last point); Cmax, maximal plasma concentration; Tmax, the time take to reach Cmax; T1/2, the time taken to reach 50% of C max ; MRT INF , mean residence time (infinite approximation); MRT last , mean residence time (the last time point); F%, bioavailability) were calculated using noncompartmental analysis provided by WinNonlin Professional 5.2 software (Pharsight Corporation).
  • Table D Summary of pharmacokinetics parameters for MRTX1133 and compound 241 in mice.
  • AUClast T1/2 Compound Dose F(%) (hr*ng/mL) (h) [ ] xamp e . e erm na on o a -max ma ce u ar cy o ox c concentration (CC50) of compounds on cancer cell lines with mutated G12D (AsPC-1 cell line), G12C(MIA PaCa-2 cell line) and WT (BxPC-3) form of KRAS.
  • Table E Table E.
  • CC50 half-maximal cellular cytotoxic concentration

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Abstract

La présente invention concerne les composés de formule (A) inhibiteurs de KRAS(G12D). Les inhibiteurs décrits ici peuvent être utiles dans le traitement de maladies ou de troubles associés à KRAS(G12D), tels que le cancer du poumon, le cancer du pancréas, le cancer colorectal et al. En particulier, l'invention concerne des composés et des compositions pharmaceutiques inhibant KRAS(G12D), des méthodes de traitement de maladies ou de troubles associés à KRAS(G12D), et des procédés de synthèse de ces composés.
PCT/US2024/051673 2023-10-17 2024-10-16 Inhibiteurs de kras(g12d) Pending WO2025085580A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146613A1 (fr) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2021168193A1 (fr) * 2020-02-20 2021-08-26 Beta Pharma, Inc. Dérivés de pyridopyrimidine en tant qu'inhibiteurs de kras
WO2022002102A1 (fr) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Composés de quinazoline, leurs procédés de préparation et leurs utilisations
WO2022187527A1 (fr) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Dérivés de quinazoline nitrile en tant qu'inhibiteurs de kras
WO2023081840A1 (fr) * 2021-11-05 2023-05-11 Frontier Medicines Corporation Inhibiteurs de kras g12c

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146613A1 (fr) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2021168193A1 (fr) * 2020-02-20 2021-08-26 Beta Pharma, Inc. Dérivés de pyridopyrimidine en tant qu'inhibiteurs de kras
WO2022002102A1 (fr) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Composés de quinazoline, leurs procédés de préparation et leurs utilisations
WO2022187527A1 (fr) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Dérivés de quinazoline nitrile en tant qu'inhibiteurs de kras
WO2023081840A1 (fr) * 2021-11-05 2023-05-11 Frontier Medicines Corporation Inhibiteurs de kras g12c

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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