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WO2025085580A1 - Kras(g12d) inhibitors - Google Patents

Kras(g12d) inhibitors 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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French (fr)
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

The present invention is directed to the compounds of Formula (A) inhibitors of KRAS(G12D). The inhibitors described herein can be useful in the treatment of diseases or disorders associated with KRAS(G12D), such as Lung cancer, Pancreatic cancer, Colorectal cancer et al. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting KRAS(G12D), methods of treating diseases or disorders associated with KRAS(G12D), and methods of synthesizing these compounds.

Description

KRAS(G12D) Inhibitors FIELD OF INVENTION
[0001] The present invention is directed to inhibitors of Kirsten rat sarcoma virus with G12D mutation - KRAS(G12D). The inhibitors described herein can be useful in the treatment of diseases or disorders associated with KRAS(G12D), such as pancreatic cancers, colorectal cancers, and lung cancers by inducing durable responses. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting KRAS(G12D), methods of treating diseases or disorders associated with KRAS(G12D), and methods of synthesizing these compounds.
BACKGROUND
[0002] The oncogenic impacts of the KRAS gene were first reported in 1980s, making KRAS one of the first identified oncogenes. It is known that KRAS protein functions as a molecular switch: it responds to upstream EGFR activation and regulates the downstream MAPK and PI3K/mT0R pathways, eventually controlling cell proliferation, differentiation, and survival.
[0003] Clinical data have implicated the driver mutations of the KRAS residue Glyl2 (G12), and basic studies have shown that such mutations impair both this enzyme’s intrinsic and GTPase-activating protein (GAP)-stimulated GTP hydrolysis activity promoting oncogenesis. Despite nearly four decades of efforts, no direct KRAS inhibitor has been approved for medical use. There is consensus that the difficulty in developing direct KRAS inhibitors relates on the one hand to the picomolar affinity of GTP and GDP to KRAS (the intracellular concentrations of these metabolites are much higher), and on the other hand to an absence of suitable deep pockets for allosteric regulation.
[0004] One major breakthrough for KRAS inhibition was the discovery of an allosteric switch-II pocket (S-IIP) that is induced by covalent inhibitors of KRAS bearing the G12C driver mutation. Studies have shown that induction of S-IIP results from covalent bond formation between the electrophilic acryloyl moieties of these inhibitors and the nucleophilic thiol moiety of the Cys residue at position 12. These KRAS(G12C) inhibitors have shown promising results in recent clinical trials, although it is notable that they exclusively target KRAS in inactive state. Despite these progresses with inhibitors of KRAS(G12C), the most prevalent and oncogenic G12 mutant variant is KRAS(G12D), which is estimated to impact about 50% patients with pancreatic ductal adenocarcinoma [0005] Pancreatic cancer is an aggressive disease that is notoriously resistant to treatment. Many cancer types and most pancreatic cancers are driven by mutations in a gene called KRAS, so researchers have long sought drugs that block the actions of mutant KRAS proteins made from these altered genes. But many efforts to develop drugs that block the cancer-fueling effects of mutant KRAS proteins have been unsuccessful.
[0006] Pancreatic cancer is the third leading cause of cancer death in the United States and often is diagnosed at a late stage, when treatment options are limited and the prognosis is poor.
[0007] Various strategies have been testified for targeting KRAS(G12D), including those using indole-based small molecules to target a switch-I/II pocket, a compound (KAL- 21404358) to target the Pl 10 site, a pan-RAS inhibitor (compound 3144) to target the A59 site, and a cyclic peptide (KD2) to target KRAS(G12D). However, no one of these molecules targets KRAS(G12D) with suitably low (micromolar) concentration. A compound targeting the aspartic acid residue of KRAS(G12D) may somehow bind to KRAS(G12D) (similar to that formed between inhibitors and the cysteine residue of KRAS(G12C)), as a result may induce an allosteric pocket. This would perhaps enable pharmacological inhibition of this more prevalent oncodriver-mutation-bearing KRAS variant. However, these inhibitors are also associated with off-target effects, likely due to binding and inhibiting some non-KRAS small GTPases, which warrants further structural optimizations.
[0008] Although many studies have been done on KRAS G12D inhibitors to date, work is still underway to overcome KRAS G12D inhibitor resistance, bioavailability, efficiency and solubility those are significant problems in patients’ treatment.
SUMMARY
[0009] A first aspect of the invention relates to compounds of Formula (A):
A), or a pharmaceuticall automer thereof,
Figure imgf000004_0001
wherein: W is selected from CHRw, NH, and -CH=CH-; wherein Rw and R5 together form a double bond; Q is selected from CRq and N; Rq is halogen; G is selected from N and CRg; Rg is selected from H, -NH2, -CH=NH; R1 is selected from H, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 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; R2 is C1-C6 alkyl; R3 is selected from H and C1-C6 alkyl; or R2 and R3 together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R4 is selected from H and C1-C6 alkyl; R5 is selected from H, C1-C6 alkyl; or R and R together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, wherein W is NH; R6 is selected from H, F, -CHF2, and -CH=CH2; R7 is selected from -NH2, -OH, and -SH; or R7 and Rg 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; R8 is selected from H, halogen; R9 is selected from H, halogen, C1-C6 alkyl; R10 is selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen; or R9 and R10 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, -NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl; R11 is selected from H, halogen; provided that when W is CHRw, then R6 is selected from F, -CHF2, and -CH=CH2; provided that when W is NH, then R6 is selected from F, -CHF2, and -CH=CH2; and provided that when W is -CH=CH-, then R6 is selected from H, F, -CHF2, and -CH=CH2. [0010] In some embodiments, the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. [0011] Another aspect of the invention relates to a method of treating a disease or disorder associated with KRAS(G12D). The method comprises administering to a patient in need of a treatment for diseases or disorders associated with KRAS(G12D) an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0012] Another aspect of the invention is directed to a method of inhibiting of KRAS(G12D). The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0013] 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). [0014] 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). [0015] 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 treating or preventing a disease or disorder disclosed herein. [0016] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof. [0017] 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 a disease or disorder disclosed herein. [0018] The present invention further provides methods of treating a disease or disorder associated with KRAS(G12D), 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. [0019] The present invention provides inhibitors of KRAS(G12D) that are therapeutic agents in the treatment of diseases and disorders. [0020] 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. [0021] 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. [0022] 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 Stromal Tumor (GIST); Tatton-Brown- Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RB1); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1) 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. [0023] In some aspects, 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). [0024] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein. [0025] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure. [0026] In some aspects, 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. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control. [0028] Other features and advantages of the disclosure will be apparent from the following detailed description and claims DETAILED DESCRIPTION [0029] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with the KRAS(G12D) by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein. [0030] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties. Definitions [0031] The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. [0032] The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise. [0033] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have 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. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, – OH, –CN, –COOH, –CH2CN, –O-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) 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, – OC(O)O(C1-C6) alkyl, –NH2, –NH((C1-C6) alkyl), –N((C1-C6) alkyl)2, –NHC(O)(C1-C6) alkyl, –C(O)NH(C1-C6) alkyl, –S(O)2(C1-C6) alkyl, –S(O)NH(C1-C6)alkyl, and – S(O)N((C1-C6)alkyl)2. The 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. [0035] As used herein, the term “unsubstituted” means that the specified group bears no substituents. [0036] Unless otherwise specifically defined, the term "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. Exemplary substituents include, but are not limited to, –H, -halogen, –O-(C1-C6)alkyl, (C1-C6)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((C1-C6)alkyl), –N((C1-C6)alkyl)2, –S(O)2-(C1-C6) alkyl, –S(O)NH(C1-C6)alkyl, and – S(O)N((C1-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings 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. [0037] Unless otherwise specifically defined, "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. Unless otherwise specifically defined, fused means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. 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]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3- b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4- b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro- 2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2- b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl, imidazo[1,2- a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H- pyrazolo [1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4- d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, 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-dihydro-6H- pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2- a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H- pyrido[2,3-b]puyrrolo[1,2-d][1,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H- spiro[cyclopropane-1,8’-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9’-onyl. [0038] Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine. [0039] 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. [0040] “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. [0041] “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. Examples of alkenyl groups 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. [0042] 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. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted. [0043] The term “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 C1-C6 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-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. [0044] “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. Examples of 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. [0045] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” 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. Examples of 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. [0046] The term “aromatic” means a planar ring having 4n + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs. [0047] The term haloalkyl as used herein 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. [0048] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc. [0049] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N. [0050] “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. One or more of the carbon atoms can be substituted with a heteroatom. [0051] The term “spiroheterocycloalkyl”, “spiroheterocycle”, or “spiroheterocyclyl” 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). [0052] The term "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. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. [0053] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. [0054] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2H and 14C). Deuterated (i.e., 2H or D) and carbon-14 (i.e., 14C) 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. [0055] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water- soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2- disulfonate), benzenesulfonate, 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, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. [0056] 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. [0057] 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. [0058] The term "carrier", as used in this disclosure, 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. [0059] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder. [0060] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated. [0061] The term "administer", "administering", or "administration" as used in this disclosure 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. [0062] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound [0063] The term “salt’ refers to pharmaceutically acceptable salts [0064] The term “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. [0065] “KRAS(G12D) inhibitor” as used herein refer to compounds of Formula (A) and/or compositions comprising a compound of Formula(A) which inhibits KRAS(G12D). [0066] 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. Generally, for administering therapeutic agents (e.g. compounds or compositions of Formula A (and/or additional agents) described herein) for therapeutic purposes, 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. For example, 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] In one aspect, the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: A), wherein W, Q, G, R1
Figure imgf000017_0001
, , , , , , , , , scribed herein. [0068] It is understood that, for a compound of Formula (A), W, Q, G, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 can each be, where applicable, selected from the groups described herein, and any group described herein for any W, Q, G, R1, R2, R3, R4, R5, R6, R , 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, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11. [0069] In some embodiments, the compounds of Formula (A) have the structure of Formula (I): I), or a pharmaceutic , isotopic derivative,
Figure imgf000018_0001
or tautomer thereof, wherein Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 are as described herein. [0070] It is understood that, for a compound of Formula (I), Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11. [0071] In some embodiments, the compounds of Formula (A) have the structure of Formula (II):
I), or a pharmaceuti , isotopic derivative,
Figure imgf000019_0001
or tautomer thereof, wherein Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 are as described herein. [0072] It is understood that, for a compound of Formula (II), Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11. [0073] In some embodiments, the compounds of Formula (A) have the structure of Formula (III): I), or a pharmaceuti
Figure imgf000019_0002
, , , , isotopic derivative, or tautomer thereof, wherein Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 are as described herein. [0074] It is understood that, for a compound of Formula (III), Q, G, R , R , R , R , R , R , R9, R10 and R11 can each be, where applicable, selected from the groups described herein, and any group described herein for any Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11 can be combined, where applicable, with any group described herein for one or more of the remainders of Q, G, R1, R2, R3, R6, R7, R8, R9, R10 and R11. [0075] In some embodiments, the compound is of Formula (I-A): R6 A), or a pharmaceut isotopic derivative,
Figure imgf000020_0001
or tautomer thereof. [0076] In some embodiments, the compound is of Formula (I-A-1): 1), or a pharmaceu
Figure imgf000020_0002
sotopic derivative, or tautomer thereof. [0077] In some embodiments, the compound is of Formula (I-A-1-a):
a), or a pharmace otopic derivative,
Figure imgf000021_0001
or tautomer thereof. [0078] In some embodiments, the compound is of Formula (I-A-1-a-I): F -I), or a pharma
Figure imgf000021_0002
opic derivative, or tautomer thereof. [0079] In some embodiments, the compound is of Formula (I-A-1-a-I-A): A),
Figure imgf000021_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0080] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1): 1), or a phar c derivative,
Figure imgf000022_0001
or tautomer thereof. [0081] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1-a): a), or a pha
Figure imgf000022_0002
derivative, or tautomer thereof. [0082] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1-a-I):
-I), or a ph derivative,
Figure imgf000023_0001
or tautomer thereof. [0083] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1-b): b), or a pha
Figure imgf000023_0002
derivative, or tautomer thereof. [0084] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1-b-I): -I),
Figure imgf000023_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0085] In some embodiments, the compound is of Formula (I-A-1-a-II): II), or a pharmac topic derivative,
Figure imgf000024_0001
or tautomer thereof. [0086] In some embodiments, the compound is of Formula (I-A-1-a-II-A): A), or a pharm
Figure imgf000024_0002
pic derivative, or tautomer thereof. [0087] In some embodiments, the compound is of Formula (I-A-1-a-II-A-1):
1), or a phar ic derivative,
Figure imgf000025_0001
or tautomer thereof. [0088] In some embodiments, the compound is of Formula (I-A-1-a-II-A-1-a): a), or a phar
Figure imgf000025_0002
c derivative, or tautomer thereof. [0089] In some embodiments, the compound is of Formula (I-A-1-a-II-A-1-a-I): -I),
Figure imgf000025_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0090] In some embodiments, the compound is of Formula (I-A-1-a-II-A-1-b): b), or a phar c derivative,
Figure imgf000026_0001
or tautomer thereof. [0091] In some embodiments, the compound is of Formula (I-A-1-a-II-A-1-b-I): -I), or a pha
Figure imgf000026_0002
derivative, or tautomer thereof. [0092] [0093] In some embodiments, the compound is of Formula (I-A-1-b):
b), or a pharmace otopic derivative,
Figure imgf000027_0001
or tautomer thereof. [0094] In some embodiments, the compound is of Formula (I-A-1-b-I): -I), or a pharma
Figure imgf000027_0002
opic derivative, or tautomer thereof. [0095] In some embodiments, the compound is of Formula (I-A-1-b-I-A): F A),
Figure imgf000027_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0096] In some embodiments, the compound is of Formula (I-A-1-b-I-A-1): F 1), or a phar ic derivative,
Figure imgf000028_0001
or tautomer thereof. [0097] In some embodiments, the compound is of Formula (I-A-1-b-I-A-1-a): F a), or a phar
Figure imgf000028_0002
c derivative, or tautomer thereof. [0098] In some embodiments, the compound is of Formula (I-A-1-b-I-A-1-a-I):
-I), or a pha derivative,
Figure imgf000029_0001
or tautomer thereof. [0099] In some embodiments, the compound is of Formula (I-A-1-b-I-A-1-a-II): F II), or a ph
Figure imgf000029_0002
derivative, or tautomer thereof. [0100] In some embodiments, the compound is of Formula (I-A-1-b-I-B): F B),
Figure imgf000029_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0101] In some embodiments, the compound is of Formula (I-A-1-b-I-B-1): F 1), or a phar c derivative,
Figure imgf000030_0001
or tautomer thereof. [0102] In some embodiments, the compound is of Formula (I-A-1-b-I-B-1-a): a), or a pha
Figure imgf000030_0002
derivative, or tautomer thereof. [0103] In some embodiments, the compound is of Formula (I-A-1-b-II):
II), or a pharmac topic derivative,
Figure imgf000031_0001
or tautomer thereof. [0104] In some embodiments, the compound is of Formula (I-A-1-b-II-A): A), or a pharm
Figure imgf000031_0002
pic derivative, or tautomer thereof. [0105] In some embodiments, the compound is of Formula (I-A-1-b-II-A-1): F 1),
Figure imgf000031_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0106] In some embodiments, the compound is of Formula (I-A-1-b-II-A-1-a): F a), or a phar ic derivative,
Figure imgf000032_0001
or tautomer thereof. [0107] In some embodiments, the compound is of Formula (I-A-1-b-II-A-1-a-I): -b-II-A-1-a-I), or a phar
Figure imgf000032_0002
rug, isotopic derivative, or tautomer thereof. [0108] In some embodiments, the compound is of Formula (I-A-1-b-II-A-1-a-II):
II), or a pha derivative,
Figure imgf000033_0001
or tautomer thereof. [0109] In some embodiments, the compound is of Formula (I-A-1-b-II-B): B), or a pharm
Figure imgf000033_0002
pic derivative, or tautomer thereof. [0110] In some embodiments, the compound is of Formula (I-A-1-b-II-B-1): F 1),
Figure imgf000033_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0111] In some embodiments, the compound is of Formula (I-A-1-b-II-B-1-a): a), or a phar c derivative,
Figure imgf000034_0001
or tautomer thereof. [0112] In some embodiments, the compound is of Formula (I-B): B), or a pharmaceut
Figure imgf000034_0002
isotopic derivative, or tautomer thereof. [0113] In some embodiments, the compound is of Formula (I-B-1):
1), or a pharmaceu sotopic derivative,
Figure imgf000035_0001
or tautomer thereof. [0114] In some embodiments, the compound is of Formula (I-B-1-a): a), or a pharmace
Figure imgf000035_0002
otopic derivative, or tautomer thereof. [0115] In some embodiments, the compound is of Formula (I-B-1-a-I): F -I),
Figure imgf000035_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0116] In some embodiments, the compound is of Formula (I-B-1-a-I-A): A), or a pharm ic derivative,
Figure imgf000036_0001
or tautomer thereof. [0117] In some embodiments, the compound is of Formula (I-B-1-a-I-A-1): 1), or a phar
Figure imgf000036_0002
c derivative, or tautomer thereof. [0118] In some embodiments, the compound is of Formula (I-B-1-a-I-A-1-a):
a), or a pha derivative,
Figure imgf000037_0001
or tautomer thereof. [0119] In some embodiments, the compound is of Formula (I-A-1-a-I-A-1-a-I): -I), or a ph
Figure imgf000037_0002
derivative, or tautomer thereof. [0120] In some embodiments, the compound is of Formula (I-B-1-a-I-A-1-b): b),
Figure imgf000037_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0121] In some embodiments, the compound is of Formula (I-B-1-a-I-A-1-b-I): -I), or a ph derivative,
Figure imgf000038_0001
or tautomer thereof. [0122] In some embodiments, the compound is of Formula (I-B-1-a-II): II), or a pharmac
Figure imgf000038_0002
topic derivative, or tautomer thereof. [0123] In some embodiments, the compound is of Formula (I-B-1-a-II-A):
A), or a pharm pic derivative,
Figure imgf000039_0001
or tautomer thereof. [0124] In some embodiments, the compound is of Formula (I-B-1-a-II-A-1): 1), or a phar
Figure imgf000039_0002
ic derivative, or tautomer thereof. [0125] In some embodiments, the compound is of Formula (I-B-1-a-II-A-1-a): a),
Figure imgf000039_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0126] In some embodiments, the compound is of Formula (I-B-1-a-II-A-1-a-I): -I), or a pha derivative,
Figure imgf000040_0001
or tautomer thereof. [0127] In some embodiments, the compound is of Formula (I-B-1-a-II-A-1-b): -a-II-A-1-b), or a phar
Figure imgf000040_0002
g, isotopic derivative, or tautomer thereof. [0128] In some embodiments, the compound is of Formula (I-B-1-a-II-A-1-b-I):
-I), or a pha derivative,
Figure imgf000041_0001
or tautomer thereof. [0129] In some embodiments, the compound is of Formula (I-B-1-b): b), or a pharmace
Figure imgf000041_0002
otopic derivative, or tautomer thereof. [0130] In some embodiments, the compound is of Formula (I-B-1-b-I): F -I),
Figure imgf000041_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0131] In some embodiments, the compound is of Formula (I-B-1-b-I-A): F A), or a pharm pic derivative,
Figure imgf000042_0001
or tautomer thereof. [0132] In some embodiments, the compound is of Formula (I-B-1-b-I-A-1): 1), or a phar
Figure imgf000042_0002
c derivative, or tautomer thereof. [0133] In some embodiments, the compound is of Formula (I-B-1-b-I-A-1-a):
F a), or a phar c derivative,
Figure imgf000043_0001
or tautomer thereof. [0134] In some embodiments, the compound is of Formula (I-B-1-b-I-A-1-a-I): -I), or a pha
Figure imgf000043_0002
derivative, or tautomer thereof. [0135] In some embodiments, the compound is of Formula (I-B-1-b-I-A-1-a-II): F II),
Figure imgf000043_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0136] In some embodiments, the compound is of Formula (I-B-1-b-I-B): F B), or a pharm ic derivative,
Figure imgf000044_0001
or tautomer thereof. [0137] In some embodiments, the compound is of Formula (I-B-1-b-I-B-1): F 1), or a phar
Figure imgf000044_0002
c derivative, or tautomer thereof. [0138] In some embodiments, the compound is of Formula (I-B-1-b-I-B-1-a):
a), or a pha derivative,
Figure imgf000045_0001
or tautomer thereof. [0139] In some embodiments, the compound is of Formula (I-B-1-b-II): II), or a pharmac
Figure imgf000045_0002
topic derivative, or tautomer thereof. [0140] In some embodiments, the compound is of Formula (I-B-1-b-II-A): -b-II-A),
Figure imgf000045_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0141] In some embodiments, the compound is of Formula (I-B-1-b-II-A-1): F 1), or a pharm ic derivative,
Figure imgf000046_0001
or tautomer thereof. [0142] In some embodiments, the compound is of Formula (I-B-1-b-II-A-1-a): F a), or a phar
Figure imgf000046_0002
ic derivative, or tautomer thereof. [0143] In some embodiments, the compound is of Formula (I-B-1-b-II-A-1-a-I):
-I), or a phar c derivative,
Figure imgf000047_0001
or tautomer thereof. [0144] In some embodiments, the compound is of Formula (I-B-1-b-II-A-1-a-II): II), or a pha
Figure imgf000047_0002
derivative, or tautomer thereof. [0145] In some embodiments, the compound is of Formula (I-B-1-b-II-B): B),
Figure imgf000047_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0146] In some embodiments, the compound is of Formula (I-B-1-b-II-B-1): F 1), or a pharm ic derivative,
Figure imgf000048_0001
or tautomer thereof. [0147] In some embodiments, the compound is of Formula (I-B-1-b-II-B-1-a): a), or a phar
Figure imgf000048_0002
c derivative, or tautomer thereof. [0148] In some embodiments, the compound is of Formula (II-A):
A), or a pharmaceut isotopic derivative,
Figure imgf000049_0001
or tautomer thereof. [0149] In some embodiments, the compound is of Formula (II-A-1): 1), or a pharmace
Figure imgf000049_0002
sotopic derivative, or tautomer thereof. [0150] In some embodiments, the compound is of Formula (II-A-1-a):
a), or a pharmace otopic derivative,
Figure imgf000050_0001
or tautomer thereof. [0151] In some embodiments, the compound is of Formula (II-A-1-a-I): -I), or a pharma
Figure imgf000050_0002
opic derivative, or tautomer thereof. [0152] In some embodiments, the compound is of Formula (II-A-1-a-I-A):
A), or a phar ic derivative,
Figure imgf000051_0001
or tautomer thereof. [0153] In some embodiments, the compound is of Formula (II-A-1-a-I-A-1): 1), or a pha
Figure imgf000051_0002
c derivative, or tautomer thereof. [0154] In some embodiments, the compound is of Formula (II-A-1-a-I-A-1-a):
ve,
Figure imgf000052_0001
[0155] In some embodiments, the compound is of Formula (II-A-1-a-I-A-1-a-I): ve,
Figure imgf000052_0002
[0156] In some embodiments, the compound is of Formula (II-A-1-a-I-A-1-b):
Figure imgf000052_0003
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,
Figure imgf000053_0001
[0158] In some embodiments, the compound is of Formula (II-A-1-a-II): II), or a pharmac
Figure imgf000053_0002
topic derivative, or tautomer thereof. [0159] In some embodiments, the compound is of Formula (II-A-1-a-II-A):
A), or a pharm pic derivative,
Figure imgf000054_0001
or tautomer thereof. [0160] In some embodiments, the compound is of Formula (II-A-1-a-II-A-1): 1), or a phar
Figure imgf000054_0002
ic derivative, or tautomer thereof. [0161] In some embodiments, the compound is of Formula (II-A-1-a-II-A-1-a):
a), or a phar c derivative,
Figure imgf000055_0001
or tautomer thereof. [0162] In some embodiments, the compound is of Formula (II-A-1-a-II-A-1-a-I): -I), or a pha
Figure imgf000055_0002
derivative, or tautomer thereof. [0163] In some embodiments, the compound is of Formula (II-A-1-a-II-A-1-b):
Figure imgf000055_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0164] In some embodiments, the compound is of Formula (II-A-1-a-II-A-1-b-I): -I), or a pha derivative,
Figure imgf000056_0001
or tautomer thereof. [0165] In some embodiments, the compound is of Formula (II-A-1-b): b), or a pharmace
Figure imgf000056_0002
otopic derivative, or tautomer thereof. [0166] In some embodiments, the compound is of Formula (II-A-1-b-I):
-I), or a pharma opic derivative,
Figure imgf000057_0001
or tautomer thereof. [0167] In some embodiments, the compound is of Formula (II-A-1-b-I-A): A), or a pharm
Figure imgf000057_0002
pic derivative, or tautomer thereof. [0168] In some embodiments, the compound is of Formula (II-A-1-b-I-A-1):
1), or a phar ic derivative,
Figure imgf000058_0001
or tautomer thereof. [0169] In some embodiments, the compound is of Formula (II-A-1-b-I-A-1-a): a), or a phar
Figure imgf000058_0002
derivative, or tautomer thereof. [0170] In some embodiments, the compound is of Formula (II-A-1-b-I-A-1-a-I):
I), or a ph derivative,
Figure imgf000059_0001
or tautomer thereof. [0171] In some embodiments, the compound is of Formula (II-A-1-b-I-A-1-a-II): I), or a ph
Figure imgf000059_0002
derivative, or tautomer thereof. [0172] In some embodiments, the compound is of Formula (II-A-1-b-I-B):
B), or a pharm ic derivative,
Figure imgf000060_0001
or tautomer thereof. [0173] In some embodiments, the compound is of Formula (II-A-1-b-I-B-1): 1), or a pha
Figure imgf000060_0002
c derivative, or tautomer thereof. [0174] In some embodiments, the compound is of Formula (II-A-1-b-I-B-1-a):
Figure imgf000060_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0175] In some embodiments, the compound is of Formula (II-A-1-b-I-C): C), or a pharm pic derivative,
Figure imgf000061_0001
or tautomer thereof. [0176] In some embodiments, the compound is of Formula (II-A-1-b-I-C-1): ve,
Figure imgf000061_0002
[0177] In some embodiments, the compound is of Formula (II-A-1-b-I-C-1-a):
ve,
Figure imgf000062_0001
[0178] In some embodiments, the compound is of Formula (II-A-1-b-I-C-1-a-I): I), or a ph
Figure imgf000062_0002
derivative, or tautomer thereof. [0179] In some embodiments, the compound is of Formula (II-A-1-b-I-C-1-a-I-A):
A), or vative,
Figure imgf000063_0001
or tautomer thereof. [0180] In some embodiments, the compound is of Formula (II-A-1-b-II): II), or a pharmac
Figure imgf000063_0002
topic derivative, or tautomer thereof. [0181] In some embodiments, the compound is of Formula (II-A-1-b-II-A):
A), or a pharma pic derivative,
Figure imgf000064_0001
or tautomer thereof. [0182] In some embodiments, the compound is of Formula (II-A-1-b-II-A-1): 1), or a pharm
Figure imgf000064_0002
ic derivative, or tautomer thereof. [0183] In some embodiments, the compound is of Formula (II-A-1-b-II-A-1-a):
a), or a phar ic derivative,
Figure imgf000065_0001
or tautomer thereof. [0184] In some embodiments, the compound is of Formula (II-A-1-b-II-A-1-a-I): -I), or a phar
Figure imgf000065_0002
c derivative, or tautomer thereof. [0185] In some embodiments, the compound is of Formula (II-A-1-b-II-A-1-a-II):
II), or a pha derivative,
Figure imgf000066_0001
or tautomer thereof. [0186] In some embodiments, the compound is of Formula (II-A-1-b-II-B): B), or a pharm
Figure imgf000066_0002
pic derivative, or tautomer thereof. [0187] In some embodiments, the compound is of Formula (II-A-1-b-II-B-1):
1), or a phar ic derivative,
Figure imgf000067_0001
or tautomer thereof. [0188] In some embodiments, the compound is of Formula (II-A-1-b-II-B-1-a): a), or a phar
Figure imgf000067_0002
c derivative, or tautomer thereof. [0189] In some embodiments, the compound is of Formula (II-A-1-b-II-C):
Figure imgf000067_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0190] In some embodiments, the compound is of Formula (II-A-1-b-II-C-1): 1), or a pharm ic derivative,
Figure imgf000068_0001
or tautomer thereof. [0191] In some embodiments, the compound is of Formula (II-A-1-b-II-C-1-a): a), or a phar
Figure imgf000068_0002
c derivative, or tautomer thereof. [0192] In some embodiments, the compound is of Formula (II-A-1-b-II-C-1-a-I):
-I), or a pha derivative,
Figure imgf000069_0001
or tautomer thereof. [0193] In some embodiments, the compound is of Formula (II-A-1-b-II-C-1-a-I-A): A), or a
Figure imgf000069_0002
rivative, or tautomer thereof. [0194] In some embodiments, the compound is of Formula (II-A-2):
2), or a pharmaceu sotopic derivative,
Figure imgf000070_0001
or tautomer thereof. [0195] In some embodiments, the compound is of Formula (II-A-2-a): a), or a pharmace
Figure imgf000070_0002
otopic derivative, or tautomer thereof. [0196] In some embodiments, the compound is of Formula (II-A-2-a-I):
-I), or a pharma opic derivative,
Figure imgf000071_0001
or tautomer thereof. [0197] In some embodiments, the compound is of Formula (II-A-2-a-I-A): A), or a phar
Figure imgf000071_0002
ic derivative, or tautomer thereof. [0198] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1):
1), or a pha derivative,
Figure imgf000072_0001
or tautomer thereof. [0199] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1-a): ve,
Figure imgf000072_0002
[0200] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1-a-I):
ve,
Figure imgf000073_0001
[0201] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1-b): b), or a pha
Figure imgf000073_0002
derivative, or tautomer thereof. [0202] In some embodiments, the compound is of Formula (II-A-2-a-I-A-1-b-I):
-I), or a ph derivative,
Figure imgf000074_0001
or tautomer thereof. [0203] In some embodiments, the compound is of Formula (II-A-2-a-II): II), or a pharmac
Figure imgf000074_0002
topic derivative, or tautomer thereof. [0204] In some embodiments, the compound is of Formula (II-A-2-a-II-A):
A), or a pharm pic derivative,
Figure imgf000075_0001
or tautomer thereof. [0205] In some embodiments, the compound is of Formula (II-A-2-a-II-A-1): 1), or a phar
Figure imgf000075_0002
ic derivative, or tautomer thereof. [0206] In some embodiments, the compound is of Formula (II-A-2-a-II-A-1-a):
a), or a phar c derivative,
Figure imgf000076_0001
or tautomer thereof. [0207] In some embodiments, the compound is of Formula (II-A-2-a-II-A-1-a-I): ve,
Figure imgf000076_0002
[0208] In some embodiments, the compound is of Formula (II-A-2-a-II-A-1-b):
b), or a phar c derivative,
Figure imgf000077_0001
or tautomer thereof. [0209] In some embodiments, the compound is of Formula (II-A-2-a-II-A-1-b-I): -I), or a pha
Figure imgf000077_0002
derivative, or tautomer thereof. [0210] In some embodiments, the compound is of Formula (II-A-2-b):
b), or a pharmace otopic derivative,
Figure imgf000078_0001
or tautomer thereof. [0211] In some embodiments, the compound is of Formula (II-A-2-b-I): -I), or a pharma
Figure imgf000078_0002
opic derivative, or tautomer thereof. [0212] In some embodiments, the compound is of Formula (II-A-2-b-I-A):
A), or a pharm pic derivative,
Figure imgf000079_0001
or tautomer thereof. [0213] In some embodiments, the compound is of Formula (II-A-2-b-I-A-1): 1), or a phar
Figure imgf000079_0002
ic derivative, or tautomer thereof. [0214] In some embodiments, the compound is of Formula (II-A-2-b-I-A-1-a):
a), or a phar derivative,
Figure imgf000080_0001
or tautomer thereof. [0215] In some embodiments, the compound is of Formula (II-A-2-b-I-A-1-a-I): -I), or a pha
Figure imgf000080_0002
derivative, or tautomer thereof. [0216] In some embodiments, the compound is of Formula (II-A-2-b-I-A-1-a-II):
II), or a ph derivative,
Figure imgf000081_0001
or tautomer thereof. [0217] In some embodiments, the compound is of Formula (II-A-2-b-I-B): B), or a pharm
Figure imgf000081_0002
ic derivative, or tautomer thereof. [0218] In some embodiments, the compound is of Formula (II-A-2-b-I-B-1):
1), or a pha c derivative,
Figure imgf000082_0001
or tautomer thereof. [0219] In some embodiments, the compound is of Formula (II-A-2-b-I-B-1-a): a), or a ph
Figure imgf000082_0002
derivative, or tautomer thereof. [0220] In some embodiments, the compound is of Formula (II-A-2-b-I-C):
C), or a pharm pic derivative,
Figure imgf000083_0001
or tautomer thereof. [0221] In some embodiments, the compound is of Formula (II-A-2-b-I-C-1): ve,
Figure imgf000083_0002
[0222] In some embodiments, the compound is of Formula (II-A-2-b-I-C-1-a):
a), or a pha derivative,
Figure imgf000084_0001
or tautomer thereof. [0223] In some embodiments, the compound is of Formula (II-A-2-b-I-C-1-a-I): -I), or a ph
Figure imgf000084_0002
derivative, or tautomer thereof. [0224] In some embodiments, the compound is of Formula (II-A-2-b-I-C-1-a-I-A):
ve,
Figure imgf000085_0001
[0225] In some embodiments, the compound is of Formula (II-A-2-b-II): II), or a pharmac
Figure imgf000085_0002
topic derivative, or tautomer thereof. [0226] In some embodiments, the compound is of Formula (II-A-2-b-II-A):
A), or a pharma pic derivative,
Figure imgf000086_0001
or tautomer thereof. [0227] In some embodiments, the compound is of Formula (II-A-2-b-II-A-1): 1), or a pharm
Figure imgf000086_0002
ic derivative, or tautomer thereof. [0228] In some embodiments, the compound is of Formula (II-A-2-b-II-A-1-a):
a), or a phar ic derivative,
Figure imgf000087_0001
or tautomer thereof. [0229] In some embodiments, the compound is of Formula (II-A-2-b-II-A-1-a-I): -I), or a phar
Figure imgf000087_0002
c derivative, or tautomer thereof. [0230] In some embodiments, the compound is of Formula (II-A-2-b-II-A-1-a-II):
II), or a pha derivative,
Figure imgf000088_0001
or tautomer thereof. [0231] In some embodiments, the compound is of Formula (II-A-2-b-II-B): B), or a pharm
Figure imgf000088_0002
pic derivative, or tautomer thereof. [0232] In some embodiments, the compound is of Formula (II-A-2-b-II-B-1):
1), or a phar ic derivative,
Figure imgf000089_0001
or tautomer thereof. [0233] In some embodiments, the compound is of Formula (II-A-2-b-II-B-1-a): a), or a phar
Figure imgf000089_0002
c derivative, or tautomer thereof. [0234] In some embodiments, the compound is of Formula (II-A-2-b-II-C):
C), or a pharma pic derivative,
Figure imgf000090_0001
or tautomer thereof. [0235] In some embodiments, the compound is of Formula (II-A-2-b-II-C-1): 1), or a pharm
Figure imgf000090_0002
ic derivative, or tautomer thereof. [0236] In some embodiments, the compound is of Formula (II-A-2-b-II-C-1-a):
a), or a phar c derivative,
Figure imgf000091_0001
or tautomer thereof. [0237] In some embodiments, the compound is of Formula (II-A-2-b-II-C-1-a-I): -I), or a pha
Figure imgf000091_0002
derivative, or tautomer thereof. [0238] In some embodiments, the compound is of Formula (II-A-2-b-II-C-1-a-I-A):
A), or a rivative,
Figure imgf000092_0001
or tautomer thereof. [0239] In some embodiments, the compound is of Formula (II-B): B), or a pharmaceut
Figure imgf000092_0002
isotopic derivative, or tautomer thereof. [0240] In some embodiments, the compound is of Formula (II-B-1):
1), or a pharmaceu sotopic derivative,
Figure imgf000093_0001
or tautomer thereof. [0241] In some embodiments, the compound is of Formula (II-B-1-a): a), or a pharmace
Figure imgf000093_0002
otopic derivative, or tautomer thereof. [0242] In some embodiments, the compound is of Formula (II-B-1-a-I):
-I), or a pharma opic derivative,
Figure imgf000094_0001
or tautomer thereof. [0243] In some embodiments, the compound is of Formula (II-B-1-a-I-A): A), or a pharm
Figure imgf000094_0002
ic derivative, or tautomer thereof. [0244] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1):
1), or a pha c derivative,
Figure imgf000095_0001
or tautomer thereof. [0245] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1-a): ve,
Figure imgf000095_0002
[0246] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1-a-I):
Figure imgf000095_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0247] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1-b): ve,
Figure imgf000096_0001
[0248] In some embodiments, the compound is of Formula (II-B-1-a-I-A-1-b-I): -I), or a ph
Figure imgf000096_0002
derivative, or tautomer thereof. [0249] In some embodiments, the compound is of Formula (II-B-1-a-II):
II), or a pharmac topic derivative,
Figure imgf000097_0001
or tautomer thereof. [0250] In some embodiments, the compound is of Formula (II-B-1-a-II-A): A), or a pharm
Figure imgf000097_0002
pic derivative, or tautomer thereof. [0251] In some embodiments, the compound is of Formula (II-B-1-a-II-A-1):
1), or a phar ic derivative,
Figure imgf000098_0001
or tautomer thereof. [0252] In some embodiments, the compound is of Formula (II-B-1-a-II-A-1-a): a), or a phar
Figure imgf000098_0002
c derivative, or tautomer thereof. [0253] In some embodiments, the compound is of Formula (II-B-1-a-II-A-1-a-I):
Figure imgf000098_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0254] In some embodiments, the compound is of Formula (II-B-1-a-II-A-1-b): b), or a phar c derivative,
Figure imgf000099_0001
or tautomer thereof. [0255] In some embodiments, the compound is of Formula (II-B-1-a-II-A-1-b-I): -I), or a pha
Figure imgf000099_0002
derivative, or tautomer thereof. [0256] In some embodiments, the compound is of Formula (II-B-1-b):
b), or a pharmace otopic derivative,
Figure imgf000100_0001
or tautomer thereof. [0257] In some embodiments, the compound is of Formula (II-B-1-b-I): -I), or a pharma
Figure imgf000100_0002
opic derivative, or tautomer thereof. [0258] In some embodiments, the compound is of Formula (II-B-1-b-I-A):
A), or a pharm pic derivative,
Figure imgf000101_0001
or tautomer thereof. [0259] In some embodiments, the compound is of Formula (II-B-1-b-I-A-1): 1), or a phar
Figure imgf000101_0002
ic derivative, or tautomer thereof. [0260] In some embodiments, the compound is of Formula (II-B-1-b-I-A-1-a):
Figure imgf000102_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0261] In some embodiments, the compound is of Formula (II-B-l-b-I-A-l-a-I):
Figure imgf000102_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0262] In some embodiments, the compound is of Formula (II-B-l-b-I-A-l-a-II):
Figure imgf000103_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0263] In some embodiments, the compound is of Formula (II-B-l-b-I-B):
Figure imgf000103_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0264] In some embodiments, the compound is of Formula (II-B-l-b-I-B-1):
Figure imgf000104_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0265] In some embodiments, the compound is of Formula (II-B-l-b-I-B-l-a):
Figure imgf000104_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0266] In some embodiments, the compound is of Formula (II-B-l-b-I-C):
Figure imgf000104_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0267] In some embodiments, the compound is of Formula (II-B-1 -b-I-C-1 ):
Figure imgf000105_0001
or tautomer thereof.
[0268] In some embodiments, the compound is of Formula (II-B-l-b-I-C-l-a):
Figure imgf000105_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0269] In some embodiments, the compound is of Formula (II-B-1 -b-I-C-1 -a-I):
Figure imgf000106_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0270] In some embodiments, the compound is of Formula (II-B-l-b-I-C-l-a-I-A):
Figure imgf000106_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0271] In some embodiments, the compound is of Formula (II-B-1 -b-II):
Figure imgf000107_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0272] In some embodiments, the compound is of Formula (II-B-l-b-II-A):
Figure imgf000107_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0273] In some embodiments, the compound is of Formula (II-B-l-b-II-A-1):
Figure imgf000108_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0274] In some embodiments, the compound is of Formula (II-B-l-b-II-A-l-a):
Figure imgf000108_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0275] In some embodiments, the compound is of Formula (II-B-l-b-II-A-l-a-I):
Figure imgf000109_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0276] In some embodiments, the compound is of Formula (II-B-l-b-II-A-l-a-II):
Figure imgf000109_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0277] In some embodiments, the compound is of Formula (II-B-l-b-II-B):
Figure imgf000110_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0278] In some embodiments, the compound is of Formula (II-B-l-b-II-B-1):
Figure imgf000110_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0279] In some embodiments, the compound is of Formula (II-B-l-b-II-B-l-a):
Figure imgf000110_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0280] In some embodiments, the compound is of Formula (II-B-l-b-II-C):
Figure imgf000111_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0281] In some embodiments, the compound is of Formula (II-B-l-b-II-C-1):
Figure imgf000111_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0282] In some embodiments, the compound is of Formula (II-B-l-b-II-C-1 -a):
Figure imgf000112_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0283] In some embodiments, the compound is of Formula (II-B-l-b-II-C-l-a-I):
Figure imgf000112_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0284] In some embodiments, the compound is of Formula (II-B-l-b-II-C-l-a-I-A):
Figure imgf000113_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0285] In some embodiments, the compound is of Formula (II-B-2):
Figure imgf000113_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0286] In some embodiments, the compound is of Formula (II-B-2-a):
Figure imgf000114_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0287] In some embodiments, the compound is of Formula (II-B-2-a-I):
Figure imgf000114_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0288] In some embodiments, the compound is of Formula (II-B-2-a-I-A):
Figure imgf000115_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0289] In some embodiments, the compound is of Formula (II-B-2-a-I-A-l):
Figure imgf000115_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0290] In some embodiments, the compound is of Formula (II-B-2-a-I-A-l-a):
Figure imgf000116_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0291] In some embodiments, the compound is of Formula (II-B-2-a-I-A- l-a-I):
Figure imgf000116_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0292] In some embodiments, the compound is of Formula (II-B-2-a-I-A-l-b):
Figure imgf000117_0001
or tautomer thereof.
[0293] In some embodiments, the compound is of Formula (II-B-2-a-I-A-l-b-I):
Figure imgf000117_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0294] In some embodiments, the compound is of Formula (II-B-2-a-II):
Figure imgf000118_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0295] In some embodiments, the compound is of Formula (II-B-2-a-II-A):
Figure imgf000118_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0296] In some embodiments, the compound is of Formula (II-B-2-a-II-A-l):
Figure imgf000119_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0297] In some embodiments, the compound is of Formula (II-B-2-a-II-A-l-a):
Figure imgf000119_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0298] In some embodiments, the compound is of Formula (II-B-2-a-II-A-l-a-I):
Figure imgf000120_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0299] In some embodiments, the compound is of Formula (II-B-2-a-II-A- l-b):
Figure imgf000120_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0300] In some embodiments, the compound is of Formula (II-B-2-a-II-A-l-b-I):
Figure imgf000121_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0301] In some embodiments, the compound is of Formula (II-B-2-b):
Figure imgf000121_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0302] In some embodiments, the compound is of Formula (II-B-2-b-I):
Figure imgf000122_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0303] In some embodiments, the compound is of Formula (II-B-2-b-I-A):
Figure imgf000122_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0304] In some embodiments, the compound is of Formula (II-B-2-b-I-A-l):
Figure imgf000123_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0305] In some embodiments, the compound is of Formula (II-B-2-b-I-A-l-a):
Figure imgf000123_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0306] In some embodiments, the compound is of Formula (II-B-2-b-I-A-l-a-I):
Figure imgf000124_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0307] In some embodiments, the compound is of Formula (II-B-2-b-I-A- l-a-II):
Figure imgf000124_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0308] In some embodiments, the compound is of Formula (II-B-2-b-I-B):
Figure imgf000125_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0309] In some embodiments, the compound is of Formula (II-B-2-b-I-B-l):
Figure imgf000125_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0310] In some embodiments, the compound is of Formula (II-B-2-b-I-B-l-a):
Figure imgf000126_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0311] In some embodiments, the compound is of Formula (II-B-2-b-I-C):
Figure imgf000126_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0312] In some embodiments, the compound is of Formula (II-B-2-b-I-C-l):
Figure imgf000127_0001
or tautomer thereof.
[0313] In some embodiments, the compound is of Formula (II-B-2-b-I-C-l-a):
Figure imgf000127_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0314] In some embodiments, the compound is of Formula (II-B-2-b-I-C-l-a-I):
Figure imgf000128_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0315] In some embodiments, the compound is of Formula (II-B-2-b-I-C-l-a-I-A):
Figure imgf000128_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
[0316] In some embodiments, the compound is of Formula (II-B-2-b-II):
Figure imgf000129_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0317] In some embodiments, the compound is of Formula (II-B-2-b-II-A):
Figure imgf000129_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0318] In some embodiments, the compound is of Formula (II-B-2-b-II-A-l):
Figure imgf000130_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0319] In some embodiments, the compound is of Formula (II-B-2-b-II-A-l-a):
Figure imgf000130_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0320] In some embodiments, the compound is of Formula (II-B-2-b-II-A-l-a-I):
Figure imgf000131_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0321] In some embodiments, the compound is of Formula (II-B-2-b-II-A- l-a-II):
Figure imgf000131_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0322] In some embodiments, the compound is of Formula (II-B-2-b-II-B):
Figure imgf000132_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0323] In some embodiments, the compound is of Formula (II-B-2-b-II-B-l):
Figure imgf000132_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0324] In some embodiments, the compound is of Formula (II-B-2-b-II-B-l-a):
Figure imgf000133_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0325] In some embodiments, the compound is of Formula (II-B-2-b-II-C):
Figure imgf000133_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0326] In some embodiments, the compound is of Formula (II-B-2-b-II-C-l):
Figure imgf000134_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0327] In some embodiments, the compound is of Formula (II-B-2-b-II-C-l-a):
Figure imgf000134_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0328] In some embodiments, the compound is of Formula (II-B-2-b-II-C-l-a-I):
Figure imgf000135_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0329] In some embodiments, the compound is of Formula (II-B-2-b-II-C-l-a-I-A):
Figure imgf000135_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0330] In some embodiments, the compound is of Formula (III-A):
Figure imgf000136_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0331] In some embodiments, the compound is of Formula (III-A-1):
Figure imgf000136_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0332] In some embodiments, the compound is of Formula (III-A-l-a):
Figure imgf000136_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0333] In some embodiments, the compound is of Formula (III-A-l-a-I):
Figure imgf000137_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0334] In some embodiments, the compound is of Formula (III-A-l-a-I-A):
Figure imgf000137_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0335] In some embodiments, the compound is of Formula (III-A-l-a-I-A-1):
Figure imgf000138_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0336] In some embodiments, the compound is of Formula (III-A-l-a-I-A-l-a):
Figure imgf000138_0002
or tautomer thereof.
[0337] In some embodiments, the compound is of Formula (III-A-l-a-I-A-l-a-I):
Figure imgf000138_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0338] In some embodiments, the compound is of Formula (III-A-l-a-I-A-l-b):
Figure imgf000139_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0339] In some embodiments, the compound is of Formula (III-A-l-a-I-A-l-b-I):
Figure imgf000139_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0340] In some embodiments, the compound is of Formula (III-A-l-a-II):
Figure imgf000140_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0341] In some embodiments, the compound is of Formula (III-A-l-a-II-A):
Figure imgf000140_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0342] In some embodiments, the compound is of Formula (III-A-l-a-II-A-1):
Figure imgf000140_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0343] In some embodiments, the compound is of Formula (III-A-l-a-II-A-l-a):
Figure imgf000141_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0344] In some embodiments, the compound is of Formula (III-A-l-a-II-A-l-a-I):
Figure imgf000141_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0345] In some embodiments, the compound is of Formula (III-A-l-a-II-A-l-b):
Figure imgf000142_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0346] In some embodiments, the compound is of Formula (III-A-l-a-II-A-l-b-I):
Figure imgf000142_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0347] In some embodiments, the compound is of Formula (III-A-l-b):
Figure imgf000142_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0348] In some embodiments, the compound is of Formula (III-A- 1-b-I):
Figure imgf000143_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0349] In some embodiments, the compound is of Formula (III-A- 1-b-I- A):
Figure imgf000143_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0350] In some embodiments, the compound is of Formula (III-A- 1-b-I-A-l):
Figure imgf000144_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0351] In some embodiments, the compound is of Formula (III-A-l-b-I-A-l-a):
Figure imgf000144_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0352] In some embodiments, the compound is of Formula (III-A-l-b-I-A-l-a-I):
Figure imgf000144_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0353] In some embodiments, the compound is of Formula (III-A-l-b-I-A-l-a-II):
Figure imgf000145_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0354] In some embodiments, the compound is of Formula (III-A-l-b-II):
Figure imgf000145_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0355] In some embodiments, the compound is of Formula (III-A-l-b-II- A):
Figure imgf000146_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0356] In some embodiments, the compound is of Formula (III-A-l-b-II-A-1):
Figure imgf000146_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0357] In some embodiments, the compound is of Formula (III-A-l-b-II-A-1 -a):
Figure imgf000146_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0358] In some embodiments, the compound is of Formula (III-A-l-b-II-A-l-a-I):
Figure imgf000147_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0359] In some embodiments, the compound is of Formula (III-A-l-b-II-A-l-a-II):
Figure imgf000147_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0360] In some embodiments, the compound is of Formula (III-A-l-b-II-B):
Figure imgf000148_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0361] In some embodiments, the compound is of Formula (III-A- 1 -b-II-B-1 ):
Figure imgf000148_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0362] In some embodiments, the compound is of Formula (III-A-l-b-II-B-l-a):
Figure imgf000148_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0363] In some embodiments, the compound is of Formula (III-B):
Figure imgf000149_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0364] In some embodiments, the compound is of Formula (III-B-1):
Figure imgf000149_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0365] In some embodiments, the compound is of Formula (III-B-1 -a):
Figure imgf000149_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0366] In some embodiments, the compound is of Formula (III-B-l-a-I):
Figure imgf000150_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0367] In some embodiments, the compound is of Formula (III-B-l-a-I-A):
Figure imgf000150_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0368] In some embodiments, the compound is of Formula (III-B-l-a-I-A-1):
Figure imgf000151_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0369] In some embodiments, the compound is of Formula (III-B-l-a-I-A-l-a):
Figure imgf000151_0002
or tautomer thereof.
[0370] In some embodiments, the compound is of Formula (III-B-l-a-I-A-l-a-I):
Figure imgf000151_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0371] In some embodiments, the compound is of Formula (III-B-l-a-I-A-l-b):
Figure imgf000152_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0372] In some embodiments, the compound is of Formula (III-B-l-a-I-A-l-b-I):
Figure imgf000152_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0373] In some embodiments, the compound is of Formula (III-B-l-a-II):
Figure imgf000153_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0374] In some embodiments, the compound is of Formula (III-B-l-a-II-A):
Figure imgf000153_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0375] In some embodiments, the compound is of Formula (III-B-l-a-II-A-1):
Figure imgf000153_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0376] In some embodiments, the compound is of Formula (III-B-l-a-II-A-l-a):
Figure imgf000154_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0377] In some embodiments, the compound is of Formula (III-B-l-a-II-A-l-a-I):
Figure imgf000154_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0378] In some embodiments, the compound is of Formula (III-B-l-a-II-A-l-b):
Figure imgf000155_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0379] In some embodiments, the compound is of Formula (III-B-1 -a-II-A-1 -b-I):
Figure imgf000155_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0380] In some embodiments, the compound is of Formula (III-B-l-b):
Figure imgf000155_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0381] In some embodiments, the compound is of Formula (III-B-l-b-I):
Figure imgf000156_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0382] In some embodiments, the compound is of Formula (III-B-l-b-I-A):
Figure imgf000156_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0383] In some embodiments, the compound is of Formula (III-B-l-b-I-A-1):
Figure imgf000157_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0384] In some embodiments, the compound is of Formula (III-B-l-b-I-A-l-a):
Figure imgf000157_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0385] In some embodiments, the compound is of Formula (III-B-l-b-I-A-l-a-I):
Figure imgf000157_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0386] In some embodiments, the compound is of Formula (III-B-l-b-I-A-l-a-II):
Figure imgf000158_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0387] In some embodiments, the compound is of Formula (III-B-1 -b-II):
Figure imgf000158_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0388] In some embodiments, the compound is of Formula (III-B-l-b-II-A):
Figure imgf000159_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0389] In some embodiments, the compound is of Formula (III-B-1 -b-II-A-1 ):
Figure imgf000159_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0390] In some embodiments, the compound is of Formula (III-B-1 -b-II-A-1 -a):
Figure imgf000159_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0391] In some embodiments, the compound is of Formula (III-B-l-b-II-A-l-a-I):
Figure imgf000160_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0392] In some embodiments, the compound is of Formula (III-B-l-b-II-A-l-a-II):
Figure imgf000160_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0393] In some embodiments, the compound is of Formula (III-B-l-b-II-B):
Figure imgf000161_0001
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0394] In some embodiments, the compound is of Formula (III-B-1 -b-II-B-1 ):
Figure imgf000161_0002
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
[0395] In some embodiments, the compound is of Formula (III-B-l-b-II-B-l-a):
Figure imgf000161_0003
or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0396] In some embodiments, the compound is of Formula (A). In some embodiments, the compound is of Formula (I). In some embodiments, the compound is of Formula (II). In some embodiments, the compound is of Formula (III). [0397] In some embodiments, the compound is of Formula (A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0398] In some embodiments, the compound is of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0399] In some embodiments, the compound is of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0400] In some embodiments, the compound is of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0401] In some embodiments, W is selected from CHRw, NH, and -CH=CH-, wherein Rw and R5 together form a double bond. [0402] In some embodiments, W is CHRw, wherein Rw and R5 together form a double bond. [0403] In some embodiments, W is NH. [0404] In some embodiments, W is -CH2=CH2-. [0405] In some embodiments, Q is selected from CRq and N, wherein Rq is halogen. [0406] In some embodiments, Q is CRq, wherein Rq is halogen. [0407] In some embodiments, Q is CF. [0408] In some embodiments, Q is CCl. [0409] In some embodiments, Q is CBr. [0410] In some embodiments, Q is N. [0411] In some embodiments, G is selected from N and CRg. [0412] In some embodiments, G is N. [0413] In some embodiments, G is CRg, wherein Rg is selected from H, -NH2, -CH=NH. [0414] In some embodiments, G is C-NH2. [0415] In some embodiments, G is CH. [0416] In some embodiments, R1 is selected from H, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 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. [0417] In some embodiments, R1 is H. [0418] In some embodiments, R1 is halogen. [0419] In some embodiments, R1 is F. [0420] In some embodiments, R2 is C1-C6 alkyl. [0421] In some embodiments, R2 is methyl. [0422] In some embodiments, R3 is selected from H and C1-C6 alkyl. [0423] In some embodiments, R3 is H. [0424] In some embodiments, R3 is C1-C6 alkyl. [0425] In some embodiments, R2 and R3 together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy. [0426] In some embodiments, R2 and R3 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle comprising one nitrogen atom. [0427] In some embodiments, R4 is selected from H and C1-C6 alkyl. [0428] In some embodiments, R4 is H. [0429] In some embodiments, R4 is C1-C6 alkyl. [0430] In some embodiments, R5 is selected from H, C1-C6 alkyl. [0431] In some embodiments, R5 is H. [0432] In some embodiments, R5 is C1-C6 alkyl. [0433] In some embodiments, R4 and R5 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, wherein W is NH. [0434] In some embodiments, R6 is selected from H, F, -CHF2, and -CH=CH2. [0435] In some embodiments, R6 is H. [0436] In some embodiments, R6 is F. [0437] In some embodiments, R6 is -CHF2. [0438] In some embodiments, R6 is -CH=CH2. [0439] In some embodiments, R4 is H, W is CHRw, wherein Rw and R5 together form a double bond, R6 is F. [0440] In some embodiments, R4 is H, W is CHRw, wherein Rw and R5 together form a double bond, R6 is F. [0441] In some embodiments, R4 and R5 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, W is NH, R6 is -CH=CH2. [0442] In some embodiments, R4 and R5 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, W is NH, R6 is -CHF2. [0443] In some embodiments, R4 is H, W is -CH=CH-, R5 is H, R6 is H. [0444] In some embodiments, R7 is selected from -NH2 and -SH. [0445] In some embodiments, R7 is -NH2. [0446] In some embodiments, R7 and Rg 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. [0447] In some embodiments, R7 and Rg 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. [0448] In some embodiments, R7 and Rg together with the atoms to which they are attached and any intervening atoms, form a 5 membered heteroaryl comprising two nitrogen atoms. [0449] In some embodiments, R7 and Rg 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. [0450] In some embodiments, R7 and Rg 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. [0451] In some embodiments, R8 is selected from H, halogen. [0452] In some embodiments, R8 is H. [0453] In some embodiments, R8 is halogen. [0454] In some embodiments, R8 is F. [0455] In some embodiments, R9 is selected from H, halogen, C1-C6 alkyl. [0456] In some embodiments, R9 is H. [0457] In some embodiments, R9 is halogen. [0458] In some embodiments, R9 is F. [0459] In some embodiments, R9 is C1-C6 alkyl. [0460] In some embodiments, R9 is methyl. [0461] In some embodiments, R10 is selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen. [0462] In some embodiments, R10 is H. [0463] In some embodiments, R10 is C1-C6 alkyl. [0464] In some embodiments, R10 is methyl. [0465] In some embodiments, R10 is C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen. [0466] In some embodiments, R10 is methyl, wherein the alkyl is optionally substituted with one or more halogen . [0467] In some embodiments, R10 is -CF3. [0468] In some embodiments, R9 and R10 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, -NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl. [0469] In some embodiments, R9 and R10 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 C2-C6 alkynyl group. [0470] In some embodiments, R9 and R10 together with the atoms to which they are attached and any intervening atoms, form a substituted 6 membered ar . [0471] In some embodiments, R11 is selected from H, halogen.
Figure imgf000165_0001
[0472] In some embodiments R11 is H [0473] In some embodiments, R11 is halogen. [0474] In some embodiments, R11 is F. [0475] In some embodiments, 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. Certain examples of the compound of Formula A # Structure IUPAC Name - - 2- - - 2-
Figure imgf000166_0001
ģ Structure IUPAC Name - - 2- - - - - - - - - -
Figure imgf000167_0001
ģ Structure IUPAC Name - - - - 8- - - - 2- 8- - - 2-
Figure imgf000168_0001
ģ Structure IUPAC Name 8- - 2- - 2- - - - - -
Figure imgf000169_0001
ģ Structure IUPAC Name - - - - ]- - - - ]- -
Figure imgf000170_0001
ģ Structure IUPAC Name - - ]- - - - - - - -
Figure imgf000171_0001
ģ Structure IUPAC Name - - - - - ]- - - ]- -
Figure imgf000172_0001
ģ Structure IUPAC Name - 2- ]- - - -
Figure imgf000173_0001
ģ Structure IUPAC Name - - - - 2- - - - 2-
Figure imgf000174_0001
ģ Structure IUPAC Name F - - - 2- - - - - - - - -
Figure imgf000175_0001
ģ Structure IUPAC Name - - - - 8- - - 2- 8- - - - 2-
Figure imgf000176_0001
ģ Structure IUPAC Name 8- - - 2- - - - -
Figure imgf000177_0001
ģ Structure IUPAC Name - - ]- - - ]- -
Figure imgf000178_0001
ģ Structure IUPAC Name ]- - - - - - - - -
Figure imgf000179_0001
ģ Structure IUPAC Name - - - - - ]- - - - ]- -
Figure imgf000180_0001
ģ Structure IUPAC Name - ]- - - - -
Figure imgf000181_0001
ģ Structure IUPAC Name - - - - - - - -
Figure imgf000182_0001
ģ Structure IUPAC Name - - - - - - - - - - -
Figure imgf000183_0001
ģ Structure IUPAC Name H N - - - - 8- - - 5- - 8- - 5- -
Figure imgf000184_0001
ģ Structure IUPAC Name 8- - 2- 5- - - - - -
Figure imgf000185_0001
ģ Structure IUPAC Name - - - - ]- - - - ]- -
Figure imgf000186_0001
ģ Structure IUPAC Name - - ]- - - - - 2- - - - 2-
Figure imgf000187_0001
ģ Structure IUPAC Name - - - 2- - - ]- - - ]- -
Figure imgf000188_0001
ģ Structure IUPAC Name H N CHF2 - 2- ]- - - 2- - 2-
Figure imgf000189_0001
ģ Structure IUPAC Name - 2- - - -
Figure imgf000190_0001
ģ Structure IUPAC Name F - - - - - - - - -
Figure imgf000191_0001
ģ Structure IUPAC Name H N - - - - 8- - 5- - 8- - - 5- -
Figure imgf000192_0001
ģ Structure IUPAC Name 8- - 5- - - - - -
Figure imgf000193_0001
ģ Structure IUPAC Name - - ]- - - ]- -
Figure imgf000194_0001
ģ Structure IUPAC Name ]- - - - - - 2- - - - 2-
Figure imgf000195_0001
ģ Structure IUPAC Name - - - - 2- - ]- - - - ]- -
Figure imgf000196_0001
ģ Structure IUPAC Name - ]- - - - 2- - 2-
Figure imgf000197_0001
ģ Structure IUPAC Name - - 2- l- - l- -
Figure imgf000198_0001
ģ Structure IUPAC Name l- - l- - - l- - -
Figure imgf000199_0001
ģ Structure IUPAC Name l- n- n- e - - -
Figure imgf000200_0001
ģ Structure IUPAC Name - l- l-
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
# Structure IUPAC Name
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
# F - - )-
Figure imgf000248_0001
one o t e compounds descrbed n Table 1. [0482] In some embodiments, 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. [0483] In some embodiments, the compound is a salt of any acid described in the Table 2 and any one of the compounds described in Table 1. [0484] Table 2. Pharmaceutical acceptable acid forming salts with the Compound of Formulas (A). 1-hydroxy-2-naphthoic ethanesulfonic acid; methanesulfonic acid; id f i id hhl 15di lf ic
Figure imgf000248_0002
caproic acid (hexanoic lauric acid; sulfuric acid; acid); maleic acid; tartaric acid (+ L); the
Figure imgf000249_0001
p . [0486] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1. [0487] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1. [0488] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1. [0489] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1. [0490] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1. [0491] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1. [0492] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1. [0493] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1. [0494] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1. [0495] In some aspects, 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. [0496] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0497] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0498] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0499] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1. [0500] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, 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. [0501] In some embodiments, the isotopic derivative is a deuterium labeled compound. [0502] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein. [0503] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, 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). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from 2H, 13C, 14C, 15N, 18O, 29Si, 31P, and 34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with 2H with regard to one or more atoms thereof). [0504] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof. [0505] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof. [0506] In some embodiments, 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. [0507] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1. [0508] It is understood that 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%. [0509] In some embodiments, 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). As used herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium. [0510] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, 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. [0511] 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. Further, substitution with deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. [0512] In some embodiments, the compound is a 18F labeled compound. [0513] In some embodiments, the compound is a 33S labeled compound, a 34S labeled compound, a 35S labeled compound, a 36S labeled compound, or any combination thereof. . [0514] It is understood that the 18F, 33S, 34S, 35S, and/or 36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, 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 18F, 33S, 34S, 35S, and/or 36S labeled reagent for a non-isotope labeled reagent.
[0515] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned 18F, 33S, 34S, 35S, and 36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,, 18F, 33S, 34S, 35S, and/or 36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.
[0516] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.
[0517] 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.
[0518] 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. In addition, 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. [0519] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.
[0520] As used herein, 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.”
[0521] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.
[0522] As used herein, the term “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.” When one chiral center is present, 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. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
[0523] As used herein, the term “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.
[0524] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.
[0525] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.
[0526] As used herein, the term “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.
[0527] As used herein, the term “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. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose. [0528] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others. [0529] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. 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 “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. 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”.
[0530] 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.
[0531] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.
[0532] It is to be understood that the compounds of 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).
[0533] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, 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.
[0534] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, 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.
[0535] As used herein, the term “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.
[0536] As used herein, the term “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). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
[0537] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein. [0538] As used herein, the term “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. Examples of 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.
[0539] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated 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.
[0540] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.
[0541] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of present disclosure include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (A), (I), (II), or (III). Examples of tautomeric forms 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.
Figure imgf000258_0001
keto enol enolate
[0542] Compounds of any one of the Formulae disclosed herein containing an amine function may also form A-oxides. A reference herein to a compound of Formula (A) that contains an amine function also includes the A-oxide. Where a compound contains several amine functions, 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 peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. More particularly, 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.
[0543] 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.
[0544] Accordingly, 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.
[0545] 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. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.
[0546] 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). Further suitable pharmaceutically acceptable 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. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(CI-C4 alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups. [0547] 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 C1-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N- ethyl-N-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof. [0548] 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. Examples of 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. [0549] 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). Method of Synthesizing the Compounds [0550] 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. [0551] 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). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (A) and of Formula (I), (II) and (III). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
[0552] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
Preparation of Compounds
[0553] 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. By way of example, 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.
GENERAL PROCEDURE
[0554] In general, the compounds of present invention can be prepared using sequences of reactions presented at the Scheme 1. [0555] Scheme 1
Figure imgf000262_0001
[0556] It must be understood that any of the compounds at the Scheme 1, any of substituents in these compounds can be further modified at any step of presented sequences to provide modified derivatives of these compounds useful for preparation of compounds of present disclosure.
[0557] 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.
[0558] It should be obvious for specialist in this field that any of compound of the present invention obtained according to the procedures described above may be a subject for further transformation and modification that will let to obtain other compound of the invention.
Biological Assays
[0559] 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. For example, 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.
[0560] Furthermore, 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. These 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. Pharmaceutical Compositions
[0562] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, 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. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.
[0563] As used herein, the term “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.
[0564] 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. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided 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.
[0565] 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.
[0566] 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. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles 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. Alternatively, 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.
[0567] 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 on 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.
[0568] 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.
[0569] Any suitable solubility enhancing agent can be used. Examples of 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 ether, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y- cyclodextrin, and trimethyl-'y-cyclodextrin, and mixtures thereof.
[0570] Any suitable chelating agent can be used. Examples of 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.
[0571] Any suitable preservative can be used. 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, 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.
[0572] In some embodiments, 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.
[0573] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. [0574] 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.
[0575] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), 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. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.
[0576] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof.
[0577] The formulation may further comprise a wetting agent. Suitable classes of 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.
[0578] 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. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[0579] According to a further aspect of the disclosure there is provided 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.
[0580] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.
[0581] The 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).
[0582] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents. [0583] 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.
[0584] 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.
[0585] 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.
Methods of Use
[0586] In some aspects, 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.
[0587] In some aspects, 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.
[0588] In some aspects, 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.
[0589] In some embodiments, 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.
[0590] The compounds of the invention are also useful in treating diseases associated with KRAS(G12D). For example, 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); Costello Syndrome (CSTLO); Skin Melanoma; Gastrointestinal Stromal Tumor (GIST); Tatton-Brown- Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RBI); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1) 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.
[0591] The compounds of the invention are also useful in treating diseases associated with KRAS(G12D). For example, 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); Costello Syndrome (CSTLO); Skin Melanoma; Gastrointestinal Stromal Tumor (GIST); Tatton-Brown- Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RBI); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I) - (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
[0592] In some embodiments, the disease or disorder is a Lung Cancer (LNCR).
[0593] In some embodiments, the disease or disorder is a Pancreatic Cancer (PNCA).
[0594] In some embodiments, the disease or disorder is a Colorectal Cancer (CRC).
[0595] In some aspects, 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.
[0596] In some aspects, 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.
[0597] In some aspects, the present disclosure provides a method of treating or preventing 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.
[0598] In some aspects, 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. [0599] In some aspects, 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.
[0600] In some aspects, 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.
[0601] In some aspects, 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).
[0602] In some aspects, 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.
[0603] In some aspects, 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.
[0604] In some aspects, 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.
[0605] In some aspects, 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.
[0606] In some aspects, 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.
[0607] In some aspects, 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. [0608] In some aspects, 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.
[0609] In some aspects, 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.
[0610] In some aspects, 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).
[0611] In some aspects, 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.
[0612] In some aspects, 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.
[0613] In some aspects, 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.
[0614] In some aspects, 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.
[0615] In some aspects, 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.
[0616] In some aspects, 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. [0617] In some aspects, 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.
[0618] In some aspects, 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.
[0619] 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.
[0620] In some embodiments, the inhibitor of KRAS(G12D) is a compound of the present disclosure.
[0621] 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.
[0622] The present disclosure also provides a method of treating a disease or disorder in which KRAS(G12D) is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.
[0623] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.
Routes of Administration
[0624] 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).
[0625] 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, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
EXAMPLES
General synthetical procedures and examples of the compound’s preparation.
[0626] All reagents were commercial and were used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using Merck TLC Aluminum sheets silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40/75, 40-75 pm) purchased by Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR operating at 400 MHz for 1H. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. Data is reported as follows: s = singlet, br. = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets; coupling constants in Hz; integration.
[0627] Abbreviations used in the following examples and elsewhere herein are:
ACN acetonitrile
AcOH acetic acid aq. aqueous
DAST diethylamino sulfur trifluoride
DCM dichloromethane
DIPEA A/Y-diisopropylethylamine
DMF A,A-dimethyl formamide
DMSO dimethyl sulfoxide
EA ethyl acetate
ESI electro spray ionization h hour(s)
HPLC high pressure (or performance) liquid chromatography
LCMS liquid chromatography mass spectrometry
M molar
MHz megahertz min minutes NMR nuclear magnetic resonance PE petroleum ether rt room temperature s solid sat. saturated
TFA trifluoracetic acid
THF tetrahydrofuran
Examples of the Final Compound
[0628] In the Table 3 presented analytical data for certain non-limiting examples of the compound of Formula (A).
[0629] Table 3 Selected examples of the compound of Formula (A)
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
Figure imgf000315_0001
Figure imgf000316_0001
Figure imgf000317_0001
Figure imgf000318_0001
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Figure imgf000322_0001
Figure imgf000323_0001
Figure imgf000324_0001
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Synthesis of Building Blocks
Synthesis of 2,7-dichloro-4-(l-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine (P7)
Figure imgf000359_0001
[0630] Preparation 1. tert-Butyl 1-(hydroxymethyl)-3-trityl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (P1). To a solution of tert-butyl 1-formyl-3-trityl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5.70 g, 90 % purity, 10.6 mmol) in MeOH (50 mL) was added NaBH4 (200 mg, 5.29 mmol) at 0℃. The reaction was stirred at rt for 1 h. Then the mixture was quenched with water (30 mL) and extracted with EA (50 mL) twice. The combined organic layers were washed with brine (50 mL), dried over Na2SO4(s) and concentrated in vacuo to afford the title compound P1 (5.7 g, 90 % purity from 1H NMR, 99 % yield) as a white solid. 1H NMR (400 MHz, CDCl3), δ: 7.49 (s, 6H), 7.27 - 7.23 (m, 6H), 7.15 - 7.11 (m, 3H),
Figure imgf000359_0002
. 8 - 4.96 (m, 1H), 4.10 - 4.09 (m, 1H), 3.72 - 3.60 (m, 2H), 2.98 - 2.95 (m, 2H), 2.43 - 2.36 (m, 1H), 2.29 - 2.23 (m, 1H), 2.01 - 1.92 (m, 2H), 1.76 - 1.58 (m, 2H), 1.19 (s, 9H). [0631] Preparation 2. 3-Benzyl 8-(tert-butyl) 1-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-3,8-dicarboxylate (P2). To a solution of tert-butyl 1-(hydroxymethyl)-3-trityl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate P1 (5.7 g, 10.6 mmol) in DCM (50 mL) was added 4M HCl/1,4-dioxane (17 mL) at 0℃. After stirred at 0℃ for 1 h, the mixture was removed the solvent to give a residue. To a solution of the residue and benzyl carbonochloridate (2.00 g, 11.7 mmol) in THF (20 mL) was added sat. NaHCO3 solution (20 mL). The reaction mixture was stirred at 0℃ for 2 h. Then, the mixture was extracted with EA (50 mL) twice. The organic layers were dried over Na2SO4(s) and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography (PE:EA = 3: 1) to afford the title compound P2 (3.18 g, 90 % purity from 1H NMR, 72 % yield) as a yellow oil. LCMS (ESI): RT = 2.41 min, mass calc. for C20H28N2O5376.2, m/z found 277.3 [M+H-100]+.1H NMR (400 MHz, CDCl3), δ: 7.37 - 7.33 (m, 5H), 5.18 - 5.14 (m, 2H), 4.28 - 4.22 (m, 1H), 3.91 - 3.69 (m, 4H), 3.37 - 3.25 (m, 1H), 3.12 - 2.98 (m, 1H), 1.92 - 1.87 (m, 1H), 1.77 - 1.59 (m, 3H), 1.47 (s, 9H). [0632] Preparation 3. Benzyl 1-(hydroxymethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (P3). To a solution of 3-benzyl 8-(tert-butyl) 1-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane- 3,8-dicarboxylate P2 (2.01 g, 90 % purity, 4.81 mmol) in DCM (10 mL) was added TFA (10 mL) at 0℃. After stirred at 0℃ for 1 h, the mixture was quenched with sat. NaHCO3 solution (20 mL) and extracted with DCM (20 ml) twice. The combined organic layers were concentrated under pressure to give a residue. A solution of the residue, 4- nitrobenzenesulfonyl chloride (1.01 g, 4.56 mmol) and K2CO3 (630 mg, 4.56 mmol) in ACN (10 mL) and H2O (10 mL). After, the solution was stirred at rt for overnight. The mixture was extracted with EA (20 mL) twice and the organic layers were dried over Na2SO4(s) and filtered. The filtrate was concentrated to give a residue which was purified by C18 (ACN : water = 30 % - 60 %) to afford the title compound P3 (690 mg, 90% purity from 1H NMR, 28% yield) as a yellow solid. LCMS (ESI): RT = 2.12 min, mass calc. for C21H23N3O7S 461.1, m/z found 462.3 [M+H]+.1H NMR (400 MHz, DMSO-d6), δ: 8.37 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.8 Hz, 2H), 7.37 - 7.33 (m, 5H), 5.14 - 5.04 (m, 3H), 4.47 - 4.44 (m, 1H), 3.98 - 3.97 (m, 1H), 3.88 - 3.79 (m, 2H), 3.63 - 3.61 (m, 1H), 3.20 - 2.92 (m, 2H), 1.75 - 1.48 (m, 4H). [0633] Preparation 4. Benzyl 1-formyl-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (P4). To a solution of benzyl 1-(hydroxymethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate P3 (590 mg, 90 % purity, 1.15 mmol) in DCM (10 mL) was added Dess-Martin (1.08 g, 2.55 mmol) at 0℃. After stirred at 0℃ for 1 h, the mixture was quenched with sat. NaHCO3 solution (20 mL) and extracted with DCM (20 ml) twice. The combined organic layers were washed with sat. NaHCO3 solution (20 mL) twice, dried over Na2SO4(s) and filtered. The filtrate was concentrated to afford the desired product P4 (800 mg, 60 % purity from 1H NMR, 91 % yield) as yellow solids. 1H NMR (400 MHz, CDCl3), δ: 9.70 (s, 1H), 8.38 (d, J = 8.8 Hz, 2H), 8.04 - 8.00 (m, 2H), 7.37 - 7.32 (m, 5H), 5.15 (s, 2H), 4.31 - 4.18 (m, 2H), 3.99 - 3.85 (m, 1H), 3.50 - 3.35 (m, 2H), 2.01 - 1.71 (m, 4H). [0634] Preparation 5. Benzyl 1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate (P5). To a solution of benzyl 1-formyl-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate P4 (800 mg, 60 % purity, 1.04 mmol) in DCM (20 mL) was added DAST (195 mg, 1.21 mmol) at 0℃. After stirred at rt overnight, the mixture was quenched with sat. NaHCO3 solution (20 mL) and extracted with DCM (20 ml) twice. The combined organic layers were dried over Na2SO4(s) and filtered. The filtrate was concentrated to leave a residue which was purified by silica gel chromatography (PE:EA = 3: 1) to afford the title compound P5 (460 mg, 90 % purity from 1H NMR, 82 % yield) as white solids. 1H NMR (400 MHz, CDCl3), δ: 8.34 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.37 - 7.33 (m, 5H), 6.50 (t, J = 55.6 Hz, 1H), 5.20 - 5.12 (m, 2H), 4.28 - 3.90 (m, 3H), 3.57 - 3.33 (m, 2H), 2.19 - 2.12 (m, 1H), 1.93 - 1.66 (m, 3H).19F NMR (376 MHz, CDCl3), δ: -125.75 - -126.61 (m, 1F), -129.12 - -130.09 (m, 1F). [0635] Preparation 6. 1-(Difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane (P6). To a solution of benzyl 1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane-3-carboxylate P5 (460 mg, 90 % purity, 0.860 mmol) in DCM (5 mL) was added HBr (33% wt. in AcOH, 5 mL) at 0℃. After stirred at 0℃ for 0.5 h, the mixture was quenched with water (20 mL) and washed with DCM (20 mL) twice. The water layers diluted with NaHCO3 (aq.) until pH = 7 and extracted with EA (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4(s) and filtered. The filtrate was concentrated to afford the desired product P6 (250 mg, 90 % purity from 1H NMR, 75 % yield) as yellow oil. LCMS (ESI): RT = 1.62 min, mass calc. for C13H15F2N3O4S 347.1, m/z found 348.2 [M+H]+. 1H NMR (400 MHz, CDCl3), δ: 8.33 (d, J = 9.2 Hz, 2H), 8.02 (d, J = 9.2 Hz, 2H), 6.46 (t J = 55.6 Hz, 1H), 4.23 - 4.22 (m, 1H),
Figure imgf000362_0001
3.37 (d, J = 12.0 Hz, 1H), 3.26 (d, J = 12.0 Hz, 1H), 2.93 (d, J = 12.0 Hz, 1H), 2.80 (d, J = 14.4 Hz, 1H), 2.20 - 2.09 (m, 2H), 1.95 - 1.89 (m, 2H).19F NMR (376 MHz, CDCl3), δ: - 126.05 - - 126.84 (m, 1F), - 128.71 - - 129.50 (m, 1F). [0636] Preparation 7. 2,7-Dichloro-4-(1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)- 3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine (P7). To a solution of 1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octane P6 (250 mg, 90 % purity, 0.648 mmol) and 2,4,7-trichloro-8- fluoropyrido[4,3-d]pyrimidine (180 mg, 0.713 mmol) in DCM (2 mL) was added DIPEA (420 mg, 3.25 mmol) at 0℃. After stirred at 0℃ for 2 h, the mixture was quenched with water (20 mL) and washed with DCM (20 mL) twice. The combined organic layers were dried over Na2SO4(s) and filtered. The filtrate was concentrated to leave a residue which was purified by silica gel chromatography (DCM:MeOH = 20:1) to afford the title compound P7 (350 mg, 90 % purity from LCMS, 86 % yield) as yellow solids. LCMS (ESI): RT = 2.46 min, mass calc. for C20H15Cl2F3N6O4S 562.0, m/z found 563.1 [M+H]+. Synthesis of 4-(4-(1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol hydrochloride salt (P11)
TIPS F Ns F Ns F O N N
Figure imgf000363_0001
p . y p y y 3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (P8). To a solution of 2,7-dichloro-4-(1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidine P7 (350 mg, 90 % purity, 0.559 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (267 mg, 1.68 mmol) in 1,4-dioxane (5 mL) was added DIPEA (216 mg, 1.68 mmol) at rt. After stirred at 85℃ overnight, the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL) twice. The combined organic layers were dried over Na2SO4(s) and filtered. The filtrate was concentrated to leave a residue which was purified by silica gel chromatography (DCM:MeOH = 20: 1) to afford the title compound P8 (330 mg, 90 % purity from 1H NMR, 77 % yield) as yellow solids. LCMS (ESI): RT = 1.91 min, mass calc. for C28H28ClF4N7O5S 685.2, m/z found 686.3 [M+H]+. 1H NMR (400 MHz, CDCl3), δ: 8.74 (s, 1H),8.38 (d, J = 9.2 Hz, 2H),8.06 (d, J = 8.8 Hz, 2H), 6.59 (t, J = 55.2 Hz, 1H), 5.34 (s, 0.5H), 5.21 (s, 0.5H), 4.75 - 4.69 (m, 1H), 4.51 - 4.46 (m, 1H), 4.39 - 4.37 (m, 1H), 4.30 - 4.25 (m, 2H), 4.19 - 4.11 (m, 1H), 3.95 - 3.90 (m, 1H), 3.27 - 3.16 (m, 3H), 3.01 - 2.93 (m, 1H), 2.25 - 1.76 (m, 10H) .19F NMR (376 MHz, CDCl3), δ: - 125.70 - - 126.49 (m, 1F), - 129.47 - - 130.28 (m, 1F), - 133.54 - - 133.55 (m, 1F), - 173.09 - - 173.11 (m, 1F). [0638] Preparation 9. 4-(1-(Difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (P9). A suspension of 7-chloro-4-(1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine P8 (330 mg, 90 % purity, 0.433 mmol), ((2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen- 1-yl)ethynyl)triisopropylsilane (443 mg, 0.864 mmol), cataCXium A-Pd G3 (31 mg, 0.043 mmol) and potassium phosphate tribasic (183 mg, 0.862 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed with nitrogen atmosphere and stirred at 100°C for 3 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4(s), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound P.9 (360 mg, 90 % purity from LCMS, 72% yield) as yellow solids. LCMS (ESI): RT = 2.75 min, mass calc. for C51H58F5N7O7SSi 1035.4, m/z found 1036.7 [M+H]+. [0639] Preparation 10. 4-(1-(Difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine (P10). A mixture of 4-(1-(difluoromethyl)-8-((4-nitrophenyl)sulfonyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine P9 (360 mg, 90 % purity, 0.313 mmol), 4-isopropylbenzenethiol (142 mg, 0.933 mmol) and K2CO3 (128 mg, 0.926 mmol) in DMF (5 mL) was stirred at rt overnight. The mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL) twice. The combined organic layers were dried over Na2SO4(s) and filtered. The filtrate was concentrated to leave a residue which was purified by silica gel chromatography (DCM:MeOH = 20:1) to afford the title compound P10 (180 mg, 90 % purity from LCMS, 61 % yield) as yellow solids. LCMS (ESI): RT = 2.42 min, mass calc. for C45H55F5N6O3Si 850.4, m/z found 851.6 [M+H]+. [0640] Preparation 11. 4-(4-(1-(Difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol hydrochloride salt (P11). To a solution of 4-(1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7- fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine P10 (180 mg, 90 % purity, 0.190 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (1 mL, 4 mmol) at 0℃. The reaction mixture was stirred at rt for 2 h. The mixture was concentrated to afford the compound P11 (150 mg, 96% purity from LCMS, 81% yield) as yellow solids. LCMS (ESI): RT = 2.61 min, mass calc. for C43H51F5N6O2Si 806.4 m/z found 807.6 [M+H]+. Synthesis of the Representative Examples of the compound [0641] Example 1. 4-(4-(1-(Difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 241).
Figure imgf000365_0001
To a solution of 4-(4-(1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin- 7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol hydrochloride salt P11 (150 mg, 96% purity, 0.171 mmol) in DMF (2 mL) and water (0.2 mL) was added cesium fluoride (130 mg, 0.853 mmol) at 25℃. The reaction mixture was stirred at 60℃ under nitrogen atmosphere for 4 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4(s), filtered and concentrated. The residue was purified by prep- HPLC (acetonitrile: 0.1% ammonium bicarbonate aqueous solution = 0% to 90%) to afford the title product compound 241 (70.0 mg, 99.18% purity from HPLC, 63% yield) as yellow solids. LCMS (ESI): RT = 0.773 min, mass calc. for C34H31F5N6O2650.2, m/z found 651.2 [M+H]+. 1H NMR (400 MHz,DMSO-d6), δ: 10.14 (s, 1H), 9.05 (d, J = 3.6 Hz, 1H), 8.00 - 7.96 (m, 1H), 7.49 - 7.39 (m,2H), 7.19 - 7.18 (m, 1H), 6.11 (t, J = 56.0 Hz, 1H), 5.35 - 5.21 (m, 1H), 4.69 (d, J = 12.4 Hz, 0.5H), 4.53 (d, J = 12.0 Hz, 0.5H), 4.42 (d, J = 12.4 Hz, 0.5H), 4.25 (d, J = 12.4 Hz, 0.5H), 4.16 - 3.88 (m, 3H), 3.76 - 3.48 (m, 3H), 3.10 - 2.80 (m, 5H), 2.13 - 2.00 (m, 3H), 1.86 - 1.69 (m, 7H).19F NMR (376 MHz, CDCl3), δ: - 110.69 - - 110.75 (m, 1F), - 125.92 - - 126.67 (m, 1F), - 128.04 - - 128.89 (m, 1F), - 140.03 - - 140.13 (m, 1F), - 172.09 - - 172.21 (m, 1F). [0642] Example 2. 4-(4-((1R,5S)-1-(Difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)- 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Compound 242) and 4-(4-((1S,5R)- 1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol (Compound 243).
Figure imgf000367_0001
, )-8- fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol 241 (54 mg, 99.18 % purity, 0.082 mmol) was separated by Chiral HPLC (IF, Method: Hex-EtOH-DEA= 60-40-0.2-20 min) to give the title products 242 (15.5 mg, 97.48 % purity from HPLC, 28.2 % yield, 99.6 % ee) and 243 (15.6 mg, 97.91 % purity from HPLC, 28.5 % yield, 100 % ee) all as yellow solids. 242: LCMS (ESI): RT = 0.945 min, mass calc. for C34H31F5N6O2 650.2 m/z found 651.0 [M+H]+. Chiral HPLC (IF, Method: Hex- EtOH- DEA= 60-40-0.2-20 min; Column: 250 mm*4.6 mm 5 um; 1 ml/min, 30 °C, 230 nm, RT = 9.227 min).1H NMR (400 MHz, DMSO- d6), δ: 10.14 (s, 1H), 9.05 (d, J = 3.6 Hz, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (t, J = 2.8 Hz, 1H), 6.25 - 5.97 (m, 1H), 5.34 - 5.21 (m, 1H), 4.69 (d, J = 12.0 Hz, 0.5H), 4.53 (d, J = 12.0 Hz, 0.5H), 4.42 (d, J = 11.6 Hz, 0.5H), 4.25 (d, J = 12.0 Hz, 0.5H), 4.13 - 4.04 (m, 2H), 3.95 - 3.89 (m, 1H), 3.76 - 3.61 (m, 2H), 3.52 (dd, J = 17.2, 12.4 Hz, 1H), 3.13 - 3.04 (m, 2H), 3.01 (s, 1H), 2.91 (s, 1H), 2.86 - 2.80 (m, 1H), 2.17 - 1.97 (m, 3H), 1.90 - 1.64 (m, 7H).19F NMR (376 MHz, DMSO- d6) δ -110.70 - -110.74 (m, 1F), -125.69 - -126.67 (m, 1F), -128.04 - -128.88 (m, 1F), - 140.03 - -140.13 (m, 1F), -172.09 - -172.21 (m, 1F). LCMS (ESI): RT = 0.944 min, mass calc. for C34H31F5N6O2 650.2 m/z found 651.0 [M+H]+. Chiral HPLC (IF, Method: Hex- EtOH- DEA= 60-40-0.2-20 min; Column: 250mm*4.6mm 5um; 1 ml/min, 30 °C, 230 nm, RT = 5.919 min). 1H NMR (400 MHz, DMSO-d6), δ: 10.15 (s, 1H), 9.05 (d, J = 4.0 Hz, 1H), 7.98 (dd, J = 8.8, 5.6 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (q, J = 2.8 Hz, 1H), 6.25 - 5.97 (m, 1H), 5.35 - 5.21 (m, 1H), 4.69 (d, J = 12.0 Hz, 0.5H), 4.53 (d, J = 12.0 Hz, 0.5H), 4.42 (d, J = 12.0 Hz, 0.5H), 4.24 (d, J = 11.6 Hz, 0.5H), 4.15 (dd, J = 10.4, 4.0 Hz, 1H), 4.02 (dd, J = 10.0, 2.0 Hz, 1H), 3.95 - 3.88 (m, 1H), 3.76 - 3.60 (m, 2H), 3.52 (dd, J = 16.8, 12.0 Hz, 1H), 3.14 - 3.04 (m, 2H), 3.01 (s, 1H), 2.91 (s, 1H), 2.86 - 2.80 (m, 1H), 2.18 - 1.96 (m, 3H), 1.86 - 1.66 (m, 7H). 19F NMR (376 MHz, DMSO-d6), δ: -110.70 - -110.76 (m, 1F), - 125.70 - -126.67 (m, 1F), -128.05 - -128.89 (m, 1F), -140.05 - -140.10 (m, 1F), -172.10 - - 172.21 (m, 1F). Biological Assays [0643] Example A. cRAF - KRAS[G12D] TR-FRET assay. 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. The reaction was carried out in assay buffer (50 mM HEPES pH 7.5, 5 mM MgCl2, 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 µl of this mix was added into 384w white ProxiPlate Plus reaction plate wells (Corning). Plate was centrifuged for 1 min at 200 g. Then 400x DMSO stock of compounds were diluted down to 10x solutions in assay buffer and 2ul of these solutions were added to reaction plate. Plate was centrifuged for 1 min at 200 g and incubated for 10 min at rt in the dark. Then 6ul 3.33x KRAS[G12D]*GDP was added, plate was centrifuged for 1 min at 200 g and incubated for 10 min at rt in the dark. Then 6 µl 3.33x cRAF mix was added, plate was centrifuged for 1 min at 200 g, incubated for 30 min at rt in the dark. The Flourescence was measured at Ex:TR, Em1/Em2: 490/520 using Microplate Reader ClarioStarPlus (BMG). 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 and wells w/o GTP-BODIPY was used for blank. [0644] 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 MgCl2, 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. 2x MAb Anti-His Tb and KRAS[G12D] mix was prepared in assay buffer and 10ul of this mix was added into 384w white ProxiPlate Plus reaction plate wells (Corning). Plate was centrifuged for 1 min at 200 g. Then 400x DMSO stock of compounds were diluted down to 10x solutions in assay buffer and 2 µl of these solutions were added to reaction plate. Plate was centrifuged for 1 min at 200 g and incubated for 10 min at rt. Then 8 µl 2.5x GTP-BODIPY tracer was added, plate was centrifuged for 1 min at 200 g, incubated for 30 min at rt in the dark. The Fluorescence was measured at Ex:TR, Em1/Em2: 490/520 using Microplate Reader ClarioStarPlus (BMG). Em1/Em2: 490/520 ratio was used to calculate tracer displacement % and IC50 values. Wells KRAS[G12D]*GDP was used as 100% KRAS[G12D] inhibition control and wells w/o GTP-BODIPY was used for blank. [0645] Example C. KRAS[G12D]*GDP - SOS1 tracer displacement TR-FRET assay. 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. The reaction was carried out in assay buffer (50 mM HEPES pH 7.5, 5 mM MgCl2, 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 µl of this mix was added into 384w white ProxiPlate Plus reaction plate wells (Corning). Plate was centrifuged for 1 min at 200 g. Then 400x DMSO stock of compounds were diluted down to 10x solutions in assay buffer and 2 µl of these solutions were added to reaction plate. Plate was centrifuged for 1 min at 200 g and incubated for 10 min at rt. Then 6 µl 3.33x KRAS[G12D]*GDP was added, plate was centrifuged for 1 min at 200 g and incubated for 10 min at rt. Then 6 µl 3.33x GTP-BODIPY tracer was added, plate was centrifuged for 1 min at 200 g, incubated for 30 min at rt in the dark. The Fluorescence was measured at Ex:TR, Em1/Em2: 490/520 using Microplate Reader ClarioStarPlus (BMG). 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 and wells w/o GTP-BODIPY was used for blank. The results of the experiment presented in the table C. 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
Figure imgf000370_0001
below:
[0646] Example D. P
Figure imgf000371_0001
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. MRTX1133 was given IV at 1 mg/kg and PO at 10 mg/kg in 5%DMSO+5%Solutol+ 90% (20% HP-β-CD); and IP at 30 mg/kg in 10% HP-β-CD in 50 mM citrate buffer pH 5.0. Compound was given IV at 2 mg/kg in aq. solution with 20% HP-β-CD, and PO at 30 mg/kg in 0.5% methylcellulose (15 cP) +0.5% Tween-80. Volume of administration for IV was 5 ml/kg, for IP and PO – 10 ml/kg. Plasma samples were collected in EDTA-containing tubes at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h after IV and IP administration, and at 0.25, 0.5, 1, 2, 4, 8, and 24 h after PO administration. Blood was collected from 3 mice/time point. Plasma samples were prepared by centrifugation of the blood, and processed using protein precipitation with MeOH (Compound) or MeCN (MRTX1133) The supernatants were transferred to a new plate for LC/MS/MS analysis. 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 Cmax; MRTINF, mean residence time (infinite approximation); MRTlast, mean residence time (the last time point); F%, bioavailability) were calculated using noncompartmental analysis provided by WinNonlin Professional 5.2 software (Pharsight Corporation). The results of the experiment presented in the table D. Table D. Summary of pharmacokinetics parameters for MRTX1133 and compound 241 in mice. AUClast T1/2 Compound Dose F(%) (hr*ng/mL) (h)
Figure imgf000372_0001
[ ] 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. The results of the experiment presented in the table E. Table E. Determination of half-maximal cellular cytotoxic 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. Mean CC50, µM
Figure imgf000372_0002
Equivalents [0648] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (A): A), or a pharmaceuticall automer thereof,
Figure imgf000373_0001
wherein: W is selected from CHRw, NH, and -CH=CH-; wherein Rw and R5 together form a double bond; Q is selected from CRq and N; Rq is halogen; G is selected from N and CRg; Rg is selected from H, -NH2, -CH=NH; R1 is selected from H, halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 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; R2 is C1-C6 alkyl; R3 is selected from H and C1-C6 alkyl; or R2 and R3 together with the atoms to which they are attached and any intervening atoms, form a 5-8 membered heterocycle, wherein the heterocycle is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy; R4 is selected from H and C1-C6 alkyl; R5 is selected from H, C1-C6 alkyl; or R4 and R5 together with the atoms to which they are attached and any intervening atoms, form a 5 membered heterocycle, wherein W is NH; R6 is selected from H, F, -CHF2, and -CH=CH2; R7 is selected from -NH2 and -SH, or R7 and Rg 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; R8 is selected from H, halogen; R9 is selected from H, halogen, C1-C6 alkyl; R10 is selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted with one or more halogen; or R9 and R10 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, -NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl; R11 is selected from H, halogen; provided that when W is CHRw, then R6 is selected from F, -CHF2, and -CH=CH2; provided that when W is NH, then R6 is selected from F, -CHF2, and -CH=CH2; and provided that when W is -CH=CH-, then R6 is selected from H, F, -CHF2, and -CH=CH2.
2. The compound of claim 1, wherein compound is of Formula (I):
(I), or a pharmaceuti or tautomer thereof.
Figure imgf000375_0001
.
3. The compound of claim 1, wherein compound is of Formula (II): II), or a pharmaceuti
Figure imgf000375_0002
or tautomer thereof.
4. The compound of claim 1, wherein compound is of Formula (III): II),
Figure imgf000375_0003
or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof.
5. The compound of claim 2, wherein compound is of Formula (I-A) or Formula (I- B): R6 ), B), or a pharmaceuti
Figure imgf000376_0001
r tautomer thereof.
6. The compound of claim 3, wherein compound is of Formula (II-A), or Formula (II- B):
A), B), or a pharmaceut
Figure imgf000377_0001
r tautomer thereof.
7. The compound of claim 4, wherein compound is of Formula (III-A), or Formula (III-B): A),
Figure imgf000377_0002
B), or a pharmaceu r tautomer thereof.
Figure imgf000378_0001
8. The compound of claim 2, wherein compound is of Formula (I-A-1) or Formula (I- B-1): 1), 1), or a pharmaceu
Figure imgf000378_0002
, , , , tautomer thereof.
9. The compound of claim 3, wherein compound is of Formula (II-A-1), Formula (II- A-2), Formula (II-B-1), or Formula (II-B-2):
Figure imgf000379_0001
2), or a pharmaceu tautomer thereof.
Figure imgf000380_0001
10. The compound of claim 4, wherein compound is of Formula (III-A-1), or Formula (III-B-1): 1), 1), or a pharmaceu
Figure imgf000380_0002
, , , , tautomer thereof.
11. A compound is selected from: # IUPAC Name 6-[4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)-2-[(2-fluoro-1,2,3,5,6,7- n- - - - - - - -
Figure imgf000381_0001
# IUPAC Name 6-[6-chloro-2-[(2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy]-4-(1- l- - - - - -
Figure imgf000382_0001
ģ IUPAC Name 6-[4-[1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-[(2- 7- - - e 2- 2- 2-
Figure imgf000383_0001
ģ IUPAC Name 6-[6-chloro-8-fluoro-2-[(2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- - - - - -
Figure imgf000384_0001
ģ IUPAC Name 6-[6-chloro-4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)-2-[(2-fluoro-1,2,3,5,6,7- - - - -
Figure imgf000385_0001
ģ IUPAC Name 4-fluoro-6-[8-fluoro-2-[(2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- - - -
Figure imgf000386_0001
ģ IUPAC Name 6-[6-chloro-4-[1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2- 2- 2- - - - - -
Figure imgf000387_0001
ģ IUPAC Name 7-(5,6-dimethyl-1H-indazol-4-yl)-2-[(1-methylpyrrolidin-2-yl)methoxy]-4- 108 - - - - - - - - e - - 8-
Figure imgf000388_0001
ģ IUPAC Name 7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-[(1-methylpyrrolidin-2- 3- 8- - - - -
Figure imgf000389_0001
ģ IUPAC Name 6-chloro-7-(5,6-dimethyl-1H-indazol-4-yl)-8-fluoro-2-[(2-fluoro-1,2,3,5,6,7- e - - - e -
Figure imgf000390_0001
ģ IUPAC Name 6-chloro-2-[(2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy]-7-(6- - 5- 5- e e - 5-
Figure imgf000391_0001
ģ IUPAC Name 4-[1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-7-(6-fluoro-5- - - - - l- 6- 6- - e
Figure imgf000392_0001
ģ IUPAC Name 7-fluoro-4-[4-(5-fluoro-3,6-dihydro-2H-pyridin-1-yl)-2-[(2-fluoro-1,2,3,5,6,7- - - - - - - - - - -
Figure imgf000393_0001
ģ IUPAC Name 4-[6-chloro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4-(1-vinyl-3,8- - - 3- - - -
Figure imgf000394_0001
ģ IUPAC Name 4-[4-[1-(difluoromethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2- - - - - 2- 2- 2- -
Figure imgf000395_0001
# IUPAC Name 4-[6-chloro-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-4- - 2- - 8- 8-
Figure imgf000396_0001
12. A pharmaceutical composition comprising the compound of any one of claims 1– 11 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12, further comprising one or more additional pharmaceutically active agents.
14. A method of inhibiting of KRAS(G12D) in a cell, comprising contacting the cell with a compound of any one of claims 1–11 or a pharmaceutical composition of claim 12 or 13.
15. The method of claim 14, wherein the contacting is in vitro or in vivo.
16. A method for the treatment or prevention of a disease or disorder associated with KRAS(G12D) comprising administering to a subject in need thereof a compound of any one of claims 1–11 or a pharmaceutical composition of claim 12 or 13.
17. The method of claim 16, wherein the disease or disorder is selected from the group consisting of 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 Stromal Tumor (GIST); Tatton-Brown- Rahman Syndrome (TBRS); Mismatch Repair Cancer Syndrome 1 (MMRCS1); Glioma Susceptibility 1 (GLM1); Retinoblastoma (RB1); Brain Cancer; Squamous Cell Carcinoma, Head and Neck (HNSCC); Down Syndrome; Tuberous Sclerosis 1 (TSC1); Deficiency Anemia; Multiple Endocrine Neoplasia, Type I (MEN1); Medulloblastoma (MDB); Hypertension, Essential (EHT); Fanconi Anemia, Complementation Group a (FANCA); Type 2 Diabetes Mellitus (T2D); Amyotrophic Lateral Sclerosis 1 (ALS1).
18. The method of claim 17, wherein the disease or disorder is Lung Cancer (LNCR).
19. The method of claim 17, wherein the disease or disorder is Pancreatic Cancer (PNCA).
20. The method of claim 17, wherein the disease or disorder is Colorectal Cancer (CRC).
21. The method of any one of claims 14-20, wherein the subject is a mammal.
22. The method of claim 21, wherein the subject is a human.
PCT/US2024/051673 2023-10-17 2024-10-16 Kras(g12d) inhibitors Pending WO2025085580A1 (en)

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Cited By (1)

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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146613A1 (en) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2021168193A1 (en) * 2020-02-20 2021-08-26 Beta Pharma, Inc. Pyridopyrimidine derivatives as kras inhibitors
WO2022002102A1 (en) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Quinazoline compounds, preparation methods and uses thereof
WO2022187527A1 (en) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Quinazoline nitrile derivatives as kras inhibitors
WO2023081840A1 (en) * 2021-11-05 2023-05-11 Frontier Medicines Corporation Kras g12c inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020146613A1 (en) * 2019-01-10 2020-07-16 Mirati Therapeutics, Inc. Kras g12c inhibitors
WO2021168193A1 (en) * 2020-02-20 2021-08-26 Beta Pharma, Inc. Pyridopyrimidine derivatives as kras inhibitors
WO2022002102A1 (en) * 2020-06-30 2022-01-06 InventisBio Co., Ltd. Quinazoline compounds, preparation methods and uses thereof
WO2022187527A1 (en) * 2021-03-05 2022-09-09 Nikang Therapeutics, Inc Quinazoline nitrile derivatives as kras inhibitors
WO2023081840A1 (en) * 2021-11-05 2023-05-11 Frontier Medicines Corporation Kras g12c inhibitors

Cited By (1)

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

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