WO2025199376A1 - Inhibiteurs de cdk2 - Google Patents

Inhibiteurs de cdk2

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Publication number
WO2025199376A1
WO2025199376A1 PCT/US2025/020780 US2025020780W WO2025199376A1 WO 2025199376 A1 WO2025199376 A1 WO 2025199376A1 US 2025020780 W US2025020780 W US 2025020780W WO 2025199376 A1 WO2025199376 A1 WO 2025199376A1
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WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
compound
halogen
alkoxy
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PCT/US2025/020780
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English (en)
Inventor
Boris Rogovoy
Nikolay Savchuk
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Padarn Therapeutics Inc
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Padarn Therapeutics Inc
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Publication of WO2025199376A1 publication Critical patent/WO2025199376A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • CDK2 Inhibitors CROSS-REFERENCE TO RELATED APPLICATIONS
  • the present invention is directed to inhibitors of CDK2.
  • the inhibitors described herein can be useful in the treatment of diseases or disorders associated with CDK2, such as autoimmune disease, Alzheimer disease, and coronavirus infection by inducing durable responses.
  • the invention is concerned with compounds and pharmaceutical compositions inhibiting CDK2, methods of treating diseases or disorders associated with CDK2, and methods of synthesizing these compounds.
  • Cyclin-dependent kinase 2 plays a pivotal part in cell cycle regulation and is involved in a range of biological processes.
  • CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation.
  • CDK2andits regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features.
  • Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.
  • Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with roles in inactivating phosphorylation of the RB 1 (pRb) tumor suppressor family and in controlling both G1/S and G2/M transitions.
  • CDK2 has been described to play a positive role in cell cycle arrest in the DNA damage response (DDR), in particular at the G2/M checkpoint.
  • CDK4/6 inhibitors Over the past decade, the clinical development of CDK4/6 inhibitors has led to practice-changing outcomes in breast cancer treatment. This has energized the field and increased interest in therapeutically targeting other members of the CDK family.
  • CDK2 was an early focus for anticancer drug discovery in the 1990s but the initial excitement was dampened owing to off-target effects of the early drugs.
  • Interest in CDK2 inhibition has now reignited with the identification of more functions for CDK2 that impact cancer biology and the possibility of developing inhibitors with greater specificity to CDK2.
  • CDK2 The broad functionality of CDK2 in proliferative and pro-survival pathways highlights it as an ideal target for mechanism-based and low-toxicity therapeutic strategies in cancer treatment.
  • CDK2 activity also impacts cell differentiation and the adaptive immune response.
  • CDK2 inhibition appears to have most potential in particular molecular landscapes or cancer subtypes
  • CDK2 inhibitors identified to date are nonselective leading to a promiscuous mode of action.
  • specific cancers can benefit from the selective inhibition of CDK2 in combination with other CDKs, which broadens the spectrum for drug development.
  • endocrine-resistant cancers could benefit from a double blockade of CDK2/CDK4 action because these cancers are so highly dependent on the G1/S axis.
  • Cancers that show cyclin E1 amplification and CDK2 dependency could benefit from CDK2/CDK7 blockade, to directly inhibit CDK2 and then prevent the activation of residual CDK2 via CDK7 inhibition.
  • a first aspect of the invention relates to compounds of Formula (A): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:
  • X is selected from O, CR 4 R 5 , SO 2 , NR 6 ; each R 1 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, - C(O)OR 8 , and -C(O)NR 8 R 9 , wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl 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 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyn
  • R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkoxy;
  • R 3 is selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, heterocyclyl, and aryl wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R 10 ;
  • R 4 is selected from halogen, -CN, -OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, - NH 2 , -CN;
  • R 5 is selected from H, halogen, C 1 -C 6 alkyl and R 6 ; or
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, R 6 ; R 6 is R 7 -L-;
  • L is selected from a bond, -C(O)-, -S(O) 2 -, -O-C(O)-, -O-CH 2 -C(O)-, -O-CH 2 - S(O) 2 -, -CH 2 -C(O)-, -NH-C(O)-, - C 1 -C 6 alkanediyl-, -C 1 -C 6 alkanediyl-O-, - C 1 -C 6 alkanediyl-C(O)-, -C 1 -C 6 alkanediyl-NH-C(O)-;
  • R 7 is selected from C 1 -C 6 alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R 8 R 9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-;
  • R 8 is selected from H, C 1 -C 6 alkyl
  • R 9 is selected from H, C 1 -C 6 alkyl; each R 10 is independently selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or two R 10 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3.
  • 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.
  • Another aspect of the invention relates to a method of treating a disease or disorder associated with CDK2.
  • the method comprises administering to a patient in need of a treatment for diseases or disorders associated with CDK2 an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • Another aspect of the invention is directed to a method of inhibiting of CDK2.
  • 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.
  • 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 CDK2.
  • 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 CDK2.
  • 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.
  • 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.
  • the present invention further provides methods of treating a disease or disorder associated with CDK2, 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.
  • the present invention provides inhibitors of CDK2 that are therapeutic agents in the treatment of diseases and disorders.
  • the present invention further provides compounds and compositions with an improved selectivity relative to known inhibitors of CDK2.
  • the present disclosure also provides agents with novel mechanisms of action toward CDK2 in the treatment of various types of diseases.
  • the present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of CDK2.
  • the present disclosure also provides agents with novel mechanisms of action toward CDK2 in the treatment of various types of diseases.
  • the present invention further provides methods of treating cancer diseases, blood diseases, immune diseases, genetic diseases, respiratory diseases, endocrine diseases, ear diseases, eye diseases, fetal diseases, metabolic diseases, neuronal diseases, skin diseases, gastrointestinal diseases, skin diseases, mental diseases, liver diseases, nephrological diseases, rare diseases, reproductive 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: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Gastric Cancer (GASC); Hepatocellular Carcinoma (HCC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Ataxia-Telangiectasia (AT); Pheochromocytoma (PCC) 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.
  • BC Breast Cancer
  • CRC Colorectal Cancer
  • LNCR Lung Cancer
  • PNCA Pancreatic Cancer
  • PC Prostate Cancer
  • 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).
  • the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part - P1-P159)
  • 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.
  • the present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with CDK2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.
  • 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, (C 1 -C 6 ) haloalkoxy, -O-(C 2 -C 6 ) alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, -OH, -OP(O)(OH) 2 , -OC(O)(C 1 -C 6
  • 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.
  • 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.
  • Exem ⁇ lary substituents include, but are not limited to, -H, -halogen, -O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, - O-(C 2 -C 6 )alkenyl, -O-(C 2 -C 6 ) alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, -OH, - OP(O)(OH) 2 , -OC(O)(C 1 -C 6 )alkyl, -C(O)(C 1 -C 6 ) alkyl, -OC(O)O(C 1 -C 6 )alkyl, -NH 2 , - NH((C 1 -C 6 )alkyl), -N((C 1 -C 6 )alkyl) 2 , -S(O) 2 -(C 1
  • 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.
  • Exem ⁇ lary 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.
  • 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.
  • Exam ⁇ les 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]
  • 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.
  • Exem ⁇ lary ring systems of these heteroaryl groups include, for exam ⁇ le, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-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]pyridin
  • 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. Exam ⁇ les of a (C 1 -C 6 ) 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
  • alkoxy groups 1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl).
  • Exam ⁇ les 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
  • alkenyl 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.
  • Exam ⁇ les 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.
  • Alkynyl refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms.
  • the “alkynyl” group contains at least one tri ⁇ le bond in the chain. Exam ⁇ les of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl.
  • An alkynyl group can be unsubstituted or substituted.
  • alkanediyl 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 C 1 -C 4 alkylene.
  • Typical alkylene groups include, but are not limited to, -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH 2 CH(CH 3 )-, - CH 2 C(CH 3 ) 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.
  • Exam ⁇ les 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.
  • aromatic means a ⁇ lanar ring having 4n + 2 electrons in a conjugated system.
  • conjugated system means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.
  • haloalkoxy refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Exam ⁇ les of 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 tri ⁇ le 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. Exam ⁇ les 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 (C 3 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms.
  • One or more of the carbon atoms can be substituted with a heteroatom.
  • 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 com ⁇ lex 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. Exam ⁇ les 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.
  • the present disclosure also contem ⁇ lates 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 Exam ⁇ les herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • 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, hydroxynaphth
  • 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 fdler, 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.
  • compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • CDK2 inhibitor refers to a compound of Formula A and/or compositions comprising a compound of Formula A which inhibits CDK2.
  • 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 exam ⁇ le, 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.
  • the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof wherein X, R 1 , R 2 , R 3 , m, and n are as described herein.
  • X, R 1 , R 2 , R 3 , m and n can each be, where ap ⁇ licable, selected from the groups described herein, and any group described herein for any X, R 1 , R 2 , R 3 , m and n can be combined, where ap ⁇ licable, with any group described herein for one or more of the remainders of X, R 1 , R 2 , R 3 , m and n.
  • the compound is of Formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:
  • X is selected from O, CR 4 R 5 , SO 2 , and NR 6 ; each R 1 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, - C(O)OR 8 , -C(O)NR 8 R 9 , and S(O) 2 R 12 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl 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 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C
  • R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkoxy;
  • R 4 is selected from halogen, -CN, -OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -CN;
  • R 3 is selected from H, halogen, C 1 -C 6 alkyl and R 6 ; or
  • R 4 and R 3 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, R 6 ;
  • R 6 is R 7 -L-
  • L is selected from a bond, -C(O)-, -S(O) 2 -, -O-C(O)-, -O-CH 2 -C(O)-, -O-CH 2 - S(O) 2 -, -CH 2 -C(O)-, -NH-C(O)-, -C 1 -C 6 alkanediyl-, -C 1 -C 6 alkanediyl-O-, -C 1 -C 6 alkanediyl-C(O)-, -C 1 -C 6 alkanediyl-NH-C(O)-.;
  • R 7 is selected from C 1 -C 6 alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R 8 R 9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH,
  • R 8 is selected from H, C 1 -C 6 alkyl;
  • R 9 is selected from H, C 1 -C 6 alkyl;
  • each R 10 is independently selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or two R 10 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 1, 2, 3, 4, and 5; r is an integer selected from 0, 1, 2, and 3.
  • the compound is of Formula (I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C):
  • the compound is of Formula (I-D): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-E): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-l-a-I):
  • the compound is of Formula (I-B-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
  • the compound is of Formula (I-B-l-a-I-A-I):
  • the compound is of Formula (I-B-l-a-I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-l-a-I-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-l-a-I-B-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-B-l-a-I-B-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A):
  • the compound is of Formula (I-C-l-a-I-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-g): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-i): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-k): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-k’):
  • the compound is of Formula (I-C-l-a-I-A-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-a-I-A-l-m):
  • the compound is of Formula (I-C-l-a-I-A-l-o):
  • the compound is of Formula (I-C-l-a-I-A-l-pq): -pq), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein p is an integer selected from 1, 2, 3, 4, and 5; a is an integer selected from 0, 1, and 2; and b is an integer selected from 1, 2, and 3.
  • the compound is of Formula (I-C-l-a-I-A-I-q):
  • the compound is of Formula (I-C-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-b-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-c-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-c-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-c-I-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-c-II):
  • R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-II-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-III-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-III-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-IV):
  • R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-IV-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-IV-A-1):
  • R a is selected from H, C 1 -C 6 alkyl, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH, C 1 -C 6 alkoxy, aryl, aryloxy.
  • the compound is of Formula (I-C-l-c-I-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-l-d-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-2-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
  • the compound is of Formula (I-C-3-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-II-A):
  • the compound is of Formula (I-C-3-a-II-A-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-III): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-IV-A):
  • the compound is of Formula (I-C-3-a-IV-A-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
  • the compound is of Formula (I-C-3-a-V): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-V-A):
  • the compound is of Formula (I-C-3-a-I-A-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
  • the compound is of Formula (I-C-3-a-V-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-I-B-l):
  • the compound is of Formula (I-C-3-a-V-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-C-3-a-I-C-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-D-l):
  • the compound is of Formula (I-D-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-D-l-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-D-l-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof
  • the compound is of Formula (I-D-l-a-I-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-D-l-a-I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (I-D-l-a-I-A-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:
  • X is selected from O, CR 4 R 5 , SO 2 , and NR 6 ;
  • Y is selected from O, NH, and S; each R 1 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, - C(O)OR 8 , -C(O)NR 8 R 9 , and S(O) 2 R 12 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl 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 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl,
  • R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkoxy;
  • R 4 is selected from halogen, -CN, -OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -Cg alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -CN;
  • R 5 is selected from H, halogen, C 1 -C 6 alkyl and R 6 ; or
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, R 6 ;
  • R 6 is R 7 -L-;
  • L is selected from a bond, -C(O)-, -S(O) 2 -, -O-C(O)-, -O-CH 2 -C(O)-, -O-CH 2 - S(O) 2 -, -CH 2 -C(O)-, -NH-C(O)-, -C 1 -C 6 alkanediyl-, -C 1 -C 6 alkanediyl-O-, -C 1 -C 6 alkanediyl-C(O)-, -C 1 -C 6 alkanediyl-NH-C(O)-;
  • R 7 is selected from C 1 -C 6 alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R 8 R 9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-;
  • R 8 is selected from H, C 1 -C 6 alkyl
  • R 9 is selected from H, C 1 -C 6 alkyl; each R 10 is independently selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or two R 10 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; each b is an integer independently selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.
  • the compound is of Formula (II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-C): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1-a): 3.1 -a), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3. I-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3. I-a-I-A-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof. [0186] In some embodiments, the compound is of Formula (II-A-3.1-a-I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (Il-A-3.1-a-I-A-l-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1-a-I-A-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1 -b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1 -b-I- A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.1-b-I-A-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3. I-b-I-A-I-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.2-a):
  • the compound is of Formula (II-A-3.2-a-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.2-a-I-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-A-3.2-a-I-A-l):
  • the compound is of Formula (II-A-3.2-a-I-A-l-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.2-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.2-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.2-b-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.2-b-I-A-l): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (II-B-3.2-b-I-A-l-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (III): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:
  • X is selected from O, CR 4 R 5 , SO 2 , and NR 6 ; each R 1 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, - C(O)OR 8 , -C(O)NR 8 R 9 , and S(O) 2 R 12 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl 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 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C
  • R 4 is selected from halogen, -CN, -OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -CN;
  • R 5 is selected from H, halogen, C 1 -C 6 alkyl and R 6 ; or
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, R 6 ;
  • R 6 is R 7 -L-
  • L is selected from a bond, -C(O)-, -S(O) 2 -, -O-C(O)-, -O-CH 2 -C(O)-, -O-CH 2 - S(O) 2 -, -CH 2 -C(O)-, -NH-C(O)-, -C 1 -C 6 alkanediyl-, -C 1 -C 6 alkanediyl-O-, -C 1 -C 6 alkanediyl-C(O)-;
  • R 7 is selected from C 1 -C 6 alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R 8 R 9 A-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-;
  • R 8 is selected from H, C 1 -C 6 alkyl
  • R 9 is selected from H, C 1 -C 6 alkyl; each R 10 is independently selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or two R 10 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; each b is an integer independently selected from 1, 2, and 3; r is an integer selected from 0, 1, 2, and 3.
  • the compound is of Formula (III-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • 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- 1-a-I):
  • 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-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • the compound is of Formula (IV): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:
  • Ar is an aryl
  • X is selected from O, CR 4 R 5 , SO 2 , and NR 6 ; each R 1 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, - C(O)OR 8 , -C(O)NR 8 R 9 , and S(O) 2 R 12 wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl 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 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C
  • R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkoxy;
  • R 4 is selected from halogen, -CN, -OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -CN;
  • R 5 is selected from H, halogen, C 1 -C 6 alkyl and R 6 ; or
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, R 6 ;
  • R 6 is R 7 -L-;
  • L is selected from a bond, -C(O)-, -S(O) 2 -, -O-C(O)-, -O-CH 2 -C(O)-, -O-CH 2 - S(O) 2 -, -CH 2 -C(O)-, -NH-C(O)-, -C 1 -C 6 alkanediyl-, -C 1 -C 6 alkanediyl-O-, -C 1 -C 6 alkanediyl-C(O)-, -C 1 -C 6 alkanediyl-NH-C(O)-;
  • R 7 is selected from C 1 -C 6 alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R 8 R 9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-;
  • R 8 is selected from H, C 1 -C 6 alkyl
  • R 9 is selected from H, C 1 -C 6 alkyl; each R 10 is independently selected from halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; two R 10 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl; m is an integer selected from 1, 2 and 3; n is an integer selected from 1, 2, and 3; p is an integer selected from 1, 2, 3, 4, and 5; r is an integer selected from 0, 1, 2, and 3.
  • the compound is of Formula (IV-A-l-a-I-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • 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). In some embodiments, the compound is of Formula (IV).
  • 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.
  • the compound is of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.
  • X is selected from O, CR 4 R 5 , S(O) q , NR 6 .
  • X is O.
  • X is CR 4 R 5 .
  • X is CF2.
  • X is S(O) q .
  • X is S.
  • X is SO 2 .
  • X is -NR 6 .
  • X is N-L-R 7 .
  • each R 1 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, -C(O)OR 8 , and -C(O)NR 8 R 9 , wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl 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 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heterocycle, aryl, and heteroaryl.
  • R 1 is -C(O)OR 8 .
  • R 1 is -C(O)OCH 3 .
  • R 1 is -C(O)NR 8 R 9 .
  • R 1 is -C(O)NH 2 .
  • R 1 is -C(O)N(CH 3 ) 2 .
  • two R 1 form a bond.
  • two R 1 form a single bond.
  • R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, wherein the alkyl, or cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkoxy.
  • R 2 is H.
  • R 2 is C 1 -C 6 alkyl. [0264] In some embodiments, R 2 is methyl.
  • R 2 is C 3 -C 10 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C 1 -C 6 alkoxy.
  • R 2 is C 3 -C 10 cycloalkyl.
  • R 3 is selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, heterocyclyl, and aryl wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R 10 .
  • R 3 is C 1 -C 6 alkyl optionally substituted with one or more R 10 .
  • R 3 is C 1 -C 6 alkyl. [0281] In some embodiments, R 3 is propyl.
  • R 3 is iso-propyl.
  • R 3 is butyl
  • R 3 is tert-butyl
  • R 3 is C 3 -C 10 cycloalkyl optionally substituted with one or more R 10 .
  • R 3 is C 3 -C 10 cycloalkyl.
  • R 3 is C 3 -C 10 monocyclic cycloalkyl.
  • R 3 is heterocyclyl optionally substituted with one or more R 10 .
  • R 3 is heterocyclyl
  • R 3 is five membered heterocyclyl.
  • R 3 is aryl optionally substituted with one or more R 10 .
  • R 3 is aryl
  • X is selected from O, CR 4 R 5 , SO 2 , NR 6 .
  • X is O.
  • X is CR 4 R 5 .
  • R 4 is selected from halogen, -CN, -OH, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 6 alkoxy, wherein the alkyl, cycloalkyl or alkoxy is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH 2 , -CN.
  • R 4 is H.
  • R 4 is halogen
  • R 4 is F.
  • R 4 is C 1 -C 6 alkyl.
  • R 4 is methyl
  • R 5 is selected from H, halogen, C 1 -C 6 alkyl and R 6 .
  • R 5 is H.
  • R 5 is halogen
  • R 5 is F.
  • R 5 is C 1 -C 6 alkyl.
  • R 5 is methyl
  • R 5 is R 6 .
  • R 5 is -L-R 7 .
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, R 6 .
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form [0340] In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form [0341] In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form [0347] In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form [0356] In some embodiments, R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • R 4 and R 5 together with the atoms to which they are attached and any intervening atoms, form
  • X is SO 2 .
  • X is NR 6 .
  • R 6 is -L-R 7 .
  • L is selected from a bond, -C(O)-, -S(O) 2 -, -O-C(O)-, -O- CH 2 -C(O)-, -O-CH 2 -S(O) 2 -, -CH 2 -C(O)-, -NH-C(O)-, -C 1 -C 6 alkanediyl-, -C 1 -C 6 alkanediyl-O-, -C 1 -C 6 alkanediyl-C(O)-, -C 1 -C 6 alkanediyl-NH-C(O)-.
  • L is a bond
  • L is a single bond.
  • L is -C(O)-.
  • L is -S(O) 2 -.
  • L is -O-C(O)-.
  • L is -O-CH 2 -C(O)-.
  • L is -O-CH 2 -S(O) 2 -.
  • L is-CH 2 -C(O)-.
  • L is-NH-C(O)-. [0372] In some embodiments, L is -C 1 -C 6 alkanediyl-.
  • L is -C 1 -C 6 alkanediyl-O-.
  • L is -C 1 -C 6 alkanediyl-C(O)-.
  • L is -CH 2 -C(O)-.
  • L is -C 1 -C 6 alkanediyl-NH-C(O)-.
  • L is -CH 2 -NH-C(O)-.
  • R 7 is selected from C 1 -C 6 alkyl-, cycloalkyl-, aryl-, heterocyclyl-, heteroaryl-, or R 8 R 9 N-, wherein the alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-.
  • R 7 is C 1 -C 6 alkyl- optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy.
  • R 7 is C 1 -C 6 alkyl.
  • R 7 is methyl
  • R 7 is ethyl
  • R 7 is propyl
  • R 7 is n-propyl
  • R 7 is /-propyl
  • R 7 is butyl
  • R 7 is tert-butyl
  • R 7 is C 1 -C 6 alkyl substituted with one or more halogen.
  • R 7 is
  • R 7 is C 1 -C 6 alkyl substituted with R 8 R 9 N-.
  • R 7 is cycloalkyl- optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-. [0393] In some embodiments, R 7 is cycloalkyl-.
  • R 7 is C 3 -C 10 monocyclic cycloalkyl.
  • R 7 is cyclopropyl
  • R 7 is cyclobutyl
  • R 7 is cyclopentyl
  • R 7 is cyclohexyl
  • R 7 is cycloalkyl- optionally substituted with one or more halogen.
  • R 7 is aryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -CG alkoxy and R 8 R 9 N-.
  • R 7 is aryl
  • R 7 is heterocyclyl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-.
  • R 7 is heterocyclyl.
  • R 7 is heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy and R 8 R 9 N-.
  • R 7 is heteroaryl
  • R 7 is 5 membered heteroaryl.
  • R 7 is 6 membered heteroaryl.
  • R 7 is 10 membered heteroaryl
  • R 7 is monocyclic heteroaryl.
  • R 7 is bicyclic heteroaryl.
  • R 8 is selected from H, C 1 -C 6 alkyl.
  • R 8 is H.
  • R 8 is C 1 -C 6 alkyl.
  • R 8 is methyl
  • R 9 is selected from H, C 1 -C 6 alkyl.
  • R 9 is H.
  • R 9 is C 1 -C 6 alkyl.
  • R 9 is methyl
  • each R 10 is independently selected from halogen, OH, C 1 - C 6 alkyl, C 1 -C 6 alkoxy.
  • R 10 is halogen
  • R 10 is F.
  • two R 10 together with the atoms to which they are attached and any intervening atoms form a 4-9 membered cycloalkyl, a 4-9 membered heterocycle, 4-9 membered heteroaryl, wherein the cycloalkyl, heterocycle or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl.
  • two R 10 together with the atoms to which they are attached and any intervening atoms form a 4-9 membered cycloalkyl is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl.
  • two R 10 together with the atoms to which they are attached and any intervening atoms form a 4-9 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl.
  • two R 10 together with the atoms to which they are attached and any intervening atoms form a 4-9 membered heterocycle optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl.
  • two R 10 together with the atoms to which they are attached and any intervening atoms form a 4-9 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, C 1 -C 6 alkyl.
  • m is an integer selected from 1 and 2.
  • m is 1.
  • m is 2.
  • n is an integer selected from 1 and 2.
  • n 1
  • n is 2.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.
  • the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
  • the compound is selected from the compounds described in
  • Table 1 [0460] Table 1 certain exam ⁇ les of the compound of Formula A
  • the compound is a pharmaceutically acceptable salt of any one of the compounds described in 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.
  • 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 Exam ⁇ les 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 (I)-(IV) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I)-(IV).
  • 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 0, 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 Exam ⁇ les described herein, by substituting a deuterium labeled reagent for a nondeuterium labeled reagent.
  • the compound is a 18 F labeled compound.
  • the compound is a 123 I labeled compound, a 124 I labeled compound, a 125 I labeled compound, a 129 I labeled compound, a 131 I labeled compound, a 135 I labeled compound, or any combination thereof.
  • the compound is a 33 S labeled compound, a 34 S labeled compound, a 33 S labeled compound, a 36 S labeled compound, or any combination thereof.
  • the 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 3 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 Exam ⁇ les described herein, by substituting a 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 1, 3 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, 123 1, 124 1, 123 I, 129 I, 131 1, 135 1, 3 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, 123 I, 124 I, 125 I, 129 I, 131 I, 133 I, 3 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 exam ⁇ le 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 exam ⁇ le, is 550 Daltons or less, for exam ⁇ le 500 Daltons or less, for exam ⁇ le 450 Daltons or less.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for exam ⁇ le, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for exam ⁇ le, an acid-addition salt with, for exam ⁇ le, an inorganic or organic acid, for exam ⁇ le 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 exam ⁇ le a sodium or potassium salt, an alkaline earth metal salt, for exam ⁇ le a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for exam ⁇ le 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.
  • isomers 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 exam ⁇ le, it is bonded to four different groups, a pair of enantiomers is possible.
  • 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 tetramethylammonium ion or diethylamine ion.
  • the substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.
  • the compounds of the present disclosure for exam ⁇ le, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Nonlimiting exam ⁇ les of hydrates include monohydrates, dihydrates, etc.
  • Nonlimiting exam ⁇ les 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 H 2 O.
  • analog refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the re ⁇ lacement of one atom by an atom of a different element or in the presence of a particular functional group, or the re ⁇ lacement 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.
  • 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 re ⁇ lacement is to create a new compound with similar biological properties to the parent compound.
  • the bioisosteric re ⁇ lacement may be physicochemically or topologically based.
  • Exam ⁇ les 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.
  • tautomeric forms include keto-, enol-, and enolate-forms, as in, for exam ⁇ le, 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 Illustrated below
  • N-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 exam ⁇ le, 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.
  • Exam ⁇ les 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 exam ⁇ le 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 Ap ⁇ lication 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.
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for exam ⁇ le, 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 exam ⁇ le, 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 C 1 -C 10 alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1 -C 10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C 1 -C 6 alkyl) 2 carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups.
  • Exam ⁇ les of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(C 1 -C 4 alkyl)piperazin-l-ylmethyl.
  • 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 exam ⁇ le, an in vivo cleavable amide thereof, for exam ⁇ le 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-/V-methylamine or diethylamine, a C 1 -C 4 alkoxy-C 2 -C 4 alkylamine such as 2 -methoxy ethylamine, 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-
  • a suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for exam ⁇ le, an in vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically acceptable amides from an amino group include, for exam ⁇ le an amide formed with C 1 -C 10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • Exam ⁇ les of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl,morpholinomethyl,piperazin-l-ylmethyl and 4-(C 1 -C 4 alkyl)piperazin- 1 -ylmethyl .
  • 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 Formula (I)-(IV) 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 em ⁇ loyed where necessary in accordance with general princi ⁇ les 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 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 exam ⁇ le, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds of present invention can be prepared using sequence of reactions presented at the Scheme 1.
  • 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 exam ⁇ le, 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. [0542] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure.
  • compositions 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 [0543] 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.
  • 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 exam ⁇ le, 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 carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for exam ⁇ le bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled 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 exam ⁇ le solutions in aqueous polyethylene glycol.
  • Exam ⁇ les 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.
  • 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.
  • Exam ⁇ les of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, randomly methylated- ⁇ - cyclodextrin, ethylated- ⁇ -cyclodextrin, triacetyl- ⁇ -cyclodextrin, peracetylated- ⁇ - cyclodextrin, carboxymethyl- ⁇ -cyclodextrin, hydroxy ethyl- ⁇ -cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl- ⁇ -cyclodextrin, glucosyl- ⁇ -cyclodextrin, sulfated P- cyclodextrin (S- ⁇ -CD), maltosyl- ⁇ -cyclodextrin, P-cyclodextrin sulfobut
  • Any suitable chelating agent can be used. Exam ⁇ les of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • any suitable preservative can be used. Exam ⁇ les 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.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhex
  • 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 aqueous vehicle may also contain a buffering agent to stabilize the pH.
  • 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 8-aminocaproic acid, and mixtures thereof.
  • 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.
  • 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.
  • 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 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 exam ⁇ le as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for exam ⁇ le as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for exam ⁇ le as a finely divided powder or a liquid aerosol), for administration by insufflation (for exam ⁇ le as a finely divided powder) or for parenteral administration (for exam ⁇ le 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 exam ⁇ le as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible
  • 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 exam ⁇ le, 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 CDK2 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 CDK2 related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the present disclosure provides a method of inhibiting of CDK2 (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 CDK2. In some embodiments, the disease or disorder is a disease or disorder in which CDK2 is im ⁇ licated. [0571] The compounds of the invention are also useful in treating diseases associated with CDK2.
  • diseases and conditions treatable according to the methods of the invention include Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous C 6 ll Carcinoma; Ataxia-Telangiectasia (AT).
  • BC Breast Cancer
  • CRC Colorectal Cancer
  • LNCR Lung Cancer
  • PNCA Pancreatic Cancer
  • PC Prostate Cancer
  • OC Ovarian Cancer
  • HCC Hepatocellular Carcinoma
  • GSC Gastric Cancer
  • BLC Bladder Cancer
  • ENDMC Endometrial Cancer
  • GBM Glioblastoma
  • the method of treatment comprises 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.
  • the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.
  • the disease or disorder is Breast Cancer (BC).
  • the disease or disorder is Endometrial Cancer (ENDMC).
  • ENDMC Endometrial Cancer
  • the disease or disorder is Glioblastoma (GBM).
  • the disease or disorder is Adenocarcinoma.
  • the disease or disorder is Squamous C 6 ll Carcinoma.
  • the disease or disorder is Ataxia-Telangiectasia (AT).
  • the present disclosure provides a method of treating or preventing a cancer 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 cancer 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 compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of CDK2 (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 cancer in a subject in need thereof.
  • the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.
  • 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 CDK2 (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 cancer in a subject in need thereof.
  • 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 cancer in a subject in need thereof.
  • the present disclosure provides compounds that function as inhibitors of CDK2 (e g., in vitro or in vivo).
  • the present disclosure therefore provides a method of inhibiting of CDK2 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 CDK2 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 present disclosure also provides a method of treating a disease or disorder in which CDK2 is im ⁇ licated 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.
  • 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, ⁇ laster, etc.); transmucosal (including, e.g., by a patch, ⁇ laster, 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 exam ⁇ le, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal
  • the crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 ⁇ m column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL/min, 15-30% ACN at 20 min, RT 16,5 min) to afford 109 (31 mg, yield 20%).
  • the crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 ⁇ m column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL/min, 20-35% ACN at 20 min, RT 13 min) to give 116 (8 mg, yield 5%).
  • the crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 ⁇ m column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL/min, 20-50% ACN at 20 min, RT 11.5 min) to afford 137 (28 mg, yield 15%).
  • the crude product was purified by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 ⁇ m column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL/min, 10- 30% ACN at 20 min, RT 16 min) to give 301 (55 mg, yield 29%).
  • Example 7 9-Cyclopentyl-7-cyclopropyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one (Compound 163).
  • Residue was purified by column chromatography (eluent: EtOAc/MeOH 10/1), followed by preparative HPLC (YMC ODS-A 250 x 20 mm, 5 ⁇ m column, ACN (with 0.1% of formic acid) and water (with 0.1% of formic acid) as eluents, flow 17 mL/min, 10-30% ACN at 20 min, RT 15 min) to obtain 9-cyclopentyl-7-methyl-2- (tetrahydropyran-4-ylamino)purin-8-one 101 (12 mg yield 10%).
  • T3P (290 mg, 0.46 mmol, 2 eq) was added in one portion to a stirred solution of 9- cyclopentyl-7-methyl-2-(4-piperidylamino)purin-8-one hydrochloride P14 (80 mg, 0.23 mmol, 1 eq), 2-(2,3-dihydro-1,4-benzodioxin-6-yl)acetic acid (CAS 17253-11 -1, 44 mg, 0.23 mmol, 1 eq) and DIPEA (120 ⁇ L, 0.69 mmol, 3 eq) in dry DMA (2 mL) at rt. The resulting mixture was stirred at rt for 16 h, diluted with brine and extracted with EtOAc.
  • Residue was purified by crystallization from EtOH to obtain 56 mg 9-(2- Azaspiro[3.3]heptan-6-yl)-7-methyl-2-[[1-(l-methylpyrazol-4-yl)sulfonyl-4- piperidyl]amino]purin-8-one hydrochloride 166 as a white solid yield 64%.
  • Example A Primary Assay Used to Determine Potency of CDK2/CyclinA2 enzymatic activity Inhibition.
  • Compound activity was determined using recombinant CDK2/CyclinA2 proteins (SignalChem, Cat# C29-10G), Histone Hl Peptide (SignalChem, Cat# H10-58) and ATP from ADP-GloTM Kinase Assay kit (Promega, Cat# V9102) in an in vitro enzymatic reaction. Final concentrations were 0.1 ng/ ⁇ L, 0.05 ⁇ g/ ⁇ L and 5 ⁇ M, respectively. The reaction was carried out in assay buffer: 40 mM TRIS-HC1 pH 7.4-7.6, 20 mM MgCh, 0.05 mM DTT, 0.1 mg/mL BSA.
  • Compound activity was determined using recombinant CDKl/CyclinA2 proteins (SignalChem, Cat# C22-18G), Histone Hl Peptide (SignalChem, Cat# H10-58) and ATP from ADP-GloTM Kinase Assay kit (Promega, Cat# V9102) in an in vitro enzymatic reaction. Final concentrations were 0.1 ng/ ⁇ L, 0.2 ⁇ g/ ⁇ L and 5 ⁇ M, respectively. The reaction was carried out in assay buffer: 40 mM TRIS-HC1 pH 7.4-7.6, 20 mM MgCL, 0.05 mM DTT, 0.1 mg/mL BSA.
  • 80x solutions of compounds in DMSO were diluted down to 2x solutions in 2x ATP and 4 ⁇ L of these solutions were added into wells with 4 ⁇ L of CDKl/CyclinA2 -Histone Hl Peptide mix. Plates were centrifuged for 1 min at 200 g and incubated for 1 h at rt. Then 4 ⁇ L of ADP-Glo reagent (Promega, ADP- GloTM Kinase Assay, Cat# V9102) per well was added. Plates were incubated for 30 min at rt.
  • ADP-Glo reagent Promega, ADP- GloTM Kinase Assay, Cat# V9102
  • CDK1/CDK2 *- IC 50 is the concentration of an inhibitor where the response (or binding) is reduced by half.
  • IC50 A ⁇ 0.05 pM; 0.05 pM ⁇ B ⁇ 0.1 pM; 0.1 pM ⁇ C ⁇ 0.5 pM; 0.5 pM ⁇ D ⁇ 1.0 pM; E > 1 0 pM
  • Example C C 6 llular Growth Inhibition Assay.
  • Com ⁇ lete culture media for cell cultures 50:50 of MCDB 105 (C 6 ll Ap ⁇ lications, USA, Cat# 117-500) and Medium 199 with Earle’s Salts (Capricorn, Germany, Cat# M199-A) for TOV-21G and RPMI-1640 (VWR, USA, Cat# 392-0429) for NIH:0VCAR- 3, ⁇ lus 10 % FBS (Gibco, USA, Cat# 10500-064 or Capricorn, Germany, Cat# HI-11A), lx Antibiotic-antimycotic (Gibco, USA, Cat# 15240-062), 2x Sodium pyruvate (Gibco, USA, Cat# 11360-070), 2x Essential amino acids (Gibco, USA, Cat# 11130-051), lx Non- Essential amino acids (Gibco, USA, Cat# 11140-050).
  • NIH:OVCAR-3 ATCC, HTB-161
  • TOV-21G ATCC, CRL-11730
  • C 6 llBIND® 384-well Flat Clear Bottom Black Polystyrene Micro ⁇ lates Corning, USA, Cat #3770
  • C 6 lls were allowed to adhere overnight at 37°C, 5% CO2.
  • 500x compounds solutions in DMSO were prepared in Compounds ⁇ late (Diamond Well Plate, Axigen, Cat#P-384-120SQ-C-S) and DMSO only control was included.
  • 1 ⁇ l of 500x compounds (Compounds ⁇ late) was added to 49 ⁇ l of com ⁇ lete culture medium into Dilution ⁇ late (Diamond Well Plate, Axigen, Cat#P-384- 120SQ-C-S), mixed and then 5 ⁇ l of 10x compounds solutions were transferred to cells ap ⁇ lying Biomek NX (384) followed by centrifugation at 100 g for 1 min. Final DMSO concentration was 0.2%.
  • CC 50 values are shown in Table B, wherein “A” corresponds to CC 50 : A ⁇ 0.1 ⁇ M, “B” corresponds to 0.1 ⁇ M ⁇ CC 50 ⁇ 1.0 ⁇ M, “C” CC 50 > 1.0 ⁇ M.

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Abstract

La présente invention concerne les composés de formule (A) - inhibiteurs de CDK2. Les inhibiteurs décrits ici peuvent être utiles dans le traitement de maladies ou de troubles associés à CDK2, tels que le cancer. En particulier, l'invention concerne des composés et des compositions pharmaceutiques inhibant CDK2, des méthodes de traitement de maladies ou de troubles associés à CDK2, et des procédés de synthèse de ces composés.
PCT/US2025/020780 2024-03-22 2025-03-20 Inhibiteurs de cdk2 Pending WO2025199376A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015877A2 (fr) * 2005-07-20 2007-02-08 Kalypsys, Inc. Inhibiteurs de la p38 kinase et procedes permettant de traiter les troubles inflammatoires
WO2013059396A2 (fr) * 2011-10-19 2013-04-25 Signal Pharmaceuticals, Llc Traitement du cancer avec des inhibiteurs de la kinase tor
US20200062758A1 (en) * 2016-11-11 2020-02-27 Hepo Pharmaceutical Co., Ltd Nitrogen-Containing Heterocyclic Compound, Preparation Method, Intermediate, Pharmaceutical Composition and use
US20230124087A1 (en) * 2020-04-23 2023-04-20 Hoffmann-La Roche Inc. Kv3 enhancers for the treatment of cognitive disorders
US11884671B2 (en) * 2018-06-15 2024-01-30 Astrazeneca Ab Purinone compounds and their use in treating cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015877A2 (fr) * 2005-07-20 2007-02-08 Kalypsys, Inc. Inhibiteurs de la p38 kinase et procedes permettant de traiter les troubles inflammatoires
WO2013059396A2 (fr) * 2011-10-19 2013-04-25 Signal Pharmaceuticals, Llc Traitement du cancer avec des inhibiteurs de la kinase tor
US20200062758A1 (en) * 2016-11-11 2020-02-27 Hepo Pharmaceutical Co., Ltd Nitrogen-Containing Heterocyclic Compound, Preparation Method, Intermediate, Pharmaceutical Composition and use
US11884671B2 (en) * 2018-06-15 2024-01-30 Astrazeneca Ab Purinone compounds and their use in treating cancer
US20230124087A1 (en) * 2020-04-23 2023-04-20 Hoffmann-La Roche Inc. Kv3 enhancers for the treatment of cognitive disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND 30 November 2012 (2012-11-30), XP093360770, Database accession no. 67363426 *

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