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WO2025076284A1 - Composés, compositions pharmaceutiques associées et leurs méthodes d'utilisation - Google Patents

Composés, compositions pharmaceutiques associées et leurs méthodes d'utilisation Download PDF

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WO2025076284A1
WO2025076284A1 PCT/US2024/049873 US2024049873W WO2025076284A1 WO 2025076284 A1 WO2025076284 A1 WO 2025076284A1 US 2024049873 W US2024049873 W US 2024049873W WO 2025076284 A1 WO2025076284 A1 WO 2025076284A1
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ring
iii
cancer
formula
compound
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Aimee USERA
Louise Kirman
Patrick Lee
Michael Burke
Joshua SACHER
John Feutrill
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Delphia Therapeutics Inc
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Delphia Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the cancer is a Wnt-mediated cancer. In some embodiments, the cancer is a p53-mediated cancer. In some embodiments, the cancer is an adenomatous polyposis coli (APC)-mediated cancer. In some embodiments, the cancer is selected from colorectal cancer (CRC) (e.g., APC colorectal cancer), small intestine (small bowel) cancer, thyroid cancer, brain cancer, pancreatic cancer, bile duct cancer, hepatoblastoma, primary effusion lymphoma (PEL), myelodysplastic syndrome (MDS), and acute myeloid lymphoma (AML).
  • CRC colorectal cancer
  • PEL primary effusion lymphoma
  • MDS myelodysplastic syndrome
  • AML acute myeloid lymphoma
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • Animal refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans, at any stage of development. In some embodiments, “animal” refers to non-human animals, at any stage of development.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • Heterocycle As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or +NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ring
  • compositions A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound disclosed herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound disclosed herein or an active metabolite or residue thereof.
  • Pharmaceutically acceptable salt As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M.
  • Subject refers to any organism to which a compound or composition is administered in accordance with the present disclosure e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.) and plants.
  • animals e.g., mammals such as mice, rats, rabbits, non-human primates, and humans; insects; worms; etc.
  • a subject is a mouse.
  • subject is a rat.
  • a subject is a non-human primate.
  • a subject is a human.
  • a subject is a patient.
  • an individual who is susceptible to a disease, disorder, and/or condition is predisposed to have that disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not have been diagnosed with the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition.
  • Treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • Unsaturated means that a moiety has one or more units of unsaturation.
  • Wild-type As used herein, the term “wild-type” has its art-understood meaning that refers to an entity having a structure and/or activity as found in nature in a “normal” (as contrasted with mutant, diseased, altered, etc.) state or context. Those of ordinary skill in the art will appreciate that wild type genes and polypeptides often exist in multiple different forms (e.g., alleles).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • the present disclosure provides a compound of formula I’: I’ or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R x is independently selected from oxo, halogen, -NO 2 , -(CH 2
  • the present disclosure provides a compound of formula I”: or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each R x is independently selected from oxo, halogen, -NO 2 , -(CH 2 )
  • Ring C is a bivalent group comprising or . In some embodiments, Ring C is a bivalent group comprising . In some embodiments, Ring C is a bivalent group comprising . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some such embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some such embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In some embodiments, Ring C has the structure . In
  • Ring A is selected from a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8- to 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [00052] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is phenyl. [00053] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a 10- membered bicyclic aryl ring. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a naphthyl ring.
  • Ring A is 2-naphthyl.
  • Ring A is a 3- to 7- membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 5- to 6-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a piperidinyl ring.
  • Ring A is a 5- to 6-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is a 6-membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is a 6-membered saturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is a piperidinyl ring optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is a 5- to 6-membered partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is a 5- to 6-membered partially unsaturated monocyclic heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen, and sulfur optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is a 3,6-dihydro-2H-pyranyl ring optionally fused to an aryl ring, wherein the bicyclic ring formed thereby is substituted with m instances of R x .
  • Ring A is an 8- to 10- membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a 9- to 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments of Formula I, I’, I”, II, II-a, III, or III- a, Ring A is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring A is a benzo[d]isoxazolyl, benzo[c][1,2,5]thiadiazolyl ring, a thiazolo[5,4-b]pyridinyl ring, or a benzo[d]thiazolyl ring.
  • Ring A is a 9- membered bicyclic heteroaryl ring having 1-4 nitrogen atoms.
  • Ring A is a 9-membered bicyclic heteroaryl ring having 1-3 nitrogen atoms. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a 9- membered bicyclic heteroaryl ring having 1-2 nitrogen atoms. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is a 9-membered bicyclic heteroaryl ring having 2-3 nitrogen atoms.
  • Ring A is a 10-membered bicyclic heteroaryl ring having 1 nitrogen atom.
  • Ring A is a quinolinyl ring or an isoquinolinyl ring.
  • Ring A is a 5,6,7,8-tetrahydroquinolinyl ring.
  • Ring A is selected from:
  • Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Ring A is .
  • R x is -N(R) 2 . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R x is -(CH 2 ) y R. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R x is -(CH 2 ) z Y. It will be appreciated that a R x group on Ring A can be independent of a R x group on Ring C. In some embodiments, a R x group on Ring A is different than a R x group on Ring C.
  • each Y is selected from –OR, -C(O)R, -CO 2 R, -OC(O)R, -C(O)N(R) 2 , -N(R)C(O)R, -SO 2 R, -SO 2 N(R) 2 , and -N(R)SO 2 R; or two instances of R x , together with the atoms to which they are attached, form a 5- to 6-membered saturated, partially unsaturated or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Y is —CO 2 R. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, Y is –OR. [00072] As defined generally above for formula I”, Y is selected from -OR, -N(R) 2 , - O(CH 2 ) 2 OR, -C(O)R, -CO 2 R, -OC(O)R, -C(O)N(R) 2 , -N(R)C(O)R, -SO 2 R, -SO 2 N(R) 2 , and - N(R)SO 2 R.
  • In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is –N(R y )-.
  • L is –CH 2 N(R y )- or –N(R y )CH 2 -. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is –N(R y )-. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is -OCH 2 - or -CH 2 O-. [00080] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is .
  • In some embodiments of Formula I, I’, I”, II, II-a, III, or III- a, L is , wherein * denotes the attachment to Ring A. [00082] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is . In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, L is , wherein * denotes the attachment to Ring A. In some embodiments of Formula I, I’, I”, II, II-a, III, or III- a, L is , wherein * denotes the attachment to Ring A.
  • R y is lower haloalkyl. In some such embodiments, R y is -CF 3 , -CH 2 F, or -CF 2 H.
  • R is –CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CD(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , or – CF 3 .
  • R is C 1-2 aliphatic optionally substituted with –(CH 2 ) 0-4 ORo, wherein Ro is hydrogen or C 1-6 aliphatic.
  • R is an optionally substituted 5- to 6-membered saturated monocyclic carbocyclic ring. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is an optionally substituted cyclopropyl or cyclobutyl ring. [00096] In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, R is an optionally substituted phenyl.
  • R is a piperidinyl ring optionally substituted with –(CH 2 ) 0-4 Ro, –(CH 2 ) 0- 4 ORo, or –(CH 2 ) 0-4 CO 2 Ro, wherein Ro is C 1-6 aliphatic.
  • Ro is substituted with –(CH 2 ) 0-2 OR ⁇ or –(CH 2 ) 0-2 OH, wherein R ⁇ is C 1-4 aliphatic.
  • In some embodiments of Formula I, I’, I”, II, II-a, III, or III-am is 0. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 1. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 2. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 3. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 2. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, m is 0-1.
  • y is 0-1. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, y is 1-2. [000101] As defined generally above, z is 0-1. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, z is 0. In some embodiments of Formula I, I’, I”, II, II-a, III, or III-a, z is 1. [000102] In some embodiments, the compound is selected from a compound in Table 1. Table 1.
  • compositions comprising a compound of this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a composition of this disclosure is formulated for administration to a subject in need of such composition.
  • a composition of this disclosure is formulated for oral administration to a subject.
  • the compounds and compositions, according to the method of the present disclosure may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, e.g., a cancer described herein.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. [000115] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. [000116] The amount of compounds of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a subject receiving these compositions.
  • a specific dosage and treatment regimen for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.
  • the present disclosure provides a composition (e.g., a pharmaceutical composition) comprising a compound of this disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a composition of this disclosure is formulated for administration to a subject in need of such composition.
  • a composition of this disclosure is formulated for oral administration to a subject.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
  • the compounds of the disclosure may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • a dose is from about 0.01 to about 1000 mg, from about 0.5 to about 100 mg, from about 1 to about 50 mg, or from about 5 to about 100 mg. Exact doses may depend upon routes of administration, forms in which compounds are administered, subjects (e.g., body weight, age, body surface area, etc.), conditions, disorders or diseases, and/or preferences and experiences of physicians.
  • a fixed dose is administered.
  • two or more doses are about the same amount.
  • one or more doses are independently more than one or more other doses.
  • one or more loading doses each independently of a higher amount are administered before one or more maintenance doses each independently of a lower amount.
  • two or more or all loading doses are about the same amount.
  • a loading dose is of a higher amount than another loading dose.
  • two or more or all maintenance doses are about the same amount. In some embodiments, a maintenance dose is of a higher amount than another maintenance dose.
  • Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • kits comprising any of the compounds and compositions described herein.
  • a kit comprises a solid composition.
  • a kit comprises a tablet, capsule, or pill.
  • a kit comprises a liquid composition.
  • a kit comprises instructions for performing any of the methods described herein. 5. Characterization and Assessment [000132] As appreciated by those skilled in the art, various technologies may be utilized to characterize and/or assess provided technologies in accordance with the present disclosure. Certain useful technologies are described in the Examples. As demonstrated, among other things, the present disclosure describes various in vitro technologies suitable for assessing and characterizing provided technologies. In some embodiments, provided technologies are characterized and/or assessed, e.g., in in vitro systems, e.g., in cells. [000133] In some embodiments, provided technologies (e.g., compounds, compositions) are characterized and/or assessed using various in vitro assays known in the art.
  • compounds are assessed using a HiBiT assay.
  • the HiBiT assay reportedly can be used to provide quantitative measurement of proteins in a system, e.g., an in vitro system, e.g., a cell or population of cells.
  • a HiBiT assay can be conducted in a high-throughput manner.
  • the protein levels can reportedly be measured through the addition of the LgBiT component to form an active nanoluciferase enzyme.
  • Luminescence generated by the nanoluciferase enzyme under assay conditions can then reportedly be quantitatively measured to provide quantitation of Small BiT-tagged protein levels.
  • HiBiT system is described in, e.g., Schwinn et al. ACS Chem Biol.2018 Feb 16;13(2):467- 474.
  • Small BiT-tagged CK1 ⁇ is used in a HiBiT assay.
  • a HiBiT assay is used to assess level of targeted protein in a system, e.g., an in vitro system.
  • a HiBit assay is used to assess level of CK1 ⁇ protein in a system, e.g., an in vitro system.
  • a HiBiT assay is used to assess level of targeted protein degradation in a system, e.g., an in vitro system, by a provided compound or composition.
  • a HiBit assay is used to assess level of CK1 ⁇ protein degradation in a system, e.g., an in vitro system, by a provided compound or composition.
  • a HiBiT assay is conducted as described herein, e.g., in an example.
  • compounds are assessed using an assay to assess level of CK1 ⁇ protein or level of CK1 ⁇ activity in a system.
  • level of CK1 ⁇ protein is assessed by an immunoassay.
  • level of CK1 ⁇ protein is assessed by Western blot. In some embodiments, level of CK1 ⁇ protein is assessed by capillary-based immunoassay. Various additional methods for assessing levels of CK1 ⁇ protein or activity are described in the art, including those described in WO 2021/222542. [000135] In some embodiments, compounds are assessed using a TOPflash assay.
  • the TOPflash assay reportedly utilizes a reporter plasmid comprising multiple (e.g., two sets of three) copies of a wild-type TCF binding site upstream of a thymidine kinase minimal promoter and luciferase open reading frame (ORF).
  • the TOPflash reporter plasmid is described in, e.g., Korinek et al. Science.1997 Mar 21;275(5307):1784-7.
  • an assay can reportedly be performed to provide quantitative measurement (through measurement of luciferase-driven luminescence) of ⁇ -catenin/TCF activity in a system (e.g., an in vitro system, e.g., a cell), which activates the expression from the luciferase ORF.
  • This quantitative measurement may reportedly be used to assess Wnt signaling pathway activation in a system.
  • a TOPflash assay is used to assess level of Wnt signaling pathway activation in a system, e.g., an in vitro system, by a provided compound or composition.
  • a TOPflash assay is used to assess level of ⁇ -catenin activity in a system, e.g., an in vitro system, by a provided compound or composition.
  • a TOPflash assay is conducted as described herein, e.g., in an example.
  • compounds are assessed using an assay to assess level of p53 protein or level of p53 activity in a system.
  • level of p53 protein is assessed by an immunoassay.
  • level of p53 protein is assessed by Western blot. In some embodiments, level of p53 protein is assessed by capillary-based immunoassay. Various additional methods for assessing levels of p53 protein or activity are described in the art, including those described in WO 2021/222542. [000137]
  • a provided compound or composition is characterized or assessed in an in vivo system. In some embodiments, a provided compound or composition is characterized or assessed in an animal, e.g., a mouse, rat, pig, dog, non-human primate, e.g., a monkey. In some embodiments, a provided compound or composition is characterized or assessed in a human.
  • a provided compound or composition is characterized in xenograft model, e.g., a xenograft mouse model.
  • xenograft model e.g., a xenograft mouse model.
  • Various xenograft models for assessment of anti-cancer and/or anti-tumor properties of compounds and compositions thereof are known in the art. [000138] Those skilled in the art reading the present disclosure will readily appreciate that other technologies, e.g., in vitro models (e.g., cell lines) for various conditions, disorders, or diseases, animals models for various conditions, disorders, or diseases, clinical trials, etc. may be designed and/or utilized to assess provided technologies (e.g., compounds, compositions, methods, etc.) in accordance with the present disclosure. 6.
  • provided technologies are useful for many purposes.
  • provided technologies e.g., compounds, compositions, methods, etc.
  • provided technologies e.g., compounds, compositions, methods, etc.
  • provided technologies e.g., compounds, compositions, methods, etc.
  • the Wnt signaling pathway which may also be referred to the Wnt/ ⁇ -catenin signaling pathway, reportedly involves a variety of proteins and modulates gene expression in cells ( Komiya, Y. and Habas, R. Organogenesis.2008 Apr;4(2):68-75). Wnt proteins are reportedly secreted glycoproteins which bind to receptors belonging to the Frizzled (Fz) family of receptors on the outside of cells. Further, the interaction of a Wnt protein with a co-receptor may also be necessary; reported co-receptors include lipoprotein receptor-related protein (LRP) 5/6 and various receptor tyrosine kinases (RTKs).
  • LRP lipoprotein receptor-related protein
  • RTKs receptor tyrosine kinases
  • the present disclosure provides a method of activating an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof.
  • the oncogenic pathway is a WNT- mediated pathway.
  • the tumor suppressor gene, p53 reportedly regulates transcription of a variety of genes, including those involved in, e.g., DNA damage repair, cell cycle progression, and apoptosis. Further, p53 has been reported as the most frequently mutated gene in human cancers, and even in cancers without a p53 mutation, reduced levels of p53 activity have been reported.
  • CK1 ⁇ involvement in p53/MDM2/MDMX pathways is discussed in, e.g., Jiang, S. et al. Cell Commun Signal.2018 May 24;16(1):23.
  • Potential downregulation of p53 through the p53/MDM2/MDMX pathway has been reported in some cancers, including, e.g., acute myeloid leukemia (AML), wherein high levels of CK1 ⁇ is associated with suppression of p53 and decreased overall survival (Xu, W. et al. Oncol Rep. 2020 Nov;44(5):1895-1904).
  • AML acute myeloid leukemia
  • modulation of one or more proteins in a p53/MDM2/MDMX pathway may be conducted to increase or decrease level of p53 protein and/or activity and/or downstream gene expression.
  • modulation of one or more proteins may modulate level of p53 protein in a system, e.g. a cell.
  • modulation of one or more proteins may modulate level of p53 activity in a system, e.g. a cell.
  • modulation of one or more proteins may modulate level of p53 binding activity in a system, e.g., a cell.
  • modulation of one or more proteins may involve increasing or decreasing a level of one or more proteins. In some embodiments, modulation of one or more proteins may involve increasing or decreasing a level of activity of one or more proteins. In some embodiments, modulation of one or more proteins may involve degradation of the one or more proteins.
  • the present disclosure provides a method of inhibiting an oncogenic pathway, the method comprising contacting a biological sample with, or administering to a subject in need thereof, a compound of formula I, or a pharmaceutically salt thereof. In some such embodiments, the oncogenic pathway is a p53-mediated pathway.
  • Casein kinase 1 ⁇ refers to a protein encoded by, in humans, the CSNK1A1 gene. CK1 ⁇ may also be known as casein kinase 1 isoform alpha, CKI-alpha, or CK1. Various CK1 ⁇ sequences are readily available to those of skill in the art, including NCBI Reference Protein Sequences Accession Nos. NP_001020276.1, NP_001883.4, NP_001258670.1, and NP_001258671.1.
  • CK1 ⁇ reportedly also phosphorylates APC, which in turn assists in the association of APC with ⁇ -catenin (Ferrarese, A. et al. Biochemistry.2007 Oct 23;46(42):11902-10).
  • studies have suggested potential additional roles for CK1 ⁇ in cellular functioning due to widespread localization in the cell and ubiquitous expression of the protein in different types of cells and tissues (Jiang, S. et al. Cell Commun Signal.2018 May 24;16(1):23).
  • a provided compound interacts with a CK1 ⁇ polypeptide or protein. In some embodiments, a provided compound binds a CK1 ⁇ polypeptide or protein. In some embodiments, a provided compound binds a CK1 ⁇ polypeptide or protein and binds an additional polypeptide or protein. In some embodiments, a provided compound binds a CK1 ⁇ polypeptide or protein and binds a CRBN polypeptide or protein.
  • Cereblon refers to a protein encoded by, in humans, the CRBN gene. Various CRBN sequences are readily available to those of skill in the art, including NCBI Reference Protein Sequences Accession Nos.
  • CRBN reportedly acts a substrate receptor as part of the E3 ubiquitin ligase complex, which also includes CUL4, RBX1, and DDB1. As the substrate receptor for the complex, CRBN directly binds to proteins targeted for ubiquitin-mediated degradation.
  • provided technologies modulate level of CRBN- mediated degradation of CK1 ⁇ polypeptides or proteins.
  • provided technologies increase level of CRBN-mediated degradation of CK1 ⁇ polypeptides or proteins.
  • the Wnt signaling pathway has been previously implicated as an oncogenic in a variety of cancers, including cancers comprising a mutation of APC, e.g., APC mutant colorectal cancer. Mutations of APC in such cancers reportedly provide oncogenic activation of Wnt signaling pathway and oncogenic activation of target genes by increased ⁇ -catenin stability and/or activity.
  • Wnt signaling pathway is an oncogenic pathway.
  • further perturbation of proteins in the destruction complex e.g., Axin, CK1 ⁇
  • the moiety of formula I comprises one or more atoms or groups that interact with the side chains of CK1 ⁇ Lys18, CK1 ⁇ Arg21, CRBN Glu377, and/or CRBN His353.
  • Ring A or a substituent on Ring A i.e., an R x group
  • L comprises at least one atom that interacts with CK1 ⁇ Lys18, CRBN Glu377, and/or CRBN His353.
  • a method described herein comprises administering or delivering to a subject (or contacting a biological sample with) a compound selected from those in Table 1. In some embodiments, a method described herein comprises administering or delivering to a subject (or contacting a biological sample with) a compound selected from those in Tables 1 and 2. [000158] In some embodiments, the present disclosure provides a method of modulating association of CK1 ⁇ polypeptides and CRBN polypeptides in a system, comprising administering or delivering to the system an effective amount of a provided compound or composition thereof to the system.
  • a system comprises an in vivo system. In some embodiments, a system is an in vivo system. [000164] In some embodiments, a system comprises a cell. In some embodiments, a system is a cell. In some embodiments, a cell is a tumor cell. In some embodiments, a cell is a cancer cell. In some embodiments, a system comprises a tissue. In some embodiments, a system is a tissue. In some embodiments, a system comprises a tumor. In some embodiments, a system is a tumor. In some embodiments, a system comprises an organ. In some embodiments, a system is an organ. In some embodiments, a system comprises an organism. In some embodiments, a system is an organism.
  • a level is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% compared to absence of a provided compound or composition and/or presence of a reference compound or composition.
  • a method of treating a cancer comprises administering or delivering a compound or composition thereof described herein. In some embodiments, a method of treating a cancer comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein. In some embodiments, a method of treating a cancer comprises administering or delivering a compound or composition thereof described herein and one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein. In some embodiments, a method of treating a cancer comprises administering or delivering a therapeutically effective amount of a compound or composition thereof described herein and a therapeutically effective amount of one or more cancer therapeutics, e.g., one or more cancer therapeutics described herein.
  • an additional treatment comprises or is radiation.
  • an additional treatment comprises or is one or more additional therapeutic agents.
  • an additional therapeutic agent comprises or is one or more cancer therapeutics described herein.
  • an additional therapeutic agent comprises or is an antibody or antigen binding fragment thereof.
  • an additional therapeutic agent comprises or is a cell therapy, e.g., a genetically modified cell therapy or an engineered cell therapy.
  • an additional therapeutic agent comprises or is a chemotherapeutic.
  • an additional therapeutic agent comprises or is a hormone.
  • an additional therapeutic agent comprises or is radiation.
  • an additional therapeutic agent comprises or is a vaccine.
  • an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a condition, disorder, or disease when administered alone. In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a cancer when administered alone. In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a condition, disorder, or disease when administered in combination with a provided compound or composition. In some embodiments, an additional treatment is capable of preventing, treating, ameliorating, or slowing the progression of a cancer when administered in combination with a provided compound or composition.
  • one or more cancer therapeutics are used in combination with a compound or composition described herein. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject in combination with a compound or composition described herein. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject prior to administering or delivering a compound or composition described herein to the subject. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject at the same time as administering or delivering a compound or composition described herein to the subject. In some embodiments, one or more cancer therapeutics are administered or delivered to a subject following administering or delivering a compound or composition described herein to the subject.
  • a provided compound and an additional therapeutic agent are administered or delivered in the same composition. In some embodiments, a provided compound and an additional therapeutic are administered or delivered in separate compositions.
  • Example 1.3 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-7- methoxy-1,5-naphthyridine-3-carboxamide (I-7) [000212] Synthesis of diethyl 2-(((5-methoxypyridin-3-yl)amino)methylene)malonate [000213] Into a 100 mL round-bottom flask were added 5-methoxypyridin-3-amine (2.0 g, 16.110 mmol, 1 equiv), 1,3-diethyl 2-(ethoxymethylidene) propanedioate (3.5 g, 16.110 mmol, 1.0 equiv) and EtOH (60 mL) at room temperature.
  • 5-methoxypyridin-3-amine 2.0 g, 16.110 mmol, 1 equiv
  • reaction was stirred at -60°C for 0.5 h. Then, dimethylformamide (2.59 g, 35.481 mmol, 3 equiv) was added dropwise to the reaction. The reaction was stirred at -60 °C for 15 min. Then, the reaction was stirred at -30 °C for 15 min. The reaction was detected by LCMS and desired product was obtained. The reaction was quenched by the addition of saturated ammonium chloride aqueous (50 mL) at -30 °C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated NaCl aqueous (3 x 50 mL), dried over anhydrous Na 2 SO 4 .
  • Example 1.13 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- [1,2,4]triazolo[4,3-b]pyridazine-6-carboxamide (I-30) [000280] The synthesis of Compound I-30 was completed following the procedure in Example 1.1 using [1,2,4]triazolo[4,3-b]pyridazine-6-carboxylic acid.
  • Example 1.14 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1,6-naphthyridine-2-carboxamide (I-14) [000284] The synthesis of Compound I-14 was completed following the procedure in Example 1.1 using 1,6-naphthyridine-2-carboxylic acid.
  • Example 1.16 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-benzo[d]imidazole-5-carboxamide (I-29) [000292] The synthesis of Compound I-29 was completed following the procedure in Example 1.1 using 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid.
  • Example 1.21 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1H-pyrazolo[4,3-b]pyridine-5-carboxamide (I-6) [000312] The synthesis of Compound I-6 was completed following the procedure in Example 1.1 using 1H-pyrazolo[4,3-b]pyridine-5-carboxylic acid.
  • Example 1.24 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 8-methoxy-2H-chromene-3-carboxamide (I-16) [000324] The synthesis of Compound 16 was completed following the procedure in Example 1.1 using 8-methoxy-2H-chromene-3-carboxylic acid.
  • Example 1.25 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 6-methoxy-2-naphthamide (I-15) [000328] The synthesis of Compound I-15 was completed following the procedure in Example 1.1 using 6-methoxy-2-naphthoic acid. [000329] LC-MS: (ES, m/z): [M+H] + : 444.10.
  • the resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5 ⁇ m, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 9% B to 29% B in 10 min; Wave Length: 254nm/220nm nm; RT1(min): 10.43) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1- methylpyrrolo[2,3-b]pyridine-5-carboxamide (51.4 mg, 15.21%) as an off-white solid.
  • Example 1.33 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-158) [000378] Synthesis of 6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine [000379] Into a 25mL round-bottom flask were added methylhydrazine sulfate (447.97 mg, 3.108 mmol, 1.1 equiv) and Et3N (314.48 mg, 3.108 mmol, 1.1 equiv) in MeOH at 0°C.
  • the resulting mixture was stirred for 16h at 60°C under nitrogen atmosphere.
  • the mixture was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5m; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 11% B to 26 % B in 10 min; Wave Length: 254nm/220nm nm; RT1 (min): 16.917) to afford N-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1-methylpyrazolo[3,4-d]pyrimidine-6- carboxamide (26.7 mg, 17.41%) as a yellow solid.
  • Example 1.34 Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-157) [ [000395] Into a 40 mL vial were added cyclobutyl-hydrazine hydrochloride (228.60 mg, 1.865 mmol, 1.1 equiv) and MeOH (10 mL) at room temperature. To the above mixture was added Et 3 N (566.06 mg, 5.593 mmol, 3.3 equiv) dropwise at 0°C.
  • Example 1.37 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (I-156) [000425] Into a 40 mL vial were added 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6- dione (50 mg, 0.193 mmol, 1 equiv), 1-methylpyrazolo[3,4-b]pyridine-5-carboxylic acid (34.17 mg, 0.193 mmol, 1 equiv), DMF (2 mL), DIEA (149.55 mg, 1.158 mmol, 6 equiv) and HATU (109.99 mg, 0.289 mmol, 1.5 equiv) at room temperature.
  • Example 1.40 Synthesis of (R)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)-3-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-150) [000439] Into a 25mL round-bottom flask were added 3-(5-amino-1-oxo-3H-isoindol-2-yl) piperidine-2,6-dione (200 mg, 0.771 mmol, 1 equiv), 3-methyl-1H-pyrrolo[2,3-b] pyridine-5- carboxylic acid (135.90 mg, 0.771 mmol, 1 equiv), DIEA (299.11 mg, 2.313 mmol, 3 equiv), DMF (10 mL) and HATU (439.98 mg, 1.157 mmol, 1.5 equiv) at room temperature.
  • Example 1.43 Synthesis of 1-cyclopropyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-146) [000458] Synthesis of methyl 1-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [000459] Into a 50mL round-bottom flask were added methyl 1H-pyrrolo[2,3-b] pyridine-5- carboxylate (200 mg, 1.135 mmol, 1 equiv), cyclopropylboronic acid (195.03 mg, 2.270 mmol, 2 equiv), Na 2 CO 3 (240.64 mg, 2.270 mmol, 2 equiv), Cu(OAc) 2 (206.20 mg, 1.135 mmol, 1 equiv), 2,2’-Bipyridine (I-146) [000
  • Example 1.44 Synthesis of 1-cyclobutyl-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-148) [000469] Synthesis of methyl 1-cyclobutyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [000470] In a 100 mL round-bottom flask were added methyl 1H-pyrrolo[2,3-b] pyridine-5- carboxylate (300 mg, 1.703 mmol, 1 equiv) in DMF (25 mL) and Cs 2 CO 3 (1664.46 mg, 5.109 mmol, 3 equiv) at 0 °C.
  • Example 1.58 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 2-hydroxybenzo[d]thiazole-6-carboxamide (I-159) [000551] Synthesis of 3-(tert-butoxycarbonyl)-2-oxo-2,3-dihydrobenzo[d]thiazole-6-carboxylic acid [000552] Into a 25mL round-bottom flask were added 2-hydroxy-1,3-benzothiazole-6- carboxylic acid (100 mg, 0.512 mmol, 1 equiv) in DMF (2 mL) and sodium hydride (60% in oil, 14.75 mg, 0.614 mmol, 1.2 equiv) at 0 oC.
  • Example 1.60 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 4-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-131)
  • Synthesis of methyl 4-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [000569] To a stirred mixture of methyl 4-fluoro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (150 mg, 0.773 mmol, 1 equiv) and K 2 CO 3 (160.15 mg, 1.159 mmol, 1.5 equiv) in DMF (6 mL) was added MeI (109.65 mg, 0.773 mmol, 1 equiv) dropwise at room temperature under argon atmosphere.
  • Example 1.62 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-133) [000584] Synthesis of 5-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine [000585] Into a 100 mL 3-necked round-bottom flask were added 5-bromo-3-(trifluoromethyl)- 1H-pyrrolo[2,3-b]pyridine (900 mg, 3.396 mmol, 1 equiv) and K 2 CO 3 (938.63 mg, 6.792 mmol, 2 equiv), MeI (723.00 mg, 5.094 mmol, 1.50 equiv) in DMF(10 mL) at 0°C under nitrogen atmosphere.
  • the resulting mixture was stirred for overnight at 25°C under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of Water (50 mL) at room temperature. The mixture was extracted with EtOAc (3x50mL) and the combined organic layers were dried with Na 2 SO 4 , filtered, and concentrated under vacuum. The resulting mixture was dissolved in DMF (5 mL).
  • Desired product could be detected by LCMS.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH4HCO3), 35% to 55% gradient in 20 min; detector, UV 254 nm. This resulted in methyl 1-cyclobutylpyrazolo[3,4-b]pyrazine-5- carboxylate (60 mg, 61.37%) as an off-white solid.
  • the reaction was monitored by LCMS. Desired product could be detected by LCMS.
  • the resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 5 mL).
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography, eluted with PE / EA (0:1) to afford 1-cyclobutylpyrazolo[3,4-b]pyrazine-5 - carboxylic acid (45 mg, 79.82%) as a white solid.
  • Example 1.68 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-isopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-127) [000668] Synthesis of methyl 1-isopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate [000669] Into a 40 mL vial were added methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (500 mg, 2.838 mmol, 1 equiv), NaH (102.16 mg, 4.257 mmol, 1.5 equiv), DMF (5 mL) and 2- iodopropane (530.70 mg, 3.122 mmol, 1.1 equiv) at room temperature.
  • the mixture was purged with nitrogen for 3 mins and then was pressurized to 40 atm. with carbon monoxide at 120°C for overnight.
  • the reaction mixture was cooled to room temperature and filtered to remove insoluble solids.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water , 50% to 70% gradient in 10 min; detector, UV 254 nm.to afford as a methyl 3,4-dimethyl-1H-pyrrolo[2,3-b]pyridine-5- carboxylate (171 mg, 47.12%) as a white solid.
  • Example 1.74 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 4-hydroxy-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine-6-carboxamide (I-111) [000762] Synthesis of 4-fluoro-6-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine [000763] Into a 50mL 3-necked round-bottom flask were added 4-fluoro-1- isopropylpyrazolo[3,4-d]pyrimidin-6-amine (50 mg, 0.256 mmol, 1 equiv) ,I 2 (65.01 mg, 0.256 mmol, 1 equiv) ,CH 2 I 2 (686.05 mg, 2.560 mmol, 10 equiv) ,THF (2 mL) ,(3-methylbutyl)
  • Example 1.77 Synthesis of N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)- 1-(1-methylpiperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-116) [000796] Synthesis of methyl 1-(1-methylpiperidin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5- carboxylate [000797] Into a 40 mL vial were added methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (300 mg, 1.703 mmol, 1 equiv), 4-bromo-1-methylpiperidine (454.85 mg, 2.554 mmol, 1.5 equiv) and DMF (1 mL) at room temperature.
  • the crude product was purified by Prep-HPLC with the following conditions (column, XBridge Prep; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1-(1-methylpiperidin-4- yl)pyrrolo[2,3-b]pyridine-5-carboxamide (2.8 mg, 4.77%) as a white solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Xselect CSH F-Phenyl OBD column; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford tert-butyl 4-(5- ⁇ [2- (2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]carbamoyl ⁇ pyrrolo[2,3-b]pyridin-1- yl)piperidine-1-carboxylate (9.5 mg, 54.42%) as a white solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Xselect CSH F-Phenyl OBD column; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1- (piperidin-4-yl)pyrrolo[2,3- b]pyridine-5-carboxamide (25.0 mg, 6.37%) as a white solid.
  • Example 1.82 Synthesis of 1-(sec-butyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (I-123) [000857] Synthesis of 1-(sec-butyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid [000858] Into a 50 mL round-bottom flask were added methyl 1H-pyrrolo[2,3-b]pyridine-5- carboxylate (500 mg, 2.838 mmol, 1 equiv) and DMF (5 mL) at room temperature.
  • the crude product (116 mg) was purified by Prep-HPLC with the following conditions (column, C18 silica gel; mobile phase, MeOH in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to afford N-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]-1-(sec-butyl)pyrrolo[2,3- b]pyridine-5-carboxamide (44.0 mg, 20.52%) as an off-white solid.
  • Example 1.84 Synthesis of N-(1-cyclobutyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2- (2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-carboxamide (I-93) [000887] Synthesis of 2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindoline-5-carboxylic acid [000888] A mixture of 3-(5-bromo-6-fluoro-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (400 mg, 1.173 mmol, 1 equiv), Pd(OAc) 2 (88 mg, 0.392 mmol, 0.33 equiv), H2O (124 mg, 6.883 mmol, 5.87 equiv), DIEA (133 mg, 1.029
  • the resulting mixture was stirred at 60°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched with Water/Ice at room temperature. The resulting mixture was extracted with CH 2 Cl 2 (3 x 70 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 0% to 40% gradient in 30 min; detector, UV 254 nm.
  • the product was purified by Prep-HPLC to afford N-(4-cyclobutoxypyrimidin-2-yl)-2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindole-5-carboxamide (7.7 mg, 3.62%) as a white solid.
  • the resulting mixture was stirred for 16 h at 60 °C under nitrogen atmosphere.
  • the reaction was quenched with water (3 mL).
  • the reaction mixture was extracted with EA (30 mL).
  • the organic layer was washed with water (3 x 10 mL), dried over anhydrous Na 2 SO 4 . After filtrated, the filtrate was concentrated under reduced pressure.
  • Example 1.94 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-N-(1-isopropyl-3-methyl- 1H-pyrazolo[3,4-d]pyrimidin-6-yl)-1-oxoisoindoline-5-carboxamide (I-102) [000986] Synthesis of 1-isopropyl-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine [000987] Into a 8mL vial were added 6-chloro-1-isopropyl-3-methylpyrazolo[3,4-d]pyrimidine (100 mg, 0.475 mmol, 1 equiv) in NH3(g) in MeOH (2 mL).
  • Example 1.96 Synthesis of N-(1-cyclobutyl-3-methyl-1H-pyrrolo[2,3-b]pyridin- 5-yl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxamide (I-101) [0001007] Synthesis of 1-cyclobutyl-3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine [0001008] Into a 40 mL vial were added 3-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (300 mg, 1.693 mmol, 1 equiv), Cs 2 CO 3 (827.59 mg, 2.540 mmol, 1.5 equiv), DMF (5 mL) and iodocyclobutane (369.84 mg, 2.032 mmol, 1.2 equiv) at room temperature.
  • Desired product could be detected by LCMS.
  • the resulting mixture was filtered and the filter cake was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol/L NH 4 HCO 3 ), 30% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in 1-cyclobutyl-3-methylpyrrolo[2,3-b]pyridin-5-amine (240 mg, 91.92%) as a brown solid.
  • the final reaction mixture was irradiated with microwave radiation at 0 °C for 1 h.
  • the reaction was monitored by LCMS. About 70% product.
  • the resulting mixture was concentrated under vacuum.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 5% to 95% gradient in 25 min; detector, UV 220 nm.
  • Step 1 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carboxylic acid
  • Pd(OAc) 2 418 mg, 1.86 mmol
  • DCC 2.6 g, 12.6 mmol
  • triethylamine 2.6 g, 125 mmol
  • Xantphos (1.08 g, 1.86 mmol) and formic acid (10 g, 217 mmol) and the reaction heated at 100 °C for 3 h.
  • Step 3 N-(5-cyclobutoxypyrazin-2-yl)-2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline- 5-carboxamide
  • TEA 73.5 mg, 0.73 mmol
  • 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5- carbonyl chloride 74 mg, 0.24 mmol.
  • Example 1.103 Synthesis of 5-(benzofuran-2-yl)-N-((4'-fluoro-[1,1'-biphenyl]-4- yl)methyl)pyrimidin-4-amine (I-165) [0001116] Step 1: 6-cyclobutoxypyridazin-3-amine [0001117] To a solution of Na (19.5 mg, 0.84 mmol) in cyclobutanol (2 mL) was added 6- chloropyridazin-3-amine (100 mg, 0.77 mmol) and TBAI (10 mg) and the reaction heated at 110 °C for 3 h.
  • Step 2 5-(benzofuran-2-yl)-N-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)pyrimidin-4- amine
  • HATU 118.7 mg, 0.31 mmol
  • DIEA 121.0 mg, 0.94 mmol
  • Example 1.105 Synthesis of N-(4-cyclobutoxypyrimidin-2-yl)-3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)benzamide (I-231) [0001124] Step 1: 3-((2-carboxyethyl)amino)benzoic acid [0001125] To a solution of 3-aminobenzoic acid (5.0 g, 36.46 mmol) in toluene (100 mL) was added acrylic acid (3.42 g, 47.4 mmol) and the reaction heated at reflux for 48 h.
  • Step 4 N-(4-cyclobutoxypyrimidin-2-yl)-3-(2,4-dioxotetrahydropyrimidin-1(2H)- yl)benzamide
  • TEA 612 mg, 6.05 mmol
  • DMAP 7.4 mg, 0.06 mmol
  • 3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)benzoyl chloride 305 mg, 1.21 mmol.
  • the reaction was stirred at room temperature for 2 h then the solvent was removed under vaccuum.
  • Step 3 N-(4-cyclobutoxypyrimidin-2-yl)-2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindoline-5-carboxamide
  • Step 3 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl chloride
  • a solution of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (150 mg, 0.64 mmol) in SOCl2 (3 mL) was heated at reflux for 4 h.
  • the reaction was concentrated to afford 4- (2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl chloride (160 mg, quant.) as a yellow oil which was used in next step without further purification.
  • Step 1 4-chloro-6-methoxypyridin-2-amine [0001209] To a solution of 4,6-dichloropyridin-2-amine (3.0 g, 18.52 mmol) in NMP (30 mL) under a N2 atmosphere was added sodium methoxide (5.0 g, 92.6 mmol) and the reaction heated at 120 °C overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 2). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated.
  • Step 3 1-cyclobutyl-4-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-5-amine
  • 1-cyclobutyl-4-cyclopropyl-5-nitro-1H-pyrrolo[2,3-b]pyridine 100 mg, 0.39 mmol
  • Fe power 163 mg, 2.92 mmol
  • NH4Cl 31 mg, 0.58 mmol

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Abstract

La présente invention concerne des composés, des compositions pharmaceutiquement acceptables de ceux-ci, et des méthodes d'utilisation de ceux-ci.
PCT/US2024/049873 2023-10-06 2024-10-04 Composés, compositions pharmaceutiques associées et leurs méthodes d'utilisation Pending WO2025076284A1 (fr)

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WO2025232888A1 (fr) * 2024-05-10 2025-11-13 Shanghai Degron Biomedical Technology Co., Ltd. Agents de dégradation de wee1 et leurs utilisations

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WO2019038717A1 (fr) * 2017-08-23 2019-02-28 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
US20190076542A1 (en) * 2016-05-10 2019-03-14 C4 Theraprutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
US11548870B2 (en) * 2019-11-19 2023-01-10 Bristol-Myers Squibb Company Compounds useful as inhibitors of helios protein

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US3929880A (en) * 1971-08-21 1975-12-30 Merck Patent Gmbh Process for the preparation of oxocarboxylic acid amides and oxocarboxylic acids
US20190076542A1 (en) * 2016-05-10 2019-03-14 C4 Theraprutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2019038717A1 (fr) * 2017-08-23 2019-02-28 Novartis Ag Dérivés de 3-(1-oxoisoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
US11548870B2 (en) * 2019-11-19 2023-01-10 Bristol-Myers Squibb Company Compounds useful as inhibitors of helios protein

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DATABASE PUBCHEM COMPOUND 23 October 2012 (2012-10-23), ANONYMOUS: "3-(Cyclopentylmethyl)piperidine-2,6-dione", XP093303099, Database accession no. 64159481 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025232888A1 (fr) * 2024-05-10 2025-11-13 Shanghai Degron Biomedical Technology Co., Ltd. Agents de dégradation de wee1 et leurs utilisations

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