WO2024148210A1 - Modulateurs de kinase 12 cycline-dépendante et leurs utilisations thérapeutiques - Google Patents

Modulateurs de kinase 12 cycline-dépendante et leurs utilisations thérapeutiques Download PDF

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WO2024148210A1
WO2024148210A1 PCT/US2024/010390 US2024010390W WO2024148210A1 WO 2024148210 A1 WO2024148210 A1 WO 2024148210A1 US 2024010390 W US2024010390 W US 2024010390W WO 2024148210 A1 WO2024148210 A1 WO 2024148210A1
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mmol
compound
salt
alkyl
etoac
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PCT/US2024/010390
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Thomas Daniel Aicher
Jiamin GU
Jinshan Chen
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Allianthera (Suzhou) Biopharmaceutical Co., Ltd.
Allianthera Boston Inc.
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Publication of WO2024148210A1 publication Critical patent/WO2024148210A1/fr

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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
    • 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
    • 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

Definitions

  • Cyclin-dependent kinase 12 is an important transcription-associated CDK. Cyclin-dependent kinases (CDKs) are a group of serine/threonine protein kinases that play crucial roles in various cellular processes by regulating cell cycle and gene transcription.
  • CDK12 shows versatile roles in regulating gene transcription, RNA splicing, translation, DNA damage response, cell cycle progression, and cell proliferation. Recently, increasing evidence demonstrates the important role of CDK12 in various human cancers, illustrating it as both a biomarker of cancer and a potential target for cancer therapy.
  • CDK12 also is known to have an important role in DNA repair and homologous recombination, and thus is directly implicated in enabling cancers to survive exposure to poly ADP ribose polymerase (PARP) inhibitors, such as olaparib. Therefore, loss of CDK12 protein or inactivation of CDK12 kinase activity leads to genome instability and renders cells more sensitive to eradication.
  • PARP poly ADP ribose polymerase
  • CDK12 targets including ATR and histones
  • ATR and histones are involved in multiple DNA repair pathways, including mismatch repair.
  • defects in mismatch repair have been found to confer sensitivity of cells to cancer immunotherapy.
  • modulators of CDK12 could help the immune system eradicate cells expressing aberrant levels of CDK12 in subjects.
  • CDK12 also is known to play a role in regulating cell cycle progression and cell proliferation. Specifically, deletion of CDK12 has been shown to prolong the cell cycle. Long-term depletion of CDK12 has many effects including inducing cell accumulation in G2/M phase, inducing the G1/S cell cycle progression defect, and inducing the decreased expression of some crucial DNA replication genes e.g.
  • compounds that modulate the CDK12 pathway can used in the treatment of cancer and cancer- related disorders and diseases including breast cancer, ovarian cancer, prostate cancer, and gastric cancer.
  • ring A is a 5-7-membered heterocycle comprising 0 or 1 additional ring nitrogen atoms, and ring A can be optionally substituted with 1 to 3 C 1-3 alkyl substituents
  • ring B is phenyl or a 6-10-membered heteroaryl comprising 1 or 2 ring nitrogen atoms
  • X is CH or N
  • n is 0, 1, or 2
  • R 1 is halo, CN, SOC 1-3 alkyl, or SO 2 C 1-3 alkyl
  • each R 2 is independently halo, CN, OH, –C 0-6 alkylene-N(R N ) 2 , CO 2 R N , COR N , C
  • compositions comprising the compounds as disclosed herein.
  • methods of treating or preventing a disease or disorder associated with aberrant CDK12 activity in a subject comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein.
  • CDK12 modulators such as compounds of Formula (I): , and pharmaceutically acceptable salts thereof wherein ring A, ring B, X, n, R 1 , R 2 , R 3 , R 4 , R 5 , R a , and R N are as described herein.
  • ring A is a 5-7-membered heterocycle comprising 0 or 1 additional ring nitrogen atoms.
  • ring A can be optionally substituted with 1 to 3 C 1-3 alkyl substituents.
  • ring A is pyrrolidine, piperidine, 3-azabicyclo[3.1.0]hexane, or azepane.
  • ring A is piperidinine.
  • ring A is piperidinine and is substituted with 1 or 2 C 1-3 alkyl substituents.
  • ring B can be phenyl or a 6-10-membered heteroaryl comprising 1 or 2 ring nitrogen atoms.
  • ring B is phenyl, pyridine, pyrimidine, pyrazine, pyridazine, quinolone, or 4a,5,6,7-tetrahydro-1,6-naphthyridine.
  • ring B is phenyl or pyridyl.
  • X can be CH or N. In various cases, X is CH. In some cases, X is N.
  • the compound has a structure of Formula (Ib): [0017] As disclosed herein, R 1 can be halo, CN SOC 1-3 alkyl, or SO 2 C 1-3 alkyl. In various cases, R 1 is halo, CN or SO 2 C 1-3 alkyl. In some cases, R 1 is F, Cl, CN, or SO 2 CH3. In some cases, R 1 is F. [0018] As disclosed herein, n can be 0, 1, or 2. In various cases, n is 0. In some cases, n is 1 or 2.
  • each R 2 can independently be halo, CN, OH, –C 0-6 alkylene-N(R N ) 2 , CO 2 R N , COR N , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, –C 1-6 hydroxyalkyl, –OC 2-6 hydroxyalkyl, –OC 2-6 alkylene-N(R N ) 2 , CON(R N ) 2 , CON(R N )-4-8-membered heterocycle, C(O)-4-8-membered heterocycle, –[O] 0-1 -4-8 membered heterocycle, or – [O] 0-1 -5-10 membered heteroaryl, wherein each heterocycle and heteroaryl comprises 1, 2, or 3 ring heteroatoms selected from N, O, and S, and the heterocycle or heteroaryl is optionally substituted with 1 or 2 C 1-6 alkyl, and when ring B is a heterocycle or
  • each R 2 is independently halo, CN, OH, –C 0-6 alkylene-N(R N ) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, –C 1-6 hydroxyalkyl, –OC 2- 6 hydroxyalkyl, –OC 2-6 alkylene-N(R N ) 2 , CON(R N ) 2 , –[O] 0-1 -4-8 membered heterocycle.
  • each R 2 is independently Br, CN, OH, C 1-6 haloalkyl, –C 0-6 alkylene-N(R N ) 2 , OC 2-6 hydroxyalkyl, –OC 2-6 alkylene-N(R N ) 2 , or – [O] 0-1 -4-8 membered heterocycle.
  • at least one R 2 is oxo.
  • R 3 can be H, halo, CN, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 3 is halo or CN.
  • R 3 is Cl or CN.
  • R 4 can be phenyl or a 5-10-membered heteroaryl comprising 1 to 3 ring atoms independently selected from N, O, and S, and R 4 is optionally substituted with 1, 2, or 3 R a .
  • R 4 is indole, 1,7-dihydropyrazolo[1,5-a]pyridine, indazole, benzo[d]imidazole, 4,5,6,7-tetrahydropyrazolo[1,5- a]pyrazine, imidazo[1,2-a]pyridine, pyrazolo[4,3-b]pyridine, [1,2,4]triazolo[4,3-a]pyridine, benzo[d][1,2,3]triazole, phenyl, pyridine, pyrazole, or imidazole.
  • R 4 is indole, 1,7-dihydropyrazolo[1,5-a]pyridine, indazole, benzo[d]imidazole, phenyl, pyridine, pyrazole, or imidazole. In some cases, R 4 is substituted with 1, 2, or 3 R a .
  • R 5 can be H or C 1-3 alkyl. In various cases, R 5 is H. In some cases, R 5 is C 1-3 alkyl. In some cases, R 5 is CH 3 .
  • each R a can independently be halo, OH, CON(R N ) 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 hydroxyalkyl, CO 2 C 1-6 alkyl, C 0-6 alkylene-N(R N ) 2 , or a 4-6-membered heterocycle comprising 1 or 2 ring atoms selected from N, O, and S.
  • each R a is independently halo, C 1-6 alkoxy, C 1-6 alkyl, CO 2 C 1-6 alkyl, C 1-6 hydroxyalkyl, or a 4-6-membered heterocycle comprising 1 or 2 ring atoms selected from N, O, and S.
  • each R a is independently F, Cl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, or a 4-6-membered heterocycle comprising 1 or 2 ring atoms selected from N, O, and S.
  • each R N can independently be H, C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 alkylene-N(C 1- 3 alkyl) 2 , or two R N groups, together with a nitrogen to which they are each attached, form a 4-10 membered heterocycle comprising 0-2 additional ring heteroatoms independently selected from N, O, and S, and can be optionally substituted with 1 or 2 C 1-6 alkyl.
  • each R N is independently H or C 1-6 alkyl.
  • Compounds as disclosed herein include those as provided in Table A, or a pharmaceutically acceptable salt thereof. Table A.
  • a compound as disclosed herein is selected from the group consisting of or a pharmaceutically acceptable salt of any of the foregoing.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure.
  • isomeric e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational
  • the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in this disclosure, unless only one of the isomers is specifically indicated.
  • stereoisomers refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • the compounds disclosed herein can exist as a single stereoisomer, or as a mixture of stereoisomers. Stereochemistry of the compounds shown herein indicate a relative stereochemistry, not absolute, unless discussed otherwise.
  • a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least more than 50% of the indicated stereoisomer, diastereomer, or enantiomer, and in some cases, at least 90% or 95% of the indicated stereoisomer, diastereomer, or enantiomer.
  • the compounds disclosed herein that have a double bond can exhibit E or Z (not shown) stereochemistry. In some cases, the compounds of Formula (I) exhibit E stereochemistry. In various cases, the compounds of Formula (I) exhibit Z stereochemistry at the double bond.
  • the compounds of Formula (I) can have any stereochemical configuration at any sp 3 carbon atoms. In some cases, the compounds of the disclosure are optically pure.
  • optically pure refers to the predominant presence of one enantiomer of a compound if multiple stereochemical configurations can exist (e.g., at least 99% enantiomeric excess).
  • all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • the compounds of the disclosure are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • alkyl refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms, for example, one to twenty carbon atoms, or one to ten carbon atoms.
  • C n means the alkyl group has “n” carbon atoms.
  • C 6 alkyl refers to an alkyl group that has 6 carbon atoms.
  • C 1-7 alkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (i.e., 1 to 6 carbon atoms), as well as all subgroups (e.g., 1-5, 2-5, 3-6, 1, 2, 3, 4, 5, and 6 carbon atoms).
  • alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2- methylpropyl), and t-butyl (1,1-dimethylethyl).
  • an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.
  • alkylene refers to a bivalent saturated aliphatic radical.
  • Cn means the alkylene group has "n" carbon atoms, e.g., a C 1 alkylene is CH 2 .
  • a heterocycle can be a 8-10 membered bicyclic, bridged, fused, or spirocyclic group having 1 or 2 or 3 ring heteroatoms selected from N, O, and S in the bicyclic ring.
  • heterocycle groups include piperidine, piperazine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, oxazepane, thiazole, pyrrole, and pyridine.
  • heteroaryl refers to a cyclic aromatic ring having heteroatoms in the ring (e.g., a monocyclic aromatic ring with 5-6 total ring atoms, or a fused bicyclic ring with 10 total ring atoms), and containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur atom in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted.
  • halo refers to refers to a fluoro (F), chloro (Cl), bromo (Br), or iodo (I) group.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxyl group (OH).
  • OH hydroxyl group
  • groups include but are not limited to, hydroxymethyl, hydroxyethyl, and the like.
  • a “substituted” functional group is a functional, group having at least one hydrogen radical that is substituted with a non-hydrogen radical (i.e., a substituent).
  • non-hydrogen radicals include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkyl, alkynyl, ether, aryl, heteroaryl, heterocycle, hydroxyl, oxy (or oxo), alkoxyl, ester, thioester, acyl, carboxyl, cyano, nitro, amino, sulfhydryl, and halo.
  • substituents can be bound to the same carbon or different carbon atoms.
  • acid addition salts can be prepared in situ during the final isolation and purification of the compounds.
  • acid addition salts can be prepared by 1) reacting the purified compound in its free-base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.
  • acid addition salts might be a more convenient form for use and use of the salt amounts to use of the free basic form.
  • Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, o
  • base addition salts can be prepared by 1) reacting the purified compound in its acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed.
  • base addition salt might be more convenient and use of the salt form inherently amounts to use of the free acid form.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium, lithium, and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N + (C 1 - 4 alkyl) 4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein.
  • Basic addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include the sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. The sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Suitable inorganic base addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide and the like.
  • Suitable amine base addition salts are prepared from amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use.
  • Ammonia ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, dietanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine and the like.
  • compositions that include an effective amount of compounds of the disclosure and one or more pharmaceutically acceptable excipients.
  • an "effective amount” includes a “therapeutically effective amount” and a “prophylactically effective amount.”
  • therapeutically effective amount refers to an amount effective in treating and/or ameliorating a disease or condition in a subject.
  • prophylactically effective amount refers to an amount effective in preventing and/or substantially lessening the chances of a disease or condition in a subject.
  • patient and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans).
  • the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • the compounds of the disclosure can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds can be administered all at once, as for example, by a bolus injection, multiple times, e.g., by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
  • 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.
  • embedding compositions examples include polymeric substances and waxes. 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 polethylene glycols and the like.
  • the active compounds can also be in microencapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the pharmaceutical compositions may be formulated in a suitable ointment, cream, lotion, or gel, containing the active component suspended or dissolved in one or more carriers, and any needed preservatives or buffers as may be required.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • 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.
  • Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • 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.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the 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.
  • 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.
  • 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 for rectal or vaginal administration are specifically suppositories which can be prepared by mixing the compounds described herein 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.
  • Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • 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.
  • the unit dosage form can be the same or different for each dose.
  • the compounds of the disclosure can be administered to a subject or patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient.
  • the specific dosage and dosage range that will be used can potentially depend on a number of factors, including the requirements of the subject or patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular subject or patient is within the ordinary skill in the art.
  • CDK12 Cyclin-dependent kinase 12
  • CDK12 Cyclin-dependent kinase 12
  • CDC6 Cell division cycle 6
  • CDT1 CDT1
  • the disclosure provides a method of modulating cyclin-dependent kinase 12 (CDK12) comprising contacting the CDK12 with a therapeutically effective amount of a compound or salt disclosed herein or a formulation thereof, in an amount effective to modulate CDK12 activity.
  • the contacting occurs in vitro.
  • the contacting occurs in vivo.
  • the contacting comprises administering to a subject in need thereof.
  • the terms “patient” and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (i.e., non-human animals) and humans.
  • the patient is a mammal (e.g., human).
  • the subject suffers from cancer.
  • the cancer is breast cancer, ovarian cancer, prostate cancer, or gastric cancer.
  • the terms “treating”, “treat” or “treatment” and the like can include preventative (e.g., prophylactic) and palliative treatment.
  • the disease or disorder is cancer.
  • the disease or disorder is breast cancer, ovarian cancer, prostate cancer, or gastric cancer.
  • Another aspect of the disclosure provides the use of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a formulation thereof in the treatment of a disease or disorder associated with aberrant CDK12 activity in a subject, where the treatment increases activity of the subject’s immune system to eradicate cells associated with aberrant CDK12 activity.
  • the disease or disorder is cancer.
  • the cancer is breast cancer, ovarian cancer, prostate cancer, or gastric cancer.
  • R 4 is indole, 1,7- dihydropyrazolo[1,5-a]pyridine, indazole, benzo[d]imidazole, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyridine, pyrazolo[4,3-b]pyridine, [1,2,4]triazolo[4,3-a]pyridine, benzo[d][1,2,3]triazole, phenyl, pyridine, pyrazole, or imidazole. 21.
  • a pharmaceutical formulation comprising the compound or salt of any one of embodiments 1 to 29 and a pharmaceutically acceptable excipient.
  • a method of modulating CDK12 activity comprising contacting the CDK12 with the compound or salt of any one of embodiments 1 to 29 in an amount effective to modulate CDK12 activity.
  • 32. A method of treating a disease or disorder associated with aberrant CDK12 activity in a subject, comprising administering to the subject a therapeutically effective amount of the compound or salt of any one of embodiments 1 to 29.
  • 33. The method of embodiment 32, wherein the disease or disorder is cancer.
  • 34. The method of embodiment 33, wherein the cancer is breast cancer, ovarian cancer, prostate cancer, or gastric cancer. 35.
  • Boc-C-6 (2.8 g, yield: 53.6 %) as a yellow solid.
  • reaction mixture was stirred at 120 °C for 16 h.
  • the LCMS showed the desired MS was detected.
  • the reaction mixture was added water and extracted with EtOAc, the organic layer was washed with brine, dried over Na 2 SO 4 , filtered and concentrated to get crude product which was purified by flash chromatography (eluting with PE/EtOAc from 100/0 to 85/15 in 15 mins) to afford tert-butyl 4-((5-methyl-4-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (650.0 mg, yield: 45.2%) as a white solid.
  • Boc-C-59 (1.1 g, yield: 57.8%) as yellow solid.
  • the compounds of the disclosure were prepared by carboxylic acid / amine condensation reactions, as noted in the below scheme: [0244] The following compounds were synthesized by common carboxylic acid-amine condensation reactions, e.g., conditions (A) or (B) as described below. [0245] (A) To a solution of corresponding carboxylic acid (0.5 mmol) in DMF (5 mL) was added HATU (1.0 mmol) and N, N-Diisopropylethylamine (1.5 mmol) at 25°C. After 20 min, intermediate C (0.55 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at 1 h for 25 °C. The desired mass was detected on LC-MS.
  • reaction solution was stirred at rt for 3 h.
  • the LCMS showed the desired MS was detected.
  • the mixture was concentrated and was purified by prep-HPLC (columns: Gemini 5 um C18150 x 21.2 mm, mobile phase: ACN – H 2 O (0.1% FA), gradient: 50 - 70, 12 min) to afford final compound.

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Abstract

L'invention concerne des composés ayant une structure de formule (I), et des sels pharmaceutiquement acceptables de ceux-ci, qui peuvent agir en tant que modulateurs de la kinase 12 cycline-dépendante (CDK12). L'invention concerne en outre des méthodes de traitement du cancer et de maladies et de troubles liés au cancer, tels que le cancer du sein, le cancer de l'ovaire, le cancer de la prostate et le cancer de l'estomac.
PCT/US2024/010390 2023-01-05 2024-01-05 Modulateurs de kinase 12 cycline-dépendante et leurs utilisations thérapeutiques WO2024148210A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007089768A2 (fr) * 2006-01-30 2007-08-09 Exelixis, Inc. 4-aryl-2-amino-pyrimidines ou 4-aryl-2-aminoalkyl-pyrimidines utilisées comme modulateurs de la jak-2 et leurs procédés d'utilisation
KR20120021370A (ko) * 2010-07-28 2012-03-09 한국과학기술연구원 ＩＫＫ-β 저해제로 작용하는 2-아자사이클릭아미노-4-페닐피리미딘 유도체
WO2014165065A1 (fr) * 2013-03-13 2014-10-09 Janssen Pharmaceutica Nv Composés de pipéridine substituée et leur utilisation en tant que modulateurs des récepteurs d'orexine
WO2015058163A2 (fr) * 2013-10-18 2015-04-23 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007089768A2 (fr) * 2006-01-30 2007-08-09 Exelixis, Inc. 4-aryl-2-amino-pyrimidines ou 4-aryl-2-aminoalkyl-pyrimidines utilisées comme modulateurs de la jak-2 et leurs procédés d'utilisation
KR20120021370A (ko) * 2010-07-28 2012-03-09 한국과학기술연구원 ＩＫＫ-β 저해제로 작용하는 2-아자사이클릭아미노-4-페닐피리미딘 유도체
WO2014165065A1 (fr) * 2013-03-13 2014-10-09 Janssen Pharmaceutica Nv Composés de pipéridine substituée et leur utilisation en tant que modulateurs des récepteurs d'orexine
WO2015058163A2 (fr) * 2013-10-18 2015-04-23 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S. M. BERGE ET AL., J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19

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