WO2023160572A1 - Dérivé de pyrazole, composition pharmaceutique et utilisation - Google Patents

Dérivé de pyrazole, composition pharmaceutique et utilisation Download PDF

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Publication number
WO2023160572A1
WO2023160572A1 PCT/CN2023/077595 CN2023077595W WO2023160572A1 WO 2023160572 A1 WO2023160572 A1 WO 2023160572A1 CN 2023077595 W CN2023077595 W CN 2023077595W WO 2023160572 A1 WO2023160572 A1 WO 2023160572A1
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alkyl
compound
pharmaceutically acceptable
halogenated
stereoisomer
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PCT/CN2023/077595
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English (en)
Chinese (zh)
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胡璞
陆居权
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楚浦创制（武汉）医药科技有限公司
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Priority to CN202380021711.4A priority Critical patent/CN118696044A/zh
Publication of WO2023160572A1 publication Critical patent/WO2023160572A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the invention relates to the technical field of medicine, in particular to a pyrazole derivative, a pharmaceutical composition and its application.
  • CDKs Cyclin-dependent kinases
  • CDK2 activity is of interest to researchers because dysregulation of CDK2 activity occurs frequently in a variety of human cancers.
  • CDK2 plays a key role in promoting G1/S transition and S phase progression.
  • CDK2 forms a complex with cyclin E (Cyclin E), phosphorylates members of the retinoblastoma family (pRb, etc.), leads to the release and activation of E2F transcription factors, and promotes the transition of the cell cycle from G1 phase to S phase, thereby making CDK2/ Cyclin A is activated to promote cell cycle DNA synthesis, replication and other processes.
  • Cyclin E cyclin E
  • pRb retinoblastoma family
  • Cyclin E1 copy number gain and overexpression have been identified in ovarian cancer, gastric cancer, endometrial cancer, breast cancer and other cancers, and are positively correlated with poor prognosis of the corresponding tumors.
  • ER+ breast cancer cells the high expression of Cyclin E2 is often accompanied by hormone therapy resistance (Mol. Cancer Ther., 2012, 11, 1488-1499), and the amplification or overexpression of Cyclin E is associated with poor prognosis of breast cancer are closely related (N. Engl. J. Med, 2002, 347, 1566-1575).
  • the amplification of Cyclin E has also been reported to have a certain contribution to the drug resistance of trastuzumab (Proc. Natl. Acad.
  • Cyclin E also plays an important role in the progression of triple-negative breast cancer (Breast Care, 2011, 6, 273-278) or inflammatory breast cancer (Oncotarget, 2017, 8, 14897-14911). Therefore, CDK2 may become an important anti-tumor target.
  • the object of the present invention is to provide a pyrazole derivative with good selectivity for CDK2 activity inhibition.
  • the first aspect of the present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:
  • R 1 is selected from H, halogen, C 1 - 6 alkyl, halogenated C 1 - 6 alkyl, C 3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, nitro, isocyano, -( CH 2 ) n R 5 ;
  • R 5 is selected from -CN, -OR 6, -NR 6 R 7 , -C(O)OR 6 , -C(O)R 6 , -S(O) 2 R 6 , -P(O)(OR 6 ) 2 , -O-alicyclic group, -O-aliphatic heterocyclic group, -O-aryl group, -O-heteroaryl group or -C(O)-heteroaryl group, wherein the alicyclic group, aliphatic Cyclic, aryl, heteroaryl are unsubstituted or substituted by one or more R 0 ;
  • R is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl , cyano, amino, nitro or hydroxyl;
  • R 6 and R 7 are each independently selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl , C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, aryl or heteroaryl base;
  • n 0, 1, 2, 3 or 4;
  • Ring A is selected from
  • X is each independently N or CR6 ;
  • R is selected from H, hydroxyl , C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-7 cycloalkyl or 3-7 membered heterocycloalkyl ;
  • R 2 and R 3 are each independently selected from H, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-7 cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C 3 -7 cycloalkyl and 3-7 membered heterocycloalkyl are unsubstituted or substituted by one or more R9 ;
  • R 9 is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl , cyano, amino, nitro or hydroxyl ;
  • R 4 is selected from H, halogen, amino, hydroxy or C 1 -C 6 alkyl.
  • the compound has a structure shown in any one of formulas (I-1) to (I-3):
  • the compound has a structure shown in formula (I-4):
  • R 1 is selected from H, halogen, C 3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, nitro, isocyano, -(CH 2 ) n R 5 ;
  • n 1, and the R 1 is -CH 2 R 5 , at this time, the compound has the structure shown in formula (I-5):
  • the R 5 is selected from -CN, -OR 6 or -NR 6 R 7 ;
  • the R 6 and R 7 are each independently selected from H, C 1-6 alkyl or halogenated C 1-6 alkyl.
  • R 5 is selected from -CN, -OC 1-3 alkyl , -N(H)C 1-3 alkyl , -N (C 1-3 alkyl)(C 1-3 alkyl ).
  • the R 2 is selected from H, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
  • the R 3 is selected from H, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 3-7 cycloalkyl or 3-7 membered heterocycloalkyl, wherein the C 3-7 Cycloalkyl and 3-7 membered heterocycloalkyl are unsubstituted or substituted with one or more R 9 .
  • said R 2 is selected from H;
  • the R 3 is selected from H, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, unsubstituted or 5-membered heterocycloalkyl substituted by one R 9 .
  • the R 9 is selected from halogen, C 1-6 alkyl or halogenated C 1-6 alkyl; the heteroatom of the 5-membered heterocycloalkyl is an oxygen atom.
  • R4 is selected from H, F or methyl.
  • R is selected from C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, cyano, amino, nitro or hydroxyl.
  • R 8 is selected from H, C 1-6 alkyl , halogenated C 1-6 alkyl, C 3-7 cycloalkyl or 3-7 membered heterocycloalkyl.
  • the compounds include but are not limited to the following structures:
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the compound described in the first aspect of the present invention, or its pharmaceutically acceptable salt, or its stereoisomer and the pharmaceutical composition described in the third aspect of the present invention in the preparation of treatment or prevention and CDK2 activity related or by Drug applications for diseases mediated by CDK2 activity.
  • the disease associated with or mediated by CDK2 activity is cancer.
  • the present inventor unexpectedly found a compound as shown in formula (I).
  • the compound has unexpected inhibitory activity on CDK2, can be used to treat various cancers with high expression of Cyclin E, and especially has excellent therapeutic effect on cancer patients resistant to CDK4/6 inhibitors. Based on the above findings, the inventors have accomplished the present invention.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reaction with the free acid or base in water or an organic solvent or a mixture of both. Forms of these compounds are prepared by reacting stoichiometric amounts of the appropriate base or acid.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
  • the following formula (A) means that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2).
  • the following formula (B) means that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) It exists as a mixture of isomers.
  • the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). It exists in the form of a mixture.
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible.
  • tautomers For tautomers. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enol Amine isomerization.
  • Valence isomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. white.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • substituents can be arbitrary on the basis of chemically achievable.
  • any variable eg R 1
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R 1 , with independent options for each case of R 1 .
  • combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site is connected with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "3-7 membered ring” means a “ring” with 3-7 atoms arranged around it.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. It is preferably C 1-4 alkyl, which may be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, tert-butyl and sec-butyl).
  • C 1-6 alkoxy denotes those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom. It is preferably C 1-3 alkoxy. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino denotes those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group. Preferably it is C 1-3 alkylamino.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 etc.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the terms “5-membered heteroaryl” and “5-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-membered heteroaryl” means a single ring consisting of 5 ring atoms with a conjugated ⁇ -electron system. Cyclic group whose 1, 2, 3 or 4 ring atoms are independently selected Heteroatoms from O, S and N, the remainder being carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , where p is 1 or 2).
  • a 5-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 etc.; similarly, n to n +m means that the number of atoms on the ring is from n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-member
  • C 3-7 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 7 carbon atoms, which includes monocyclic and bicyclic systems, wherein bicyclic systems include spiro rings, fused rings and bridge ring.
  • the C 3-7 cycloalkyl group includes C 3-6 , C 4-6 , C 4-5 , C 5-7 or C 5-6 cycloalkyl group; it can be monovalent, divalent or multivalent .
  • Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the term "3-7 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 7 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, fused and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 3-7-membered heterocycloalkyl group includes 5-7-membered, 3-membered, 4-membered, 5-membered, 6-membered and 7-membered heterocycloalkyl groups and the like.
  • 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidin,
  • 3-7 membered nitrogen-containing heterocycloalkyl means a 3-7 membered heterocycloalkyl group containing at least one N atom.
  • Cycloaliphatic refers to a saturated or partially unsaturated all-carbocyclic ring system. Where “partially unsaturated” refers to ring moieties that include at least one double or triple bond, “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moiety.
  • Non-limiting examples include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptyl rings Alkenyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • Heteroalicyclic group means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated alicyclic group are replaced by a heteroatom selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2) Substituted, but not including -OO-, -OS- or -SS- ring moieties, the remaining ring atoms are carbon.
  • Non-limiting examples include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings, oxazolidine rings , piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, azetidine- 2-keto ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidin-2,5-dione ring, piperidin-2-one ring, dihydrofuran-2(3H )-keto ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2-one ring, piperazin-2-
  • Non-limiting examples of partially unsaturated monoheterocyclic rings include 1,2-dihydroazetidinium rings, 1,2-dihydrooxetidine rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3-
  • Aryl and “aromatic ring” are used interchangeably and both refer to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, which Can be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl.
  • C 6-10 aryl refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having A group of shared 6 or 10 ⁇ electrons) where each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted.
  • “5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5 to 6 membered heteroaryl” means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-ox
  • 8 to 10 membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include indolyl, isoindolyl, indazolyl, benzene Triazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazole, benzoxazolyl, benzisoxazolyl, benzoxadiazole Base, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl , pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naph
  • Heteroatom means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxyl protecting group” or “mercapto protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxy group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl, and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-formyl Oxybenzyl (P
  • substituted substituents independently selected from " in the present invention means that when more than one hydrogen on the group is replaced by a substituent, the types of the substituents may be the same or different, so The selected substituents are each independent species.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, buccal and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like.
  • the compounds of the present invention contained in these formulations may be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions and the like.
  • the above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods.
  • the aforementioned carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, grape Sugar, sucrose, etc.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compounds can form solutions or suspensions with the above-mentioned carriers.
  • compositions of the present invention are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of a compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease, etc.
  • the therapeutically effective amount of the compound of the present invention or its pharmaceutically acceptable salt or its stereoisomer contained in the said pharmaceutical composition of the present invention or said pharmaceutical composition is preferably 0.1mg-5g/kg (body weight ).
  • Patient means an animal, preferably a mammal, more preferably a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treating means alleviating, delaying progression, attenuating, preventing, or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention is commercially available.
  • Pd/C stands for palladium on carbon
  • H2 stands for hydrogen
  • N2 stands for nitrogen
  • mL stands for milliliter
  • MeNH2 stands for dimethylamine
  • BBr3 stands for boron tribromide.
  • step 1
  • reaction solution was slowly poured into saturated ammonium chloride solution (3.00 mL), Ethyl acetate (3.00 mL*3) extracted three times.
  • the organic phases were combined, washed once with saturated brine (3.00 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was purified by preparative HPLC (preparative column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water(TFA)-ACN]; B%: 22%-52%, 7mins).
  • step 1
  • compound 2-5 (101mg, 260umol, 98.8% purity, 1.00eq) was dissolved in 2-methyltetrahydrofuran (1.00mL), and 1,1-carbonyldiimidazole (127mg, 780umol, 3.00eq) and 4-Dimethylaminopyridine (6.36 mg, 52.0 umol, 0.200 eq). The air was replaced with N 2 3 times, and stirred at 20 °C for 1 h under N 2 .
  • Compound 2-6 (237mg, 2.34mmol, 9.00eq) and triethylamine (263mg, 2.60mmol, 362uL, 10.0eq) were added sequentially.
  • step 1
  • Triethylamine (79.0mg, 780umol, 109uL, 3.00eq), N,N-dimethylformamide (1.00mL) and compound 3-1 (193mg, 1.56mmol, 6.00eq) were added in sequence.
  • the reaction solution was poured into water (6.00 mL), and extracted 3 times with ethyl acetate (10.0 mL*3). Combine the organic phases, saturated aqueous sodium chloride (10.0 mL) was washed once, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-2.
  • step 1
  • reaction solution was poured into 0-5°C ice water (15.0 mL), adjusted to pH 6-8 with saturated aqueous sodium bicarbonate solution, and extracted three times with dichloromethane (20.0 mL*3).
  • the organic phases were combined, washed twice with a saturated aqueous sodium chloride solution (30.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • the crude product was purified and lyophilized by HPLC (preparative column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN]; B%: 10%-40%, 10min) to obtain compound 4.
  • step 1
  • reaction solution was poured into 0-5°C ice water (50.0 mL), adjusted to pH 6-8 with saturated aqueous sodium bicarbonate solution, and extracted three times with dichloromethane (50.0 mL*3). The organic phases were combined, washed twice with saturated aqueous sodium chloride solution (50.0 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5-1.
  • LCMS: m/z 463.9(M+H) + .
  • reaction solution was slowly poured into water (10 mL), extracted 3 times with ethyl acetate (10 mL*3), washed 3 times with saturated aqueous sodium chloride solution (10 mL*3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, Concentration of the filtrate gave crude product.
  • the crude product was purified and lyophilized by HPLC (preparative column: column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(HCl)-ACN]; B%: 11%-41%, 10min) to obtain compound 7 .
  • CDK2/CyclinE 1 was purchased from Xingnokang.
  • Ulight-4E-BP1 polypeptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer.
  • High-purity ATP was purchased from Promega.
  • EDTA was purchased from Sigma. Nivo Multilabel Analyzer (PerkinElmer).
  • Kinase buffer preparation Kinase buffer contains 50mM HEPES, 1mM EDTA, 10mM MgCl 2 , 0.01% Brij-35, PH7.4 Add 2.38g HEPES, 58mg EDTA, 406mg MgCl 2 , 20mg Brij-35 to 200ml buffer, adjust pH to 7.4.
  • Dilute enzyme, Ulight-4E-BP1 polypeptide, ATP and inhibitors in Kinase Buffer Dilute the Eu-anti-phospho-tyrosine antibody to a concentration of 8nM/L with detection buffer.
  • the compound to be tested was diluted 5 times to the 8th concentration, that is, diluted from 4 ⁇ M to 0.0512 nM with a row gun, and the final concentration of DMSO was 4%, and a double-well experiment was set up.
  • Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters (log(inhibitor)vs.response in GraphPad Prism --Variable slope mode derived).
  • Table 1 provides the CDK2/CyclinE 1 enzymatic inhibitory activity of the compounds of the present invention.
  • CDK1/CyclinB1 was purchased from CARNA.
  • Ulight-4E-BP1 polypeptide, Eu-anti-phospho-tyrosine antibody, and 1X detection buffer were purchased from PerkinElmer.
  • High-purity ATP was purchased from Promega.
  • EDTA was purchased from Sigma. Nivo Multilabel Analyzer (PerkinElmer).
  • Kinase buffer preparation Kinase buffer contains 50mM HEPES, 1mM EDTA, 10mM MgCl2, 0.01% Brij-35, PH7.4 Add 2.38g HEPES, 58mg EDTA, 406mg MgCl2, 20mg Brij-35, Adjust pH to 7.4.
  • the compound to be tested was diluted 5 times to the 8th concentration, that is, diluted from 4 ⁇ M to 0.0512 nM with a row gun, and the final concentration of DMSO was 4%, and a double-well experiment was set up.
  • Add 2.5 ⁇ L inhibitor concentration gradients, 5 ⁇ L CDK1/CyclinB1 enzyme (0.5 ng), 2.5 ⁇ L substrate and ATP mixture (4mMATP, 200nM Ulight-4E-BP1 polypeptide) to the microwell plate, and the final concentration gradient of the compound is now 1 ⁇ M diluted to 0.0128 nM, ATP and substrate at final concentrations of 1 mM and 50 nM.
  • the reaction system was placed at 25°C for 60 minutes.
  • Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters (log(inhibitor)vs.response in GraphPad Prism --Variable slope mode derived).
  • Table 1 provides the CDK1/CyclinB 1 enzymatic inhibitory activity of the compounds of the present invention.
  • GSK3 ⁇ Active was purchased from SignalChem; GSK3Substrate was purchased from SignalChem; ADP-Glo Kinase Assay was purchased from Promega; Kinase assay buffer III was purchased from SignalChem; Nivo multi-label analyzer (PerkinElmer).
  • the compound to be tested was diluted to 100 ⁇ M with 100% DMSO as the first concentration, and then diluted 5 times to the eighth concentration with a row gun, that is, diluted from 100 ⁇ M to 0.0013 ⁇ M.
  • Each concentration point of the compound was diluted 20 times with 1X kinase buffer to prepare a compound working solution containing 5% DMSO, and 1 ⁇ L of the compound concentration gradient working solution was added to the microplate to set up duplicate wells.
  • Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate, and the value of IC50 can be obtained by curve fitting with four parameters (log(inhibitor)vs.response- in GraphPad Prism -Variable slope mode derived).
  • Table 1 provides the enzymatic inhibitory activity of the compounds of the present invention on GSK3 ⁇ .
  • Negative control wells read as wells containing 1% DMSO solvent
  • 1640 medium, fetal bovine serum, and penicillin/streptomycin antibiotics were purchased from Vicente.
  • CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.
  • OVCAR3 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision Multilabel Analyzer (PerkinElmer).
  • the OVCAR3 cells were seeded in a white 384-well plate, with 40 ⁇ L of cell suspension per well, which contained 300 OVCAR3 cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 5 times to the 8th concentration, that is, diluted from 2000 ⁇ M to 0.00512 ⁇ M with a row gun, and a double-well experiment was set up.
  • Compound concentrations ranged from 10 [mu]M to 0.026 nM were transferred to the cell plate.
  • Cell plates were cultured in a carbon dioxide incubator for 7 days. Prepare another cell plate, and read the signal value on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • Table 1 provides the inhibitory activity of the compounds of the present invention on the proliferation of OVCAR3 cells.
  • 1640 medium, fetal bovine serum, and penicillin/streptomycin antibiotics were purchased from Vicente.
  • CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.
  • T-47D cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Envision Multilabel Analyzer (PerkinElmer).
  • Sow T-47D cells in white 384-well plates 40 ⁇ L of cell suspension per well, which contains 300 T-47D cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 5 times to the 8th concentration, that is, diluted from 2000 ⁇ M to 0.00512 ⁇ M with a row gun, and a double-well experiment was set up.
  • Compound concentrations ranged from 10 [mu]M to 0.026 nM were transferred to the cell plate.
  • Cell plates were cultured in a carbon dioxide incubator for 7 days. Prepare another cell plate, and read the signal value on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • Example-Min Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate, and the value of IC50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • Table 1 provides the inhibitory activity of the compounds of the present invention on the proliferation of T-47D cells.
  • the compound of the present invention has good activity on CDK2 kinase. Inhibitory activity against CDK1 kinase is not strong, and inhibitory activity against GSK3 ⁇ is not strong. Good selectivity for CDK1 and GSK3 ⁇ . And it has good cell anti-proliferation activity on OVCAR3 and T47D.

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Abstract

L'invention concerne un dérivé de pyrazole, une composition pharmaceutique et une utilisation. Le dérivé de pyrazole a une structure représentée par la formule (I). Le dérivé de pyrazole présente une bonne sélectivité pour inhiber l'activité de CDK2.
PCT/CN2023/077595 2022-02-24 2023-02-22 Dérivé de pyrazole, composition pharmaceutique et utilisation WO2023160572A1 (fr)

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WO2024153158A1 (fr) * 2023-01-19 2024-07-25 楚浦创制（武汉）医药科技有限公司 Dérivé de pyrazole, sel pharmaceutiquement acceptable, stéréoisomère, composition pharmaceutique et utilisation associée
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