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WO2025082274A1 - Composé thiocarbonyle et son utilisation - Google Patents

Composé thiocarbonyle et son utilisation Download PDF

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Publication number
WO2025082274A1
WO2025082274A1 PCT/CN2024/124361 CN2024124361W WO2025082274A1 WO 2025082274 A1 WO2025082274 A1 WO 2025082274A1 CN 2024124361 W CN2024124361 W CN 2024124361W WO 2025082274 A1 WO2025082274 A1 WO 2025082274A1
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compound
alkyl
ring
mmol
added
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Chinese (zh)
Inventor
胡璞
陆居权
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Starg Wuhan Pharmaceutical Technology Co Ltd
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Starg Wuhan Pharmaceutical Technology Co Ltd
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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
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present application relates to the field of medical technology, and in particular to thiocarbonyl compounds and applications thereof.
  • DGK ⁇ belongs to the dioxygenase family and consists of four subunits. Its structure includes an ⁇ / ⁇ / ⁇ proteasome and a catalytic active center with two selenocysteine binding sites. The activity of DGK ⁇ is affected by a variety of regulatory factors, including protein modification, phosphorylation and ubiquitination.
  • DGK ⁇ plays a vital role in cell metabolism. It mainly participates in the tricarboxylic acid cycle (TCA cycle), oxidizing acetyl-CoA to pyruvate to generate energy for cell use. In addition, DGK ⁇ is also involved in fatty acid synthesis, cholesterol synthesis and glucose metabolism.
  • TCA cycle tricarboxylic acid cycle
  • acetyl-CoA oxidizing acetyl-CoA to pyruvate to generate energy for cell use.
  • DGK ⁇ is also involved in fatty acid synthesis, cholesterol synthesis and glucose metabolism.
  • DGK ⁇ In addition to its metabolic function, DGK ⁇ also plays an important role in signal transduction. It can regulate multiple signaling pathways, such as the PI3K/Akt/mTOR pathway, the AMPK pathway, and calcium ion channels. Through these signaling pathways, DGK ⁇ participates in regulating processes such as cell proliferation, survival, differentiation, and migration.
  • DGK ⁇ also plays an important role in tumor occurrence and development. Abnormal expression or activity changes of DGK ⁇ are associated with the occurrence of various cancers, including breast cancer, colorectal cancer, liver cancer, and pancreatic cancer. Therefore, treatment targeting DGK ⁇ may become a promising anti-cancer strategy.
  • DGK ⁇ as a key enzyme, plays an important role in cell metabolism, signal transduction and immune response.
  • In-depth study of the function and regulatory mechanism of DGK ⁇ is of great significance for understanding the occurrence and development of diseases and provides broad prospects for the development of new therapeutic strategies.
  • the first aspect of the present application provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from a benzene ring or a 5-6 membered heteroaryl group
  • Ring B is selected from a benzene ring or a 5-6 membered heteroaryl group
  • each R 1 is independently selected from H, D, F, Cl, Br, OH, CN, NH 2 , NO 2 , C 1-3 alkyl, OC 1-3 alkyl, NHC 1-3 alkyl and N(C 1-3 alkyl) 2 , wherein the C 1-3 alkyl, OC 1-3 alkyl, NHC 1-3 alkyl and N(C 1-3 alkyl) 2 are optionally substituted by 1, 2, 3 or 4 R a ; each R 2 is independently selected from H, D, F, Cl, Br, OH, CN, NH 2 , NO 2 , C 1-3 alkyl, OC 1-3 alkyl, NHC 1-3 alkyl and N(C 1-3 alkyl) 2 and C(O)NHR 21 , wherein the C 1-3 alkyl, OC 1-3 alkyl, NHC 1-3 alkyl and N(C 1-3 alkyl) 2 are optionally substituted by 1, 2, 3 or 4 R b ;
  • R 21 is selected from H, C 1-3 alkyl and OR;
  • Ra is selected from the group consisting of H, D, F, Cl, Br, OH, CN, NH2 , NO2 , C1-3 alkyl, OC1-3 alkyl, NHC1-3 alkyl, and N( C1-3 alkyl) 2 ;
  • Rb is selected from the group consisting of H, D, F, Cl, Br, OH, CN, NH2 , NO2 , C1-3 alkyl, OC1-3 alkyl, NHC1-3 alkyl, N( C1-3 alkyl) 2 , and C(O)NHR;
  • R is selected from H, C 1-3 alkyl, phenyl, halogen-substituted phenyl, benzyl and halogen-substituted benzyl;
  • n is selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1, 2, 3 and 4.
  • Ra is selected from H, D, F, Cl, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 and NHCH 2 CH 3 , and other variables are as defined herein;
  • R b is selected from H, D, F, Cl, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 and C(O)NHR, and other variables are as defined herein;
  • R is selected from H, CH 3 , CH 2 CH 3 , phenyl, halogen-substituted phenyl, benzyl and halogen-substituted benzyl, and other variables are as defined herein;
  • Ring A is selected from a benzene ring, and other variables are as defined herein;
  • Ring A is selected from a 5-membered heteroaryl group, and the other variables are as defined herein;
  • the above 5-membered heteroaryl group is selected from Other variables are as defined in this application;
  • Ring A is selected from a 6-membered heteroaryl group, and the other variables are as defined herein;
  • the above 6-membered heteroaryl group is selected from Other variables are as defined in this application;
  • Ring B is selected from a benzene ring, and other variables are as defined herein;
  • Ring B is selected from a 5-membered heteroaryl group, and the other variables are as defined herein;
  • the above 5-membered heteroaryl group is selected from Other variables are as defined in this application;
  • Ring B is selected from a 6-membered heteroaryl group, and the other variables are as defined herein;
  • the above 6-membered heteroaryl group is selected from Other variables are as defined in this application;
  • each R 1 is independently selected from H, D, F and Cl, and the other variables are as defined in the present application;
  • each R 2 is independently selected from H, D, F, Cl, CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 and C(O)NHR 21 , said CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 and NHCH 2 CH 3 are optionally substituted with 1, 2, 3 or 4 R b , and other variables are as defined herein;
  • the compound is selected from:
  • the compound is selected from:
  • the second aspect of the present application provides the use of the above-mentioned compound, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and treating a disease associated with diacylglycerol kinase activity.
  • the third aspect of the present application provides a pharmaceutical composition, which includes the compound described in the first aspect of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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 the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present application, which are prepared by reacting the compounds with specific substituents found in the present application with relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, Organic amine or magnesium salt or similar salt.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present application contain basic and acidic functional groups, and can thus be converted into any base or acid addition salt.
  • the pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the compounds of the present application may exist in specific geometric or stereoisomeric forms.
  • the present application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which fall within the scope of the present application.
  • Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the term “isomer excess” or “enantiomeric excess” refers 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 content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers and 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 present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate is generated from an amine).
  • the compounds of the present application may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds may be labeled with radioactive isotopes, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present application, whether radioactive or not, are included in the scope of the present application.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • the type and number of substituents can be any on the basis of chemical achievable.
  • any variable eg, R 1
  • its definition on each occurrence is independent.
  • the group may be optionally substituted with up to two R 1 , and each occurrence of R 1 has independent options.
  • substituents and/or variations thereof are permitted 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 listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "3-7 membered ring” refers to a “ring” having 3-7 atoms arranged around it.
  • Alicyclic refers to a saturated or partially unsaturated all-carbon ring system. Wherein “partially unsaturated” refers to a ring portion including at least one double bond or triple bond, and “partially unsaturated” is intended to cover rings with multiple unsaturated sites, but is not intended to include aryl or heteroaryl moieties as defined herein.
  • Non-limiting examples include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, cycloheptyl rings, cycloheptatrienyl rings, cyclopentanone rings, cyclopentane-1,3-dione rings, etc.
  • Alicyclic group refers to a saturated or partially unsaturated alicyclic group in which 1, 2 or 3 ring carbon atoms are replaced by heteroatoms selected from nitrogen, oxygen or S(O) t (wherein t is an integer from 0 to 2), but does not include the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Non-limiting examples include an oxetane ring, an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydropyrrole ring, a piperidine ring, a pyrroline ring, an oxazolidine ring, a piperazine ring, a dioxolane ring, a dioxane ring, a morpholine ring, a thiomorpholine ring, a thiomorpholine-1,1-dioxide, a tetrahydropyran ring, an azetidine-2-one ring, an oxetane-2-one ring, a pyrrolidine-2-one ring, a pyrrolidine-2,5-dione ring, a piperidine-2-one ring, a dihydrofur
  • Non-limiting examples of partially unsaturated monocyclic heterocycles include 1,2-dihydroazetidine ring, 1,2-dihydrooxetadiene ring, 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-oxadiazolidine ring, 1,6-dihydropyrimidine ring, 4,5,6,7-tetrahydro-1H-1,3-diaze
  • Aryl and “aromatic ring” are used interchangeably, and both refer to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated ⁇ electron system, which group may be fused with a cycloalkyl ring, a heterocycloalkyl ring, a cycloalkenyl ring, a heterocycloalkenyl ring, or a heteroaryl group.
  • C6-10 aryl refers to a monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms, and non-limiting examples of aryl include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and refer to a group of a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic arrangement) having ring carbon atoms and ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes a ring system in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings.
  • the heteroaryl ring may be optionally substituted.
  • “5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl having 5 to 10 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5- to 6-membered heteroaryl” refers to a monocyclic heteroaryl group having 5 to 6 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include thienyl, furanyl, 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-oxadiazolyl, 1,2,5-o
  • 8- to 10-membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms, non-limiting examples of which include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl,
  • heteroatom refers to nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings.
  • C 1-3 alkyl is used to refer to a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).
  • halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • the terms “5-6 membered heteroaromatic ring” and “5-6 membered heteroaryl” can be used interchangeably, and the term “5-6 membered heteroaryl” means a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ electron system, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • Examples of the 5-6 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-oxazolyl, 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 and
  • 5-membered heteroaromatic ring and “5-membered heteroaryl” are used interchangeably in this application.
  • the term “5-membered heteroaryl” refers to a monocyclic group with a conjugated ⁇ electron system consisting of 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom.
  • Examples of 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-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2 H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazo
  • Cn -n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3, C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13.
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction).
  • a substitution reaction e.g., a nucleophilic substitution reaction.
  • representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol 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-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl 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 (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (
  • the compounds of the present application or their pharmaceutically acceptable salts, or their stereoisomers can be used in a suitable dosage form with one or more pharmaceutical carriers.
  • These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (e.g., subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules and syrups.
  • the compounds of the present application contained in these preparations can be solid powders or particles; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or water-in-oil emulsions, etc.
  • the above dosage forms can be made from active compounds and one or more carriers or excipients via a common pharmaceutical method.
  • non-toxic carriers include but are not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, etc.
  • Carriers for liquid preparations include water, saline, aqueous glucose solution, ethylene glycol and polyethylene glycol, etc.
  • the active compound can form a solution or suspension with the above carriers.
  • compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of the compound administered is determined by factors such as the specific 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 the compound of the present invention that will induce 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.
  • the therapeutically effective amount of the compound of the present application or its pharmaceutically acceptable salt, or its stereoisomer contained in the pharmaceutical composition or the pharmaceutical composition of the present application is preferably 0.1 mg-5 g/kg (body weight).
  • Patient refers to 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.
  • Treatment means to lessen, slow the progression, attenuate, prevent, or maintain an existing disease or condition (eg, cancer). Treatment also includes curing, preventing the development of, or alleviating to some extent, one or more symptoms of a disease or condition.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
  • the structure of the compounds of the present application can be confirmed by conventional methods known to those skilled in the art. If the present application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, with the light source being CuK ⁇ radiation and the scanning mode being: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • SXRD single crystal X-ray diffraction
  • the solvents used in the present application can be obtained commercially.
  • the following abbreviations are used in the present application: FA represents formic acid; NH 2 CN represents cyanamide; K 2 CO 3 represents potassium carbonate; DMF represents N,N-dimethylformamide; prep-HPLC represents preparative high performance liquid chromatography; HCl represents hydrochloric acid; PE represents petroleum ether; EA represents ethyl acetate; Lawessons reagent represents Lawesson's reagent; DPPP represents bis(diphenylphosphino)propane; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; psi is a unit of pressure, representing pounds-force per square inch.
  • the compounds of the present application have DGK ⁇ inhibitory activity, specifically have a DGK ⁇ inhibitory activity of 0.1-500nM, preferably 1-200nM, more preferably 1-50nM, further preferably 1-20nM, further preferably 0.1-10nM, further preferably 0.1-5nM and 0.1-1nM.
  • the compounds of the present application can effectively activate T cells, thereby achieving the effect of inhibiting tumors.
  • Analytical method (Analytical column: Chiralpak AD-3 50x4.6mm ID, 3um mobile phase: Phase A for CO 2 , and Phase B for IPA (0.05% DEA); gradient: B in A from 5% to 40%; flow rate: 3mL/min; detector: PDA; column temperature: 35 degrees; back pressure: 100Bar).
  • the crude product was purified by high performance liquid chromatography (FA condition: preparation column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water(FA)-ACN]; gradient: 30%-60% B over 10min) to obtain compound 3-4.
  • compound 4-1 (1.50 g, 8.84 mmol) was dissolved in acetonitrile (24 mL), and then compound NH 2 CN (408 mg, 9.73 mmol, 408 ⁇ L) and DBU (1.35 g, 8.84 mmol, 1.33 mL) were added. After reacting at 25°C for one hour, compound 1-2 (2.03 g, 8.84 mmol) and DBU (673 mg, 4.42 mmol, 666 ⁇ L) were added, and reacted at 25°C for 3 hours. After adding water (60 mL), the reaction system was filtered, and the filter cake was washed three times with water (1 mL*3) and dried at 45°C to obtain a crude product.
  • compound 4-2 (1.80 g, 5.00 mmol), compound 1-4 (1.14 g, 7.50 mmol), K 2 CO 3 (3.46 g, 25.0 mmol) were dissolved in DMF (30 mL) and stirred at room temperature for 1 hour.
  • a yellow solid precipitated from the reaction system which was filtered after adding water (80 mL).
  • the filter cake was washed three times with water (5 mL*3) and dried at 45°C to obtain a crude product.
  • the crude product was slurried in ethyl acetate (30 mL) for half an hour and then filtered.
  • the filter cake was washed three times with ethyl acetate (5 mL*3) and dried at 45°C to obtain compound 4-3.
  • compound 5-1 (1.00 g, 6.87 mmol) was dissolved in tetrahydrofuran (70 mL), and compound TEA (4.85 g, 47.9 mmol, 6.67 mL) and compound 5-2 (1.50 g, 13.0 mmol, 1000 ⁇ L) were added, and the mixture was reacted at 25°C for 12 hours.
  • the reaction solution was concentrated to remove tetrahydrofuran (70 mL) and ethyl acetate (80 mL) was added, and the organic phase was washed three times with saturated sodium chloride aqueous solution (20 mL*3) to obtain compound 5-3.
  • 1 HNMR: (400 MHz, CDCl 3 ) ⁇ 7.29 (t, J 8.4 Hz, 1H), 6.99-6.85 (m, 2H).
  • compound 5-3 (960 mg, 5.12 mmol) was dissolved in acetonitrile (18 mL), and then compound NH 2 CN (236 mg, 5.63 mmol, 236 ⁇ L) and DBU (778 mg, 5.12 mmol, 771 ⁇ L) were added. After reacting at 25°C for one hour, compound 1-2 (1.17 g, 5.12 mmol) and DBU (389 mg, 2.56 mmol, 385 ⁇ L) were added, and the reaction was continued at 25°C for 12 hours. A yellow solid precipitated from the reaction system, which was filtered after adding water (30 mL).
  • the filter cake was washed three times with ethyl acetate (5 mL*3) and dried at 45°C to obtain a crude product.
  • the crude product was slurried in ethyl acetate (5 mL) for half an hour and then filtered.
  • the filter cake was washed three times with ethyl acetate (1 mL*3) and dried at 45°C to obtain compound 5-4.
  • compound 5-4 (1.35 g, 3.57 mmol), compound 1-4 (814 mg, 5.36 mmol), K 2 CO 3 (2.47 g, 17.8 mmol) were dissolved in DMF (20 mL) and stirred at room temperature for 1 hour.
  • a yellow solid precipitated from the reaction system which was filtered after adding water (60 mL).
  • the filter cake was washed three times with water (5 mL*3) and dried at 45°C to obtain a crude product.
  • the crude product was slurried in ethyl acetate (20 mL) for half an hour and then filtered.
  • the filter cake was washed three times with ethyl acetate (2 mL*3) and dried at 45°C to obtain compound 5-5.
  • compound 6-1 (1.00 g, 5.37 mmol) was dissolved in 1,4-dioxane (10.0 mL), and then liquid bromine (1.03 g, 6.45 mmol, 332 ⁇ L) was added, and the mixture was reacted at 25°C for one hour.
  • Water 200 mL was added to the reaction system, and the mixture was extracted three times with ethyl acetate (80 mL*3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was directly used in the next step to obtain compound 6-2.
  • compound 1-1 700 mg, 4.57 mmol was dissolved in acetonitrile (10.0 mL), and then compound NH 2 CN (211 mg, 5.03 mmol, 211 ⁇ L) and DBU (765 mg, 5.03 mmol, 757 ⁇ L) were added, and after reacting at 25°C for one hour, compound 6-2 (1.40 g, 5.28 mmol) was added, and reacted at 25°C for one hour. Water (20.0 mL) was added to the reaction system, and the mixture was filtered to obtain compound 6-3 (1.50 g, 3.95 mmol).
  • Example 7 Compounds 7_P1 and 7_P2
  • compound 7-1 (2.00 g, 14.6 mmol) was dissolved in acetonitrile (10.0 mL), potassium carbonate (6.09 g, 44.0 mmol) and compound 7-2 (3.28 g, 17.6 mmol) were added, and the mixture was reacted at 80°C for 12 hours.
  • Water (30.0 mL) was added to the reaction system, and the pH was adjusted to 3 with 1 M dilute hydrochloric acid, and the mixture was filtered. The filter cake was directly used for the next step.
  • Compound 7-3 was obtained.
  • compound 7-3 (1.60 g, 8.24 mmol) was dissolved in dimethylacetamide (16.0 mL), and then compound 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.37 g, 12.3 mmol) and 1-hydroxy-7-azabenzotriazole (1.68 g, 12.3 mmol, 1.73 mL) were added, and after reacting at 25°C for half an hour, compound 7-4 (1.05 g, 8.24 mmol, 1.00 eq) and N,N-diisopropylethylamine (4.26 g, 32.9 mmol, 5.74 mL, 4.00 eq) were added, and then the reaction was continued at 25°C for 1.5 hours.
  • compound 7-5 (1.80 g, 5.93 mmol) was dissolved in tetrahydrofuran (20.0 mL), and compound pyridinium tribromide (2.08 g, 6.52 mmol) was added, and the mixture was reacted at 25°C for 1 hour.
  • Water 200 mL was added to the system, and the mixture was extracted 3 times with ethyl acetate (80 mL*3).
  • the organic phases were combined, washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which could be directly used in the next step to obtain compound 7-6.
  • compound 1-1 (256 mg, 1.67 mmol) was dissolved in acetonitrile (2.00 mL), and compound NH 2 CN (77.3 mg, 1.84 mmol, 77.35 ⁇ L) and DBU (381 mg, 2.51 mmol, 378 ⁇ L) were added, and the mixture was reacted at 25° C. for one hour, and then compound 7-6 (640 mg, 1.67 mmol) was added, and the mixture was reacted at 25° C. for one hour. Water (6.00 mL) was added to the reaction system, and the mixture was filtered to obtain compound 7-7.
  • Example 8 Compounds 8_P1 and 8_P2
  • Compound 8-3 was separated by SFC (separation conditions: preparation column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [CO 2 -i-PrOH]; B%: 45%, isocratic elution) to obtain compound 8_P1 and compound 8_P2.
  • Example 10 Compounds 10_P1 and 10_P2
  • compound 10-1 (1.50 g, 10.3 mmol) was dissolved in tetrahydrofuran (100 mL), and triethylamine (7.30 g, 72.1 mmol) and thiophosgene (2.25 g, 19.5 mmol) were added, and the mixture was reacted at 25°C for 12 hours.
  • the reaction solution was concentrated to remove tetrahydrofuran (100 mL) and ethyl acetate (150 mL) was added, and the organic phase was washed 3 times with saturated sodium chloride aqueous solution (30 mL*3) to obtain compound 10-2.
  • compound 10-2 (1.86 g, 9.91 mmol) was dissolved in acetonitrile (30 mL), and then aminonitrile (458 mg, 10.9 mmol, 458 ⁇ L) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.51 g, 9.91 mmol, 1.49 mL) were added, and after reacting at 25°C for one hour, compound 9-1 (2.55 g, 9.91 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (754 mg, 4.96 mmol, 747 ⁇ L) were added, and reacted at 25°C for 2 hours. A yellow solid precipitated in the reaction system, which was filtered, and the filter cake was washed three times with acetonitrile (5 mL*3) and dried at 45°C to obtain compound 10-3.
  • compound 10-3 (3.33 g, 8.21 mmol) was dissolved in N, N-dimethylformamide (50 mL), and compound 1-4 (1.87 g, 12.3 mmol) and potassium carbonate (2.47 g, 17.8 mmol) were added. After stirring at 90°C for 0.5 hours, the reaction system was monitored and LCMS showed the peak of the target product. Water (100 mL) was added to the reaction system and then filtered. The mixture was extracted three times with ethyl acetate (30 mL*3). The combined organic phase was washed three times with water (10 mL*3) and concentrated to obtain a crude product.
  • compound 10-4 (2.46 g, 5.16 mmol) was dissolved in tetrahydrofuran (24 mL) and water (24 mL), and then lithium hydroxide monohydrate (1.08 g, 25.7 mmol) was added and stirred at room temperature for 0.5 hours.
  • Water (50 mL) was added to the reaction system, and ethyl acetate (30 mL*3) was extracted three times to remove impurities.
  • the aqueous phase was adjusted to pH 2 with dilute hydrochloric acid (1 M), extracted three times with ethyl acetate (30 mL*3), and the combined organic phase was concentrated to obtain a crude product.
  • compound 10-5 (1.20 g, 2.59 mmol) and compound 2-4 (496 mg, 3.11 mmol) were dissolved in N,N-dimethylformamide (20 mL), and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.18 g, 3.11 mmol) and N,N-diisopropylethylamine (1.01 g, 7.78 mmol, 1.35 mL) were added. The mixture was stirred at room temperature for 0.5 hours. Water (100 mL) was added to the reaction system and then filtered.
  • Compound 10-7 was separated by SFC (separation conditions: preparation column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: [CO 2 -ACN/i-PrOH (0.1% NH 3 ⁇ H 2 O)]; B%: 60%, isocratic elution) to obtain compound 10_P1 and compound 10_P2.
  • Analytical conditions (Analytical column: (S, S) Whelk-O1 50*4.6 mm ID, 3.5 um; Mobile phase: Phase A for CO 2 , and Phase B for MeOH (0.05% DEA); Gradient: 30% to 60% MeOH (0.05% DEA) in CO 2 , Flow rate: 3 mL/min; Detector: PDA; Column temperature: 35°C; Back pressure: 100 Bar).
  • Analytical conditions (Analytical column: (S,S) Whelk-O1 50*4.6mm ID, 3.5um; Mobile phase: Phase A for CO 2 , and Phase B for MeOH (0.05% DEA); Gradient: 30% to 60% MeOH (0.05% DEA) in CO 2 , Flow rate: 3mL/min; Detector: PDA; Column temperature: 35°C; Back pressure: 100Bar).
  • Example 11 Compounds 11_P1 and 11_P2
  • compound 3-1 500 mg, 2.92 mmol
  • compound 9-1 750 mg, 2.92 mmol
  • aminonitrile 500 mg, 2.92 mmol
  • 1,8-diazabicyclo[5.4.0]undec-7-ene 444 mg, 2.92 mmol
  • 1,8-diazabicyclo[5.4.0]undec-7-ene 222 mg, 1.46 mmol, 220 ⁇ L, 0.5 eq
  • compound 11-1 550 mg, 1.41 mmol
  • 2-bromopropionamide 322 mg, 2.12 mmol
  • potassium carbonate 976 mg, 7.06 mmol
  • N,N-dimethylformamide 6.00 mL
  • the mixture was added with water (20.0 mL) and extracted with ethyl acetate (20.0 mL) three times.
  • the organic phases were combined, washed once with saturated sodium chloride aqueous solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11-2.
  • compound 11-2 (870 mg, 1.89 mmol), monohydrate and lithium hydroxide (396 mg, 9.45 mmol, 5 eq) were dissolved in tetrahydrofuran (9.0 mL) and water (9.0 mL) and stirred at 25°C for 1 hour. Water (10 mL) was added to the reaction mixture and extracted 3 times with ethyl acetate (10 mL) to remove impurities.
  • compound 11-3 (690 mg, 1.55 mmol), compound 2-4 (370 mg, 2.32 mmol), N,N-diisopropylethylamine (998 mg, 7.73 mmol, 1.35 mL) and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (881 mg, 2.32 mmol) were dissolved in N,N-dimethylformamide (7.0 mL) and stirred at 25°C for 2 hours. The mixture was added with water (20.0 mL) and extracted with ethyl acetate (20.0 mL).
  • compound 11-4 (200 mg, 362 ⁇ mol) was dissolved in dichloromethane (5.0 mL), and then Lawesson's reagent (73.3 mg, 181 ⁇ mol) was added, and then stirred at 25°C for 30 minutes. Water (20.0 mL) was added to the system, and extracted with dichloromethane (20.0 mL*3) three times.
  • Test Example 1 In vitro activity test
  • Cryopreserved human PBMC (SAILYIBIO, WPBZ1012T01) was revived with 1640 medium (Invitrogen, A10491-01) containing 10% inactivated FBS (GIBCO, 10099-141) and 1% P/S.
  • T cells in PBMC were sorted out using a T cell sorting kit (STEMCELL, 17951) and incubated overnight.
  • 96-well plates were coated with CD3 antibodies (eBioscience, 16-0037-85). T cells were collected overnight, cell suspensions were prepared with culture medium, and planted in CD3-coated 96-well plates (Coring, 3599). Diluted test substances were added to each well and cultured in a 37°C, 5% CO 2 incubator for 24 hours. The supernatant was collected by centrifugation and stored at -80°C.
  • IL-2 was detected according to the instructions of ELISA (Sizhengbai, CHE0003).
  • the compound of the present application has excellent DGK ⁇ inhibitory activity and effectively activates T cell activity.

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Abstract

La présente demande se rapporte au domaine technique des médicaments. L'invention concerne un composé thiocarbonyle et son utilisation. L'invention concerne plus précisément un composé tel que représenté par la formule (I).
PCT/CN2024/124361 2023-10-17 2024-10-12 Composé thiocarbonyle et son utilisation Pending WO2025082274A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029066A2 (fr) * 2002-09-26 2004-04-08 Rib-X Pharmaceuticals, Inc. Composes heterocycliques bifonctionnels et procedes de fabrication et d'utilisation de ces composes
CN106029659A (zh) * 2014-01-06 2016-10-12 理森制药股份公司 谷氨酰胺酶抑制剂
CN115697980A (zh) * 2020-04-24 2023-02-03 拜耳公司 作为dgkzeta抑制剂用于免疫活化的取代的氨基噻唑

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004029066A2 (fr) * 2002-09-26 2004-04-08 Rib-X Pharmaceuticals, Inc. Composes heterocycliques bifonctionnels et procedes de fabrication et d'utilisation de ces composes
CN106029659A (zh) * 2014-01-06 2016-10-12 理森制药股份公司 谷氨酰胺酶抑制剂
CN115697980A (zh) * 2020-04-24 2023-02-03 拜耳公司 作为dgkzeta抑制剂用于免疫活化的取代的氨基噻唑
CN115697979A (zh) * 2020-04-24 2023-02-03 拜耳公司 作为用于免疫激活的dgkzeta抑制剂的取代的氨基噻唑类

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Title
MATTHEW J. RIESE, EDMUND K. MOON, BRYON D. JOHNSON, STEVEN M. ALBELDA: "Diacylglycerol Kinases (DGKs): Novel Targets for Improving T Cell Activity in Cancer", FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, vol. 4, XP055611385, DOI: 10.3389/fcell.2016.00108 *

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