WO2018228435A1 - 作为gls1抑制剂的化合物 - Google Patents

作为gls1抑制剂的化合物 Download PDF

Info

Publication number
WO2018228435A1
WO2018228435A1 PCT/CN2018/091083 CN2018091083W WO2018228435A1 WO 2018228435 A1 WO2018228435 A1 WO 2018228435A1 CN 2018091083 W CN2018091083 W CN 2018091083W WO 2018228435 A1 WO2018228435 A1 WO 2018228435A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
isomer
acceptable salt
compound according
Prior art date
Application number
PCT/CN2018/091083
Other languages
English (en)
French (fr)
Inventor
廖勇刚
刘超男
韦昌青
吴颢
陈曙辉
Original Assignee
南京明德新药研发股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to EP18818915.3A priority Critical patent/EP3640250B1/en
Priority to JP2019568772A priority patent/JP7275053B2/ja
Priority to CN201880038963.7A priority patent/CN110741003B/zh
Priority to US16/621,902 priority patent/US11254666B2/en
Priority to ES18818915T priority patent/ES2903182T3/es
Publication of WO2018228435A1 publication Critical patent/WO2018228435A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to a novel class of compounds which are inhibitors of GLS1, in particular to compounds of formula (I) or pharmaceutically acceptable salts thereof.
  • Glutamine is the most abundant amino acid in the human body. It is a non-essential amino acid. It is partially taken up by the amidation of glutamic acid and ammonia derived from hydrazine metabolism, and partially converted by glucose-derived ⁇ -ketoglutaric acid. Ammonia action and subsequent amidation are produced. Glutaminase 1 (GLS1) can promote the decomposition of glutamine into glutamic acid and ammonium ions, which are subsequently converted to ⁇ -KG ( ⁇ -ketoglutaric acid) by glutamate dehydrogenase. The alpha-KG then enters the TCA (tricarboxylic acid cycle) cycle to provide energy and a source of macromolecular material.
  • TCA tricarboxylic acid cycle
  • glutamine metabolism produces a carbon source that supports the synthesis and lipogenesis of OAA (oxaloacetate), acetyl-CoA, and citric acid; meanwhile, it provides a nitrogen source to support purines, pyrimidines, and DNA and NADPH (nicotinamide glands).
  • OAA oxaloacetate
  • acetyl-CoA acetyl-CoA
  • citric acid meanwhile, it provides a nitrogen source to support purines, pyrimidines, and DNA and NADPH (nicotinamide glands).
  • purines pyrimidines
  • DNA and NADPH nicotinamide glands
  • NADPH nicotinamide glands
  • ATP adenosine-triphosphate
  • Glutamine metabolism restriction can effectively inhibit cancer cell growth.
  • a specific inhibitor of GLS1 can induce cell death in cancer cells.
  • glutaminase inhibitors CB-839 developed by Calithera Biosciences, and 968 compounds developed by Cornell University are undergoing clinical trials.
  • the present invention provides a compound of the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 or selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 , respectively, or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-6 alkyl, C 1 -6 heteroalkyl;
  • R 3 is selected from H
  • R 1 and R 3 are joined together to form a C 3-6 cycloalkyl group
  • Ring B is selected from the group consisting of: phenyl, 5-6 membered heteroaryl;
  • n is selected from: 0, 1, 2 or 3;
  • R is selected from: H, F, Cl, Br, I, OH, NH 2 or selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R';
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 ;
  • R 1 is selected from H, or R 1 and R 3 are joined together to form a C 3-6 cycloalkyl group, the "*" carbon atom is not a chiral carbon atom;
  • R 1 is not selected from H
  • the "*" carbon atom is a chiral carbon atom, and is present as a (R) or (S) single enantiomer or as an enantiomer;
  • hetero of the C 1-6 heteroalkyl, 5-6 membered heteroaryl is selected from the group consisting of N, -O-, -S-, -NH-;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from H, F, Cl, Br, I, OH, NH 2 or selected from 1 , 2 or 3 R' substituted: C 1-3 alkyl, C 1-3 alkoxy.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from H, F, Cl, Br, I, OH, NH 2 or selected from 1 , 2 or 3 R' substituted: Me, Et,
  • the compound, the isomer thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, CF 3 , Et ,
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 or selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R, C 1-3 alkoxy.
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, CF 3 , Et,
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy.
  • R 2 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, CF 3 ,
  • n is selected from the group consisting of: 0, 1, or 2.
  • the structural unit From:
  • the ring B is selected from the group consisting of phenyl and pyridine.
  • the structural unit From:
  • the structural unit From:
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from H, F, Cl, Br, I, OH, NH 2 or selected from 1 , 2 or 3 R' substituted: C 1-3 alkyl, C 1-3 alkoxy, other variables as defined herein.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from H, F, Cl, Br, I, OH, NH 2 or selected from 1 , 2 or 3 R' substituted: Me, Et, Other variables are as defined by the present invention.
  • the compound, the isomer thereof, or a pharmaceutically acceptable salt thereof wherein R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, CF 3 , Et , Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 or selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R, C 1-3 alkoxy, other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , Me, CF 3 , Et, Other variables are as defined by the present invention.
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 or independently selected from, optionally substituted by 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, other variables are as defined herein.
  • R 2 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , Me, CF 3 ,
  • n is selected from: 0, 1 or 2, and other variables are as defined herein.
  • Ring B is selected from the group consisting of phenyl, pyridine, and other variables are as defined herein.
  • the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • R 1 , R 2 , R 3 are as defined in the present invention.
  • R 1 is selected from H, or R 1 and R 3 are joined together to form a C 3-6 cycloalkyl group, the "*" carbon atom is not a chiral carbon atom;
  • R 1 is not selected from H
  • the "*" carbon atom is a chiral carbon atom, and is present as a (R) or (S) single enantiomer or as an enantiomer;
  • the invention also provides a compound of the formula:
  • the above compound is selected from the group consisting of
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a GLS1 inhibitor.
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms. All such compounds are contemplated by the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers , (D)-isomer, (L)-isomer, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • a double bond structure exists in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is bonded to two different substituents (including a nitrogen atom) Of the double bonds, a pair of lone pairs of electrons on the nitrogen atom are considered as a substituent to which they are attached), if a wavy line is used between the atom on the double bond and the substituent in the compound
  • the linkage means the (Z) isomer, the (E) isomer or a mixture of the two isomers of the compound.
  • the following formula (A) indicates that the compound exists as a single isomer of the formula (A-1) or the formula (A-2) or two isomers of the formula (A-1) and the formula (A-2) The mixture is present;
  • the following formula (B) indicates that the compound exists as a single isomer of formula (B-1) or formula (B-2) or two of formula (B-1) and formula (B-2) A mixture of isomers is present.
  • the following formula (C) indicates that the compound exists as a single isomer of the formula (C-1) or the formula (C-2) or two isomers of the formula (C-1) and the formula (C-2) The mixture is present.
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the 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 one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug.
  • Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” means that the subsequently described event or condition may, but is not necessarily, to occur, and that the description includes instances in which the event or condition occurs and instances in which the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent.
  • X when X is vacant in AX, the structure is actually A.
  • the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example, The medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from 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 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • 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 (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), 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 t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • 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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the compounds of the present invention Compared with the existing GLS1 inhibitors, the compounds of the present invention have significant GLS1 inhibitory effects, and the solubility, metabolic stability and drug efficacy are greatly improved, the toxicity is lowered, and there is a remarkable and unexpected unexpected drug-forming potential.
  • Figure 1 Relative body weight change (%) of test article on mouse lung cancer 3LL cells subcutaneously transplanted tumor female C57/BL6 model.
  • IP intraperitoneal injection
  • PO oral administration
  • QW once a week
  • QD once a day.
  • Relative body weight changes were calculated based on animal body weight at the start of dosing. Data points represent the percentage change in average body weight within the group, and error bars represent standard errors (SEM).
  • Step 1 Compound 1-1 (18 g, 120.82 mmol,), Compound 2-2 (24.20 g, 120.82 mmol) was added to DMF (180 mL), then potassium carbonate (33.40 g, 241.65 mmol), 100 ° C Stir for 3 hours. After completion of the reaction, the mixture was extracted with EtOAc (EtOAc m. Used directly in the next step. MS ESI calcd for C 14 H 21 ClN 4 O 2 [M + H] +314, found 314.
  • Step 2 Compound 1-3 (7.4 g, crude) was taken in MeOH (10 mL) then EtOAc EtOAc EtOAc (EtOAc: EtOAc After stirring at ° C for 2 hours, the reaction was completed and directly filtered to give the crude compound 1-4.
  • MS ESI calculated for C 14 H 22 N 4 O 2 [M+H] + 279, found 279.
  • Step 3 Compound 1-4 (7.1 g, crude) was added to trifluoroacetic acid (10 mL), and stirred at 25 ° C for 2 hr. MS ESI calculated for C 9 H 14 N 4 [M+H] + 179, found 179.
  • Step 4 Compound 1-5 (4.5 g, crude) and compound 1-6 (4.55 g, 25.25 mmol) were added to ethanol (45 mL), then sodium hydrogen carbonate (12.73 g, 151.49 mmol) After stirring at ° C for 2 hours, the reaction was directly filtered, and the solvent was evaporated to give a crude compound 1-7. MS ESI calculated for C 11 H 15 N 7 S [M+H]+278, found 278.
  • Step 5 Compound potassium hydroxide (3.25 g, 57.86 mmol) was added to methanol (30 mL) and then slowly added dropwise at 0 ° C to compound 1-8 (2 g, 10.52 mmol) and compound 1-9 (3.19 g, A mixed solution of 12.62 mmol) in methanol (20 mL). The reaction was stirred at 25 ° C for 19 hours. After completion of the reaction, it was extracted with tert-butyl methyl ether (100 ml) and water (100 ml).
  • Step 6 Compound 1-7 (110.86 mg, 399.73 ⁇ mol), compound 1-10 (0.2 g, 799.45 ⁇ mol) and diisopropylethylamine (154.98 mg, 1.20 mmol) were added to DMF (2 mL). Then, T3P (713.19 ⁇ l, 1.20 mmol, 50% purity) was added, and the reaction was stirred at 25 ° C for 2 hours. After completion of the reaction, ethyl acetate (50 ml * 3) and water (50 ml) were evaporated.
  • the final concentration of each component in the final prepared experimental buffer was: 50 mM Tris-HCl pH 8.0, 0.25 mM EDTA, 150 mM K 2 HPO 4 , 0.1 mg/mL BSA, 1 mM DTT, 0.01% Triton X-100
  • solution A contains: L-glutamine (L-glutamine), NAD + (nicotinamide adenine dinucleotide) and GLDH (glutamate dehydrogenase)
  • concentration of each component in the final experimental reaction system is: 4.5mM L-glutamine, 2mM NAD+4U/ml GLDH
  • the 1X assay buffer was used to configure the "solution B"--2X enzyme solution (solution B containing the enzyme GLS1) in the experiment, and the final concentration of GLS1 was 2nM in the final experimental reaction system.
  • the experimental plate is the pre-experiment experiment Labcete ECHO prepared plate containing the compound gradient concentration and the corresponding DMSO solution:
  • test plate was taken out, and 20 ⁇ L of solution B (enzyme GLS1 solution) was added to columns 2 to 23 of the experimental plate, and then 20 ⁇ Lassay buffer was added to columns 1 and 24 of the experimental plate, and columns 1 and 24 were used as Min control in the experimental system. ;
  • the membrane was sealed and the plate was incubated at 23 ° C for 1 hour;
  • the compounds designed in accordance with the invention exhibit good GLS1 enzyme inhibitory activity.
  • AUC 0-inf area under the plasma concentration-time curve from time 0 to extrapolation to infinity
  • Bioavailability Bioavailability.
  • the compounds of the present invention have good oral bioavailability in small or rat, and higher exposure is beneficial to produce good in vivo efficacy.
  • OBJECTIVE To evaluate the efficacy of test compounds in the subcutaneous xenograft tumor of murine lung cancer 3LL cells in a C57/BL6 nude mouse model.
  • mice female C57/BL6 nude mice, 6-8 weeks old, weighing 18-22 g; supplier: Shanghai Lingchang Biotechnology Co., Ltd.
  • Mouse lung cancer 3LL cells were cultured in vitro in a single layer, cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 2 mM glutamine, cultured at 37 ° C 5% CO 2 . Passage was routinely digested with trypsin-EDTA twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and inoculated.
  • 0.1 mL of 2 x 10 6 3LL cells were subcutaneously inoculated into the right back of each C57/BL6. Group administration was started when the average tumor volume reached 66 mm 3 .
  • PD-1 Bioxcell, lot number 5792-210715/665417S1
  • PD-L1 Bioxcell, lot number: 665717O1B/66571713
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • TGI (%) [1- (mean tumor volume at the end of administration of a treatment group - mean tumor volume at the start of administration of the treatment group) / (mean tumor volume at the end of treatment of the solvent control group - The average tumor volume at the start of treatment in the solvent control group) was ⁇ 100%.
  • the effects of the test compound on the body weight of the animal were examined, and the daily behavior of the animal was routinely examined, the amount of water intake (only visual inspection), appearance signs or other abnormal conditions were examined.
  • the number of animal deaths and side effects in the group were recorded based on the number of animals in each group.
  • the weight of experimental animals was used as a reference indicator for indirect determination of drug toxicity. None of the drug-administered groups in this model showed significant weight loss, no morbidity or death.
  • the effect of the test substance on the body weight of the female C57/BL6 model of subcutaneous transplantation of mouse lung cancer 3LL cells was shown in Fig. 1.
  • mice lung cancer 3LL cells subcutaneously transplanted tumor female C57/BL6 model
  • the tumor volume changes of each group after treatment were as shown in Table 5.
  • Example 17 Antitumor efficacy evaluation of Example 17 on mouse lung cancer 3LL xenograft model
  • the c.p value is based on the tumor volume.
  • the tumor volume of the tumor control mice reached 2081 mm 3 12 days after the start of administration.
  • the tumor volume of the PD-L1 monotherapy group was 877 mm 3 and 1442 mm 3 , respectively, and the T/C was 40% and 65%, respectively, and the P value was 0.000, 0.110.

Abstract

式(Ⅰ)所示的作为GLS1抑制剂的化合物或其药学上可接受的盐。

Description

作为GLS1抑制剂的化合物
相关申请的引用
本申请主张于2017年06月13日提交的中国专利申请CN201710444039.6的优先权，其内容在此并入本申请。
技术领域
本发明涉及新的一类作为GLS1抑制剂的化合物，具体涉及式(Ⅰ)所示化合物或其药学上可接受的盐。
技术背景
谷氨酰胺是人体最丰富的氨基酸，是一种非必需氨基酸，部分由谷氨酸与衍生自嘌呤代谢的氨的酰胺化从循环中摄取，部分由葡萄糖衍生的α-酮戊二酸的转氨作用和随后的酰胺化产生。谷氨酰胺水解酶1(glutaminase1，GLS1)能促进谷氨酰胺分解成谷氨酸和铵离子,谷氨酸随后通过谷氨酸脱氢酶转化为α-KG(α-酮戊二酸)，然后α-KG进入TCA(三羧酸循环)循环以提供能量和大分子材料来源。更重要的是，谷氨酰胺代谢产生碳源支持OAA(草酰乙酸)、乙酰辅酶A和柠檬酸的合成和脂肪生成；同时，提供氮源支持于嘌呤、嘧啶和DNA和NADPH(烟酰胺腺嘌呤二核苷酸磷酸)和GSH(谷胱甘肽)的合成以维持氧化还原稳态。作为合成许多氨基酸、蛋白质、核苷酸和其他生物重要分子的前体。
谷氨酰胺在细胞生长和增殖中起关键作用。众所周知，癌细胞以耗散的方式利用葡萄糖通过有氧糖酵解产生ATP(腺苷-三磷酸),同时，为了满足快速增殖，癌细胞必须使用另一种能量源谷氨酰胺的氧化磷酸化产生ATP。由于在增殖细胞特别是癌细胞中来自TCA循环的柠檬酸盐的持续损失，需要大量补充TCA中间体，增加谷氨酰胺消耗用于合成代谢需求，与正常组织相比，在大多数癌细胞中谷氨酰胺需求增加和消耗加快，GLS1活性也比正常细胞高得多。升高的谷氨酰胺代谢不仅为癌细胞的生长和增殖提供能量和底物，而且使谷氨酰胺成为癌症治疗中的有效候选物。
谷氨酰胺代谢限制可有效抑制癌细胞生长，作为谷氨酰胺代谢的第一个关键酶，GLS1的特异性抑制剂在癌细胞中能诱导细胞死亡。有两种报道的谷氨酰胺酶抑制剂Calithera Biosciences公司开发的CB-839，Cornell大学开发的968化合物正在进行临床试验。
目前，仍然存在开发新的谷氨酰胺酶抑制剂用于治疗与细胞增殖相关的疾病的需求。
发明内容
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2018091083-appb-000001
其中，
R 1选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
R 3选自H；
或者R 1和R 3连接在一起形成一个C 3-6环烷基；
环B选自：苯基、5-6元杂芳基；
n选自：0、1、2或3；
R选自：H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：C 1-6烷基、C 1-6杂烷基；
R’选自：F、Cl、Br、I、OH、NH 2；
当R 1选自H，或者R 1和R 3连接在一起形成一个C 3-6环烷基时，带“*”碳原子不为手性碳原子；
当R 1不选自H，带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
所述C 1-6杂烷基、5-6元杂芳基之“杂”选自N、-O-、-S-、-NH-；
上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2018091083-appb-000002
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其中，R选自：H、F、Cl、Br、I、OH、NH 2、Me、CF 3、Et、
Figure PCTCN2018091083-appb-000003
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。
本发明的一些方案中，上述R 1选自：H、F、Cl、Br、I、OH、NH 2、Me、CF 3、Et、
Figure PCTCN2018091083-appb-000004
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、CF 3、
Figure PCTCN2018091083-appb-000005
本发明的一些方案中，上述n选自：0、1或2。
本发明的一些方案中，上述结构单元
Figure PCTCN2018091083-appb-000006
选自：
Figure PCTCN2018091083-appb-000007
本发明的一些方案中，上述环B选自：苯基、吡啶。
本发明的一些方案中，上述结构单元
Figure PCTCN2018091083-appb-000008
选自：
Figure PCTCN2018091083-appb-000009
Figure PCTCN2018091083-appb-000010
本发明的一些方案中，上述结构单元
Figure PCTCN2018091083-appb-000011
选自：
Figure PCTCN2018091083-appb-000012
Figure PCTCN2018091083-appb-000013
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基，其他变量如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：Me、Et、
Figure PCTCN2018091083-appb-000014
其他变量如本发明所定义。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其中，R选自：H、F、Cl、Br、I、OH、NH 2、Me、CF 3、Et、
Figure PCTCN2018091083-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自：H、F、Cl、Br、I、OH、NH 2、Me、CF 3、Et、
Figure PCTCN2018091083-appb-000016
其他变量如本发明所定义。
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基，其他变量如本发明所定义。
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、CF 3、
Figure PCTCN2018091083-appb-000017
本发明的一些方案中，上述n选自：0、1或2，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018091083-appb-000018
选自：
Figure PCTCN2018091083-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，上述环B选自：苯基、吡啶，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018091083-appb-000020
选自：
Figure PCTCN2018091083-appb-000021
Figure PCTCN2018091083-appb-000022
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2018091083-appb-000023
选自：
Figure PCTCN2018091083-appb-000024
Figure PCTCN2018091083-appb-000025
其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自：
Figure PCTCN2018091083-appb-000026
其中，
n、R 1、R 2、R 3如本发明所定义。
当R 1选自H，或者R 1和R 3连接在一起形成一个C 3-6环烷基时，带“*”碳原子不为手性碳原子；
当R 1不选自H，带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
本发明还提供了下式化合物：
Figure PCTCN2018091083-appb-000027
本发明的一些方案中，上述化合物，其选自：
Figure PCTCN2018091083-appb-000028
本发明还提供了一种药物组合物，包括治疗有效量上述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述的化合物或其药学上可接受的盐或者上述组合物在制备治疗GLS1抑制剂相关药物上的应用。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2018091083-appb-000029
和楔形虚线键
Figure PCTCN2018091083-appb-000030
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2018091083-appb-000031
和直形虚线键
Figure PCTCN2018091083-appb-000032
表示立体中心的相对构型，用波浪线
Figure PCTCN2018091083-appb-000033
表示楔形实线键
Figure PCTCN2018091083-appb-000034
或楔形虚线键
Figure PCTCN2018091083-appb-000035
或用波浪线
Figure PCTCN2018091083-appb-000036
表示直形实线键
Figure PCTCN2018091083-appb-000037
和直形虚线键
Figure PCTCN2018091083-appb-000038
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2018091083-appb-000039
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。
Figure PCTCN2018091083-appb-000040
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％， 或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。 当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2018091083-appb-000041
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2018091083-appb-000042
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2018091083-appb-000043
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥 上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基、4H-1,2,4-***基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原 子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3 -异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰 基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；EDTA代表乙二胺四乙酸；BSA代表牛血清蛋白；DTT代表二硫苏糖醇；T3P代表1-丙基磷酸酐。
化合物经手工或者
Figure PCTCN2018091083-appb-000044
软件命名，市售化合物采用供应商目录名称。
本发明化合物与现有的GLS1抑制剂相比，具有显著的GLS1抑制作用，并且溶解性、代谢稳定性以及药效有很大的提升，毒性有降低，具有显著甚至意料不到的成药潜力。
附图说明
图1：受试物对小鼠肺癌3LL细胞皮下移植肿瘤雌性C57/BL6模型的相对体重变化(％)。
IP：腹腔注射；PO：口服给药；QW：1周1次；QD：1天1次。
相对体重变化基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比，误差线代表标准误(SEM)。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1&2：化合物1&2
Figure PCTCN2018091083-appb-000045
步骤1:将化合物1-1(18g,120.82mmol,)，化合物2-2(24.20g,120.82mmol)，加入到DMF(180mL)中，然后加入碳酸钾(33.40g,241.65mmol)，100℃搅拌3小时。反应完毕后用乙酸乙酯(100ml*3)和水(100ml)萃取，有机相用饱和食盐水(400ml)洗，用无水硫酸钠干燥浓缩后得到化合物1-3粗品。直接用于下一步反应。MS ESI计算值C 14H 21ClN 4O 2[M+H]+314，实测值314.
步骤2:将化合物1-3(7.4g，粗品)加入到甲醇(10mL)中，然后在25℃加化合物甲酸铵固体(14.92g,236.58mmol,)10％干钯碳(0.78g)，40℃搅拌2小时，反应完毕后直接过滤得目标化合物1-4粗品。MS ESI计算值C 14H 22N 4O 2[M+H]+279，实测值279.
步骤3:将化合物1-4(7.1g，粗品)加入三氟乙酸(10mL)中，25℃搅拌2小时，反应完毕后直接浓缩得目标化合物1-5粗品。MS ESI计算值C 9H 14N 4[M+H]+179，实测值179.
步骤4:将化合物1-5(4.5g，粗品)和化合物1-6(4.55g,25.25mmol)加入到乙醇(45mL)中，然后加入碳酸氢钠(12.73g,151.49mmol)，反应于90℃搅拌2小时，反应完毕后直接过滤，蒸干溶剂得化合物1-7粗品。MS ESI计算值C 11H 15N 7S[M+H]+278，实测值278.
步骤5:将化合物氢氧化钾(3.25g,57.86mmol)加入到甲醇(30mL)中，然后在0℃缓慢滴加到化合物1-8(2g,10.52mmol)和化合物1-9(3.19g,12.62mmol)的甲醇(20mL)混合溶液。反应在25℃搅拌19小时，反应完毕后用叔丁基甲基醚(100ml)和水(100ml)萃取，水相用稀盐酸酸化到pH＝5，然后用乙酸乙酯(20ml*3)萃取，有机相用饱和食盐水(80ml)洗涤，无水硫酸钠干燥浓缩后柱层析(石油醚:乙酸乙酯＝1:1)得到化合物1-10。 1H NMR(400MHz,CHLOROFORM-d)δppm 3.47(s,3H),4.83(s,1H),7.23(d,J＝5.2Hz,1H),7.35(s,1H),7.40-7.44(m,2H),10.38(brs,1H).
步骤6:将化合物1-7(110.86mg,399.73μmol)，化合物1-10(0.2g,799.45μmol)和二异丙基乙基胺(154.98mg,1.20mmol)加入到DMF(2mL)中，然后加入T3P(713.19μl,1.20mmol,50％纯度)，反应于25℃搅拌2小时，反应完毕后用乙酸乙酯(50ml*3)和水(50ml)萃取，有机相用无水硫酸钠干燥浓缩后经制备TCL(二氯甲烷：甲醇＝20:1)分离，然后经手性HPLC(色谱柱:AD(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]；B％:35％-35％,)拆分得到化合物1或2。C 21H 22F 3N 7O 3S[M+H]+510，实测值510.异构体1(实施例1)保留时间5.87min； 1H NMR(400MHz,METHANOL-d4)δppm 1.50-1.64(m,2H),2.18(br d,J＝10.04Hz,2H),3.17-3.29(m,2H),3.49(s,3H),3.88–3.93(m,1H),4.33(br d,J＝13.55Hz,2H),5.01(s,1H),7.28-7.33(m,2H),7.38-7.46(m,2H),7.49-7.55(m,2H),8.47(d,J＝3.51Hz,1H).
异构体2(实施例2)保留时间6.30min, 1H NMR(400MHz,METHANOL-d4)δppm 1.51-1.63(m,2H),2.18(br d,J＝10.04Hz,2H),3.18-3.27(m,2H),3.49(s,3H),3.88–3.93(m,1H),4.33(br d,J＝13.55Hz,2H),5.01(s,1H),7.27-7.33(m,2H),7.38-7.46(m,2H),7.48-7.55(m,2H),8.47(d,J＝3.51Hz,1H). 表1中所示化合物可用化合物1或2类似方法而制备：
表1
手性保留时间未加说明的实施例采用的商业化的手性羧酸制备
Figure PCTCN2018091083-appb-000046
Figure PCTCN2018091083-appb-000047
Figure PCTCN2018091083-appb-000048
实验例1：GLS1耦合反应***中的化合物的活性测试
试剂和仪器如表2所示：
表2
Figure PCTCN2018091083-appb-000049
反应试剂的准备：
相关的反应试剂应在实验当天准备：
配制1X assay buffer
最终配制的实验用buffer中各个组分的终浓度为：50mM Tris-HCl pH 8.0，0.25mM EDTA，150mM K 2HPO 4，0.1mg/mL BSA，1mM DTT，0.01％Triton X-100
配制2X的实验用组分溶液：
将试剂取出并放在冰上自然融化待用；
使用1X assay buffer来配置实验中的“溶液A”(溶液A包含：L-glutamine(L-谷氨酰胺)，NAD+(烟酰胺腺嘌呤二核苷酸)和GLDH(谷氨酸脱氢酶)，并使得各个组分在最终的实验反应体系中，形成终浓度分别为：4.5mM L-glutamine，2mM NAD+4U/ml GLDH
使用1X assay buffer来配置实验中的“溶液B”---2X酶溶液(溶液B含有酶GLS1)，并使得GLS1在最终的实验反应体系中，形成GLS1终浓度为：2nM。
实验操作步骤：
实验板即实验前实验Labcyte公司ECHO准备好的含有化合物梯度浓度和相应的DMSO溶液的板子：
取出实验板，并向实验板的第2～23列，加入20μL溶液B(酶GLS1溶液)，再向实验板的第1和24列加入20μLassay buffer，1和24列作为实验***中的Min control；
离心1000转/秒，30秒；
封膜，并将板子置于23℃孵育1小时；
I孵育1h之后，向实验板的1～24列(即全板加样)加入20μL溶液A；
离心1000转/秒，30秒；
将实验板置于SpectraMax 340PC上，动态模式下连续读板20min(读板间隔设为1分钟)。
化合物抑制活性结果见表3。
表3化合物抑制活性结果
实施例 GLS1(IC 50)
5 B
7 B
8 B
9 B
16 B
17 A
*    A<200nM；200nM≤B≤1000nM；C>1000nM
实验结论：
本发明所设计的化合物展示了良好的GLS1酶抑制活性。
实验例2：化合物药代动力学评价
实验目的：测试化合物在小鼠体内药代动力学
实验材料：
C57BL/6小鼠(雌性,7～9周龄，上海斯莱克)
实验操作：将试验化合物溶解后得到的澄清溶液分别经尾静脉注射和灌胃给予雌性C57BL/6小鼠(C57BL/6)体内(过夜禁食，7～9周龄)。给予受试化合物后，静脉注射组在0.0833,0.25,0.5,1,2,4,6,8和24小时，灌胃组在0.0833,0.25,0.5,1,2,4,6,8和24小时，分别从下颌静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version 6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。测试结果如下：
表4化合物在小鼠中的PK测试结果
PK参数 实施例2 实施例17
T 1/2(hr) 3.70 2.52
C max(nM) 11800 11600
AUC 0-inf(nM.hr) 43931 26141
Bioavailability(％) a 58.7 91.3
注：T 1/2：半衰期；C max：达峰浓度；
AUC 0-inf：从0时间到外推至无穷大时的血浆浓度-时间曲线下面积；
Bioavailability：生物利用度。
结论：本发明的化合物在小或大鼠中都有良好的口服生物利用度,较高的暴露量,有利于产生良好的体内药效。
实验例3鼠肺癌3LL细胞皮下异种移植肿瘤C57/BL6裸小鼠模型的体内药效学研究:
实验目的：研究待测化合物对鼠肺癌3LL细胞皮下异种移植瘤在C57/BL6裸小鼠模型体内药效进行评估
实验动物:雌性C57/BL6裸小鼠,6－8周龄，体重18-22克；供应商：上海灵畅生物科技有限公司
实验方法与步骤:
3.1细胞培养
小鼠肺癌3LL细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素，100μg/mL链霉素和2mM谷氨酰胺，37℃5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
3.2肿瘤细胞接种(肿瘤接种)
将0.1mL 2×10 6个3LL细胞皮下接种于每只C57/BL6的右后背。肿瘤平均体积达到66mm 3时开始分组给药。
3.3受试物的配制:
受试化合物配制成1mg/mL的澄清溶液，溶媒为0.2％Tween 80,25％HPBCD(羟丙基-β-环糊精),10mM柠檬酸盐缓冲液,PH＝4。PD-1(Bioxcell，批号5792-210715/665417S1)加入到过滤的PBS(磷酸缓冲液)中，混合均匀，得到8.25mg/ml澄清的溶液备用。PD-L1(Bioxcell，批号：665717O1B/66571713)加入到过滤的PBS中，混合均匀，得到5.5mg/ml澄清的溶液备用。
3.4肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)】×100％。
相对肿瘤增殖率T/C(％)：计算公式如下：T/C％＝T RTV/C RTV×100％(T RTV：治疗组RTV平均值； C RTV：阴性对照组RTV平均值)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝V t/V 0，其中V 0是分组给药时(即d 0)测量所得肿瘤体积，V t为某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。
3.5统计分析
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表5)。基于给药后第12天的数据进行统计学分析评估组间差异。多组间比较用one-way ANOVA进行分析，应用Dunnet(2-sided)法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
3.6实验动物日常观察
实验中考察受试化合物对动物体重影响，同时例行检查动物日常行为活动，摄食摄水量(仅目测)，外观体征或其它不正常情况。基于各组动物数量记录组内动物死亡数和副作用。
3.7试验结果
3.7.1动物体重
实验动物的体重作为间接测定药物毒性的参考指标。在此模型中所有给药组均未显示有显著性体重下降，无发病或死亡现象。受试物对小鼠肺癌3LL细胞皮下移植肿瘤雌性C57/BL6模型的体重影响，结果如图1所示。
3.7.2肿瘤体积
给予小鼠肺癌3LL细胞皮下移植肿瘤雌性C57/BL6模型实施例17治疗后各组肿瘤体积变化如表5所示。
表5.实施例17对小鼠肺癌3LL移植瘤模型的抑瘤药效评价
(基于给药后第12天肿瘤体积计算得出)
Figure PCTCN2018091083-appb-000050
注：
“--”不需计算
a.平均值±SEM。
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T 21-T 0)/(V 21-V 0)]×100)计算。
c.p值根据肿瘤体积计。
3.8结论
在小鼠肺癌3LL细胞移植瘤模型中，开始给药后12天，溶剂对照组荷瘤鼠的瘤体积达到2081mm 3。
PD-1单药组，PD-L1单药组的肿瘤体积分别为877mm 3,1442mm 3，T/C分别为40％,65％，P值为0.000,0.110。受试物实施例17分别和PD-1和PD-L1联合后，T/C分别为39％和43％，p值为0.000和0.001，均有显著的肿瘤抑制作用。

Claims (18)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2018091083-appb-100001
    其中，
    R 1选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
    R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-6烷基、C 1-6杂烷基；
    R 3选自H；
    或者R 1和R 3连接在一起形成一个C 3-6环烷基；
    环B选自：苯基、5-6元杂芳基；
    n选自：0、1、2或3；
    R选自：H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：C 1-6烷基、C 1-6杂烷基；R’选自：F、Cl、Br、I、OH、NH 2；
    当R 1选自H，或者R 1和R 3连接在一起形成一个C 3-6环烷基时，带“*”碳原子不为手性碳原子；
    当R 1不选自H，带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；所述C 1-6杂烷基、5-6元杂芳基之“杂”选自N、-O-、-S-、-NH-；
    上述杂原子或杂原子团的数目分别独立地选自1、2、3或4。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：C 1-3烷基、C 1-3烷氧基。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，R选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R’取代的：Me、Et、
    Figure PCTCN2018091083-appb-100002
  4. 根据权利要求3所述化合物、其异构体或其药学上可接受的盐，其中，R选自：H、F、Cl、Br、I、OH、NH 2、Me、CF 3、Et、
    Figure PCTCN2018091083-appb-100003
  5. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自H、F、Cl、Br、I、OH、NH 2，或选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。
  6. 根据权利要求5所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自：H、F、Cl、Br、I、OH、 NH 2、Me、CF 3、Et、
    Figure PCTCN2018091083-appb-100004
  7. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2，或分别独立地选自任选被1、2或3个R取代的：C 1-3烷基、C 1-3烷氧基。
  8. 根据权利要求7所述化合物、其异构体或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、I、OH、NH 2、Me、CF 3、
    Figure PCTCN2018091083-appb-100005
  9. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，n选自：0、1或2。
  10. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018091083-appb-100006
    选自：
    Figure PCTCN2018091083-appb-100007
  11. 根据权利要求1～4任意一项所述化合物或其药学上可接受的盐，其中，环B选自：苯基、吡啶。
  12. 根据权利要求1～4任意一项所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018091083-appb-100008
    选自：
    Figure PCTCN2018091083-appb-100009
  13. 根据权利要求8或12所述化合物、其异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2018091083-appb-100010
    选自：
    Figure PCTCN2018091083-appb-100011
    Figure PCTCN2018091083-appb-100012
  14. 根据权利要求1～13任意一项所述化合物、其异构体或其药学上可接受的盐，其选自：
    Figure PCTCN2018091083-appb-100013
    其中，
    n、R 1、R 2、R 3如权利要求1～13所定义；
    当R 1选自H，或者R 1和R 3连接在一起形成一个C 3-6环烷基时，带“*”碳原子不为手性碳原子；
    当R 1不选自H，带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；
  15. 下式化合物：
    Figure PCTCN2018091083-appb-100014
    Figure PCTCN2018091083-appb-100015
  16. 根据权利要求15所述化合物，其选自：
    Figure PCTCN2018091083-appb-100016
  17. 一种药物组合物，包括治疗有效量的根据权利要求1～16任意一项所述的化合物或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  18. 根据权利要求1～16任意一项所述的化合物或其药学上可接受的盐或者权利要求17的组合物在制备GLS1抑制剂相关药物上的应用。
PCT/CN2018/091083 2017-06-13 2018-06-13 作为gls1抑制剂的化合物 WO2018228435A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP18818915.3A EP3640250B1 (en) 2017-06-13 2018-06-13 Compound as gls1 inhibitor
JP2019568772A JP7275053B2 (ja) 2017-06-13 2018-06-13 Ｇｌｓ１阻害剤としての化合物
CN201880038963.7A CN110741003B (zh) 2017-06-13 2018-06-13 作为gls1抑制剂的化合物
US16/621,902 US11254666B2 (en) 2017-06-13 2018-06-13 Compound as GLS1 inhibitor
ES18818915T ES2903182T3 (es) 2017-06-13 2018-06-13 Compuesto como inhibidor GLS1

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710444039.6 2017-06-13
CN201710444039 2017-06-13

Publications (1)

Publication Number Publication Date
WO2018228435A1 true WO2018228435A1 (zh) 2018-12-20

Family

ID=64658956

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/091083 WO2018228435A1 (zh) 2017-06-13 2018-06-13 作为gls1抑制剂的化合物

Country Status (6)

Country Link
US (1) US11254666B2 (zh)
EP (1) EP3640250B1 (zh)
JP (1) JP7275053B2 (zh)
CN (1) CN110741003B (zh)
ES (1) ES2903182T3 (zh)
WO (1) WO2018228435A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440199B (zh) * 2020-03-11 2023-02-24 中国药科大学 大环类谷氨酰胺酶gls1抑制剂或其可药用的盐、其制备方法及用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104220070A (zh) * 2011-11-21 2014-12-17 卡利泰拉生物科技公司 谷氨酰胺酶的杂环抑制剂
CN105051041A (zh) * 2012-11-16 2015-11-11 卡利泰拉生物科技公司 杂环谷氨酰胺酶抑制剂
WO2016054388A1 (en) * 2014-10-03 2016-04-07 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Glutaminase inhibitors
CN105960405A (zh) * 2014-01-06 2016-09-21 理森制药股份公司 谷氨酰胺酶抑制剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201409624D0 (en) * 2014-05-30 2014-07-16 Astrazeneca Ab 1,3,4-thiadiazole compounds and their use in treating cancer
ES2794868T3 (es) * 2015-06-30 2020-11-19 Univ Texas Inhibidores de GLS1 para el tratamiento de enfermedades
US10323028B2 (en) * 2015-11-30 2019-06-18 Astrazeneca Ab 1,3,4-thiadiazole compounds and their use in treating cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104220070A (zh) * 2011-11-21 2014-12-17 卡利泰拉生物科技公司 谷氨酰胺酶的杂环抑制剂
CN105051041A (zh) * 2012-11-16 2015-11-11 卡利泰拉生物科技公司 杂环谷氨酰胺酶抑制剂
CN105960405A (zh) * 2014-01-06 2016-09-21 理森制药股份公司 谷氨酰胺酶抑制剂
CN106029659A (zh) * 2014-01-06 2016-10-12 理森制药股份公司 谷氨酰胺酶抑制剂
WO2016054388A1 (en) * 2014-10-03 2016-04-07 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Glutaminase inhibitors

Also Published As

Publication number Publication date
ES2903182T3 (es) 2022-03-31
EP3640250A4 (en) 2020-04-22
JP7275053B2 (ja) 2023-05-17
JP2020523369A (ja) 2020-08-06
US11254666B2 (en) 2022-02-22
EP3640250A1 (en) 2020-04-22
US20200216436A1 (en) 2020-07-09
CN110741003A (zh) 2020-01-31
EP3640250B1 (en) 2021-12-15
CN110741003B (zh) 2021-07-23

Similar Documents

Publication Publication Date Title
EP3555070B1 (en) Amine-substituted heterocyclic compounds as ehmt2 inhibitors and methods of use thereof
WO2018184590A1 (zh) 作为A 2A受体抑制剂的[1,2,4]***并[1,5-c]嘧啶衍生物
EP3333157B1 (en) Vinyl compounds as fgfr and vegfr inhibitors
WO2016192563A1 (zh) Janus激酶抑制剂
EP3587420B1 (en) Tri-cycle compound and applications thereof
RO111847B1 (ro) Izomer optic al //4-(1,4,5,6-tetrahidro-4-metil-6-oxo-3-piridazinil) - fenil/ hidrazono/propandinitrilului, procedeu de preparare a acestuia si intermediari pentru realizarea procedeului
KR102254660B1 (ko) Ａ2ａ수용체 억제제로서의 축합 고리 유도체
WO2019085933A1 (zh) 作为Wee1抑制剂的大环类化合物及其应用
JP2018511634A (ja) Ｂ−ｒａｆキナーゼのマレイン酸塩、結晶形、調整方法、及びその使用
WO2020052647A1 (zh) 作为lsd1抑制剂的杂螺环类化合物及其应用
WO2018157820A1 (zh) 氮杂环丁烷衍生物
WO2018103757A1 (zh) 作为ccr2/ccr5受体拮抗剂的联苯化合物
WO2018228435A1 (zh) 作为gls1抑制剂的化合物
EP3738961B1 (en) Heterocyclic compound as csf-1r inhibitor and use thereof
US20220267321A1 (en) Azaindole pyrazole compounds as cdk9 inhibitors
CN116425770A (zh) 作为Cdc7抑制剂的四并环类化合物
JP7026852B2 (ja) チアジアゾール誘導体及びｇｌｓ１阻害剤としてのその使用
WO2018028557A1 (zh) 三环类化合物及其应用
CN111057069B (zh) 一种环状化合物、其应用及组合物
WO2018228476A1 (zh) 苯并咪唑类化合物及其应用
WO2022228365A1 (zh) 六元杂芳并脲环的衍生物及其应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18818915

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019568772

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018818915

Country of ref document: EP

Effective date: 20200113