[go: up one dir, main page]

WO2021129817A1 - Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk) - Google Patents

Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk) Download PDF

Info

Publication number
WO2021129817A1
WO2021129817A1 PCT/CN2020/139508 CN2020139508W WO2021129817A1 WO 2021129817 A1 WO2021129817 A1 WO 2021129817A1 CN 2020139508 W CN2020139508 W CN 2020139508W WO 2021129817 A1 WO2021129817 A1 WO 2021129817A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
present
ring
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2020/139508
Other languages
English (en)
Chinese (zh)
Inventor
潘志祥
贺海鹰
江志赶
夏建华
张蕾
张臣
黎健
陈曙辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medshine Discovery Inc
Original Assignee
Medshine Discovery Inc
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 Medshine Discovery Inc filed Critical Medshine Discovery Inc
Priority to CN202080090142.5A priority Critical patent/CN114846008B/zh
Publication of WO2021129817A1 publication Critical patent/WO2021129817A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a kind of compound with KHK inhibitory effect or a pharmaceutically acceptable salt thereof, and its application in the preparation of a medicine for treating diseases related to abnormal expression of KHK kinase. Specifically, it relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
  • Non-alcoholic fatty liver disease has a high prevalence in developed countries and regions, about 15%-40%, of which 10-20% of NAFLD patients will develop non-alcoholic steatohepatitis (NASH). It is estimated that NASH worldwide The incidence of NASH is 5 to 7%, and the incidence in diabetic population will increase to 22%. It is worth noting that about 15 to 25% of NASH patients will develop cirrhosis. NASH is currently the second leading cause of liver transplantation in the United States and is expected to become the number one cause of liver transplantation in the United States in 2020. There is currently no approved treatment for NASH.
  • fructose is quickly phosphorylated by fructose kinase Ketohexokinase (KHK) into fructose-1-phosphate.
  • KHK fructose kinase Ketohexokinase
  • the further metabolites produced by fructose-1-phosphate entering the cell will become the substrate of gluconeogenesis and de novo fat synthesis (DNL), leading to increased liver lipid synthesis and insulin resistance, thereby increasing oxidative stress and inflammation, and accelerating NAFLD and NASH
  • KHK is the rate-limiting enzyme that metabolizes fructose to fructose-1-phosphate, and is an important target for regulating fructose metabolism. Therefore, inhibition of KHK can effectively inhibit fructose metabolism and the resulting lipid accumulation, oxidative stress, inflammation and insulin resistance, which can be used for NASH treatment.
  • the present invention provides a compound represented by the following formula (F) or a pharmaceutically acceptable salt thereof, which is selected from:
  • L 1 is selected from a single bond, NH, CH 2 and O;
  • L 3 is independently selected from a single bond, NH, CH 2, and O, the NH and CH 2 optionally substituted with 1, 2 or 3 R a;
  • Z 1 , Z 2 and Z 3 are each independently selected from N or CH;
  • R 1 is H, C 1-3 alkyl, C 1-3 alkoxy, oxo, cyano, hydroxyl, said C 1-3 alkyl may be optionally substituted with 1, 2 or 3 R a ;
  • R 2 is selected from
  • R 3 is selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, said C 1 -3 alkyl, C 1-3 alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5- to 6-membered heteroaryl group optionally substituted with 1, 2 or 3 R a;
  • Ring A is selected from cyclobutyl, bicyclo[2.2.2]octyl, 4 to 8 membered heterocycloalkyl, C 6-10 aryl and 5 to 8 membered heteroaryl, the cyclobutyl, 4 ⁇ 8-membered heterocycloalkyl, C 6-10 aryl and 5-8 membered heteroaryl are optionally substituted with n R b ;
  • Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
  • Each R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1-3 alkyl and C 1 -3 Alkoxy is optionally substituted with 1, 2 or 3 F;
  • n is selected from 1, 2 and 3;
  • n is selected from 0, 1, 2 and 3;
  • p is selected from 1, 2, 3 and 4;
  • any two adjacent R 1 can be further cyclized into a 3- to 6-membered ring, and the formed ring is optionally substituted by n R b ; the adjacent R 1 is connected to On adjacent carbons, that is, the ring formed by the cyclization may be directly connected to the six-membered aromatic ring or the six-membered heteroaromatic ring directly connected to R 1 to further form a fused-ring structural unit.
  • the above-mentioned R 3 is selected from hydrogen, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , cyclopropyl, cyclobutyl, The -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , cyclopropyl, cyclobutyl, Optionally substituted with 1,2 or 3 substituents R a.
  • the above-mentioned ring A is selected from cyclobutyl, phenyl, indanyl and 5-6 membered heteroaryl, and the phenyl, indanyl and 5-6 membered heteroaryl are either Choose to be replaced by n R b .
  • any two adjacent R 1 can be further cyclized into a 3- to 6-membered ring, and the 3- to 6-membered ring group is selected from a 3- to 6-membered ring Alkyl and 3-6 membered heterocycloalkyl, said 3-6 membered heterocycloalkyl contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
  • L 1 is selected from a single bond and NH
  • Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
  • n is selected from 1, 2 and 3;
  • Ring A is selected from cyclobutyl, bicyclo[2.2.2]octyl, 6-8 membered heterocycloalkyl, C 6-10 aryl and 5-8 membered heteroaryl.
  • the cyclobutyl, C 6-10 aryl groups and 5-8 membered heteroaryl groups are optionally substituted with 1, 2 or 3 R b ;
  • Each R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1-3 alkyl and C 1 -3 Alkoxy is optionally substituted with 1, 2 or 3 F;
  • heterocycloalkyl and heteroaryl contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • each of the above Ra is selected from F and C 1-3 alkyl, and other variables are as defined in the present invention.
  • each of the aforementioned Ras is selected from F and methyl, and other variables are as defined in the present invention.
  • the -CH CH-, -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 3 -and
  • R a substituents R a, the other variables are as defined in the present invention.
  • each of the above-mentioned R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, CH 3 , CF 3 , OCH 3 , OCF 3 and CN, and other variables are as described in the present invention. definition.
  • each of the above-mentioned R b is independently selected from F, Cl, Br, CH 3 and CN, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from cyclobutyl, phenyl, indanyl and 5-6 membered heteroaryl, and the phenyl, indanyl and 5-6 membered heteroaryl are either Optionally replaced by 1, 2 or 3 R b .
  • the above-mentioned ring A is selected from cyclobutyl, Phenyl, indanyl, pyridyl, pyrazolyl, thienyl and thiazolyl, the cyclobutyl, Phenyl, indanyl, pyridyl, thienyl and thiazolyl are optionally substituted with 1, 2 or 3 R b .
  • the above-mentioned ring A is selected from Said Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
  • L 1 is selected from a single bond and NH
  • L 2 is selected from a single bond, -(CH 2 ) m -and The -(CH 2 ) m -and Optionally substituted with 1, 2 or 3 R a;
  • Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
  • n 0, 1, 2 and 3;
  • Ring A is selected from phenyl, pyridyl and thiazolyl, and the phenyl, pyridyl and thiazolyl are optionally substituted with 1 or 2 R b ;
  • Each R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1-3 alkyl and C 1
  • the -3 alkoxy group is optionally substituted with 1, 2 or 3 F.
  • the aforementioned L 2 is selected from a single bond, -CH 2 -, -CHF-, -CF 2 -, -CH 2 CH 2 -, and Other variables are as defined in the present invention.
  • the above-mentioned L 2 is selected from a single bond, -CH 2 -, -CH 2 CH 2 -, and Other variables are as defined in the present invention.
  • each of the above R b is independently selected from F, Cl, Br, I, NH 2 , OH, CH 3 , CF 3 , OCH 3 and OCF 3 , and other variables are as defined in the present invention.
  • each of the above R b is independently selected from F and Cl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Said Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
  • L 1 is selected from a single bond and NH
  • L 2 is selected from a single bond, -(CH 2 ) m -and The -(CH 2 ) m -and Optionally substituted with 1, 2 or 3 R a;
  • Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
  • n 0, 1, 2 and 3;
  • Ring A is selected from phenyl and 5- to 8-membered heteroaryl, the phenyl and 5- to 8-membered heteroaryl are optionally substituted with 1, 2 or 3 R b ;
  • Each R b is independently selected from F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1-3 alkyl and C 1-3
  • the alkoxy group is optionally substituted with 1, 2 or 3 F.
  • R a is selected from F and C 1-3 alkyl and the other variables are as defined in the present invention.
  • the aforementioned L 2 is selected from a single bond, -CH 2 -, -CHF-, -CF 2 -, -CH 2 CH 2 -, and Other variables are as defined in the present invention.
  • the above-mentioned L 2 is selected from a single bond, -CH 2 -, -CH 2 CH 2 -, and Other variables are as defined in the present invention.
  • each of the above R b is independently selected from F, Cl, Br, I, NH 2 , OH, CH 3 , CF 3 , OCH 3 and OCF 3 , and other variables are as defined in the present invention.
  • each of the above R b is independently selected from F and Cl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl and 5- to 6-membered heteroaryl are optionally substituted with 1, 2, or 3 R b .
  • the above-mentioned ring A is selected from Said Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Said Optionally substituted by 1, 2 or 3 halogens, other variables are as defined in the present invention.
  • the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
  • L 1 is selected from a single bond and NH
  • Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
  • n is selected from 1, 2 and 3;
  • Ring A is selected from cyclobutyl, phenyl and 5-8 membered heteroaryl groups, the cyclobutyl, phenyl and 5-8 membered heteroaryl groups are optionally substituted with 1, 2 or 3 R b ;
  • Each R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1-3 alkyl and C 1 -3 Alkoxy is optionally substituted with 1, 2 or 3 F;
  • the “5- to 8-membered heteroaryl group” contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • each of the above Ra is selected from F and C 1-3 alkyl, and other variables are as defined in the present invention.
  • each of the aforementioned Ras is selected from F and methyl, and other variables are as defined in the present invention.
  • the -CH CH-, -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 3 -and
  • R a substituents R a, the other variables are as defined in the present invention.
  • each of the above-mentioned R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, CH 3 , CF 3 , OCH 3 , OCF 3 and CN, and other variables are as described in the present invention. definition.
  • each of the above-mentioned R b is independently selected from F, Cl, Br, CH 3 and CN, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from cyclobutyl, phenyl and 5- to 6-membered heteroaryl.
  • the phenyl and 5- to 6-membered heteroaryl are optionally substituted by 1, 2 or 3 R b replace.
  • the above-mentioned ring A is selected from cyclobutyl, phenyl, pyridyl, pyrazolyl, thienyl and thiazolyl, and the cyclobutyl, phenyl, pyridyl, thienyl and thiazolyl are any Optionally replaced by 1, 2 or 3 R b .
  • the above-mentioned ring A is selected from Said Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
  • L 1 is selected from a single bond and NH
  • Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
  • n is selected from 1, 2 and 3;
  • Ring A is selected from cyclobutyl, C 6-10 aryl and 5-8 membered heteroaryl.
  • the cyclobutyl, C 6-10 aryl and 5-8 membered heteroaryl are optionally selected by 1, 2 or 3 R b substitutions;
  • Each R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, C 1-3 alkyl, C 1-3 alkoxy and CN, the C 1-3 alkyl and C 1 -3 Alkoxy is optionally substituted with 1, 2 or 3 F;
  • the “5- to 8-membered heteroaryl group” contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • each of the above Ra is selected from F and C 1-3 alkyl, and other variables are as defined in the present invention.
  • each of the aforementioned Ras is selected from F and methyl, and other variables are as defined in the present invention.
  • the -CH CH-, -CH 2 -, -CH 2 CH 2 -, -(CH 2 ) 3 -and
  • R a substituents R a, the other variables are as defined in the present invention.
  • each of the above-mentioned R b is independently selected from H, F, Cl, Br, I, NH 2 , OH, CH 3 , CF 3 , OCH 3 , OCF 3 and CN, and other variables are as described in the present invention. definition.
  • each of the above-mentioned R b is independently selected from F, Cl, Br, CH 3 and CN, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from cyclobutyl, phenyl, indanyl and 5-6 membered heteroaryl, and the phenyl, indanyl and 5-6 membered heteroaryl are either Optionally replaced by 1, 2 or 3 R b .
  • the above-mentioned ring A is selected from cyclobutyl, phenyl, indanyl, pyridyl, pyrazolyl, thienyl and thiazolyl, and the cyclobutyl, phenyl, indanyl , Pyridyl, thienyl and thiazolyl are optionally substituted with 1, 2 or 3 R b .
  • the above-mentioned ring A is selected from Said Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R 1 , R 3 , R b , ring A, L 1 , L 2 and L 3 are as defined in any one of the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • rings A and L 2 are as defined in any one of the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • L 2 and R b are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
  • the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of drugs for treating diseases related to KHK inhibitors.
  • the above application is characterized in that the KHK inhibitor-related drug is a drug for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable 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 the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound 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 salts.
  • the acid addition salt can be obtained by contacting the compound 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 including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, 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 methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (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), and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolid
  • 5-6 membered ring means a cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl group consisting of 5 to 6 ring atoms. Group or heteroaryl.
  • the ring includes a single ring, as well as a double ring system such as a spiro ring, a parallel ring and a bridged ring. Unless otherwise specified, the ring optionally contains 1, 2, or 3 heteroatoms independently selected from O, S, and N.
  • the 5-6 membered ring includes a 5-membered ring, a 6-membered ring, and the like.
  • 5-6 membered ring includes, for example, phenyl, pyridyl, piperidinyl and the like; on the other hand, the term “5-6 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes a ring system containing at least one ring, where each "ring" independently meets the above definition.
  • the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 4 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 4-8 membered heterocycloalkyl group includes 4-5 membered, 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • 4-8 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazolidin
  • the term "6-8 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 6 to 8 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring system includes spiro, fused, and bridged rings.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 6-8 membered heterocycloalkyl group includes 6, 7, and 8-membered heterocycloalkyl groups.
  • C 6-10 aromatic ring and “C 6-10 aryl” can be used interchangeably in the present invention.
  • C 6-10 aromatic ring or “C 6-10 aryl” means that A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which can be a monocyclic, fused bicyclic or fused tricyclic system, at least one of which is aromatic. It may be monovalent, divalent or multivalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10 and C 6 aryl groups and the like. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.), and indane.
  • 5-8 membered heteroaryl ring and “5-8 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-8 membered heteroaryl group” means a ring consisting of 5 to 8 ring atoms. It is composed of a cyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a single ring or a fused bicyclic ring system, where each ring is aromatic.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-8 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-8 membered heteroaryl group includes 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups and the like.
  • Examples of the 5-8 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, 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-isoxazolyl, etc.), thiazolyl (including 2-thi
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, 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,
  • halogen or halogen by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • 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 you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted 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.
  • the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and/or variants thereof are only permitted 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 connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • 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-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-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 groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt
  • eq stands for equivalent, equivalent
  • min stands for minutes
  • DCM dichloromethane
  • PE stands for petroleum ether
  • DMSO dimethyl sulfoxide
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • Cbz stands for benzyloxycarbonyl.
  • Boc represents tert-butoxycarbonyl is an amine protecting group
  • rt represents room temperature
  • O/N represents overnight
  • THF represents tetrahydrofuran
  • Boc 2 O represents di-tert-butyl dicarbonate
  • TFA represents three Fluoroacetic acid
  • DIPEA stands for diisopropylethylamine
  • iPrOH stands for 2-propanol
  • mp stands for melting point
  • Prep-HPLC stands for preparative high performance liquid chromatography
  • TLC stands for thin layer chromatography.
  • the compound of the present invention has a strong inhibitory activity on human KHK enzyme.
  • Preparation buffer contains 50mM HEPES, 140mM KCl, 3.5mM MgCl 2 , 0.01% BSA, pH 7.4.
  • Dilution of the compound starts from a concentration of 500 ⁇ M, 3 times dilution at 9 concentration points, the final concentration of the compound in the reaction system starts from 10 ⁇ M, and the final concentration of dimethyl sulfoxide (DMSO) is 2%.
  • DMSO dimethyl sulfoxide
  • the first well of each row is the positive control of the compound, that is, the same volume of buffer is added to replace the compound and fructokinase; the last well is the negative control of the compound, that is, the same volume of buffer is added to replace the compound.
  • Compound number KHK IC 50 Compound number KHK IC 50 WX001 110nM WX021 73nM WX002 44nM WX022 110nM WX003 230nM WX023 310nM WX004 340nM WX024 38nM WX005 600nM WX025 22nM WX006 230nM WX026 210nM WX007 180nM WX027 110nM WX008 140nM WX028 130nM WX009 110nM WX029 52nM WX010 180nM WX030 38nM WX011 41nM WX031 570nM
  • the compound of the present invention has strong inhibitory activity on human KHK enzyme.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé ayant un effet inhibiteur de CHK ou un sel pharmaceutiquement acceptable de celui-ci, et son utilisation dans la préparation de médicaments pour des maladies liées à une expression anormale de CHK. L'invention concerne spécifiquement un composé tel que représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/139508 2019-12-25 2020-12-25 Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk) Ceased WO2021129817A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080090142.5A CN114846008B (zh) 2019-12-25 2020-12-25 具有果糖激酶(khk)抑制作用的嘧啶类化合物

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN201911358838 2019-12-25
CN201911358838.7 2019-12-25
CN202010042678 2020-01-15
CN202010042678.1 2020-01-15
CN202010236877.6 2020-03-30
CN202010236877 2020-03-30
CN202010365947.8 2020-04-30
CN202010365947 2020-04-30
CN202011051355.5 2020-09-29
CN202011051355 2020-09-29

Publications (1)

Publication Number Publication Date
WO2021129817A1 true WO2021129817A1 (fr) 2021-07-01

Family

ID=76574858

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/139508 Ceased WO2021129817A1 (fr) 2019-12-25 2020-12-25 Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk)

Country Status (2)

Country Link
CN (1) CN114846008B (fr)
WO (1) WO2021129817A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135390A1 (fr) * 2020-12-25 2022-06-30 四川海思科制药有限公司 Inhibiteur de cétohexokinase et son utilisation
WO2023151473A1 (fr) * 2022-02-09 2023-08-17 上海研健新药研发有限公司 Inhibiteur de khk, son procédé de préparation et son utilisation
WO2024125482A1 (fr) * 2022-12-13 2024-06-20 华领医药技术（上海）有限公司 Composé utilisé comme inhibiteur de cétohexokinase, son utilisation et composition le contenant
US12145921B2 (en) 2021-12-20 2024-11-19 Nimml Institute Aromatic immunoregulatory compounds for treatment of inflammatory diseases
JP2024544794A (ja) * 2021-12-24 2024-12-04 エルジー・ケム・リミテッド （ｓ）－２－（２－メチルアゼチジン－１－イル）ピリミジン誘導体およびそれを含む医薬組成物
US12410160B2 (en) 2021-03-29 2025-09-09 Gilead Sciences, Inc. KHK inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114181198B (zh) * 2020-09-15 2025-07-15 山东轩竹医药科技有限公司 嘧啶衍生物类己酮糖激酶抑制剂及其用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473469A (zh) * 2015-12-29 2018-08-31 辉瑞公司 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷
WO2020257171A1 (fr) * 2019-06-17 2020-12-24 Eli Lilly And Company Composés pyrazole disubstitués utilisés en tant qu'inhibiteurs de cétohexokinase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473469A (zh) * 2015-12-29 2018-08-31 辉瑞公司 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷
WO2020257171A1 (fr) * 2019-06-17 2020-12-24 Eli Lilly And Company Composés pyrazole disubstitués utilisés en tant qu'inhibiteurs de cétohexokinase

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135390A1 (fr) * 2020-12-25 2022-06-30 四川海思科制药有限公司 Inhibiteur de cétohexokinase et son utilisation
US12410160B2 (en) 2021-03-29 2025-09-09 Gilead Sciences, Inc. KHK inhibitors
US12145921B2 (en) 2021-12-20 2024-11-19 Nimml Institute Aromatic immunoregulatory compounds for treatment of inflammatory diseases
JP2024544794A (ja) * 2021-12-24 2024-12-04 エルジー・ケム・リミテッド （ｓ）－２－（２－メチルアゼチジン－１－イル）ピリミジン誘導体およびそれを含む医薬組成物
EP4434982A4 (fr) * 2021-12-24 2025-03-12 LG Chem, Ltd. Dérivé de (s)-2-(2-méthylazétidin-1-yl)pyrimidine et composition pharmaceutique le comprenant
WO2023151473A1 (fr) * 2022-02-09 2023-08-17 上海研健新药研发有限公司 Inhibiteur de khk, son procédé de préparation et son utilisation
WO2024125482A1 (fr) * 2022-12-13 2024-06-20 华领医药技术（上海）有限公司 Composé utilisé comme inhibiteur de cétohexokinase, son utilisation et composition le contenant

Also Published As

Publication number Publication date
CN114846008A (zh) 2022-08-02
CN114846008B (zh) 2024-05-28

Similar Documents

Publication Publication Date Title
WO2021129817A1 (fr) Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk)
JP7461499B2 (ja) オクタヒドロピラジノジアザナフチリジンジオン化合物
WO2020035065A1 (fr) Dérivé de pyrazole en tant qu'inhibiteur de ret
WO2021093839A1 (fr) Composé pyrrolopyrimidine utilisé comme inhibiteur de btk et son utilisation
CN114846009B (zh) 具有khk抑制作用的化合物
WO2020239076A1 (fr) DÉRIVÉS DE PYRIDAZINONE CONSTITUANT DES AGONISTES DU RÉCEPTEUR DE LA THYROXINE DE TYPE β ET LEUR UTILISATION
CN114502561A (zh) Lsd1抑制剂
CN114761407A (zh) 作为高选择性ros1抑制剂的化合物及其应用
JP2021514997A (ja) ピラゾロピリミジン誘導体及びその使用
CN114591315A (zh) 一种组织蛋白酶c小分子抑制剂
WO2020063965A1 (fr) Dérivé de pyrazolopyrimidine en tant qu'inhibiteur de trk sélectif
KR102668124B1 (ko) Pd-l1 면역조절제인 비닐 피리딘 카르복사미드 화합물
CN112601746B (zh) 吡唑并嘧啶衍生物及其作为pi3k抑制剂的应用
JP7545622B2 (ja) ５，６－ジドヒロチエノ［３，４－ｈ］キナゾリン系化合物
CN114008046A (zh) 作为cdk9抑制剂的氮杂吲哚连吡唑类化合物
WO2020094084A1 (fr) Dérivé tricyclique utilisé comme inhibiteur de ret
CN117500808A (zh) 蒽类化合物、其制备方法和医药用途
KR102500569B1 (ko) 선택적 btk 키나제 억제제로서의 피라졸로피리딘계 화합물
KR102754529B1 (ko) Pd-l1 면역조절제인 플루오로 비닐 벤즈아미드 화합물
WO2022156765A1 (fr) Composé tricyclique lié à la pyrazolopyrazine et son application
WO2021164742A1 (fr) Composés de quinoléine
WO2024051727A1 (fr) Dérivé de pyrazole, composition pharmaceutique et utilisation
CN113811530B (zh) 作为糜酶抑制剂的嘧啶酮类化合物及其应用
CN116867791A (zh) 三并环类化合物及其应用
CN117534663A (zh) 稠合的三并环衍生物及其在药学上的应用

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: 20906103

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20906103

Country of ref document: EP

Kind code of ref document: A1