WO2021129817A1 - Pyrimidine-based compound having inhibitory effect of ketohexokinase (khk) - Google Patents
Pyrimidine-based compound having inhibitory effect of ketohexokinase (khk) Download PDFInfo
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- 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
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- acceptable salt
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- 0 C[C@](CC1)N1c1nc(IICC2=CC=C/C=C\C(I*C(O)=O)=CC2)cc(C(F)(F)F)n1 Chemical compound C[C@](CC1)N1c1nc(IICC2=CC=C/C=C\C(I*C(O)=O)=CC2)cc(C(F)(F)F)n1 0.000 description 7
- RLYCRLGLCUXUPO-UHFFFAOYSA-N Cc(c(N)ccc1)c1N Chemical compound Cc(c(N)ccc1)c1N RLYCRLGLCUXUPO-UHFFFAOYSA-N 0.000 description 1
- MWHJEWBLTYDUKD-UHFFFAOYSA-N Cc1c[s]c(I)c1 Chemical compound Cc1c[s]c(I)c1 MWHJEWBLTYDUKD-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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- 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.
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Abstract
Description
本申请主张如下优先权This application claims the following priority
CN2019113588387，申请日：2019-12-25；CN2019113588387, application date: 2019-12-25;
CN2020100426781，申请日：2020-01-15；CN2020100426781, application date: 2020-01-15;
CN2020102368776，申请日：2020-03-30；CN2020102368776, application date: 2020-03-30;
CN2020103659478，申请日：2020-04-30；CN2020103659478, application date: 2020-04-30;
CN2020110513555，申请日：2020-09-29。CN2020110513555, application date: 2020-09-29.
本发明涉及一类具有KHK抑制作用的化合物或其药学上可接受的盐，及其在制备治疗KHK激酶异常表达相关疾病的药物中的应用。具体涉及式(I)所示化合物及其药学上可接受的盐。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.
非酒精性脂肪性肝病(NAFLD)在发达国家和地区患病率高，约15％～40％，其中10～20％NAFLD患者会发展为非酒精性脂肪性肝炎(NASH)，估计世界范围NASH的发病率在5～7％，在糖尿病人群中发病率会提高至22％，值得注意的是，NASH患者中约有15～25％会发展成为肝硬化。NASH目前是美国肝移植的第二大病因，预计在2020年将会成为美国肝移植的第一大病因，目前尚无任何获准的治疗NASH药物。Non-alcoholic fatty liver disease (NAFLD) 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.
最近的研究发现高果糖饮食是造成NASH的重要原因。果糖进入肝脏后会迅速被果糖激酶Ketohexokinase(KHK)磷酸化成为果糖-1-磷酸。果糖-1-磷酸进入细胞后进一步产生的代谢产物会成为糖异生和脂肪从头合成(DNL)的底物，导致肝脏脂质合成增加及胰岛素抵抗从而增加氧化应激和炎症，加快NAFLD和NASH的发病过程。KHK是果糖代谢为果糖-1-磷酸的限速酶，是调节果糖代谢的重要靶点。因此抑制KHK可以有效的抑制果糖代谢及其造成的脂质堆积、氧化应激、炎症和胰岛素抵抗，从而用于NASH治疗。Recent studies have found that a high-fructose diet is an important cause of NASH. After entering the liver, fructose is quickly phosphorylated by fructose kinase Ketohexokinase (KHK) into fructose-1-phosphate. 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 The course of disease. 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.
发明内容Summary of the invention
本发明提供了下式(F)所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula (F) or a pharmaceutically acceptable salt thereof, which is selected from:
其中，among them,
L 1选自单键、NH、CH 2和O； L 1 is selected from a single bond, NH, CH 2 and O;
L
2选自单键、O、-CH＝CH-、-(CH
2)
m-和
L 3分别独立地选自单键、NH、CH 2和O，所述NH和CH 2任选被1、2或3个R a取代； 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和Z 3分别独立地选自N或CH； Z 1 , Z 2 and Z 3 are each independently selected from N or CH;
R 1为H、C 1-3烷基、C 1-3烷氧基、氧代、氰基、羟基，所述的C 1-3烷基可任选被1、2或3个R a取代； 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选自
R 3选自氢、C 1-3烷基，C 1-3烷氧基，3～6元环烷基，3～6元杂环烷基，5～6元杂芳基，所述C 1-3烷基，C 1-3烷氧基，3～6元环烷基，3～6元杂环烷基，5～6元杂芳基任选被1、2或3个R a取代； 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;
环A选自环丁基、二环[2.2.2]辛烷基、4～8元杂环烷基、C 6-10芳基和5～8元杂芳基，所述环丁基、4～8元杂环烷基、C 6-10芳基和5～8元杂芳基任选被n个R b取代； 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 ;
各R a独立地选自F、Cl、Br、I、NH 2、OH和C 1-3烷基； Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
各R b独立地选自H、F、Cl、Br、I、NH 2、OH、C 1-3烷基、C 1-3烷氧基和CN，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； 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;
m选自1、2和3；m is selected from 1, 2 and 3;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
p选自1、2、3和4；p is selected from 1, 2, 3 and 4;
当p大于等于2时，任意两个相邻的R 1可进一步环化为3～6元环，所形成的的环任选被n个R b取代；所述相邻的R 1是连接在相邻的碳上的，即，所述环化所形成的环可以与R 1所直接相连的六元芳环或六元杂芳环进一步组成为并环的结构单元。 When p is greater than or equal to 2, 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.
本发明的一些方案中，上述R
3选自氢、-CH
3，-CH
2CH
3，-OCH
3，-OCH
2CH
3，环丙基，环丁基，
本发明的一些方案中，上述环A选自环丁基、苯基、二氢化茚基和5～6元杂芳基，所述苯基、二氢化茚基和5～6元杂芳基任选被n个R b取代。 In some embodiments of 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 Choose to be replaced by n R b .
本发明的一些方案中，当p大于等于2时，任意两个相邻的R 1可进一步环化为3～6元环时，所述的3～6元环基选自3～6元环烷基和3～6元杂环烷基，所述的3～6元杂环烷基包含1、2或3个独立选自O、S和N的杂原子。 In some aspects of the present invention, when p is greater than or equal to 2, 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.
本发明提供了下式(I)所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
其中，among them,
L 1选自单键和NH； L 1 is selected from a single bond and NH;
L
2选自单键、-CH＝CH-、-(CH
2)
m-和
各R a独立地选自F、Cl、Br、I、NH 2、OH和C 1-3烷基； Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
m选自1、2和3；m is selected from 1, 2 and 3;
环A选自环丁基、二环[2.2.2]辛烷基、6～8元杂环烷基、C 6-10芳基和5～8元杂芳基，所述环丁基、C 6-10芳基和5～8元杂芳基任选被1、2或3个R b取代； 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 ;
各R b独立地选自H、F、Cl、Br、I、NH 2、OH、C 1-3烷基、C 1-3烷氧基和CN，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； 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;
所述“杂环烷基和杂芳基”包含1、2或3个独立选自O、S和N的杂原子。The "heterocycloalkyl and heteroaryl" contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述各R a选自F和C 1-3烷基，其它变量如本发明所定义。 In some embodiments of the present invention, each of the above Ra is selected from F and C 1-3 alkyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述各R a选自F和甲基，其它变量如本发明所定义。 In some aspects of the present invention, each of the aforementioned Ras is selected from F and methyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述L
2选自单键、-CH＝CH-、-CH
2-、-CH
2CH
2-、-(CH
2)
3-和
本发明的一些方案中，上述L
2选自单键、-CH＝CH-、-CH
2-、-CH
2CH
2-、-CH(CH
3)-、-CH(CH
3)CH
2-、-C(CH
3)
2-和
本发明的一些方案中，上述各R b独立地选自H、F、Cl、Br、I、NH 2、OH、CH 3、CF 3、OCH 3、OCF 3和CN，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述各R b独立地选自F、Cl、Br、CH 3和CN，其它变量如本发明所定义。 In some aspects of the present invention, 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.
本发明的一些方案中，上述环A选自环丁基、苯基、二氢化茚基和5～6元杂芳基，所述苯基、二氢化茚基和5～6元杂芳基任选被1、2或3个R b取代。 In some embodiments of 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 .
本发明的一些方案中，上述环A选自环丁基、
本发明的一些方案中，上述环A选自
本发明的一些方案中，上述环A选自
本发明提供了下式(I)所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
其中，among them,
L 1选自单键和NH； L 1 is selected from a single bond and NH;
L
2选自单键、-(CH
2)
m-和
各R a独立地选自F、Cl、Br、I、NH 2、OH和C 1-3烷基； Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
m选自0、1、2和3；m is selected from 0, 1, 2 and 3;
环A选自苯基、吡啶基和噻唑基，所述苯基、吡啶基和噻唑基任选被1或2个R b取代； Ring A is selected from phenyl, pyridyl and thiazolyl, and the phenyl, pyridyl and thiazolyl are optionally substituted with 1 or 2 R b ;
各R b独立地选自H、F、Cl、Br、I、NH 2、OH、C 1-3烷基、C 1-3烷氧基和CN，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代。 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.
本发明的一些方案中，上述R a选自F和甲基，其它变量如本发明所定义。 Some aspects of the present invention, the above-described F and R a is selected from methyl, the other variables are as defined in the present invention.
本发明的一些方案中，上述L
2选自单键、-CH
2-、-CHF-、-CF
2-、-CH
2CH
2-、和
本发明的一些方案中，上述L
2选自单键、-CH
2-、-CH
2CH
2-、和
本发明的一些方案中，上述各R b独立地选自F、Cl、Br、I、NH 2、OH、CH 3、CF 3、OCH 3和OCF 3，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述各R b独立地选自F和Cl，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述环A选自
本发明的一些方案中，上述环A选自
本发明提供了下式(I)所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
其中，among them,
L 1选自单键和NH； L 1 is selected from a single bond and NH;
L
2选自单键、-(CH
2)
m-和
各R a独立地选自F、Cl、Br、I、NH 2、OH和C 1-3烷基； Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
m选自0、1、2和3；m is selected from 0, 1, 2 and 3;
环A选自苯基和5～8元杂芳基，所述苯基和5～8元杂芳基任选被1、2或3个R b取代； 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 ;
各R b独立地选自F、Cl、Br、I、NH 2、OH、C 1-3烷基、C 1-3烷氧基和CN，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代。 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.
本发明的一些方案中，上述R a选自F和C 1-3烷基，其它变量如本发明所定义。 Some aspects of the present invention, the above R a is selected from F and C 1-3 alkyl and the other variables are as defined in the present invention.
本发明的一些方案中，上述R a选自F和甲基，其它变量如本发明所定义。 Some aspects of the present invention, the above-described F and R a is selected from methyl, the other variables are as defined in the present invention.
本发明的一些方案中，上述L
2选自单键、-CH
2-、-CHF-、-CF
2-、-CH
2CH
2-、和
本发明的一些方案中，上述L
2选自单键、-CH
2-、-CH
2CH
2-、和
本发明的一些方案中，上述各R b独立地选自F、Cl、Br、I、NH 2、OH、CH 3、CF 3、OCH 3和OCF 3，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述各R b独立地选自F和Cl，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述环A选自苯基和5～6元杂芳基，所述苯基和5～6元杂芳基任选被1、2或3个R b取代。 In some embodiments of 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 .
本发明的一些方案中，上述环A选自
本发明的一些方案中，上述环A选自
本发明提供了下式(I)所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
其中，among them,
L 1选自单键和NH； L 1 is selected from a single bond and NH;
L
2选自单键、-CH＝CH-、-(CH
2)
m-和
各R a独立地选自F、Cl、Br、I、NH 2、OH和C 1-3烷基； Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
m选自1、2和3；m is selected from 1, 2 and 3;
环A选自环丁基、苯基和5～8元杂芳基，所述环丁基、苯基和5～8元杂芳基任选被1、2或3个R b取代； 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 ;
各R b独立地选自H、F、Cl、Br、I、NH 2、OH、C 1-3烷基、C 1-3烷氧基和CN，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； 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;
所述“5～8元杂芳基”包含1、2或3个独立选自O、S和N的杂原子。The "5- to 8-membered heteroaryl group" contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述各R a选自F和C 1-3烷基，其它变量如本发明所定义。 In some embodiments of the present invention, each of the above Ra is selected from F and C 1-3 alkyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述各R a选自F和甲基，其它变量如本发明所定义。 In some aspects of the present invention, each of the aforementioned Ras is selected from F and methyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述L
2选自单键、-CH＝CH-、-CH
2-、-CH
2CH
2-、-(CH
2)
3-和
本发明的一些方案中，上述L
2选自单键、-CH＝CH-、-CH
2-、-CH
2CH
2-、-CH(CH
3)-、-C(CH
3)
2-和
本发明的一些方案中，上述各R b独立地选自H、F、Cl、Br、I、NH 2、OH、CH 3、CF 3、OCH 3、OCF 3和CN，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述各R b独立地选自F、Cl、Br、CH 3和CN，其它变量如本发明所定义。 In some aspects of the present invention, 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.
本发明的一些方案中，上述环A选自环丁基、苯基和5～6元杂芳基，所述苯基和5～6元杂芳基任选被1、2或3个R b取代。 In some embodiments of 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.
本发明的一些方案中，上述环A选自环丁基、苯基、吡啶基、吡唑基、噻吩基和噻唑基，所述环 丁基、苯基、吡啶基、噻吩基和噻唑基任选被1、2或3个R b取代。 In some embodiments of the present invention, 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 .
本发明的一些方案中，上述环A选自
本发明的一些方案中，上述环A选自
本发明提供了下式(I)所示化合物或其药学上可接受的盐，其选自：The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:
其中，among them,
L 1选自单键和NH； L 1 is selected from a single bond and NH;
L
2选自单键、-CH＝CH-、-(CH
2)
m-和
各R a独立地选自F、Cl、Br、I、NH 2、OH和C 1-3烷基； Each R a is independently selected from F, Cl, Br, I, NH 2, OH and C 1-3 alkyl;
m选自1、2和3；m is selected from 1, 2 and 3;
环A选自环丁基、C 6-10芳基和5～8元杂芳基，所述环丁基、C 6-10芳基和5～8元杂芳基任选被1、2或3个R b取代； 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;
各R b独立地选自H、F、Cl、Br、I、NH 2、OH、C 1-3烷基、C 1-3烷氧基和CN，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个F取代； 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;
所述“5～8元杂芳基”包含1、2或3个独立选自O、S和N的杂原子。The "5- to 8-membered heteroaryl group" contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
本发明的一些方案中，上述各R a选自F和C 1-3烷基，其它变量如本发明所定义。 In some embodiments of the present invention, each of the above Ra is selected from F and C 1-3 alkyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述各R a选自F和甲基，其它变量如本发明所定义。 In some aspects of the present invention, each of the aforementioned Ras is selected from F and methyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述L
2选自单键、-CH＝CH-、-CH
2-、-CH
2CH
2-、-(CH
2)
3-和
本发明的一些方案中，上述L
2选自单键、-CH＝CH-、-CH
2-、-CH
2CH
2-、-CH(CH
3)-、-C(CH
3)
2-和
本发明的一些方案中，上述各R b独立地选自H、F、Cl、Br、I、NH 2、OH、CH 3、CF 3、OCH 3、OCF 3和CN，其它变量如本发明所定义。 In some aspects of 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.
本发明的一些方案中，上述各R b独立地选自F、Cl、Br、CH 3和CN，其它变量如本发明所定义。 In some aspects of the present invention, 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.
本发明的一些方案中，上述环A选自环丁基、苯基、二氢化茚基和5～6元杂芳基，所述苯基、二氢化茚基和5～6元杂芳基任选被1、2或3个R b取代。 In some embodiments of 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 .
本发明的一些方案中，上述环A选自环丁基、苯基、二氢化茚基、吡啶基、吡唑基、噻吩基和噻唑基，所述环丁基、苯基、二氢化茚基、吡啶基、噻吩基和噻唑基任选被1、2或3个R b取代。 In some embodiments of the present invention, 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 .
本发明的一些方案中，上述环A选自
本发明的一些方案中，上述环A选自
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
其中，R 1、R 3、R b、环A、L 1、L 2和L 3如本发明任意一项所定义。 Wherein, 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.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
其中，环A和L 2如本发明任意一项所定义。 Wherein, rings A and L 2 are as defined in any one of the present invention.
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
其中，L 2和R b如本发明所定义。 Wherein, L 2 and R b are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are also some schemes of the present invention that come from any combination of the above-mentioned variables.
本发明还提供下述化合物或其药学上可接受的盐：The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
本发明还提供下述化合物或其药学上可接受的盐：The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:
本发明还提供了上述的化合物或其药学上可接受的盐在制备治疗KHK抑制剂相关疾病的药物上的应用。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.
在本发明的一些方案中，上述的应用，其特征在于，所述KHK抑制剂相关药物是用于治疗非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)的药物。In some aspects of the present invention, 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).
定义和说明Definition and description
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。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered uncertain or unclear without a special definition, but should be understood in its ordinary meaning. When a trade name appears in this article, it is meant to refer to its corresponding commodity or its active ingredient.
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。The term "pharmaceutically acceptable" as used herein 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.
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。The term "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. When the compound of the present invention contains a relatively acidic functional group, 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. When the compound of the present invention contains a relatively basic functional group, 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 acidic functional groups, which can be converted into any base or acid addition salt.
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。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.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "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.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但 不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term "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.
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "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.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "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. Are 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. In addition, for the "3-6 membered heterocycloalkyl group", 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, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperazinyl Pyridyl and so on.
除非另有规定，“5-6元环”表示由5至6个环原子组成的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所述的环包括单环，也包括螺环、并环和桥环等双环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述5-6元环包括5元、6元环等。“5-6元环”包括例如苯基、吡啶基和哌啶基等；另一方面，术语“5-6元杂环烷基”包括哌啶基等，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。Unless otherwise specified, "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. The term "ring" also includes a ring system containing at least one ring, where each "ring" independently meets the above definition.
除非另有规定，术语“4-8元杂环烷基”本身或者与其他术语联合分别表示由4至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-8元杂环烷基包括4-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。4-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, 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. Are 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. In addition, for the "4-8 membered heterocycloalkyl group", 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. Examples of 4-8 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, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperazinyl Ridinyl or dioxepanyl and the like.
除非另有规定，术语“6～8元杂环烷基”本身或者与其他术语联合分别表示由6至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“6-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述6-8元杂环烷基包括6元、7元和8元杂环烷基。 Unless otherwise specified, 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. Are 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. In addition, for the "6-8 membered heterocycloalkyl group", 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.
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或 稠合三环体系，其中至少有一个环是芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)、二氢化茚。 Unless otherwise specified, the terms "C 6-10 aromatic ring" and "C 6-10 aryl" can be used interchangeably in the present invention. The term "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 π-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.
除非另有规定，本发明术语“5-8元杂芳环”和“5-8元杂芳基”可以互换使用，术语“5-8元杂芳基”表示由5至8个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环或稠合双环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-8元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-8元杂芳基包括5-7元、5-6元、5元和6元杂芳基等。所述5-8元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "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 π-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. 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 5-8 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-thiazolyl, etc.) , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -Pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "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 π-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, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -Pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers. isomer.
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。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.
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。Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
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。Unless otherwise specified, the term "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.
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。Unless otherwise specified, the term "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.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键
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％。Unless otherwise specified, 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%.
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％。Unless otherwise stated, 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% .
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)。The 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. Alternatively, 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. In addition, 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).
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。 The compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, 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. Compared with undeuterated drugs, 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.
术语“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。The term "optional" or "optionally" refers to the event or condition described later that may but not necessarily occur, and the description includes a situation in which the event or condition occurs and a situation in which the event or condition does not occur .
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。The term "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. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "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.
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。When any variable (such as R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group can optionally be substituted with up to two Rs, and R has independent options in each case. In addition, combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
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。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。 When the number of a substituent is 0, it means that the substituent is absent. For example, -A-(R) 0 means that the structure is actually -A.
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。When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
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。When one of the variables is selected from a single bond, it means that the two connected groups are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
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，
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
除非另有规定，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个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members. For example, "5-7 membered ring" refers to a "ring" in which 5-7 atoms are arranged around.
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。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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-butyldimethylsilyl (TBS) and so on. The term "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.
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。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.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐；eq代表当量、等量；min代表分钟；DCM代表二氯甲烷；PE代表石油醚；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；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；iPrOH代表2-丙醇；mp代表熔点；Prep-HPLC代表制备高效液相色谱；TLC代表薄层层析色谱。 The present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt; eq stands for equivalent, equivalent; min stands for minutes; DCM stands for dichloromethane; PE stands for petroleum ether; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; Cbz stands for benzyloxycarbonyl. An amine protecting group; 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.
化合物依据本领域常规命名原则或者使用
技术效果Technical effect
作为新型的KHK抑制剂，本发明化合物对人源KHK酶有很强的抑制活性。As a new type of KHK inhibitor, the compound of the present invention has a strong inhibitory activity on human KHK enzyme.
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。The present invention will be described in detail through the following examples, but it is not meant to impose any disadvantageous restriction on the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. Will be obvious.
中间体A-1Intermediate A-1
合成路线：synthetic route:
步骤1：化合物A-1_2的合成Step 1: Synthesis of compound A-1_2
将A-1_1(300mg,1.82mmol)溶于DCM(15mL)中，然后缓慢加入DIPEA(234.72mg,316.33μL)和Boc 2O(475.63mg,500.66μL)，反应在25℃下搅拌2小时，通过TLC(PE:EtOAc＝10:1)发现反应完全。减压浓缩得到粗产品，粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:40)过柱纯化，得到化合物A-1_2。 1H NMR(400MHz,CDCl 3)δppm 1.36-1.49(m,9H)3.43-3.55(m,2H)3.57-3.67(m,3H)6.50-6.67(m,1H)6.76-6.92(m,1H)7.11-7.19(m,2H)。 A-1_1 (300mg, 1.82mmol) was dissolved in DCM (15mL), then DIPEA (234.72mg, 316.33μL) and Boc 2 O (475.63mg, 500.66μL) were slowly added, and the reaction was stirred at 25°C for 2 hours. The reaction was found to be complete by TLC (PE:EtOAc=10:1). Concentrate under reduced pressure to obtain a crude product, and the crude product is purified by an automatic column machine (100-200 mesh, eluent PE:EtOAc=100:1-100:40) to obtain compound A-1_2. 1 H NMR (400MHz, CDCl 3 ) δppm 1.36-1.49(m,9H)3.43-3.55(m,2H)3.57-3.67(m,3H)6.50-6.67(m,1H)6.76-6.92(m,1H) 7.11-7.19 (m, 2H).
步骤2：化合物A-1_3的合成Step 2: Synthesis of compound A-1_3
在0℃下将化合物A-1_2(200mg,753.85μmol)溶于THF(10mL)中，加入六甲基磷酰三胺(270.18mg,264.88μL)和二异丙基胺的THF溶液(2M,942.31μL)，反应在0℃搅拌1小时；然后加入1,2-二溴乙烷(380.99mg,153.01μL)，反应恢复到15℃并在15℃搅拌2小时。通过TLC(PE:EtOAc＝10:1)检测，发现反应完全，溶剂直接减压浓缩得到粗产品。粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:50)过柱纯化，得到化合物A-1_3。 1H NMR(400MHz,CDCl 3)δppm 1.44(s,9H)1.47-1.54(m,4H)3.53(s,3H)6.38(br s,1H)6.90-6.98(m,1H)7.09-7.15(m,2H)7.34(s,1H)。 Compound A-1_2 (200mg, 753.85μmol) was dissolved in THF (10mL) at 0°C, hexamethylphosphoric triamide (270.18mg, 264.88μL) and diisopropylamine THF solution (2M, 942.31 μL), the reaction was stirred at 0°C for 1 hour; then 1,2-dibromoethane (380.99 mg, 153.01 μL) was added, the reaction was restored to 15°C and stirred at 15°C for 2 hours. By TLC (PE:EtOAc=10:1) detection, it was found that the reaction was complete, and the solvent was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:50) to obtain compound A-1_3. 1 H NMR(400MHz, CDCl 3 )δppm 1.44(s,9H)1.47-1.54(m,4H)3.53(s,3H)6.38(br s,1H)6.90-6.98(m,1H)7.09-7.15(m , 2H) 7.34 (s, 1H).
步骤3：化合物A-1的合成Step 3: Synthesis of compound A-1
将化合物A-1_3(150mg,514.86μmol)溶于HCl/MeOH(4mol/L,15mL)溶液中，然后在15℃下搅拌反应2小时。通过TLC(PE:EtOAc＝10:1)发现反应完全，溶剂直接减压浓缩得到粗产品A-1用于下一步反应。Compound A-1_3 (150 mg, 514.86 μmol) was dissolved in HCl/MeOH (4 mol/L, 15 mL) solution, and then the reaction was stirred at 15° C. for 2 hours. The reaction was found to be complete by TLC (PE:EtOAc=10:1), and the solvent was directly concentrated under reduced pressure to obtain the crude product A-1 for the next reaction.
中间体E-9Intermediate E-9
合成路线：synthetic route:
步骤1：化合物E-9的合成Step 1: Synthesis of compound E-9
N 2保护下于0℃向甲氧甲酰基亚甲基三苯基膦(1.98g,5.91mmol)的DCM(10mL)溶液中滴加化合物E-9_1(1.00g,4.93mmol)的DCM(10mL)溶液，混合物在10℃下搅拌30min，TLC(PE:EtOAc＝5:1)显示反应结束。反应液减压浓缩，残留物用溶剂(5％PE/EtOAc混合溶剂，50mL)室温打浆10min，过滤，用PE(50mL)洗涤滤饼，滤液浓缩的到粗品。用过柱机(硅胶柱：20g，洗脱剂：石油醚/乙酸乙酯，梯度：0-30％，流速：35mL/min)进行纯化，得到化合物E-9。1H NMR(400MHz,CDCl 3)δ＝7.72(dd,J＝2.0,6.4Hz,1H),7.58(d,J＝16.0Hz,1H),7.44(ddd,J＝2.0,4.8,8.4Hz,1H),7.14(t,J＝8.4Hz,1H),6.37(d,J＝16.0Hz,1H),3.81(s,3H)。 To the DCM (10mL) solution of methoxyformylmethylenetriphenylphosphine (1.98g, 5.91mmol) under the protection of N 2 was added dropwise compound E-9_1 (1.00g, 4.93mmol) in DCM (10mL) ) Solution, the mixture was stirred at 10°C for 30 min, TLC (PE:EtOAc=5:1) indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was slurried with a solvent (5% PE/EtOAc mixed solvent, 50 mL) at room temperature for 10 min, filtered, and the filter cake was washed with PE (50 mL), and the filtrate was concentrated to a crude product. Purification was performed with a column machine (silica gel column: 20 g, eluent: petroleum ether/ethyl acetate, gradient: 0-30%, flow rate: 35 mL/min) to obtain compound E-9. 1H NMR (400MHz, CDCl 3 )δ = 7.72 (dd, J = 2.0, 6.4 Hz, 1H), 7.58 (d, J = 16.0 Hz, 1H), 7.44 (ddd, J = 2.0, 4.8, 8.4 Hz, 1H), 7.14 (t, J = 8.4 Hz, 1H), 6.37 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H).
参照中间体E-9的合成方法(步骤1中分别用苯甲醛片段E替代化合物E-9_1)，合成下表中各中间体。Referring to the synthesis method of intermediate E-9 (in step 1, benzaldehyde fragment E was used to replace compound E-9_1), the intermediates in the following table were synthesized.
实施例1Example 1
合成路线：synthetic route:
步骤1：化合物WX001_1的合成Step 1: Synthesis of compound WX001_1
称取B-1(215.20mg,991.82μmol)放入100mL的反应瓶，并加入DCM(5mL)溶解，干冰乙醇浴冷却反应体系至-60℃，缓慢滴加A-2(200mg,991.82μmol)的DCM(5mL)溶液，然后再缓慢滴加DIPEA(294.82mg,397.33μL,2.3eq)。反应在-60℃搅拌1小时，然后升温至25℃搅拌12小时。TLC(PE:EtOAc＝3:1)监测原料消失并有新点生成。粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:30)过柱纯化，得到化合物WX001_1。 1H NMR(400MHz,CDCl 3)δ＝7.48-7.36(m,1H),7.35-7.28(m,2H),7.23(br d,J＝7.6Hz,1H),6.87(s,1H),3.75(s,3H),3.70(s,2H)。 Weigh B-1 (215.20 mg, 991.82 μmol) into a 100 mL reaction flask, and add DCM (5 mL) to dissolve, cool the reaction system to -60°C in a dry ice ethanol bath, and slowly add A-2 (200 mg, 991.82 μmol) dropwise DCM (5mL) solution, and then slowly drip DIPEA (294.82mg, 397.33μL, 2.3eq). The reaction was stirred at -60°C for 1 hour, then heated to 25°C and stirred for 12 hours. TLC (PE:EtOAc=3:1) monitors the disappearance of the starting material and the formation of new spots. The crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:30) to obtain compound WX001_1. 1 H NMR(400MHz,CDCl 3 )δ=7.48-7.36(m,1H),7.35-7.28(m,2H),7.23(br d,J=7.6Hz,1H), 6.87(s,1H), 3.75 (s, 3H), 3.70 (s, 2H).
步骤2：化合物WX001_2的合成Step 2: Synthesis of compound WX001_2
称取化合物WX001_1(180mg,520.68μmol)和C-1的盐酸盐(83.57mg,781.01μmol,1.5eq)放入100mL反应瓶，加入THF(5mL)溶解，然后缓慢滴加DIPEA(134.58mg,181.38μL,2.0eq)，反应在70℃搅拌2小时。TLC(PE:EtOAc＝3:1)监测原料消失并有新点生成。反应液浓缩得到粗产品，粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:40)过柱纯化，得到化合物WX001_2。 1H NMR(400MHz,CDCl 3)δ＝7.46(s,1H),7.35-7.30(m,2H),7.06(td,J＝2.0,6.0Hz,1H),6.73(s,1H),6.25(s,1H),4.58-4.49(m,1H),4.13-4.00(m,2H),3.73(s,3H),3.64(s,2H),2.51-2.42(m,1H),2.00(tdd,J＝6.4,9.2,10.8Hz,1H),1.55(d,J＝6.4Hz,3H)。 Weigh compound WX001_1 (180mg, 520.68μmol) and C-1 hydrochloride (83.57mg, 781.01μmol, 1.5eq) into a 100mL reaction flask, add THF (5mL) to dissolve, and then slowly add DIPEA (134.58mg, 181.38 μL, 2.0 eq), and the reaction was stirred at 70°C for 2 hours. TLC (PE:EtOAc=3:1) monitors the disappearance of the starting material and the formation of new spots. The reaction solution was concentrated to obtain a crude product, and the crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:40) to obtain compound WX001_2. 1 H NMR (400MHz, CDCl 3 )δ = 7.46 (s, 1H), 7.35-7.30 (m, 2H), 7.06 (td, J = 2.0, 6.0 Hz, 1H), 6.73 (s, 1H), 6.25 ( s, 1H), 4.58-4.49 (m, 1H), 4.13-4.00 (m, 2H), 3.73 (s, 3H), 3.64 (s, 2H), 2.51-2.42 (m, 1H), 2.00 (tdd, J = 6.4, 9.2, 10.8 Hz, 1H), 1.55 (d, J = 6.4 Hz, 3H).
步骤3：化合物WX001的合成Step 3: Synthesis of compound WX001
将化合物WX001_2(200mg,473.23μmol)溶解在THF(4mL)中，滴加LiOH.H 2O(59.57mg,1.42mmol,3.0eq)的水(4mL)溶液，反应体系在20℃搅拌2小时。TLC(PE:EtOAc＝3:1)显示反应完成。浓缩去除溶剂，加入50mL水稀释后，用稀盐酸(1N)调节至弱酸性(pH＝6)，再用EtOAc萃取(15mL×3)，所有有机相合并后，无水硫酸钠干燥，过滤旋干得到粗品。粗产品使用Prep-HPLC(分离方法：Welch Xtimate C18 150mm*25mm*5μm；流动相:[水(0.225％FA)-ACN]；B(ACN)％:45％-75％,8分钟)进行纯化，得到化合物WX001。 Compound WX001_2 (200 mg, 473.23 μmol) was dissolved in THF (4 mL), and LiOH.H 2 O (59.57 mg, 1.42 mmol, 3.0 eq) in water (4 mL) was added dropwise, and the reaction system was stirred at 20° C. for 2 hours. TLC (PE:EtOAc=3:1) showed that the reaction was complete. Concentrate to remove the solvent, add 50mL of water to dilute, adjust to weak acidity (pH=6) with dilute hydrochloric acid (1N), and then extract with EtOAc (15mL×3). After all organic phases are combined, dry with anhydrous sodium sulfate, filter and spin. Dry to get crude product. The crude product was purified using Prep-HPLC (separation method: Welch Xtimate C18 150mm*25mm*5μm; mobile phase: [water (0.225%FA)-ACN]; B(ACN)%: 45%-75%, 8 minutes) , Compound WX001 was obtained.
参照实施例1中的合成方法(步骤1中分别用片段A替代化合物A-2)，合成下表中各实施例。With reference to the synthesis method in Example 1 (in step 1, fragment A was used to replace compound A-2 respectively), the examples in the following table were synthesized.
实施例6Example 6
合成路线：synthetic route:
步骤1：化合物E-1的合成Step 1: Synthesis of compound E-1
将WX006_1(0.8g,3.29mmol),D-1(1.25g,4.94mmol)加入到50mL反应瓶中，用二氧六环(10mL)溶解，加入醋酸钾(968.90mg,9.87mmol)，Pd(dppf)Cl 2(134.37mg,183.64μmol)，反应在90℃下搅拌12小时。LCMS检测显示反应完成，向反应液中加入20mL的水，使用EtOAc(20mL×2)萃取，合并有机相，用饱和食盐水(20mL)洗涤后，旋蒸至干。粗品经过自动过柱机(100～200目,洗脱剂PE:EtOAc＝100:1～100:10)过柱纯化，得到化合物E-1。 1H NMR(400MHz,CDCl 3)δ7.61-7.55(m,2H),7.25-7.21(m,2H),3.60(s,3H),2.89(t,J＝8.0Hz,2H),2.62-2.51(m,2H),1.27(s,12H)。 Add WX006_1 (0.8g, 3.29mmol), D-1 (1.25g, 4.94mmol) to a 50mL reaction flask, dissolve with dioxane (10mL), add potassium acetate (968.90mg, 9.87mmol), Pd( dppf) Cl 2 (134.37 mg, 183.64 μmol), and the reaction was stirred at 90°C for 12 hours. LCMS detection showed that the reaction was complete. 20 mL of water was added to the reaction solution, extracted with EtOAc (20 mL×2), and the organic phases were combined, washed with saturated brine (20 mL), and then evaporated to dryness by rotary evaporation. The crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:10) to obtain compound E-1. 1 H NMR (400MHz, CDCl 3 ) δ7.61-7.55 (m, 2H), 7.25-7.21 (m, 2H), 3.60 (s, 3H), 2.89 (t, J = 8.0Hz, 2H), 2.62 2.51 (m, 2H), 1.27 (s, 12H).
步骤2：化合物WX006_2的合成Step 2: Synthesis of compound WX006_2
将化合物E-1(0.2g,689.27μmol)和B-1(200.00μL,921.76μmol)加入到50mL反应瓶中，用甲苯(1mL)/EtOH(0.5mL)/H 2O(0.5mL)溶解，加入K 2CO 3(254.79mg,1.84mmol,2eq)，Pd(PPh 3) 4(53.26mg,46.09μmol)，反应在90℃下搅拌9小时。LCMS检测到产物MS。将反应加入20mL水中，用EtOAc(20mL×2)萃取，有机相合并，用饱和食盐水(20mL)洗涤，有机相旋干。粗品经过自动过柱机(100～200目， 洗脱剂PE:EtOAc＝100:1～100:40)过柱纯化，得到化合物WX006_2。 1H NMR(400MHz,CDCl 3)δ8.08-7.92(m,3H),7.55-7.44(m,2H),3.74-3.68(s,3H),3.10(t,J＝7.7Hz,2H),2.78-2.70(m,2H)。 Compound E-1 (0.2g, 689.27μmol) and B-1 (200.00μL, 921.76μmol) were added to a 50mL reaction flask and dissolved with toluene (1mL)/EtOH (0.5mL)/H 2 O (0.5mL) , K 2 CO 3 (254.79 mg, 1.84 mmol, 2eq), Pd(PPh 3 ) 4 (53.26 mg, 46.09 μmol) were added, and the reaction was stirred at 90° C. for 9 hours. The product MS was detected by LCMS. The reaction was added to 20 mL of water, extracted with EtOAc (20 mL×2), the organic phases were combined, washed with saturated brine (20 mL), and the organic phase was spin-dried. The crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:40) to obtain compound WX006_2. 1 H NMR (400MHz, CDCl 3 ) δ8.08-7.92 (m, 3H), 7.55-7.44 (m, 2H), 3.74-3.68 (s, 3H), 3.10 (t, J = 7.7Hz, 2H), 2.78-2.70 (m, 2H).
步骤3：化合物WX006_3的合成Step 3: Synthesis of compound WX006_3
将化合物WX006_2(120mg,348.11μmol)和C-1的盐酸盐(74.47mg,696.23μmol)加入到10mL拇指瓶中，用THF(1mL)溶解，再加入DIPEA(121.27μL,696.23μmol)，反应在70℃下搅拌9小时，LCMS检测显示反应完成。将反应液直接旋干得到粗品WX006-3。粗品直接用于下一步反应。Compound WX006_2 (120mg, 348.11μmol) and C-1 hydrochloride (74.47mg, 696.23μmol) were added to a 10mL thumb bottle, dissolved with THF (1mL), and then DIPEA (121.27μL, 696.23μmol) was added to the reaction. After stirring at 70°C for 9 hours, LCMS detection showed that the reaction was complete. The reaction solution was directly spin-dried to obtain crude product WX006-3. The crude product was directly used in the next reaction.
步骤4：化合物WX006的合成Step 4: Synthesis of compound WX006
将化合物WX006_3(120mg,316.31μmol)加入到10mL拇指瓶中，用THF(2mL)及H 2O(2mL)溶解，再加入LiOH.H 2O(13.27mg,316.31μmol)，反应在20℃下搅拌12小时，LCMS检测显示反应完成。将反应液直接旋干，加入MeOH(3mL)溶解并过滤，滤液用Prep-HPLC(分离方法：Welch Xtimate C18 150mm*25mm*5μm；流动相:[水(0.225％FA)-ACN]；B(ACN)％:45％-75％,8分钟)进行纯化，得到化合物WX006。 Compound WX006_3 (120mg, 316.31μmol) was added to a 10mL thumb bottle, dissolved with THF (2mL) and H 2 O (2mL), and then LiOH.H 2 O (13.27mg, 316.31μmol) was added, and the reaction was carried out at 20°C. After stirring for 12 hours, LCMS detection showed that the reaction was complete. The reaction solution was spin-dried directly, and MeOH (3mL) was added to dissolve and filtered. The filtrate was used Prep-HPLC (separation method: Welch Xtimate C18 150mm*25mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B( ACN)%: 45%-75%, 8 minutes) for purification to obtain compound WX006.
参照实施例6中的合成方法(步骤2中用芳基片段E替代化合物E-1)，合成下表中各实施例。With reference to the synthesis method in Example 6 (in step 2, aryl fragment E was used instead of compound E-1), the examples in the following table were synthesized.
实施例8Example 8
合成路线：synthetic route:
步骤1：化合物WX008_1的合成Step 1: Synthesis of compound WX008_1
在100mL圆底瓶中，向F-1(1.30g,11.06mmol)的DMF(10mL)溶液中加入NaH(737.34mg,18.44mmol,60％)，反应在-10℃下搅拌30分钟，再慢慢滴加B-1(2g,9.22mmol)，反应在-10℃下继续搅拌1小时，LCMS显示反应完成。将反应液慢慢倒入冰水(20mL)中淬灭后，EtOAc(20mL×2)萃取，合并有机相，用饱和食盐水(20mL)洗涤，有机相旋干。粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:40)过柱纯化，得到化合物WX008_1。 1H NMR(400MHz,DMSO-d 6)δ11.40(s,1H),8.16(s,1H),1.56-1.40(m,9H)。 In a 100mL round bottom flask, NaH (737.34mg, 18.44mmol, 60%) was added to the DMF (10mL) solution of F-1 (1.30g, 11.06mmol), and the reaction was stirred at -10°C for 30 minutes, then slowly B-1 (2g, 9.22mmol) was slowly added dropwise, the reaction was continued to stir at -10°C for 1 hour, and LCMS showed that the reaction was complete. The reaction solution was slowly poured into ice water (20 mL) for quenching, and then extracted with EtOAc (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL), and the organic phase was spin-dried. The crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:40) to obtain compound WX008_1. 1 H NMR (400MHz, DMSO-d 6 ) δ 11.40 (s, 1H), 8.16 (s, 1H), 1.56-1.40 (m, 9H).
步骤2：化合物WX008_2的合成Step 2: Synthesis of compound WX008_2
在100mL茄形瓶中加入化合物WX008_1(2g,6.72mmol)，用DCM(10mL)溶解，再慢慢加入TFA(17.89mL,241.65mmol)，反应在20℃下搅拌12小时，LCMS显示反应完成。将反应液直接旋干，加入EtOAc(40mL)并用饱和碳酸氢钠溶液(20mL×2)洗涤，有机相旋干，得到化合物WX008_2。 1H NMR(400MHz,DMSO-d 6)δ8.32-7.89(m,2H),6.86-6.77(m,1H)。 Compound WX008_1 (2g, 6.72mmol) was added to a 100mL eggplant flask, dissolved with DCM (10mL), and then TFA (17.89mL, 241.65mmol) was added slowly, and the reaction was stirred at 20°C for 12 hours. LCMS showed that the reaction was complete. The reaction solution was spin-dried directly, EtOAc (40 mL) was added and washed with saturated sodium bicarbonate solution (20 mL×2), and the organic phase was spin-dried to obtain compound WX008_2. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.32-7.89 (m, 2H), 6.86-6.77 (m, 1H).
步骤3：化合物WX008_3的合成Step 3: Synthesis of compound WX008_3
N 2保护下在10mL拇指瓶中，将化合物WX008_2(0.2g,1.01mmol),G-1(232.92mg,1.01mmol)，碳酸铯(989.60mg,3.04mmol)加入到THF(5mL)中，再加入Pd 2(dba) 3(46.35mg,50.62μmol)和Xantphos(29.29mg,50.62μmol)，反应在70℃下搅拌12小时，LCMS显示反应完成。将反应液过滤，并用EtOAc(20mL)洗涤，滤液用水(20mL)洗涤后，将有机相直接旋干。粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:40)过柱纯化，得到化合物WX008_3。1H NMR(400MHz,CDCl 3)δ8.48-8.39(m,1H),8.34(d,J＝5.0Hz,1H),8.18(br s,1H),7.37-7.30(m,1H),7.04(dd,J＝1.1,5.1Hz,1H),6.73-6.65(m,1H),3.78(s,3H),3.70(s,2H)。 Under the protection of N 2 in a 10 mL thumb bottle, add compound WX008_2 (0.2 g, 1.01 mmol), G-1 (232.92 mg, 1.01 mmol), and cesium carbonate (989.60 mg, 3.04 mmol) to THF (5 mL). Pd 2 (dba) 3 (46.35 mg, 50.62 μmol) and Xantphos (29.29 mg, 50.62 μmol) were added, and the reaction was stirred at 70° C. for 12 hours. LCMS showed that the reaction was complete. The reaction solution was filtered and washed with EtOAc (20 mL). After the filtrate was washed with water (20 mL), the organic phase was directly spin-dried. The crude product was purified by automatic column passing machine (100～200 mesh, eluent PE:EtOAc=100:1～100:40) to obtain compound WX008_3. 1H NMR (400MHz, CDCl 3 )δ8.48-8.39(m ,1H),8.34(d,J=5.0Hz,1H),8.18(br s,1H),7.37-7.30(m,1H),7.04(dd,J=1.1,5.1Hz,1H),6.73-6.65 (m, 1H), 3.78 (s, 3H), 3.70 (s, 2H).
步骤4：化合物WX008_4的合成Step 4: Synthesis of compound WX008_4
将化合物WX008_3(0.1g,288.44μmol)，C-1的盐酸盐(74.47mg,696.23μmol)加入到10mL拇 指瓶中，用THF(1mL)溶解，再加入DIPEA(111.83mg,865.32μmol,150.72μL)，反应在70℃下搅拌12小时。LCMS显示反应完成，将反应液直接旋干，粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:50)过柱纯化，得到化合物WX008_4。1H NMR(400MHz,CDCl 3)δ8.17(d,J＝5.1Hz,1H),8.05-7.88(m,2H),6.85(d,J＝5.1Hz,1H),6.53(s,1H),4.58-4.43(m,1H),4.12-3.93(m,2H),3.65(s,3H),3.55(s,2H),2.50-2.34(m,1H),2.00-1.89(m,1H),1.49(d,J＝6.3Hz,3H)。 Compound WX008_3 (0.1g, 288.44μmol), C-1 hydrochloride (74.47mg, 696.23μmol) was added to a 10mL thumb bottle, dissolved with THF (1mL), and then DIPEA (111.83mg, 865.32μmol, 150.72) μL), the reaction was stirred at 70°C for 12 hours. LCMS showed that the reaction was complete, the reaction solution was directly spin-dried, and the crude product was purified by an automatic column machine (100-200 mesh, eluent PE:EtOAc=100:1-100:50) to obtain compound WX008_4. 1H NMR( 400MHz, CDCl 3 )δ8.17(d,J=5.1Hz,1H),8.05-7.88(m,2H),6.85(d,J=5.1Hz,1H),6.53(s,1H),4.58-4.43 (m,1H),4.12-3.93(m,2H),3.65(s,3H),3.55(s,2H),2.50-2.34(m,1H),2.00-1.89(m,1H),1.49(d , J=6.3Hz, 3H).
步骤5：化合物WX008的合成Step 5: Synthesis of compound WX008
将化合物WX008_4(0.07g,183.56μmol)加入到10mL拇指瓶中，用THF(2mL)及H 2O(2mL)溶解，再加入LiOH.H 2O(7.70mg,183.56μmol)，反应在20℃下搅拌1小时，LCMS显示反应完成。将反应液直接旋干，加入3mL的MeOH溶解并过滤，滤液使用Prep-HPLC(分离方法：Welch Xtimate C18 150mm*25mm*5μm；流动相:[水(0.225％FA)-ACN]；B(ACN)％:45％-75％,8分钟)进行纯化，得到化合物WX008。 Compound WX008_4 (0.07g, 183.56μmol) was added to a 10mL thumb bottle, dissolved with THF (2mL) and H 2 O (2mL), then LiOH.H 2 O (7.70mg, 183.56μmol) was added, and the reaction was carried out at 20°C. After stirring for 1 hour, LCMS showed that the reaction was complete. The reaction solution was spin-dried directly, and 3mL of MeOH was added to dissolve and filter. The filtrate was used Prep-HPLC (separation method: Welch Xtimate C18 150mm*25mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B(ACN) )%: 45%-75%, 8 minutes) for purification to obtain compound WX008.
参照实施例8中的合成方法(步骤3中用芳基片段G替代化合物G-1)，Referring to the synthesis method in Example 8 (in step 3, aryl fragment G was used instead of compound G-1),
合成下表中各实施例：Synthesize the examples in the following table:
实施例29Example 29
合成路线：synthetic route:
步骤1：化合物WX029_1的合成Step 1: Synthesis of compound WX029_1
将WX017_4(参考实施例8中化合物WX008_4的合成得到)(0.05g,108.87μg,)溶于DMA(2mL)中，加入Zn(CN) 2(25.57mg,217.74μmol)，Pd(t-Bu 3P) 2(55.64mg,108.87μmol)，反应在110℃下搅拌12小时。将反应液慢慢加入水(20ml)中，加入乙酸乙酯(20ml×2)萃取，有机相旋干。粗品经过自动过柱机(100～200目，洗脱剂PE:EtOAc＝100:1～100:50)过柱纯化，得到化合物WX029_1。 WX017_4 (obtained from the synthesis of compound WX008_4 in Reference Example 8) (0.05g, 108.87μg,) was dissolved in DMA (2mL), Zn(CN) 2 (25.57mg, 217.74μmol), Pd(t-Bu 3) P) 2 (55.64 mg, 108.87 μmol), and the reaction was stirred at 110°C for 12 hours. The reaction solution was slowly added to water (20ml), ethyl acetate (20ml×2) was added for extraction, and the organic phase was spin-dried. The crude product was purified by an automatic column passing machine (100-200 mesh, eluent PE:EtOAc=100:1-100:50) to obtain compound WX029_1.
步骤2：化合物WX029的合成Step 2: Synthesis of compound WX029
将化合物WX029_1(0.06g,148.01μmol)加入到10mL拇指瓶中，用THF(2mL)及H 2O(2mL)溶解，再加入LiOH.H 2O(18.63mg,444.04μmol)，反应在20℃下搅拌1小时，LCMS显示反应完成。将反应液直接旋干，加入3mL的MeOH溶解并过滤，滤液使用Prep-HPLC(分离方法：Welch Xtimate C18 150mm*25mm*5μm；流动相:[水(0.225％FA)-ACN]；B(ACN)％:45％-75％,8分钟)进行纯化，得到化合物WX029。 Compound WX029_1 (0.06g, 148.01μmol) was added to a 10mL thumb bottle, dissolved with THF (2mL) and H 2 O (2mL), and then LiOH.H 2 O (18.63mg, 444.04μmol) was added, and the reaction was carried out at 20°C. After stirring for 1 hour, LCMS showed that the reaction was complete. The reaction solution was spin-dried directly, and 3mL of MeOH was added to dissolve and filter. The filtrate was used Prep-HPLC (separation method: Welch Xtimate C18 150mm*25mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B(ACN) )%: 45%-75%, 8 minutes) for purification to obtain compound WX029.
各实施例的 1H NMR和MS数据如下表1所示： The 1 H NMR and MS data of each example are shown in Table 1:
表1: 1H NMR和MS数据 Table 1: 1 H NMR and MS data
生物测试数据Biological test data
实验例1：果糖激酶实验(KHK assay)Experimental example 1: Fructose kinase test (KHK assay)
A.主要材料A. Main materials
1.EnVision酶标仪，珀金埃尔默；1. EnVision microplate reader, PerkinElmer;
2.OptiPlate 384微孔板，珀金埃尔默，货号：6007290；2. OptiPlate 384 microplate, PerkinElmer, catalog number: 6007290;
3.重组人果糖激酶(KHK)，R&D_货号：8177-HK-020，批次号：DDFK0117092；3. Recombinant human fructokinase (KHK), R&D_Product No.: 8177-HK-020, Batch No.: DDFK0117092;
4.果糖(D(-)-Fructose)，国药_货号：36003034；4. Fructose (D(-)-Fructose), Sinopharm_Product No.: 36003034;
5.ADP-Glo试剂盒，Promega_货号：V91015. ADP-Glo kit, Promega_article number: V9101
B.方法B. Method
a)激酶反应a) Kinase reaction
1.配制缓冲液：包含50mM HEPES，140mM KCl，3.5mM MgCl 2，0.01％BSA，pH值为7.4。 1. Preparation buffer: contains 50mM HEPES, 140mM KCl, 3.5mM MgCl 2 , 0.01% BSA, pH 7.4.
2.用缓冲液配制2.5倍浓度的果糖激酶工作液，其中己酮糖激酶是50nM,果糖是12.5mM。2. Prepare a 2.5-fold concentration of fructokinase working solution with buffer, where hexulose kinase is 50 nM and fructose is 12.5 mM.
3.用缓冲液配制2.5倍浓度的三磷酸腺苷(ATP)工作液，浓度为250μM。3. Prepare 2.5 times the concentration of adenosine triphosphate (ATP) working solution with buffer solution, the concentration is 250μM.
4.稀释化合物从500μM的浓度开始，3倍稀释9个浓度点，化合物在反应体系的终浓度从10μM开始，二甲基亚砜(DMSO)的终浓度为2％。4. Dilution of the compound starts from a concentration of 500 μM, 3 times dilution at 9 concentration points, the final concentration of the compound in the reaction system starts from 10 μM, and the final concentration of dimethyl sulfoxide (DMSO) is 2%.
5.准备一块96孔板作为反应板，加入每孔6μL的2.5倍浓度的果糖激酶工作液，再加入每孔3μL的化合物工作液之后，在室温下孵育5分钟。5. Prepare a 96-well plate as a reaction plate, add 6 μL of 2.5 times the concentration of fructokinase working solution per well, and then add 3 μL of compound working solution per well, and incubate at room temperature for 5 minutes.
6.每行第一个孔为化合物的阳性对照，即加入相同体积的缓冲液来替代化合物和果糖激酶；最后一个孔为化合物的阴性对照，即加入相同体积的缓冲液来替代化合物。6. 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.
7.在96孔反应板中每孔加入6μL的ATP工作液之后启动激酶反应。激酶反应在28℃恒温加热器孵育1小时。7. Start the kinase reaction after adding 6μL of ATP working solution to each well of the 96-well reaction plate. The kinase reaction was incubated for 1 hour at a constant temperature heater at 28°C.
b)ADP-Glo检测b) ADP-Glo detection
1.准备一块384板作为检测板，先加入5μL的ADP-Glo试剂。1. Prepare a 384 plate as a detection plate, and first add 5μL of ADP-Glo reagent.
2.每孔加入5μL反应板中的激酶反应混合物，在28℃恒温加热器孵育30分钟。2. Add 5μL of the kinase reaction mixture in the reaction plate to each well, and incubate for 30 minutes in a constant temperature heater at 28°C.
3.每孔加入10μL激酶检测试剂，在28摄氏度恒温加热器孵育30分钟。3. Add 10μL of kinase detection reagent to each well, and incubate for 30 minutes in a constant temperature heater at 28 degrees Celsius.
4.将检测板放入EnVision酶标仪中读化学发光信号。4. Put the detection plate into the EnVision microplate reader to read the chemiluminescence signal.
C.实验结果：C. Experimental results:
表2：KHK体外活性测试结果Table 2: KHK in vitro activity test results
结论：本发明化合物对人源KHK酶有很强的抑制活性。Conclusion: The compound of the present invention has strong inhibitory activity on human KHK enzyme.
Claims (15)
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022135390A1 (en) * | 2020-12-25 | 2022-06-30 | 四川海思科制药有限公司 | Ketohexokinase inhibitor and use thereof |
| WO2023151473A1 (en) * | 2022-02-09 | 2023-08-17 | 上海研健新药研发有限公司 | Khk inhibitor, preparation method therefor and use thereof |
| WO2024125482A1 (en) * | 2022-12-13 | 2024-06-20 | 华领医药技术（上海）有限公司 | Compound used as ketohexokinase inhibitor, use thereof, and composition containing same |
| US12145921B2 (en) | 2021-12-20 | 2024-11-19 | Nimml Institute | Aromatic immunoregulatory compounds for treatment of inflammatory diseases |
| JP2024544794A (en) * | 2021-12-24 | 2024-12-04 | エルジー・ケム・リミテッド | (S)-2-(2-methylazetidin-1-yl)pyrimidine derivatives and pharmaceutical compositions containing the same |
| US12410160B2 (en) | 2021-03-29 | 2025-09-09 | Gilead Sciences, Inc. | KHK inhibitors |
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| CN114181198B (en) * | 2020-09-15 | 2025-07-15 | 山东轩竹医药科技有限公司 | Pyrimidine derivative hexokinases inhibitors and their uses |
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| CN108473469A (en) * | 2015-12-29 | 2018-08-31 | 辉瑞公司 | Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors |
| WO2020257171A1 (en) * | 2019-06-17 | 2020-12-24 | Eli Lilly And Company | Disubstituted pyrazole compounds as ketohexokinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108473469A (en) * | 2015-12-29 | 2018-08-31 | 辉瑞公司 | Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors |
| WO2020257171A1 (en) * | 2019-06-17 | 2020-12-24 | Eli Lilly And Company | Disubstituted pyrazole compounds as ketohexokinase inhibitors |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022135390A1 (en) * | 2020-12-25 | 2022-06-30 | 四川海思科制药有限公司 | Ketohexokinase inhibitor and use thereof |
| 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 (en) * | 2021-12-24 | 2024-12-04 | エルジー・ケム・リミテッド | (S)-2-(2-methylazetidin-1-yl)pyrimidine derivatives and pharmaceutical compositions containing the same |
| EP4434982A4 (en) * | 2021-12-24 | 2025-03-12 | LG Chem, Ltd. | (S)-2-(2-METHYLAZETIDIN-1-YL)PYRIMIDINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION COMPRISING IT |
| WO2023151473A1 (en) * | 2022-02-09 | 2023-08-17 | 上海研健新药研发有限公司 | Khk inhibitor, preparation method therefor and use thereof |
| WO2024125482A1 (en) * | 2022-12-13 | 2024-06-20 | 华领医药技术（上海）有限公司 | Compound used as ketohexokinase inhibitor, use thereof, and composition containing same |
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