WO2021259309A1 - Glp-1受体激动剂及其药物组合物和用途 - Google Patents
Glp-1受体激动剂及其药物组合物和用途 Download PDFInfo
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- WO2021259309A1 WO2021259309A1 PCT/CN2021/101735 CN2021101735W WO2021259309A1 WO 2021259309 A1 WO2021259309 A1 WO 2021259309A1 CN 2021101735 W CN2021101735 W CN 2021101735W WO 2021259309 A1 WO2021259309 A1 WO 2021259309A1
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- cycloalkyl
- heteroaryl
- aryl
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- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
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Definitions
- the present invention belongs to the field of medicine, and specifically relates to a new class of GLP-1 receptor agonists, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, and regioisomers thereof , Nitric oxide, or a mixture, and a pharmaceutical composition containing the compound and the use of the compound or the pharmaceutical composition in the preparation of a medicament for the treatment of mammalian cardiovascular and metabolic diseases and related disorders. More specifically, the compounds provided by the present invention show excellent agonistic effects on GLP-1 receptors.
- Diabetes is one of the common chronic diseases. The incidence is increasing year by year, and the age of onset is getting younger and younger. It is called the three "chronic killers" together with cardiovascular diseases and respiratory diseases. In recent years, the prevalence of diabetes in my country has risen from 1% in 1980 to 11% in 2017. Up to now, China has become the country with the largest number of diabetic patients. Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological effects, or both. The long-term high blood sugar in diabetes causes chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. Diabetes is mainly divided into type 1 diabetes and type 2 diabetes.
- Type 1 diabetes is due to the loss of insulin secretion by the autoimmune system attacking pancreatic ⁇ cells.
- Type 2 diabetes starts with abnormal insulin resistance or cells do not respond to insulin; obesity is one of the main causes of insulin resistance, so obesity can be said to be the main risk factor for type 2 diabetes.
- Type 2 diabetes patients account for about 90% of the number of diabetic patients. Therefore, the disease has become a major public health problem in developed countries with serious obesity problems and in China, where the number of obesity continues to increase.
- insulin secretagogues including Sulfonylureas, meglitinide, dipeptidyl peptidase-4 (DPP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1 R) agonists
- DPP-IV dipeptidyl peptidase-4
- GLP-1 R glucagon-like peptide-1 receptor
- GLP-1 R agonists are mainly peptide drugs injected under the skin, and liraglutide is additionally approved for the treatment of obesity ; 2) Biguanide drugs (such as metformin), which mainly reduce the production of glycogen to control blood sugar.
- Biguanide drugs often cause gastrointestinal reactions and lactic acidemia; 3) ⁇ -glucosidase inhibitors (such as acarbose), which can reduce intestinal glucose absorption, but usually cause intestinal reactions; 4) Thiazole Alkanedione drugs regulate fat metabolism by acting on specific receptors (peroxidase proliferation factor activated receptor- ⁇ ) in liver, muscle and adipose tissue, thereby increasing the sensitivity of these tissues to insulin.
- ⁇ -glucosidase inhibitors such as acarbose
- Thiazole Alkanedione drugs regulate fat metabolism by acting on specific receptors (peroxidase proliferation factor activated receptor- ⁇ ) in liver, muscle and adipose tissue, thereby increasing the sensitivity of these tissues to insulin.
- SGLT2 Sodium- Glucose cotransporter 2
- Such drugs may be related to ketoacidosis and urinary tract infections.
- GLP-1 R agonist the first GLP-1 R agonist
- GLP-1 R agonists such as liraglutide and somaglutide were subsequently marketed.
- GLP-1 R agonists have less risk of hypoglycemia.
- liraglutide and somaglutide have also shown good blood sugar lowering effects, lower glycated hemoglobin, weight loss and cardiovascular benefits in clinical trials (FDA. (2013) Pharmacology review of Saxenda TM .FDA.(2013) Pharmacology review of Saxenda TM .FDA. 2016) Pharmacology review of Semaglutide.).
- Drugs for treating diabetes are mainly divided into three categories: insulin and its analogues, chemical oral hypoglycemic agents, and GLP-1R agonists. From the perspective of the market share of GLP-1R agonists, it has reached 17% in the world, and only 2% in my country. Therefore, this type of drug has a relatively large room for growth in the country. With the in-depth study of the gut-brain axis, GLP-1 R agonists have also been studied for the treatment of Parkinson's disease (Kim, D Set al. (2017) Cell transplantation, 26.9: 1560-1571), which makes GLP- 1 R agonists will have a broader market and application scenarios in the future.
- Glucagon-like peptide-1 (GLP-1) is a long-chain incretin composed of 30 amino acids secreted by L cells, which promotes the digestion of food in the intestine. Under physiological conditions, GLP-1 has been proven to stimulate the production of insulin in a blood sugar-dependent manner, thereby increasing the absorption of blood sugar in the periphery to regulate postprandial blood sugar, reducing the secretion of glucagon, thereby reducing the production of glycogen, and inhibiting Gastric emptying and small intestine peristalsis delay the absorption of food, reduce appetite, and stimulate the proliferation of ⁇ cells (Meier, et al. (2003) Biodrugs, 17.2:93-102. Vilsboll, T. et al.
- the existing GLP-1 R agonist drugs including exenatide, liraglutide, and somaglutide are all peptide drugs that mimic the structure of natural GLP-1, so they can only be administered by injection and are relatively expensive.
- the annual cost is as high as $1,500 to $2,500 (https://www.ncbi.nlm.nih.gov/books/NBK543967/).
- Novo Nordisk has developed an oral preparation of somaglutide, due to the limited physical and chemical properties of peptide drugs, its oral availability is only 1-2%, and the daily dosage is also different from the original daily injection dosage. It will increase from 1mg to 14mg, and the cost will rise to $9,264 per year. Therefore, the need to develop GLP-1 R agonist drugs with high oral availability and a more reasonable price is particularly obvious.
- the compound of the present invention has a good GLP-1 R agonistic effect, good liver microsomal stability in humans and rats, and good pharmacokinetic properties, faster oral absorption, and better bioavailability It can be used for oral administration and has a better prospect of clinical application.
- mammal refers to, for example, primates (such as humans, males or females), cattle, sheep, goats, horses, pigs, dogs, cats, rabbits, rats, mice, fish , Birds, etc.
- the mammal is a primate. In other embodiments, the mammal is a human.
- Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
- the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or special examples, subclasses, and the present invention in the examples/implementations.
- substituents such as the compounds of the general formula above, or special examples, subclasses, and the present invention in the examples/implementations.
- substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, a substituted group may have a substituent at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
- C 1-6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
- linking substituents are described.
- the Markush variables listed for the group should be understood as the linking group.
- the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively Represents a linked alkylene group or arylene group.
- alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted with one or more substituents described in this invention.
- alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
- the alkyl group may be optionally substituted with one or more substituents described in this invention.
- alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
- alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, which includes “cis” and ""Reverse” positioning, or “E” and “Z” positioning.
- the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
- the alkenyl group may be optionally substituted with one or more substituents described in this invention.
- alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond.
- the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
- Examples of alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
- the alkynyl group may be optionally substituted with one or more substituents described in this invention.
- alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the definition as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
- alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 1-
- haloalkyl means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Examples of such include, but are not limited to, Trifluoromethyl, trifluoroethyl, 2,2,3,3-tetrafluoropropyl, trifluoromethoxy, etc.
- hydroxyalkyl used in the present invention means that an alkyl group is substituted by one or more hydroxy groups, where the alkyl group has the definition as described in the present invention. Examples of this include, but are not limited to, hydroxy Ethyl, 2-hydroxypropyl, hydroxymethyl, etc.
- cycloalkyl refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon.
- the cycloalkyl group may be a bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group.
- the cycloalkyl group comprising 3-10 carbon atoms, i.e., C 3 to C 10 cycloalkyl.
- the cycloalkyl group has 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-7 (C 3-7 ) carbon atoms.
- the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a monocyclic ring. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is tricyclic. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated.
- the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, ten Hydronaphthyl, or adamantyl.
- the cycloalkyl group can be on any ring, that is, on any aromatic or non-aromatic ring contained by the cycloalkyl group, it can be independently substituted by one or more substituents described in the present invention.
- heterocyclic group and “heterocyclic ring” are used interchangeably herein, unless otherwise specified, and refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system containing at least one non-aromatic ring;
- One or more of the non-aromatic monocyclic atoms are heteroatoms independently selected from O, S(O) 0-2 and N, and the The remaining ring atoms are all carbon atoms; and wherein one or more of the ring atoms of the polycyclic system (in certain embodiments, 1, 2, 3, or 4) are independently selected from O, S(O ) The heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
- the heterocyclic ring contains 1 or 2 heteroatoms, all of which are nitrogen atoms.
- the heterocyclic group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two One of the heteroatoms is in the aromatic ring and the other is in the non-aromatic ring.
- the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
- the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
- the heterocyclyl group may be a bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic group.
- One or more nitrogen atoms and sulfur atoms can be optionally oxidized, one or more nitrogen atoms can be optionally quaternized, and one or more carbon atoms can be optionally oxidized replace.
- Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
- the monocyclic heterocycle and polycyclic heterocycle may be connected to the main structure at any heteroatom or carbon atom that results in a stable compound.
- the polycyclic heterocyclic group can be connected to the main structure through any of its rings, including any aromatic or non-aromatic ring, regardless of whether the ring contains a heteroatom or not.
- the heterocyclic group is a "heterocycloalkyl group", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group containing at least one ring heteroatom as described in the present invention , Or 2) saturated or partially unsaturated (but not aromatic) monovalent bicyclic group or tricyclic group, in which at least one ring contains at least one heteroatom as described in the present invention.
- heterocyclic groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane Group, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothio
- Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
- the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
- the heterocyclic group is a heterocyclic group consisting of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and Oxygen atom.
- the sulfur atom of the ring can optionally be oxidized to S-oxide.
- the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
- heterocyclic groups composed of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline Group, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine Group, dioxanyl, dithianyl, thiazinyl, homopiperazinyl, homopiperidinyl,
- Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
- the heterocyclic group composed of 3-8 atoms can be optionally substituted by one or more substituents described in the present invention.
- the heterocyclic group is a heterocyclic group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and Oxygen atom.
- the sulfur atom of the ring can optionally be oxidized to S-oxide.
- the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
- the heterocyclic group composed of 3-6 atoms can be optionally substituted by one or more substituents described in the present invention.
- the heterocyclic group is a heterocyclic group consisting of 5-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur And oxygen atoms.
- the sulfur atom of the ring can optionally be oxidized to S-oxide.
- the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
- heterocyclic groups composed of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine Group, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -Thiazolidine, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine Group, piperazinyl, dioxanyl, dithianyl, thiazinyl, 2-piper
- cycloalkylalkyl means that the alkyl group may be substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl have the definitions described in the present invention. Examples of such include, but not Limited to cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexyl Ethyl and so on.
- heterocyclylalkyl includes heterocyclyl-substituted alkyl groups
- heterocyclylalkoxy includes heterocyclyl-substituted alkoxy groups in which the oxygen atom is connected to the rest of the molecule
- heterocyclic alkylamino includes heterocyclyl substituted alkylamino in which the nitrogen atom is connected to the rest of the molecule.
- heterocyclic group, alkyl group, alkoxy group and alkylamino group all have the definition as described in the present invention.
- Such examples include, but are not limited to, azetidine-1-ylmethyl, azetidine -1-ylethyl, azetidine-1-ylpropyl, pyrrol-1-ylmethyl, pyrrol-1-ylethyl, pyrrol-1-ylpropyl, morpholin-4-ylethyl Group, morpholin-4-ylethoxy, piperazin-4-ylethoxy, piperidin-4-ylethylamino, etc.
- fused bicyclic ring refers to a saturated or unsaturated fused ring system system, referring to a non-aromatic bicyclic ring system, as shown in formula (a1) , That is, ring B and ring B'share a bond. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
- Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic.
- Examples of this include, but are not limited to, hexahydro-furo[3,2-b]furan, 2,3,3a,4 ,7,7a-hexahydro-1H-indene, 7-azabicyclo[2.3.0]heptane, fused bicyclo[3.3.0]octane, fused bicyclo[3.1.0]hexane, these all contain Within the fused bicyclic ring.
- fused heterobicyclic group means a saturated or unsaturated fused ring system or bridged ring system, and refers to a non-aromatic bicyclic ring system or bridged ring system. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
- At least one ring system contains one or more heteroatoms, each of which contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to hexahydro-furo [3, 2-b]furan, 7-azabicyclo[2.3.0]heptane, 2-azabicyclo[2.2.1]heptane, octahydropyrrole[3,2-b]pyrrole, octahydropyrrole[3, 4-c]pyrrole, octahydro-1H-pyrrole[3,2-b]pyridine and the like.
- the fused heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but not limited to, H, D, F, Cl, Br, I, -OH, SH, -NH 2 , -NO 2.
- -CN, oxo ( O), N 3 , alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkoxy, haloalkoxy, alkylsulfide Group, alkylamino, haloalkylamino, -NR 1b R 1c , cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroaryl Alkyl, etc., wherein R 1b and R 1c both have the definitions described in the present invention.
- spirocyclyl indicates that one ring originates from a special cyclic carbon on another ring.
- ring A and ring B share a carbon atom in two saturated ring systems and are called “spirocyclic rings”.
- Each ring in the spiro ring is either carbocyclic or heteroalicyclic.
- Such examples include, but are not limited to, 2,7-diazaspiro[4.4]nonane-2-yl, 7-oxo-2-azaspiro[4.5]decane-2-yl, 4-azaspiro[4.5] Spiro[2.4]heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, spiro[2.4]heptan-5-yl, spiro [4.4] Nonyl, 7-hydroxy-5-azaspiro[2.4]heptan-5-yl and the like.
- spiroheterobicyclyl means that one ring originates from a special cyclic carbon on another ring. For example, as described above, ring A and ring B share a carbon atom in two saturated ring systems and are called "spirocyclic rings”.
- At least one ring system contains one or more heteroatoms, each of which contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S
- S or P is optionally substituted with one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 and such examples include, but are not limited to 4-azaspiro [2.4] Heptane-5-yl, 4-oxaspiro[2.4]heptane-5-yl, 5-azaspiro[2.4]heptane-5-yl, 7-hydroxy-5-azaspiro[2.4]heptan Alkyl-5-yl, 2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane, 1,6-diazaspiro[3.4]octane, 2, 7-diazaspiro[3.5]nonane, 1,7-diazaspiro[3.5]
- bridged ring group used in the present invention refers to a saturated or unsaturated bridged ring system, involving a non-aromatic bridged ring system, as shown in formula (a2), that is, ring A1 and ring A2 share an alkane chain or a heterocyclic ring system.
- Alkyl chain where j is 1, 2, 3 or 4.
- Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it).
- Each ring in the bridged ring is either carbocyclic or heteroalicyclic.
- bicyclo[2.2.1]heptane 2-azabicyclo[2.2.1]heptane, 1,2,3,4,4a,5,8,8a-octahydronaphthalene, these are included in the fused bicyclic or bridged ring system.
- bridged heterocyclic group refers to a saturated or unsaturated bridged ring system, referring to a non-aromatic bridged ring system. Such a system may contain independent or conjugated unsaturation, but its core structure does not contain aromatic or heteroaromatic rings (but aromatics can be used as substituents on it). And at least one ring system contains one or more heteroatoms, each of which contains a 3-7 membered ring, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where S or P is optionally substituted by one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to 2-azabicyclo [2.2.
- connection points in the ring system that are connected to the rest of the molecule, as shown in formula (a3) or (a4), which means that it can be either the E end or the E'end and the rest of the molecule. , That is, the connection modes at both ends can be interchanged.
- halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
- aryl used in the present invention, unless otherwise specified, refers to a monovalent C 6 -C 14 carbocyclic ring system containing at least one aromatic ring, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic .
- the aryl group can be connected to the main structure through any of its rings, that is, any aromatic or non-aromatic ring.
- the aryl group is phenyl, naphthyl, bicyclo[4.2.0]octyl-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl.
- aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl; said phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, and indanyl
- aralkyl refers to an alkyl group substituted with one or two aryl groups as defined in the present invention, wherein the alkyl group is related to the molecule The point where the rest is connected.
- the aralkyl group is benzyl, phenethyl-1-yl, phenethyl-2-yl, diphenylmethyl, 2,2-diphenylethyl, 3,3-diphenyl Propyl, or 3-phenylpropyl; the benzyl, phenethyl-1-yl, phenethyl-2-yl, diphenylmethyl, 2,2-diphenylethyl, 3,3 -Diphenylpropyl and 3-phenylpropyl are each optionally substituted on the ring with one or more substituents described in the present invention.
- heteroaryl refers to a monovalent monocyclic or polycyclic aromatic group in which at least one (in certain embodiments, 1, 2, 3, or 4)
- the ring atoms are heteroatoms independently selected from O, S(O) 0-2 and N in the ring.
- the heteroaryl group is connected to the rest of the molecule through any atom in the ring system, and its valence rules allow it.
- each ring of a heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and/or 1 to 4 N atoms, or a combination thereof, provided that each ring The total number of heteroatoms is 4 or less, and each ring contains at least 1 carbon atom.
- the heteroaryl group has 5-20, 5-15, 5-10, or 5-8 ring atoms. When the heteroaryl group is substituted, it can be substituted on any ring.
- monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, Pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl.
- bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzo Thiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzo Furyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrole Pyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
- tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, haridinyl, phenanthrolinyl, phenanthridine Group and phenazine group.
- the heteroaryl group is indolyl, furyl, pyridyl, pyrimidinyl, imidazolyl, or pyrazolyl; each of which is optionally substituted by 1, 2, 3, or 4 throughout this specification
- heteroarylalkyl refers to an alkyl group substituted with one or two heteroaryl groups as defined in the present invention, wherein the alkyl group Is the point of connection with the rest of the molecule.
- heteroarylalkyl group include, but are not limited to, imidazole-2-methyl, thiazole-2-methyl, furan-2-ethyl, indole-3-methyl, etc.; each of which is optionally It is substituted on any ring by one or more substituents described in the present invention.
- alkylamino includes “N-alkylamino” and "N,N-dialkylamino” in which the amino groups are each independently substituted with one or two alkyl groups.
- the alkylamino group is a lower alkylamino group with one or two Ci-6 alkyl groups attached to the nitrogen atom.
- the alkylamino group is a C 1-3 lower alkylamino group.
- Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino and so on.
- aminoalkyl includes C 1-10 straight or branched chain alkyl groups substituted with one or more amino groups.
- the aminoalkyl group is a C 1-6 "lower aminoalkyl group” substituted by one or more amino groups.
- the aminoalkyl group is substituted by one or more amino groups. Examples of C 1-4 "lower aminoalkyl" substituted by an amino group include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
- cyanoalkyl or "cyano-substituted alkyl” includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
- the cyano-substituted alkyl group is a C 1-6 "lower cyanoalkyl group” substituted with one or more cyano groups, and other examples are the cyano-substituted alkyl group.
- An alkyl group is a C 1-4 "lower cyanoalkyl group” substituted with one or more cyano groups. Examples of this include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -, etc.
- the ring system (shown in the figure below) formed by attaching a substituent to the central ring by drawing a bond represents that the substituent can be substituted at any substitutable position on any ring.
- formula b represents any position on ring A or ring B that may be substituted, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, etc.
- the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
- Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
- non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in books and literature such as ion exchange These salts.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Pheny
- Salts obtained by reaction with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1 -C 4 alkyl) 4 salts.
- the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
- Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
- the present invention provides a new class of GLP-1 receptor agonists, or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, regioisomers, and nitrogen oxides thereof , Or a mixture, and a pharmaceutical composition containing the compound, and the use of the compound or the pharmaceutical composition in the preparation of a medicament for the treatment of mammalian cardiovascular and metabolic diseases and related disorders. More specifically, the compounds provided by the present invention show excellent agonistic effects on GLP-1 receptors.
- the present invention provides a new GLP-1 receptor agonist, which is represented by formula (I):
- Z 1 and Z 2 are each independently N or CH;
- Ar 1 is C 6-10 aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 5-12 fused bicyclic group, or C 5-12 fused Heterobicyclic group, wherein said Ar 1 is optionally substituted with 0, 1, 2, 3 or 4 R 2 ;
- Cy is C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 5-12 spiro bicyclic group, C 5-12 spiro heterobicyclic group, C 5-12 fused bicyclic group, C 5-12 fused Heterobicyclic group, C 5-12 bridged ring group, or C 5-12 bridged heterocyclic group, wherein said Cy is optionally substituted with 0, 1, 2, 3 or 4 R 3 ;
- Ar 2 is a fused heteroaryl group composed of 8 ring atoms, and the ring atoms include 1, 2, 3, or 4 heteroatoms independently selected from O, S and/or N, and the Ar 2 is any Is optionally substituted by 0, 1, 2, 3 or 4 R 6 ; or Ar 2 is:
- Ar 2 is optionally substituted with 0, 1, 2, 3 or 4 R 6 ;
- X 1 , X 2 and X 3 are each independently N or -C(R 6 )-;
- X 5 is O or S
- R 5a is a C 3-10 cycloalkyl group, a C 2-9 heterocycloalkyl group, a C 6-10 aryl group, or a C 1-9 heteroaryl group, wherein the R 5a is optionally substituted by 0, 1, 2 , 3 or 4 R 5b substitutions;
- R 5c is H, C 1-6 alkyl, C 3-10 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein R 5c is any Optionally substituted by 0, 1, 2, 3 or 4 R 5b;
- R 1b , R 1c , R c , Rd , R 7a , R 7c and R 7d are independently H, D, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2 -7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl
- R 7a and R 7b are each independently H, alkali metal ion, alkaline earth metal ion, -OH, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Hydroxyalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio Group, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 Heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 Alkyl; wherein C 3-8
- n 0, 1, 2, 3, 4, or 5;
- Each of t1 and t2 is independently 1, 2, 3, or 4, respectively.
- L 1 is O, NH, or CH 2 ;
- L 2 is O, S, -N(R c )-, or -CH 2 -.
- the compound of the present invention has a structure represented by formula (II):
- Y 1 and Y 2 are each independently N or -C(R 2 )-;
- Each R 2a is independently H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1 -6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkane C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; and
- t3 is 1, 2, or 3.
- the compound of the present invention has a structure represented by formula (III):
- a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitrogen oxide, or mixture thereof wherein Y 1 and Y 2 are each independently N or -C(R 2 )-; and m is 0, 1, 2, or 3.
- the compound of the present invention has a structure represented by formula (IIIa):
- the compound of the present invention has a structure represented by formula (IV):
- a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, regioisomer, nitrogen oxide, or mixture thereof wherein Y 1 and Y 2 are each independently N or -C(R 2 )-; and m is 0, 1, 2, or 3.
- Z 3 , Z 4 and Z 5 are each independently -O-, -S-, -NH-, -(CH 2 ) m1 -NH-(CH 2 ) m2 -, -(CH 2 ) m1 -O-( CH 2 ) m2 -, -(CH 2 ) m1 -S-(CH 2 ) m2 -, or -(CH 2 ) m3 -;
- Each m1 is independently 1, 2, 3, or 4;
- Each m2 is independently 0, 1, 2, 3 or 4;
- Each m3 is independently 1, 2, 3, or 4;
- n1 0, 1, 2, 3, or 4.
- Z 6 and Z 7 are each independently N, C or -CH-, provided that a chemically stable structure is formed.
- Cy is optionally substituted with 0, 1, 2, 3 or 4 R 3 .
- X 1 , X 2 and X 3 are each independently N or -C(R 6 )-;
- X 4 is O, S, -N(R 6a )-, or -C(R 6 ) 2 -;
- X 5 is O or S
- Each R 6a is independently H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 1 -6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkane C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl or C 1-9 heteroaryl C 1-6 alkyl.
- each R 1 is independently H, D, F, Cl, Br, -OH, -NH 2 , -NO 2 , -CN, methyl, ethyl, -CF 3 , -CH 2 CF 3 , -CH 2 CN, -CH 2 CH 2 CN, -CH 2 OH, or -CH 2 CH 2 OH; n is 0, 1, 2, 3 or 4.
- R 5a is a C 3-6 cycloalkyl group, a C 3-6 heterocycloalkyl group, a C 6-10 aryl group, or a C 1-9 heteroaryl group, wherein the R 5a is optionally substituted by 0, 1, 2 , 3 or 4 R 5b substitutions;
- R 5c is H, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl, wherein R 5c is any Optionally substituted by 0, 1, 2, 3 or 4 R 5b ; and
- R 5a and R 5c are each independently
- the group consisting of C 1-4 alkoxy C 1-4 alkyl group is substituted.
- each of R 1b , R 1c , R c , Rd , R 2a , R 6a , R 7c and R 7d are each independently H, D, OH, C 1-4 alkyl, C 2 -4 alkenyl, C 2-4 alkynyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy Group, C 1-4 haloalkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkylamino, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1- 4 alkyl group, C 3-6 heterocyclic group, C 3-6 heterocyclic group, C 1-4 alkyl group, C 6-10 aryl group, C 6-10 aryl group, C 1-4 alkyl group, C 1-9 Heteroaryl or C 1-9 heteroaryl
- R 7a and R 7b are each independently H, Li + , Na + , K + , NH 4 + , Mg 2+ , Ca 2+ , C 1-4 alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocyclic group, C 3-6 heterocyclic group C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 1-4 alkane C 3-6 heterocyclyl, C 3-6 heterocyclyl, C 1-4 alkyl, C 6-10 aryl
- the present invention provides a pharmaceutical composition, the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, diluent or carrier.
- the pharmaceutical composition further comprises an additional therapeutic agent.
- the present invention provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and/or treatment of cardiovascular and metabolic diseases and related disorders in mammals.
- cardiovascular and metabolic diseases and related disorders are T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia , Insulin resistance, liver insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat cell accumulation, sleep apnea, obesity, eating disorders, Weight gain, hyperglycemia, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease caused by the use of other drugs , Hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension,
- the compound of the present invention or a pharmaceutical composition thereof may be administered in combination with another therapeutic agent.
- the use of the present invention includes administering to a mammal an amount of the compound or pharmaceutical composition of the present invention sufficient to achieve the treatment or prevention.
- the compound of the present invention When used as a medicine, the compound of the present invention is usually administered in the form of a pharmaceutical composition.
- the composition can be prepared in a manner well known in pharmaceutical technology and comprises at least one compound according to the invention according to formula I, II or III.
- the compound of the present invention is administered in a pharmaceutically effective amount.
- the amount of the compound of the present invention actually administered will usually be determined by the physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound of the present invention administered, the age, weight and response of the individual patient, and the patient’s symptoms. Severity, etc.
- the present invention comprises pharmaceutical compositions.
- Such pharmaceutical compositions comprise the compound of the invention in a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and physiologically compatible Similar.
- pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, glucose, glycerol, ethanol, and the like, and combinations thereof, and may include isotonic agents in the composition, For example sugars, sodium oxide or polyols such as mannitol or sorbitol.
- Pharmaceutically acceptable substances such as wetting agents
- auxiliary substances such as wetting or emulsifying agents, preservatives or buffers
- composition of the present invention can take a variety of forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories.
- liquid solutions e.g., injectable and infusible solutions
- dispersions or suspensions tablets, pills, powders, liposomes, and suppositories.
- the form depends on the intended mode of administration and therapeutic application.
- compositions are in the form of injectable and infusible solutions, such as those similar to those commonly used for passive immunization of humans with antibodies.
- One mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
- the antibody system is administered via intravenous infusion or injection.
- the antibody system is administered by intramuscular or subcutaneous injection.
- Oral administration of solid dosage forms can be presented, for example, in individual units, such as hard or soft capsules, pills, cachets, chains, or tablets, each containing a predetermined amount of at least one compound of the present invention.
- oral administration may be in powder or granular form.
- the oral dosage form is a sublingual form, such as a chain dose.
- the compound of formula I is conventionally combined with one or more adjuvants.
- Such capsules or tablets may contain controlled release formulations.
- the dosage form may also contain buffering agents or may be prepared with enteric coatings.
- composition for parenteral administration may be an emulsion or a sterile solution.
- propylene glycol, polyethylene glycol, vegetable oils, particularly olive oil, or injectable organic esters may be used as a solvent or carrier, and in some embodiments, ethyl oleate may be used as a solvent or carrier.
- These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be performed in several ways, in some embodiments, using a bacteriological filter, sterilization by radiation or by heating. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or any other sterile injectable medium at the time of use.
- composition for rectal administration is a suppository or a rectal capsule, which in addition to the active ingredient also contains adjuvants such as cocoa butter, semi-synthetic glycerides or polyethylene glycol.
- the composition provided by the present invention is a pharmaceutical composition or a single unit dosage form.
- the pharmaceutical composition and single unit dosage form provided by the present invention contain a preventive or therapeutically effective amount of one or more prophylactic or therapeutic agents (for example, the compound provided by the present invention or other prophylactic or therapeutic agents) and a typical one or A variety of pharmaceutically acceptable carriers or excipients.
- prophylactic or therapeutic agents for example, the compound provided by the present invention or other prophylactic or therapeutic agents
- pharmaceutically acceptable carriers or excipients for example, the compound provided by the present invention or other prophylactic or therapeutic agents
- pharmaceutically acceptable means approved by a regulatory agency of the federal or state government, or listed in the U.S. Pharmacopoeia or other recognized pharmacopoeia for use in animals, especially Human medicine.
- carrier includes diluents, adjuvants (eg, Freund's adjuvant (complete and incomplete)), adjuvants, or vehicles that are administered with the therapeutic agent.
- Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal oil, vegetable oil, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
- water can be used as a carrier.
- Saline solutions and aqueous dextrose solutions and glycerol solutions can also be used as liquid carriers, especially for injection solutions. Examples of suitable drug carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22nd edition (September 15, 2012).
- Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical field. In certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the way the dosage form is administered to the subject and the specific active ingredients in the dosage form. If necessary, the composition or single unit dosage form may also contain small amounts of wetting or emulsifying agents, or pH buffering agents.
- a suitable composition for oral administration contains an effective amount of the compound of the present invention, which can be in the form of tablets, lozenges, aqueous or oily suspensions, powders or granules, emulsions, hard or soft capsules or syrups. Or elixirs.
- Compositions for oral use can be prepared according to any method known in the field of pharmaceutical composition production. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives. , So as to provide pharmaceutically beautiful and palatable preparations.
- the tablet may contain the active ingredient and non-toxic and pharmaceutically acceptable excipients used in the production of the tablet in combination with the active ingredient.
- auxiliary materials include: for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin or arabic Gum; lubricant, such as magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or coated according to known techniques to delay their disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.
- a time delay material can be used, for example, glyceryl monostearate or glyceryl distearate can be used.
- the dosage regimen of the compound of the present invention and/or the composition containing the compound is based on many factors, including the type, age, weight, sex, and medical symptoms of the patient; the severity of the symptoms; the route of administration; and the specific compound used active. Therefore, the dosage regimen can vary widely.
- the total daily dose of the compound of the present invention used to treat the indications discussed in the present invention is generally from about 0.001 to about 100 mg/kg (ie, milligrams of the compound of the present invention per kilogram of body weight).
- the total daily dose of the compound of this invention is about 0.01 to about 30 mg/kg, and in another embodiment about 0.03 to about 10 mg/kg, and in yet another embodiment about 0.1 To about 3 mg/kg. It is not uncommon to repeatedly administer the compound of the present invention many times in a day (usually no more than 4 times). If necessary, multiple doses per day can usually be used to increase the total daily dose.
- composition for oral administration can be provided in the form of a tablet containing 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 30.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 mg of active ingredient.
- the medicament usually contains from about 0.01 mg to about 500 mg of active ingredient, or in another embodiment from about 1 mg to about 100 mg of active ingredient.
- the intravenous dose during the fixed rate infusion may range from about 0.01 to about 10 mg/kg/min.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which is used in medicine.
- the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention, which is used for the prevention and/or treatment of cardiovascular and metabolic diseases and related disorders in mammals, especially for T1D, T2DM, Prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, liver insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy , Kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat cell accumulation, sleep apnea, obesity, eating disorder, weight gain caused by the use of other drugs, excessive glucose, dyslipidemia, hyperinsulinemia, NAFLD , NASH, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease
- the compounds of the invention can be administered simultaneously with one or more other therapeutic ingredients, or before or after them.
- the compound of the present invention and another ingredient may be administered separately through the same or different administration routes, or the two may be administered together in the same pharmaceutical composition.
- the compounds of the present invention can be administered with anti-diabetic drugs, including but not limited to biguanides (such as metformin), sulfonylureas (such as tolbutamide, glibenclamide) (glibenclamide), gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride Or glipizide), thiazolidinediones (e.g., pioglitazone, rosiglitazone or lobeglitazone), glieza (e.g.
- biguanides such as metformin
- sulfonylureas such as tolbutamide, glibenclamide) (glibenclamide)
- gliclazide chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride Or glipizide
- thiazolidinediones e.
- saroglitazar e.g. nateglinide, rapaglinide
- DPP-4 dipeptidyl Peptidase 4
- glitazone e.g. sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin
- glitazone e.g.
- pioglitazone pioglitazone, rosiglitazone) , Belaglitazone (balaglitazone), revoglitazone (rivoglitazone or lobeglitazone), sodium-glucose linked transporter 2 (SGLT2) inhibitors (e.g.
- GPR40 agonists FFAR1/FFA1 agonists, such as fasiglifam
- GIP glucose-dependent insulinotropic peptide
- alpha glucosidase inhibitors such as voglibose (voglibose), acarbose or miglitol (miglitol)
- insulin or insulin analogues including pharmaceutically acceptable salts of specified medicaments and pharmaceutically acceptable solvates of said medicaments and salts Things.
- the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula I, II, III, IIIa or IV.
- the following reaction schemes and examples are used to further illustrate the content of the present invention.
- Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by refluxing and drying with sodium metal.
- Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
- Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
- reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
- the glassware is all dried.
- the chromatographic column is a silica gel column.
- Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
- 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.
- the 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard.
- TMS 0. ppm
- chloroform 7.26 ppm
- the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30mm, 3.5 microns, 6min, flow rate 0.6mL/min.
- Mobile phase 5 %-95% (the ratio of (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)), using electrospray ionization (ESI), and detecting with UV at 210nm/254nm.
- Intermediate 1-1 and 1-2 are catalyzed by metal palladium through a coupling reaction to produce intermediate 1-3; Intermediate 1-3 undergoes a metal-catalyzed reduction reaction to obtain intermediate 1-4; 1-4 and 1 -5 Under the condition of metal catalysis, the coupling reaction is carried out to obtain Intermediate 1-6; Under the action of strong acid, the protective group of 1-6 is removed to form Intermediate 1-7; 1-7 and 1-8 are in base Under natural conditions, 1-9 can be obtained by substitution reaction.
- Z 1 , Z 2 , X 1 , X 4 , W, R 1 , R 2 , R 3 , R 4 , R 5 , n, m, and n1 all have the definitions described in the present invention;
- PG is a protecting group.
- Intermediate 2-1 and 2-2 undergo a substitution reaction under the action of a strong base to produce intermediate 2-3;
- Intermediate 2-3 undergoes a coupling reaction with 2-4 under the condition of metal catalysis to obtain intermediate 2-5;
- 2-5 removes the protective group to form intermediate 2-6;
- 2-6 and 2-7 undergo substitution reaction under alkaline conditions to obtain 2-8.
- Z 1 , Z 2 , X 1 , X 2 , X 3 , W, R 1 , R 2 , R 3 , R 4 , R 5 , n, m, and n1 all have the definitions described in the present invention;
- PG means protection Group.
- N-tert-Butyloxycarbonyl-4-(6-chloropyridin-2-yl)piperidine-4-carboxylic acid (320mg) was dissolved in 1,2-dichloroethane (10mL), and the mixture was heated to 80°C Stir down. After the completion of the reaction monitored by LC-MS, the solvent was removed by concentration under reduced pressure to obtain 260 mg of the product with a yield of 100%.
- LCMS [M+H] + 297.8.
- Step 2) (S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-methylpiperazine-1- Tert-butyl formate
- Step 2 tert-Butyl 4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)piperazine-1-carboxylate
- Methyl N-Boc-4-piperidinecarboxylate (5.0g, 19.3mmol) was dissolved in dry tetrahydrofuran (50mL), the mixture was stirred at -40°C under nitrogen protection, and HMDLi (23mL, 23mmol, 1.0M ) Slowly drip into the above system. After the addition is complete, stir and react at -40°C for 0.5 hours; 2-methylthio-4-chloropyrimidine (3.0g, 18.7mmol) is dissolved in dry tetrahydrofuran (15mL), then Slowly drip into the above-mentioned mixed system.
- Step 1) 4-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester
- Step 2) 4-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-1,2,3,6-tetrahydropiperidine hydrochloride
- Step 2) 4-(6-Bromopyridin-2-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid
- 2,4-Difluoro-1-anisole (3g, 20.8mmol) was dissolved in trifluoroacetic acid (50mL), N-iodosuccinimide (5.15g, 22.9mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction is complete, the reaction system is cooled to room temperature and poured into 200 g of crushed ice. After the ice is completely melted, the solid is collected by filtration. The obtained solid was redissolved in dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by column chromatography (PE) to obtain the target product (4.52 g, 80%) as a pale yellow solid.
- PE column chromatography
- the freshly activated Zn powder (262 mg, 4.02 mmol) was charged into a round bottom flask. Under N 2 atmosphere, add N,N-dimethylacetamide (1.5mL) to the round bottom flask, and then slowly add trimethylchlorosilane (70 ⁇ L) and 1,2-dibromoethane (50 ⁇ L) to the system. ), stir the reaction until no more gas is generated in the system.
- Tert-butyl 4-iodopiperidine-1-carboxylate (1 g, 3.21 mmol) was dissolved in anhydrous N,N-dimethylacetamide, and then slowly dropped into the reaction system.
- Step 2 5-((tert-Butoxycarbonyl)(oxetan-2-ylmethyl)amino)-4-nitrothiophene-2-carboxylic acid ethyl ester
- Ethyl 4-amino-5-((tert-butoxycarbonyl)(oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (356mg, 1.0mmol) was dissolved in tetrahydrofuran (10mL) and added Acetic acid (60 mg, 1.0 mmol) was added and nitrogen gas was blown for 1 minute, then 2-chloro-1,1,1-methoxyethane (309 mg, 2.0 mmol) was added, and the mixture was sealed and reacted at 100°C for 12 hours. Then, p-toluenesulfonic acid monohydrate (19 mg, 0.1 mmol) was added to the reaction mixture, and the reaction was carried out at 75° C.
- Step 8) 5-((4-(6-(4-cyano-2-fluorobenzyloxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(oxetan- 2-ylmethyl)-4H-imidazo[4,5-d]thiazole-2-carboxylic acid
- Step 5 (5-(Dimethoxyphosphono-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)thiophen-2-yl)carbamic acid tert-butyl ester
- P-toluenesulfonic acid monohydrate (30mg, 0.16mmol) was added, and the mixture was reacted at 75°C for 1 hour. The reaction was stopped, water (20mL), ethyl acetate were added The ester (20 mL ⁇ 3) was extracted, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 590 mg of crude product, which was directly used in the next reaction.
- Step 7) (2-((4-(6-(4-chloro-2-fluorobenzyloxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-((1-ethyl Synthesis of -1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazol-5-yl)phosphonate
- Step 8) (2-((4-(6-(4-chloro-2-fluorobenzyloxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-((1-ethyl -1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazol-5-yl)phosphonic acid
- Step 2) 2-((4-(6-(4-cyano-2-fluorobenzyloxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H-imidazo[1,2-a]imidazole-5-carboxylic acid ethyl ester
- Methyl 4-picolinate (2.0g, 14.58mmol) was dissolved in acetonitrile (20mL), then O-(2,4-dinitrophenyl)hydroxylamine (2.90g, 14.58mmol) was added, and the mixture was kept at 40°C. The reaction was stirred for 24 hours. After TLC detects that the reaction is almost complete, it is cooled to room temperature, and the sample is concentrated to dryness under reduced pressure to obtain 4.9 g of crude product, which is used directly without purification.
- Step 2) 3-(1-Ethyl-1H-imidazole-2-carbonyl)-2-((4-methoxybenzyloxy)methyl)pyrazolo[1,5-a]pyridine-5- Methyl formate
- Step 2) 2-((4-(6-(4-cyano-2-fluorobenzyloxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-(4-methoxy Phenyl) imidazo[1,2-a]pyridine-6-methyl carboxylate
- Step 1) 2-((1-(6-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-yl)yl)-1-((1-yl-1H- (Imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2) 2-((1-(6-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-yl)yl)-1-((1-yl-1H- (Imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 2 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-((1- Ethyl-1H-imidazol-4-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- reaction was stopped, the reaction solution was poured into ice water (50mL), extracted with ethyl acetate (60mL ⁇ 3), the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure The solvent was evaporated, and the obtained residue was purified by column chromatography to obtain a pale yellow solid product, 2.7 g, with a yield of >99%.
- Step 1) (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-methylpiper (Azin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2 (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)-3,5-difluoropyridin-2-yl)-2-methylpiper (Azin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 4) 6-((4-(6-((4-chloro-2-fluorobenzyl)oxy)piperidin-2-yl)piperazin-1-yl)methyl)-5-((1 -Ethyl-1H-imidazol-5-yl)(hydroxy)methyl)imidazo[2,1-b]thiazole-2-carboxylic acid ethyl ester
- Ethyl thiazole-2-carboxylate (129mg, 0.2mmol) was dissolved in anhydrous tetrahydrofuran (5mL), the mixture was cooled to -40°C, isopropylmagnesium chloride (0.3mL, 1.3M) was added dropwise, and the reaction was stirred 0.5h, then add 1-ethyl-5-imidazole carboxaldehyde.
- Step 1) 2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-4-yl)piperazin-1-yl)methyl)-1- ((1-Ethyl-1H-imidazol-5-yl)methyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2) 2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-4-yl)piperazin-1-yl)methyl)-1- ((1-Ethyl-1H-imidazol-5-yl)methyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid
- Step 2) 2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)piperidin-1-yl)methyl)-1-((1- Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- 6-Bromobenzo[d]isothiazole-3-carboxylic acid (10 g, 38.75 mmol) was dissolved in methanol (100 mL), concentrated sulfuric acid (2.5 mL) was added, and the mixture was heated at 70° C. to react overnight. Stop the reaction, concentrate under reduced pressure to remove methanol, add ethyl acetate (200mL), wash with water (100mL), saturated sodium bicarbonate solution (100mL), saturated brine in turn, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a shallow The yellow solid product was 7.4 g, and the yield was 70%.
- Step 6) 6-((1-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-4-yl)((1-ethyl-1H-imidazole -5-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid methyl ester
- Step 7) 6-((1-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-4-yl)((1-ethyl-1H-imidazole -5-yl)methyl)amino)benzo[d]isothiazole-3-carboxylic acid
- Step 2) 6-(tert-Butoxycarbonyl)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazine-1 -Yl)methyl)-3-(ethoxycarbonyl)imidazo[1,2-a]pyridine-3-carboxylic acid
- Step 8) (2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1 -Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazol-5-yl)diethyl phosphate
- Step 9) (2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1 -Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazol-5-yl)monoethyl phosphate
- Example 36 (2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1 -Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazol-5-yl) diammonium phosphate
- Step 2) (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 2) 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)-3- (Hydroxymethyl)imidazo[1,2-a]pyridine-6-methyl carboxylate
- Step 2) 2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)piperazin-1-yl)methyl)-3- ((Oxetan-3-ylamino)methyl)imidazo[1,2-a]pyridine-6-carboxylic acid
- Step 2) (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 2) (S)-2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-1-(oxa Cyclobut-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Ethyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (135mg, 0.38mmol) was placed in a 25mL single-necked flask, potassium carbonate (210mg, 1.52mmol), acetonitrile (5mL) and Intermediate 11 (300mg, 0.38mmol) were added, and the mixture was heated to 60°C to react for 2.5h.
- Step 2) 6-(((4-chloro-2-fluorobenzyl)oxy)-5',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid Tert-butyl ester
- Step 1) 2-((1-(6-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-yl)yl)-1-((1-yl-1H- (Imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2 2-((1-(6-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-yl)yl)-1-((1-yl-1H- (Imidazol-5-yl)methyl)-N-hydroxy-1H-thieno[2,3-d]imidazole-5-carboxamide
- Step 1) 2-((1-(6-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-yl)yl)-1-((1-yl-1H- (Imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2) 2-((1-(6-(4-Chloro-2-fluorobenzyloxy)pyridin-2-yl)piperidin-4-yl)yl)-1-((1-yl-1H- (Imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 1) 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-yl)methyl)- 1-((1-Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2) 2-((4-(3-((4-chloro-2-fluorobenzyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-yl)methyl)- 1-((1-Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 2) 2-(Chloromethyl)-1-((1-isopropyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 4) 2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-((1- Isopropyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
- Step 1) 2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-pyridine]-1'(2'H) -Yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid ethyl ester
- Step 2) 2-((6-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-pyridine]-1'(2'H) -Yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid trifluoroacetate
- Step 2) 2-((4-(5-((4-chloro-2-fluorobenzyl)oxy)-2,4-difluorophenyl)piperidin-1-yl)methyl)-1- ((1-Ethyl-1H-imidazol-5-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
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Abstract
作为GLP-1受体激动剂的式(I)所示的杂芳基化合物、或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,和包含所述化合物的药物组合物以及使用所述化合物或其药物组合物在制备治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。所述化合物对GLP-1受体显示出优异的激动作用,具有非常好的开发前景。
Description
本发明属于药物领域,具体涉及一类新的GLP-1受体激动剂、或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,和包含所述化合物的药物组合物以及使用所述化合物或其药物组合物在制备治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。更具体地,本发明提供的化合物对GLP-1受体显示出优异的激动作用。
发明背景
糖尿病是一种常见的慢性病之一,发病率逐年增长,发病年龄越趋年轻化,和心血管疾病、呼吸系统疾病并称为三大“慢性杀手”。近年来,我国糖尿病患病率从1980年的1%上升到2017年的11%。截至目前,中国已成为糖尿病患者数量最多的国家。糖尿病是一组以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损,或两者兼有引起。糖尿病时长期存在的高血糖,导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。糖尿病主要分一型糖尿病和二型糖尿病。一型糖尿病是由于自身免疫系统攻击胰岛β细胞从而丧失分泌胰岛素的功能。二型糖尿病则是始于胰岛素抵抗作用异常或细胞对胰岛素没有反应;肥胖是胰岛素抵抗的主要原因之一,因此肥胖可以说是二型糖尿病的主要危险因素。二型糖尿病患者占糖尿病患者人数的90%左右,因此该病在肥胖问题严重的发达国家、以及肥胖人数不断攀升的中国成为主要的公共卫生健康问题。
目前有多类真对降血糖来治疗二型糖尿病的药物(Hampp,C.et al.(2014)Diabetes Care,37:1367-1374),主要是以下六类:1)促胰岛素分泌剂,包括磺脲、美格列脲、二肽基肽酶-4(DPP-IV)抑制剂、以及胰高血糖素样肽-1受体(GLP-1 R)激动剂,这类药通过作用于胰岛β细胞来促进胰岛素的分泌。然而磺脲、美格列脲和DPP-IV抑制剂缺乏有效性,而目前市面上的GLP-1 R激动剂主要是皮下注射的多肽类药物,利拉鲁肽还被额外批准用于治疗肥胖;2)双胍类药物(如二甲双胍),主要降低肝糖的产生从而控制血糖。双胍类药物经常会导致胃肠道反应和乳酸血症;3)α-葡萄糖苷酶抑制剂(如阿卡波糖),可以减少肠道葡萄糖吸收,但通常会引起肠道反应;4)噻唑烷二酮类药物,通过作用于肝、肌肉和脂肪组织内特定的受体(过氧化酶增殖因子活化受体-γ)调节脂肪代谢,进而增加这些组织对胰岛素的敏感性。经常使用这类药会导致体重增加,甚至是水肿和缺血;5)胰岛素,单独使用或与以上药物联合使用治疗严重的糖尿病,长期使用可能会引起体重上升和低血糖症;6)钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂,可以抑制葡萄糖在肾脏中的重吸收,因此降低血糖水平。这类药也许与酮酸中毒和尿道感染有关。
首个GLP-1 R激动剂艾塞那肽在2005年被FDA批准用于糖尿病治疗,随后利拉鲁肽和索玛鲁肽等GLP-1 R激动剂相继上市。相比于传统的促胰岛素分泌剂,GLP-1 R激动剂有更少的低血糖风险。同时,利拉鲁肽和索玛鲁肽也在临床试验中体现出良好的降血糖作用、降低糖化血红蛋白、降低体重和心血管获益(FDA.(2013)Pharmacology review of Saxenda
TM.FDA.(2016)Pharmacology review of Semaglutide.)。治疗糖尿病的药物主要分为胰岛素及其类似物、化学口服降糖药、GLP-1R激动剂三类。从GLP-1R激动剂市场份额看,全球达到了17%,我国仅有2%,因此,这类药物在国内的上升空间比较大。随着肠-脑轴的深入研究,GLP-1 R激动剂也被研究用于帕金森病的治疗(Kim,D.S.et al.(2017)Cell transplantation,26.9:1560-1571),这使到GLP-1 R激动剂在未来有更广阔的市场和应用场景。
胰高血糖素样肽-1(GLP-1)是由L细胞分泌的30个氨基酸组成的长链肠促胰岛素,促进肠道对食物的消化。在生理状态下,GLP-1已经被证实能够以血糖依赖的方式刺激胰岛素的生成从而使外周增加对血糖的吸收来调节餐后血糖,减少胰高血糖素的分泌进而减少肝糖的生成,抑制胃排空和小肠蠕动来延缓对食物的吸收、降低食欲,以及刺激β细胞的增殖(Meier,et al.(2003)Biodrugs,17.2:93-102.Vilsboll,T.et al.(2001)Diabetes,50:609-613)。目前已有的GLP-1 R激动剂药物包括艾塞那肽、利拉鲁肽、索玛鲁肽均为模拟天然GLP-1结构的多肽类药物,因此仅能注射给药,且成本较为昂贵,一年的花费高达$1,500到$2,500美元(https://www.ncbi.nlm.nih.gov/books/NBK543967/)。尽管诺和诺德公司已开发出索玛鲁肽的口服制剂,但由于多肽类药物的理化性质限定,其口服利用度仅1-2%,每日的用量也从原来注射用量的每日不到1mg 增加到14mg,且费用也将上升至每年$9,264美元。因此,开发出口服利用度高并且价格更合理的GLP-1 R激动剂药物的需求尤为明显。
对心血管代谢性疾病及相关病症的容易给药的预防和/或治疗仍有很大需求。本发明化合物具有良好的GLP-1 R激动效果,在人和大鼠中具有较好的肝微粒体稳定性,且具有较好的药代动力学性质,口服吸收较快,生物利用度较好,可用于口服,具备较佳的临床应用前景。
发明详述
定义和一般术语
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
本发明所使用的术语“哺乳动物”是指,例如灵长类动物(例如人类,男性或女性)、牛、绵羊、山羊、马、猪、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中,所述哺乳动物是灵长类动物。在其他实施方案中,所述哺乳动物是人。
“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例/实施方案里面特殊的例子、子类、和本发明所包含的一类化合物那样。
一般而言,术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明,一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代,那么取代基可以相同或不同地在各个位置取代。
术语“未取代的”,表示指定基团不带有取代基。
术语“任选地被…….取代”,可以与术语“未取代或被…..所取代”交换使用,即所述结构是可以未取代的或者可以被一个或多个本发明所述的取代基取代,本发明所述的取代基包括,但不限于H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自/分别独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C
1-6烷基”特别指独立公开的甲基、乙基、C
3烷基、C
4烷基、C
5烷基和C
6烷基。
在本发明的各部分,描述了连接取代基。当所述结构清楚地需要连接基团时,针对所述基团所列举的马库什变量应理解为连接基团。例如,如果所述结构需要连接基团并且针对所述变量的马库什基团定义列举了“烷基”或“芳基”,则应理解,所述“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明,烷基基团含有1-20个碳原子。在一实施方案中,烷基基团含有1-12个碳原子;在另一实施方案中,烷基基团含有1-6个碳原子;在又一实施方案中,烷基基团含有1-4个碳原子;还在一实施方案中,烷基基团含有1-3个碳原子。所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷基基团的实例包含,但并不限于,甲基(Me、-CH
3),乙基(Et、-CH
2CH
3),正丙基(n-Pr、-CH
2CH
2CH
3),异丙基(i-Pr、-CH(CH
3)
2),正丁基(n-Bu、-CH
2CH
2CH
2CH
3),异丁基(i-Bu、-CH
2CH(CH
3)
2),仲丁基(s-Bu、-CH(CH
3)CH
2CH
3),叔丁基(t-Bu、-C(CH
3)
3),正戊基(-CH
2CH
2CH
2CH
2CH
3),2-戊基 (-CH(CH
3)CH
2CH
2CH
3),3-戊基(-CH(CH
2CH
3)
2),2-甲基-2-丁基(-C(CH
3)
2CH
2CH
3),3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2),3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2),2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3),正己基(-CH
2CH
2CH
2CH
2CH
2CH
3),2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3),3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3)),2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3),3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3),4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2),3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2),2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2),2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2),3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3),正庚基,正辛基,等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp
2双键,其包括“顺”和“反”的定位,或者“E”和“Z”的定位。在一实施方案中,烯基基团包含2-8个碳原子;在另一实施方案中,烯基基团包含2-6个碳原子;在又一实施方案中,烯基基团包含2-4个碳原子。烯基基团的实例包括,但并不限于,乙烯基(-CH=CH
2)、烯丙基(-CH
2CH=CH
2)等等。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp三键。在一实施方案中,炔基基团包含2-8个碳原子;在另一实施方案中,炔基基团包含2-6个碳原子;在又一实施方案中,炔基基团包含2-4个碳原子。炔基基团的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH
2C≡CH)、1-丙炔基(-C≡C-CH
3)等等。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的定义。除非另外详细说明,所述烷氧基基团含有1-12个碳原子。在一实施方案中,烷氧基基团含有1-6个碳原子;在另一实施方案中,烷氧基基团含有1-4个碳原子;在又一实施方案中,烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。
烷氧基基团的实例包括,但并不限于,甲氧基(MeO、-OCH
3),乙氧基(EtO、-OCH
2CH
3),1-丙氧基(n-PrO、n-丙氧基、-OCH
2CH
2CH
3),2-丙氧基(i-PrO、i-丙氧基、-OCH(CH
3)
2),1-丁氧基(n-BuO、n-丁氧基、-OCH
2CH
2CH
2CH
3),2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH
2CH(CH
3)
2),2-丁氧基(s-BuO、s-丁氧基、-OCH(CH
3)CH
2CH
3),2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH
3)
3),1-戊氧基(n-戊氧基、-OCH
2CH
2CH
2CH
2CH
3),2-戊氧基(-OCH(CH
3)CH
2CH
2CH
3),3-戊氧基(-OCH(CH
2CH
3)
2),2-甲基-2-丁氧基(-OC(CH
3)
2CH
2CH
3),3-甲基-2-丁氧基(-OCH(CH
3)CH(CH
3)
2),3-甲基-l-丁氧基(-OCH
2CH
2CH(CH
3)
2),2-甲基-l-丁氧基(-OCH
2CH(CH
3)CH
2CH
3),等等。
术语“卤代烷基”,“卤代烯基”或“卤代烷氧基”表示烷基,烯基或烷氧基基团被一个或多个卤素原子所取代,这样的实例包含,但并不限于,三氟甲基、三氟乙基、2,2,3,3-四氟丙基、三氟甲氧基等。
本发明使用的术语“羟基烷基”表示烷基基团被一个或多个羟基基团所取代,其中烷基基团具有如本发明所述的定义,这样的实例包括,但并不限于羟乙基,2-羟基丙基,羟甲基等。
本发明使用的术语“环烷基”,除非另有说明,是指一价饱和或部分不饱和(但非芳香族)的单环或多环烃。在一些实施方案,所述环烷基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。在一些实施方案,所述环烷基基团包括3-10个碳原子,即C
3至C
10环烷基。在一些实施方案,所述环烷基具有3-15(C
3-15)、3-10(C
3-10)、或3-7(C
3-7)个碳原子。在一些实施方案,所述环烷基基团是单环或双环。在一些实施方案,所述环烷基基团是单环。在一些实施方案,所述环烷基基团是双环。在一些实施方案,所述环烷基基团是三环。在一些实施方案,所述环烷基基团是完全饱和的。在一些实施方案,所述环烷基基团是部分饱和的。在一些实施方案,所述环烷基基团是环丙基、环丁基、环戊基、环己基、环庚基、双环[2.1.1]己基、双环[2.2.1]庚基、十氢萘基、或金刚烷基。当环烷基被取代时,其可在任一环上,即在由环烷基包含的任何芳香环或非芳香环上,可独立地被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用,除非另有说明,是指包含至少一个非芳香环的一价单环非芳香环体系和/或多环体系;其中所述非芳香单环原子中的一个或多个(在某些实施方案,1、2、3或4个)是独立地选自O、S(O)
0-2和N的杂原子,和所述其余环原子均为碳原子;和其中所述多环体系的环原子中的一个或多个(在某些实施方案,1、2、3或4个)是独立地选自O、S(O)
0-2和N的杂原子,和所述其余环原子均为碳原子。在一些实施方案,所述杂环包含1或2个杂原子,所述杂原子均为氮原子。在一些实 施方案,所述杂环基是多环的并且在非芳香环中包含一个杂原子,或者在芳香环中包含一个杂原子,或者在芳香环中包含两个杂原子,或者包含两个杂原子其中一个在芳香环中,而另一个在非芳香环中。在一些实施方案,所述杂环基基团具有3-20、3-15、3-10、3-8、4-7、或5-6个环原子。在一些实施方案,所述杂环基是单环、双环、三环、或四环体系。在一些实施方案,所述杂环基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。一个或多个氮原子和硫原子可任选地被氧化,一个或多个氮原子可任选地被季铵化,一个或多个碳原子可任选地被
替换。一些环可以是部分或完全饱和的,或者是芳香族的,条件是杂环是非完全芳香性的。所述单环杂环和多环杂环可在任何导致稳定化合物的杂原子或碳原子上与所述主结构连接。所述多环杂环基可通过其任一环,包括任何芳香环或非芳香环,而不管所述环是否含有杂原子,连接至所述主结构上。在一些实施方案,杂环基为“杂环烷基”,其为1)如本发明所述的含有至少一个环杂原子的饱和或部分不饱和(但非芳香族)一价单环基团,或2)饱和或部分不饱和(但非芳香族)一价双环基团或三环基团,其中至少一个环含有至少一个如本发明所述的杂原子。当杂环基和杂环烷基被取代时,其可在任一环上,即在由杂环基和杂环烷基所包含的任何芳香环或非芳香环上被取代。在一些实施方案,此类杂环基包括,但不限于,环氧乙烷基、氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基,四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基,高哌嗪基,高哌啶基,氧杂环庚烷基,硫杂环庚烷基,氧氮杂
基,二氮杂
基,硫氮杂
基,苯并二噁烷基,苯并二氧杂环戊烯基,苯并呋喃酮基,苯并吡喃酮基,苯并吡喃基,二氢苯并呋喃基,苯并四氢噻吩基,苯并噻喃基,苯并噁嗪基,β-咔啉基,苯并二氢吡喃基,色酮基,噌啉基,香豆素基,十氢喹啉基,十氢异喹啉基,二氢苯并异噻嗪基,二氢苯并异噁嗪基,二氢呋喃基,二氢异吲哚基,二氢吡喃基,二氢吡唑基,二氢吡嗪基,二氢吡啶基,二氢嘧啶基,二氢吡咯基,二氧戊环基,1,4-二噻喃基,呋喃酮基,咪唑烷基,2,4-二氧-咪唑烷基,咪唑啉基,吲哚啉基,2-氧-吲哚啉基,异苯并四氢呋喃基,异苯并四氢噻吩基,异苯并二氢吡喃基,异香豆素基,异二氢吲哚基(异吲哚啉基),1-氧-异二氢吲哚基,1,3-二氧-异二氢吲哚基,异噻唑烷基,异噁唑烷基,3-氧-异噁唑烷基,吗啉基,3,5-二氧-吗啉基,八氢吲哚基,八氢异吲哚基,1-氧-八氢异吲哚基,1,3-二氧-六氢异吲哚基,噁唑烷酮基,噁唑烷基,环氧乙烷基,哌嗪基,2,6-二氧-哌嗪基,哌啶基,2,6-二氧-哌啶基,4-哌啶酮基,2-氧吡咯烷基,2,5-二氧吡咯烷基,奎宁环基,四氢异喹啉基,3,5-二氧-硫代吗啉基,噻唑烷基,2,4-二氧-噻唑烷基,四氢喹啉基,吩噻嗪基,吩噁嗪基,氧杂蒽基和1,3,5-三硫杂环己烷基。杂环基中-CH
2-基团被-C(=O)-替代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一些实施方案,杂环基为3-8个原子组成的杂环基,是指包含3-8个环原子的饱和或部分不饱和的单环,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,3-8个原子组成的杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。3-8个原子组成的杂环基的实例包括,但不限于:氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基,四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基,高哌嗪基,高哌啶基,氧杂环庚烷基,硫杂环庚烷基,氧氮杂
基,二氮杂
基,硫氮杂
基。杂环基中-CH
2-基团被-C(=O)-替代的实例包括,但不限于,2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括,但不限于,环丁砜基、1,1-二氧代硫代吗啉基。所述的3-8个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在一些实施方案,杂环基为3-6个原子组成的杂环基,是指包含3-6个环原子的饱和或部分不饱和的 单环,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,3-6个原子组成的杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述的3-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
在另一实施方案,杂环基为5-6个原子组成的杂环基,是指包含5-6个环原子的饱和或部分不饱和的单环,其中至少一个环原子选自氮、硫和氧原子。除非另外说明,5-6个原子组成的杂环基可以是碳基或氮基,且-CH
2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。5-6个原子组成的杂环基的实例包括,但不限于:吡咯烷基,2-吡咯啉基,3-吡咯啉基,吡唑啉基,吡唑烷基,咪唑啉基,咪唑烷基,四氢呋喃基,二氢呋喃基,四氢噻吩基,二氢噻吩基,1,3-二氧环戊基,二硫环戊基、2-氧代吡咯烷基、氧代-1,3-噻唑烷基、环丁砜基、四氢吡喃基,二氢吡喃基,2H-吡喃基,4H-吡喃基,四氢噻喃基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,二噁烷基,二噻烷基,噻噁烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基、1,1-二氧代硫代吗啉基。所述的5-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“环烷基烷基”表示烷基基团可被一个或多个环烷基基团所取代,其中环烷基和烷基具有如本发明所述定义,这样的实例包括,但并不限于,环丙基甲基、环丙基乙基、环丙基丙基、环丁基甲基、环丁基乙基、环戊基甲基,环戊基乙基、环戊基丙基、环己基乙基等。
术语“杂环基烷基”包括杂环基取代的烷基;术语“杂环基烷氧基”包括杂环基取代的烷氧基,其中氧原子与分子的其余部分相连;术语“杂环基烷氨基”包括杂环基取代的烷氨基,其中氮原子与分子的其余部分相连。其中杂环基、烷基、烷氧基和烷氨基均具有如本发明所述定义,这样的实例包括,但并不限于,氮杂环丁烷-1-基甲基、氮杂环丁烷-1-基乙基、氮杂环丁烷-1-基丙基、吡咯-1-基甲基,吡咯-1-基乙基、吡咯-1-基丙基、吗啉-4-基乙基、吗啉-4-基乙氧基、哌嗪-4-基乙氧基、哌啶-4-基乙基氨基等。
术语“稠合双环”,“稠环”,“稠合双环基”,“稠环基”表示饱和或不饱和的稠环体系体系,涉及非芳香族的双环体系,如式(a1)所示,即环B与环B’共有一个键。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。稠合双环中的每一个环要么是碳环要么是杂脂环族,这样的实例包括,但并不限于,六氢-呋喃并[3,2-b]呋喃,2,3,3a,4,7,7a-六氢-1H-茚,7-氮杂双环[2.3.0]庚烷,稠合双环[3.3.0]辛烷,稠合双环[3.1.0]己烷,这些都包含在稠合双环之内。并且所述稠合双环基可以是取代或未取代的,其中取代基可以是,但并不限于,H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
术语“稠合杂双环基”表示饱和或不饱和的稠环体系或桥环体系,涉及非芳香族的双环体系或桥环体系。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO
2,PO,PO
2的基团,这样的实例包括,但并不限于六氢-呋喃并[3,2-b]呋喃,7-氮杂双环[2.3.0]庚烷,2-氮杂双环[2.2.1]庚烷,八氢吡咯[3,2-b]吡咯,八氢吡咯[3,4-c]吡咯,八氢-1H-吡咯[3,2-b]吡啶等。并且所述稠合杂双环基可以是取代或未取代的,其中取代基可以是,但并不限于,H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
术语“螺环基”,“螺环”,“螺双环基”,“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如,环A和环B在两个饱和的环体系中共享一个碳原子,则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括,但并不限于2,7-二氮杂螺[4.4]壬烷-2-基,7-氧-2-氮杂螺[4.5]癸烷-2-基,4-氮杂螺[2.4]庚烷-5-基,4-氧杂螺[2.4]庚烷-5-基,5-氮杂螺[2.4]庚烷-5-基,螺[2.4] 庚烷基,螺[4.4]壬烷基,7-羟基-5-氮杂螺[2.4]庚烷-5-基等。并且所述螺双环基可以是取代或未取代的,其中取代基可以是,但并不限于,H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如,如上面所描述的,环A和环B在两个饱和的环体系中共享一个碳原子,则被称为“螺环”。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO
2,PO,PO
2的基团,这样的实例包括,但并不限于4-氮杂螺[2.4]庚烷-5-基,4-氧杂螺[2.4]庚烷-5-基,5-氮杂螺[2.4]庚烷-5-基,7-羟基-5-氮杂螺[2.4]庚烷-5-基,2,6-二氮杂螺[3.3]庚烷,2,6-二氮杂螺[3.4]辛烷,1,6-二氮杂螺[3.4]辛烷,2,7-二氮杂螺[3.5]壬烷,1,7-二氮杂螺[3.5]壬烷,3,9-二氮杂螺[5.5]十一烷等。并且所述螺杂双环基可以是取代或未取代的,其中取代基可以是,但并不限于,H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
本发明使用的术语“桥环基”表示饱和或不饱和的桥环体系,涉及非芳香族的桥环体系,如式(a2)所示,即环A1与环A2共有一个烷链或一个杂烷链,其中j为1,2,3或4。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。桥接环中的每一个环要么是碳环要么是杂脂环族,这样的实例包括,但并不限于,双环[2.2.1]庚烷,2-氮杂双环[2.2.1]庚烷,1,2,3,4,4a,5,8,8a-八氢萘,这些都包含在稠合双环或桥环的体系之内。并且所述桥环基可以是取代或未取代的,其中取代基可以是,但并不限于,H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
术语“桥杂环基”表示饱和或不饱和的桥环体系,涉及非芳香族的桥环体系。这样的体系可以包含独立的或共轭的不饱和状态,但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子,其中每一个环体系包含3-7元环,即包含1-6个碳原子和选自N,O,P,S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO,SO
2,PO,PO
2的基团,这样的实例包括,但并不限于2-氮杂双环[2.2.1]庚烷,(1R,5S)-3,6-二氮杂双环[3.1.1]庚烷,2,5-二氮杂双环[2.2.1]庚烷,(1R,5S)-8-氮杂双环[3.2.1]辛烷等。并且所述桥杂环基可以是取代或未取代的,其中取代基可以是,但并不限于,H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等,其中R
1b和R
1c均具有本发明所述定义。
如本发明所描述的,环体系中有两个连接点与分子其余部分相连,如式(a3)或(a4)所示,表示既可以是E端也可以是E’端与分子其余部分相连,即两端的连接方式可以互换方向。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
本发明使用的术语“芳基”,除非另有说明,是指包含至少一个芳环的一价C
6-C
14碳环体系,其中所述芳环体系是单环、二环、或三环。所述芳基可通过其任何环即任何芳香环或非芳香环连接至主结构上。在一些实施方案,芳基是苯基、萘基、二环[4.2.0]辛-1,3,5-三烯基、茚满基、芴基、或四氢萘基。当芳基被取代时,其可在任何环上即在由芳基包含的任何芳香环或非芳香环上被取代。在一些或任一实施方案,芳基是苯基、萘基、四氢萘基、芴基、或茚满基;所述苯基、萘基、四氢萘基、芴基、和茚满基各自任选地被所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代,在一些实施方案,包括被独立地选自H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等取代基取代,其中R
1b和R
1c均具有本发明所述定义。
本发明使用的术语“芳烷基”,除非另有说明,是指被如本发明所定义的一个或两个芳基基团取代的烷基基团,其中所述烷基基团是与分子其余部分连接的点。在一些实施方案,芳烷基是苯甲基、苯乙-1-基、苯乙-2-基、二苯基甲基、2,2-二苯基乙基、3,3-二苯基丙基、或3-苯基丙基;所述苯甲基、苯乙-1-基、苯乙-2-基、二苯基甲基、2,2-二苯基乙基、3,3-二苯基丙基、和3-苯基丙基各自任选地在环上被一个或多个本发明所描述的取代基所取代。
本发明使用的术语“杂芳基”,除非另有说明,是指一价单环或多环芳香基团,其中所述至少一个(在某些实施方案,1、2、3或4个)环原子是独立地选自所述环中的O、S(O)
0-2和N的杂原子。所述杂芳基基团是通过环体系中的任何原子,其化合价规则允许情况下,连接至分子其余部分。在一些实施方案,杂芳基基团的每个环可含有1或2个O原子、1或2个S原子、和/或1至4个N原子、或其组合,条件是每个环中杂原子的总数为4或更少,以及每个环含有至少1个碳原子。在一些实施方案,所述杂芳基具有5-20、5-15、5-10或5-8个环原子。当杂芳基被取代时,其可在任一环上进行取代。在某些实施方案,单环杂芳基基团包括但不限于,呋喃基,咪唑基,异噻唑基,异噁唑基,噁二唑基,噁唑基,吡嗪基,吡唑基,哒嗪基,吡啶基,嘧啶基,吡咯基,噻二唑基,噻唑基,噻吩基,四唑基,三嗪基和三唑基。在某些实施方案,双环杂芳基基团包括,但不限于,苯并呋喃基,苯并咪唑基,苯并异噁唑基,苯并吡喃基,苯并噻二唑基,苯并噻唑基,苯并噻吩基,苯并三唑基,苯并噁唑基,呋喃并吡啶基,咪唑并吡啶基,咪唑并噻唑基,吲嗪基,吲哚基,吲唑基,异苯并呋喃基,异苯并噻吩基,异吲哚基,异喹啉基,异噻唑基,萘啶基,噁唑并吡啶基,酞嗪基,蝶啶基,嘌呤基,吡啶并吡啶基,吡咯并吡啶基,喹啉基,喹喔啉基,喹唑啉基,噻二唑并嘧啶基和噻吩并吡啶基。在某些实施方案,三环杂芳基基团包括,但不限于,吖啶基,苯并吲哚基,咔唑基,二苯并呋喃基,咟啶基,菲咯啉基,菲啶基和吩嗪基。在一些或任一实施方案,杂芳基是吲哚基,呋喃基,吡啶基,嘧啶基,咪唑基或吡唑基;其各自任选地被1、2、3或4个本说明书通篇中所定义的基团取代,在一些实施方案,包括被独立地选自H、D、F、Cl、Br、I、-OH、SH、-NH
2、-NO
2、-CN、氧代(=O)、N
3、烷基、烯基、炔基、羟基烷基、卤代烷基、氨基烷基、氰基烷基、烷氧基、卤代烷氧基、烷硫基、烷氨基、卤代烷氨基、-NR
1bR
1c、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、或杂芳基烷基等等的基团取代,其中R
1b和R
1c均具有本发明所述定义。
本发明使用的术语“杂芳基烷基”,除非另有说明,是指被如本发明所定义的一个或两个杂芳基基团取代的烷基基团,其中所述烷基基团是与分子其余部分连接的点。所述杂芳基烷基的实例包括,但并不限于咪唑-2-甲基、噻唑-2-甲基、呋喃-2-乙基、吲哚-3-甲基等;其各自任选地在任一环上被一个或多个本发明所描述的取代基所取代。
术语“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”,其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是,烷基氨基是一个或两个C
1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是,烷基氨基是C
1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基,这样的实例包括,但并不限于,N-甲氨基,N-乙氨基,N,N-二甲氨基,N,N-二乙氨基等等。
术语“氨基烷基”包括被一个或多个氨基所取代的C
1-10直链或支链烷基基团。其中一些实施例是,氨基烷基是被一个或多个氨基基团所取代的C
1-6“较低级的氨基烷基”,另一些实施例是,氨基烷基是被一个或多个氨基基团所取代的C
1-4“较低级的氨基烷基”,这样的实例包括,但并不限于,氨甲基,氨乙基,氨丙基,氨丁基和氨己基。
术语“氰基烷基”或“氰基取代烷基”包括被一个或多个氰基所取代的C
1-10直链或支链烷基基团。其中一些实施例是,氰基取代的烷基是被一个或多个氰基基团所取代的C
1-6“较低级的氰基烷基”,另一些实施例是,氰基取代的烷基是被一个或多个氰基基团所取代的C
1-4“较低级的氰基烷基”,这样的实例包括,但并不限于,CNCH
2-、CNCH
2CH
2-、CNCH
2CH
2CH
2-、CNCH
2CHCNCH
2-等。
像本发明所描述的,取代基画一个键连接到中心的环上形成的环体系(如下图所示)代表取代基可在任一环上任何可取代的位置取代。例如,式b代表A环或B环上任何可能被取代的位置均可被取代,如式c、d、e、f、g、h、i、j、k、l、m、n、o、p、q等所示。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,与氨基基团反应形成的无机酸盐如盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐,和有机酸盐如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐,或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,丙二酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过与适当的碱反应得到的盐包括碱金属,碱土金属,铵和N
+(C
1-C
4烷基)
4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C
1-8磺酸化物和芳香磺酸化物。
发明内容
本发明提供了一类新的GLP-1受体激动剂、或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,和包含所述化合物的药物组合物以及使用所述化合物或其药物组合物在制备治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。更具体地,本发明提供的化合物对GLP-1受体显示出优异的激动作用。
一方面,本发明提供了一种新的GLP-1受体激动剂,其如式(I)所示:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中,
L
1是O、S、-N(R
c)-、-C(=O)-、或-C(R
a)(R
b)-;
L
2是O、S、-N(R
c)-、-C(=O)-、-(C(R
a)(R
b))
t1-、-X-(C(R
a)(R
b))
t1-、或-(C(R
a)(R
b))
t1-X-(C(R
a)(R
b))
t2-;
Z
1和Z
2各自独立地为N或CH;
Ar
1是C
6-10芳基、C
1-9杂芳基、C
3-8环烷基、C
2-9杂环基、C
5-12稠合双环基、或C
5-12稠合杂双环基,其中所述Ar
1任选地被0、1、2、3或4个R
2取代;
Cy是C
3-8环烷基、C
2-9杂环基、C
5-12螺双环基、C
5-12螺杂双环基、C
5-12稠合双环基、C
5-12稠合杂双环基、C
5-12桥环基、或C
5-12桥杂环基,其中所述Cy任选地被0、1、2、3或4个R
3取代;
Ar
2是8个环原子组成的稠合杂芳基、并且所述环原子包含1、2、3、或4个独立地选自O、S和/或N的杂原子,所述Ar
2任选地被0、1、2、3或4个R
6取代;或者Ar
2是:
X是O、S、-N(R
d)-、或-C(=O)-;
X
1、X
2和X
3分别独立地为N或-C(R
6)-;
X
5是O或S;
W是-C(=O)OR
7a、-S(=O)
1-2OR
7a、-P(=O)(OR
7a)(OR
7b)、-P(=O)(OR
7a)(R
7c)、-S(=O)
1-2R
7d、-C(=O)R
7d、-C(=O)N(R
7c)R
7d、-S(=O)
1-2N(R
7c)R
7d、-C(=O)N(R
7c)S(=O)
1-2R
7d、-C(=O)N(R
7c)S(=O)
1-2N(R
7c)R
7d、-C(=O)N(R
7c)C(=O)R
7d、-C(=O)N(R
7c)C(=O)N(R
7c)R
7d、-C(=O)N(R
7c)C(=S)N(R
7c)R
7d、-C(=O)N(R
7c)S(=NR
7a)
1-2R
7d、-C(=O)N(R
7c)S(=O)(=NR
7a)R
7d、
各R
1分别独立地为H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
3-8环烷基C
2-6烯基、C
3-8环烷基C
2-6炔基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-6烷基、-S(=O)
1-2R
1a、-C(=O)R
1a、-C(=O)OR
1b、-OS(=O)
1-2R
1a、-OC(=O)R
1a、-N(R
1b)C(=O)R
1a、-OC(=O)NR
1bR
1c、-NR
1bR
1c、-N(R
1b)S(=O)
1-2R
1a、或-N(R
1b)C(=O)NR
1bR
1c;
R
5是H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
1-6卤代烷基、C
1-6氰基烷基、C
1-6氨基烷基、C
1-6烷氧基C
1-6烷基、C
3-10环烷基、C
2-9杂环基、C
6-10芳基、C
1-9杂芳基、R
5c-C(=O)-、R
5c-OC(=O)-、R
5c-C(=O)O-、R
5c-NHC(=O)-、R
5c-C(=O)NH-、R
5c-L
3-C
1-6烷基-、R
5a-C
1-6烷基、或R
5a-C
1-6羟基烷基-,其中所述C
1-6烷基、C
1-6卤代烷基、C
1-6氰基烷基、C
1-6氨基烷基、C
1-6烷氧基C
1-6烷基、C
3-10环烷基、C
2-9杂环基、C
6-10芳基、C
1-9杂芳基、R
5c-C(=O)-、R
5c-OC(=O)-、R
5c-C(=O)O-、R
5c-NHC(=O)-、R
5c-C(=O)NH-、R
5c-L
3-C
1-6烷基-、R
5a-C
1-6烷基和R
5a-C
1-6羟基烷基-独立任选地被0、1、2、3或4个R
5b取代;
R
5a是C
3-10环烷基、C
2-9杂环烷基、C
6-10芳基、或C
1-9杂芳基,其中所述R
5a任选地被0、1、2、3或4个R
5b取代;
R
5c是H、C
1-6烷基、C
3-10环烷基、C
2-9杂环基、C
6-10芳基、或C
1-9杂芳基,其中所述R
5c任选地被0、1、2、3或4个R
5b取代;
L
3是O、S、-N(R
d)-、或-C(=O)-;
各R
1a、R
2、R
3、R
4、R
5b、R
6、R
a和R
b分别独立地为H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、-NR
1bR
1c、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-6烷基;其中C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基和C
1-9杂芳基C
1-6烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基和C
1-6卤代烷氧基的取代基取代;
各R
1b、R
1c、R
c、R
d、R
7a、R
7c和R
7d分别独立地为H、D、-OH、-CN、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-6烷基;其中C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基和C
1-9杂芳基C
1-6烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基和C
1-6卤代烷氧基的取代基取代;
R
7a和R
7b各自独立地为H、碱金属离子、碱土金属离子、-OH、-CN、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-6烷基;其中C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基和C
1-9杂芳基C
1-6烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基和C
1-6卤代烷氧基的取代基取代;
n是0、1、2、3、4或5;和
各t1和t2分别独立地为1、2、3或4。
在一些实施方案,其中,L
1是O、NH、或CH
2;L
2是O、S、-N(R
c)-、或-CH
2-。
在一些实施方案,本发明所述化合物式(II)所示结构:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物。
在一些实施方案,其中,Ar
1是
其中,
Y
1和Y
2分别独立地为N或-C(R
2)-;
Y
3和Y
4分别独立地为-C(=O)-、O、S、-N(R
2a)-、-(C(R
2)
2)
t3-、或-W
1-(C(R
2)
2)
t3-;
W
1是-C(=O)-、O、S、或-N(R
2a)-;
各R
2a分别独立地为H、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-6烷基;和
t3是1、2、或3。
在一些实施方案,其中,Ar
1是
在一些实施方案,本发明所述化合物具有式(III)所示结构:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中Y
1和Y
2分别独立地为N或-C(R
2)-;和m是0、1、2、或3。
在一些实施方案,本发明所述化合物具有式(IIIa)所示结构:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中m是0、1、2、或3。
在一些实施方案,本发明所述化合物具有式(IV)所示结构:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中Y
1和Y
2分别独立地为N或-C(R
2)-;和m是0、1、2、或3。
在一些实施方案,其中,Cy是
其中,
Z
3、Z
4和Z
5各自独立地为-O-、-S-、-NH-、-(CH
2)
m1-NH-(CH
2)
m2-、-(CH
2)
m1-O-(CH
2)
m2-、-(CH
2)
m1-S-(CH
2)
m2-、或-(CH
2)
m3-;
各m1分别独立地为1、2、3或4;
各m2分别独立地为0、1、2、3或4;
各m3分别独立地为1、2、3或4;和
n1是0、1、2、3或4。
在一些实施方案,其中,Cy是
其中,所述Cy任选地被0、1、2、3或4个R
3取代。
其中,
X
1、X
2和X
3分别独立地为N或-C(R
6)-;
X
4为O、S、-N(R
6a)-、或-C(R
6)
2-;
X
5是O或S;和
各R
6a分别独立地为H、C
1-6烷基、C
1-6羟基烷基、C
1-6卤代烷基、C
1-6氨基烷基、C
1-6氰基烷基、C
1-6烷氧基、C
1-6卤代烷氧基、C
1-6烷硫基、C
1-6烷氨基、C
1-6卤代烷氨基、C
3-8环烷基、C
3-8环烷基C
1-6烷基、C
2-7杂环基、C
2-7杂环基C
1-6烷基、C
6-12芳基、C
6-12芳基C
1-6烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-6烷基。
在一些实施方案,其中,W是-COOH、-COOCH
3、-COOCH
2CH
3、-COOCH
2CH
2CH
3、-COOCH(CH
3)
2、-COOCH
2CH(CH
3)
2、-P(=O)(OH)
2、-P(=O)(OCH
3)(OCH
3)、-P(=O)(O
-Na
+)(O
-Na
+)、-P(=O)(O
-NH
4
+)(O
-NH
4
+)、-P(=O)(OH)(OCH
3)、-P(=O)(OH)(OPh)、-P(=O)(OH)(OCH
2CH
3)、-P(=O)(OCH
2CH
3)(OCH
2CH
3)、
其中R
7d是H、甲基、乙基、丙基、异丙基、丁基、叔丁基、-CF
3、-CH
2CF
3、-CH
2CN、-CH
2CH
2CN、-CH
2OH、-CH
2CH
2OH、环丙基、环丁基、环戊基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡唑基、三唑基、或四唑基,其中R
7d任选地被0、1、2、3或4个独立选自H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基和C
1-4卤代烷氧基的取代基取代。
在一些实施方案,其中,各R
1分别独立地为H、D、F、Cl、Br、-OH、-NH
2、-NO
2、-CN、甲基、乙基、-CF
3、-CH
2CF
3、-CH
2CN、-CH
2CH
2CN、-CH
2OH、或-CH
2CH
2OH;n是0、1、2、3或4。
在一些实施方案,其中,R
5是H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
1-4卤代烷基、C
1-4氰基烷基、C
1-4烷氧基C
1-4烷基、C
3-6环烷基、C
3-6杂环基、C
6-10芳基、C
1-9杂芳基、R
5c-C(=O)-、R
5c-OC(=O)-、R
5c-C(=O)O-、R
5c-NHC(=O)-、R
5c-C(=O)NH-、R
5c-L
3-C
1-4烷基-、R
5a-C
1-4烷基、或R
5a-C
1-4羟基烷基-,其中所述C
1-4烷基、C
1-4卤代烷基、C
1-4氰基烷基、C
1-4烷氧基C
1-4烷基、C
3-6环烷基、C
3-6杂环基、C
6-10芳基、C
1-9杂芳基、R
5c-C(=O)-、R
5c-OC(=O)-、R
5c-C(=O)O-、R
5c-NHC(=O)-、R
5c-C(=O)NH-、R
5c-L
3-C
1-4烷基-、R
5a-C
1-4烷基和R
5a-C
1-4羟基烷基-独立任选地被0、1、2、3或4个R
5b取代;
R
5a是C
3-6环烷基、C
3-6杂环烷基、C
6-10芳基、或C
1-9杂芳基,其中所述R
5a任选地被0、1、2、3或4个R
5b取代;
R
5c是H、C
1-4烷基、C
3-6环烷基、C
3-6杂环基、C
6-10芳基、或C
1-9杂芳基,其中所述R
5c任选地被0、1、2、3或4个R
5b取代;和
L
3是O、S、-NH-、或-C(=O)-。
在一些实施方案,其中,R
5是H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基甲基、甲氧基乙基、-CF
3、-CH
2CF
3、-CH
2CH
2CN、-CH
2CH
2OH、-COOH、H
2NC(=O)-、R
5c-C(=O)-、R
5c-OC(=O)-、R
5c-NHC(=O)-、R
5c-L
3-C
1-3烷基-、R
5a、R
5a-C
1-3羟基烷基、或R
5a-C
1-3烷基;
L
3是O、S、-NH-、或-C(=O)-;和
R
5a和R
5c各自独立地为
其中所述R
5a和R
5c各自任选地被0、1、2或3个独立地选自由H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
1-4卤代烷基、C
1-4氰基烷基、C
1-4羟基烷基、C
1-4烷氧基、和
C
1-4烷氧基C
1-4烷基组成的组的基团取代。
在一些实施方案,其中所述R
5a和R
5c各自任选地被0、1、2或3个独立地选自由H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、-CF
3、-CH
2CF
3、-CH
2CHF
2、甲氧基、乙氧基、丙氧基、甲氧基甲基、环丙基、环丙基甲基、和环丁基组成的组的基团取代。
在一些实施方案,其中,各R
1a、R
2、R
3、R
4、R
5b、R
6、R
a和R
b分别独立地为H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基、C
1-4卤代烷氧基、C
1-4烷硫基、C
1-4烷氨基、C
1-4卤代烷氨基、-NR
1bR
1c、C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-10芳基、C
6-10芳基C
1-4烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-4烷基;其中C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-10芳基、C
6-10芳基C
1-4烷基、C
1-9杂芳基和C
1-9杂芳基C
1-4烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基和C
1-4卤代烷氧基的取代基取代。
在一些实施方案,各R
5b分别独立地为H、D、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、-CF
3、-CH
2CF
3、-CH
2CHF
2、甲氧基、乙氧基、丙氧基、甲氧基甲基、环丙基、环丙基甲基、或环丁基。
在一些实施方案,其中,各R
1b、R
1c、R
c、R
d、R
2a、R
6a、R
7c和R
7d分别独立地为H、D、OH、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基、C
1-4卤代烷氧基、C
1-4烷硫基、C
1-4烷氨基、C
1-4卤代烷氨基、C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-10芳基、C
6-10芳基C
1-4烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-4烷基;其中C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-10芳基、C
6-10芳基C
1-4烷基、C
1-9杂芳基和C
1-9杂芳基C
1-4烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基和C
1-4卤代烷氧基的取代基取代。
在一些实施方案,其中,R
7a和R
7b各自独立地为H、Li
+、Na
+、K
+、NH
4
+、Mg
2+、Ca
2+、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
3-6环烷基、C
3-6环烷 基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-10芳基、C
6-10芳基C
1-4烷基、C
1-9杂芳基、或C
1-9杂芳基C
1-4烷基;其中C
3-6环烷基、C
3-6环烷基C
1-4烷基、C
3-6杂环基、C
3-6杂环基C
1-4烷基、C
6-10芳基、C
6-10芳基C
1-4烷基、C
1-9杂芳基和C
1-9杂芳基C
1-4烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH
2、-NO
2、-CN、氧代(=O)、C
1-4烷基、C
2-4烯基、C
2-4炔基、C
1-4羟基烷基、C
1-4卤代烷基、C
1-4氨基烷基、C
1-4氰基烷基、C
1-4烷氧基和C
1-4卤代烷氧基的取代基取代。
在一些实施方案,其中,其为具有以下结构之一的化合物:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物。
另一方面,本发明提供了药物组合物,所述药物组合物本发明所述的化合物或其药学上可接受的盐,以及药学上可接受的辅料、稀释剂或载体。
在一些实施方案,所述药物组合物进一步包含附加治疗剂。
另一方面,本发明提供了使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防和/或治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。
在一些实施方案,其中,所述心血管代谢性疾病和相关病症是T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NASH、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血性心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征X、经前综合征、心绞痛、血栓症、动脉 粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃窃、溃病性结肠炎、高apo B脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠综合征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征、或成瘾。
在一些实施方案,本发明化合物或其药物组合物可与另外的治疗剂组合施用。
在一些实施方案,本发明所述用途包括对哺乳动物施用足以实现所述治疗或预防的量的本发明所述化合物或药物组合物。
药物组合物、制剂和用途
当用作药物时,本发明化合物通常以药物组合物形式施用。所述组合物可以以制药技术中熟知的方式制备并且包含至少一个根据式I、II或III的本发明所述化合物。通常,本发明化合物以药物有效量施用。实际施用的本发明化合物的量通常将由医师根据相关情形决定,所述情形包括待治疗病症、所选的施用途径、所施用的本发明的实际化合物、个别患者的年龄、体重和响应、患者症状的严重程度等。
在一些实施方案,本发明包含药物组合物。此类药物组合物包含以药学上可接受的载体呈示的本发明化合物。亦可有其它的药理活性物质存在。如本申请中所使用的"药学上可接受的载体"包括任何及所有的溶剂、分散介质、包膜、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂及生理上可相容的类似者。药学上可接受的载体的实例包括水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇及类似者中的一种或多种,以及它们的组合,且可在组合物中包括等渗剂,例如糖、氧化纳或多元醇,诸如甘露醇或山梨醇。药学上可接受的物质(诸如润湿剂)或少量辅助物质(诸如润湿剂或乳化剂、保存剂或缓冲剂)提高抗体或抗体部分的储存寿命或有效性。
本发明组合物可呈多种形式。这些形式包括例如液体、半固体及固体剂型,诸如液体溶液(例如可注射和可输液溶液)、分散液或悬浮液、片剂、丸剂、粉剂、脂质体和栓剂。该形式系取决于意欲给药方式及治疗应用而定。
典型的组合物系呈可注射和可输液溶液,诸如类似于那些通常用于以抗体的人类被动免疫的组合物。一种给药方式为肠胃外(例如静脉内、皮下、腹膜内、肌肉内)。在另一实施方案中,抗体系经静脉内输液或注射给予。在又另一实施方案中,抗体系经肌肉内或皮下注射给予。
固体剂型的经口给予可以例如个别单元呈示,诸如硬或软胶囊、丸剂、扁囊剂、链剂或片剂,各含有预定量的至少一种本发明化合物。在另一实施方案中,经口给予可呈粉末或颗粒形式。在另一实施方案中,经口剂型为舌下形式,诸如链剂。在此类固体剂型中,式I的化合物惯常与一种或多种助剂组合。此类胶囊或片剂可含有控制释放型配制物。在胶囊、片剂和丸剂的例子中,剂型亦可包含缓冲剂或可以肠溶衣制备。
用于肠胃外给药的组合物可以是乳剂或无菌溶液。在某些实施方案,可使用丙二醇、聚乙二醇、植物油、特别是橄榄油或可注射的有机酯作为溶剂或载体,在一些实施方案,使用油酸乙酯作为溶剂或载体。所述这些组合物还可包含佐剂,特别是润湿剂,等渗剂,乳化剂,分散剂和稳定剂。可以几种方式进行灭菌,在某些实施方案,使用细菌学过滤器,通过辐射或通过加热进行灭菌。它们也可以无菌固体组合物的形式进行制备,其可在使用时溶于无菌水或任何其他可注射的无菌介质中。
用于直肠给药的组合物为栓剂或直肠胶囊,其除了活性成分之外还含有辅料如可可脂、半合成甘油酯或聚乙二醇。
在某些实施方案,本发明提供的组合物是药物组合物或单一单位剂型。本发明提供的药物组合物和单一单位剂型包含预防或治疗有效量的一种或多种预防剂或治疗剂(例如,本发明提供的化合物或其他预防剂或治疗剂)以及典型的一种或多种药学上可接受的载体或辅料。在具体实施方案和本发明中,术语“药学上可接受的”是指由联邦或州政府的监管机构批准,或者在美国药典或其他公认的药典中列出的用于动物、特别是用于人类的药物。术语“载体”包括与治疗剂一同施用的稀释剂、佐剂(例如,弗氏佐剂(完全和不完全))、辅料或媒介物。此类药物载体可以是无菌液体,如水和油类,包括石油、动物油、植物油或合成来源的那些,如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时,水可用作载体。盐水溶液和葡萄糖水溶液以及甘油溶液也可用作液体载体,特别是用于注射溶液。合适的药物载体的实例记载在Remington:The Science and Practice of Pharmacy;医药出版社(Pharmaceutical Press);22版(2012年9月15日)中。
典型的药物组合物和剂型包含一种或多种辅料。合适的辅料对药学领域的技术人员而言是熟知的,在某些实施方案,合适的辅料包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。特定的辅料是否适合掺入药物组合物或剂型,取决于本领域众所周知的各种因素,包括但不限于将所述剂型施用于受试者的方式以及所述剂型中的特定活性成分。若需要,所述组合物或单一单位剂型还可含有少量润湿剂或乳化剂,或pH缓冲剂。
用于口服给药的适当的组合物包含有效量的本发明化合物,它可以为下列形式:片剂、锭剂、水性或油性混悬液、散剂或颗粒剂、乳剂、硬或软胶囊或糖浆或酏剂。口服使用的组合物可以根据药用组合物生产领域中已知的任何方法制备,此类组合物可以含有一或多种选自下列的成分:甜味剂、矫味剂、着色剂和防腐剂,从而提供药学上美观和可口的制剂。片剂可以包含活性成分以及与之组合的用于生产片剂的无毒的、可药用的辅料。这些辅料包括:例如,惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;成粒剂和崩解剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,或者根据已知技术包衣以延迟其在胃肠道内的崩解和吸收,从而在较长时间内提供持续作用。例如,可以采用延时材料,例如可以采用单硬脂酸甘油酯或二硬脂酸甘油酯。
本发明化合物和/或含有所述化合物的组合物的剂量方案基于许多因素,包括患者的类型、年龄、体重、性别和医学症状;症状的严重性;给药途径;及所使用的特殊化合物的活性。因此,剂量方案可广泛地改变。在一个实施方案,用于治疗本发明中所讨论的适应症的本发明化合物的总日剂量通常为约0.001至约100毫克/千克(亦即以每千克体重计毫克本发明化合物)。在另一实施方案,本发明化合物的总日剂量为约0.01至约30毫克/千克,且在另一实施方案中为约0.03至约10毫克/千克,且在又一实施方案中为约0.1至约3毫克/千克。以一天内重复施用本发明化合物很多次并不罕见(通常不超过4次)。若需要,通常可使用每天多次剂量以增加总日剂量。
用于经口给予的组合物可以片剂形式提供,其含有对患者进行症候调整的剂量的0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、30.0、50.0、75.0、100、125、150、175、200、250或500毫克活性成分。药物通常含有约0.01毫克至约500毫克活性成分,或在另一实施方案中为约1毫克至约100毫克活性成分。在固定的速率输液期间经静脉内的剂量可在约0.01至约10毫克/千克/分钟的范围内。
另一方面,本发明提供了本发明化合物或包含本发明化合物的药物组合物,其用于医学。在具体实施方案中,本发明提供了本发明化合物或包含本发明化合物的药物组合物,其用于预防和/或治疗哺乳动物心血管代谢性疾病和相关病症,尤其是可用于T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NASH、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血性心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征X、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃窃、溃病性结肠炎、高apo B脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠综合征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征、或成瘾的预防和/或治疗。
本发明化合物可以与一或多种其它治疗成分同时给药,或者在其之前或之后给药。本发明化合物可以与另一种成分通过相同或不同给药途径分别给药,或者两者在同一药用组合物中一起给药。
在一些实施方案,本发明化合物可与抗糖尿病药物一同施用,所述抗糖尿病药物包括但不限于双胍类(例如二甲双胍)、磺酰脲类(例如甲苯磺丁脲(tolbutamide)、格列本脲(glibenclamide)、格列齐特(gliclazide)、氯磺丙脲(chlorpropamide)、甲磺氮卓脲(tolazamide)、醋磺环己脲(acetohexamide)、格列吡脲(glyclopyramide)、格列美脲或格列吡嗪)、噻唑烷二酮类(例如吡咯列酮、罗格列酮或洛贝格列酮(lobeglitazone))、格列扎类 (glitazar)(例如沙格列扎(saroglitazar)、阿格列扎(aleglitazar)、莫格列扎(muraglitazar)或替格列扎(tesaglitazar))、氯茴苯酸类(例如那格列奈(nateglinide)、雷帕格列奈)、二肽基肽酶4(DPP-4)抑制剂(例如西他列汀、维格列汀、沙格列汀(saxagliptin)、林那列汀、吉密列汀(gemigliptin)、阿那列汀(anagliptin)、替格列汀(teneligliptin)、阿格列汀、翠拉列汀(trelagliptin)、杜特列汀或欧马列汀(omarigliptin))、格列酮类(glitazone)(例如吡格列酮、罗格列酮、贝拉格列酮(balaglitazone)、瑞沃格列酮(rivoglitazone)或洛贝格列酮)、钠-葡萄糖连接的转运蛋白2(SGLT2)抑制剂(例如恩格列净、卡格列净、达格列净、艾格列净(ipragliflozin)、托格列净(tofogliflozin)、依碳酸舍格列净(sergliflozin etabonate)、依碳酸瑞格列净(remog1if1ozin etabonate)或依格列净)、SGLTL1抑制剂、GPR40激动剂(FFAR1/FFA1激动剂,例如法斯利方(fasiglifam))、葡萄糖依赖性促胰岛素肽(GIP)及其类似物、α葡萄糖苷酶抑制剂(例如伏格列波糖(voglibose)、阿卡波糖或米格列醇(miglitol))或胰岛素或胰岛素类似物,包括具体指明的药剂的药学上可接受的盐及所述药剂和盐的药学上可接受的溶剂合物。
为描述本发明,以下列出了实施例。但需要理解,本发明不限于这些实施例,只是提供实践本发明的方法。
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式I、II、III、IIIa或IV所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到:本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例,除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company,安耐吉化学公司(Energy-chemical Company),上海韶远(Shanghai Shaoyuan Company),J&K Chemical Company,阿拉丁化学公司(Aladdin Chemical Company),Meryer Chemical Company,TCI Chemical Company,Xiya Reagent Company,Bidepharm Company,Macklin Company和Alfa Chemical Company,使用时均没有经过进一步纯化,除非其他方面表明。一般的试剂从汕头西陇化工厂,广东光华化学试剂厂,广州化学试剂厂,天津好寓宇化学品有限公司,天津市福晨化学试剂厂,武汉鑫华远科技发展有限公司,青岛腾龙化学试剂有限公司,和青岛海洋化工厂购买得到。
无水四氢呋喃,二氧六环,甲苯,乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯,石油醚,正己烷,N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明),反应瓶都塞上合适的橡皮塞,底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。
1H NMR谱以CDC1
3、DMSO-d
6、CD
3OD或丙酮-d
6为溶剂(以ppm为单位),用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰)、d(doublet,双峰)、t(triplet,三重峰)、m(multiplet,多重峰)、br(broadened,宽峰)、dd(doublet of doublets,双二重峰)、dt(doublet of triplets,双三重峰)。偶合常数,用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是:Agilent 6120四级杆HPLC-M(柱子型号:Zorbax SB-C18,2.1 x 30mm,3.5微米,6min,流速为0.6mL/min。流动相:5%-95%((含0.1%甲酸的CH
3CN)在(含0.1%甲酸的H
2O)中的比例),采用电喷雾电离(ESI),在210nm/254nm下,用UV检测。
纯的化合物的使用Agilent 1260 pre-HPLC或Calesep pump 250 pre-HPLC(柱子型号:NOVASEP 50/80mm DAC),在210nm/254nm用UV检测。
下面简写词的使用贯穿本发明:
CD
3OD 氘代甲醇
CDC1
3 氘代氯仿
DMF N,N-二甲基甲酰胺
DMSO-d
6 氘代二甲基亚砜
BINAP 双(三甲基硅基)胺基锂
BINAP 1,1'-联萘-2,2'-双二苯基膦
LDA 二异丙基氨基锂
x-phos 2-二环己基磷-2',4',6'-三异丙基联苯
g 克
h 小时
mL、ml 毫升
RT、rt、r.t. 室温
制备本发明公开化合物的典型合成步骤如下面的合成方案1或2所示
合成方案1:
中间体1-1与1-2在金属钯催化下,通过偶联反应,生成中间体1-3;中间体1-3经历金属催化还原反应,得到中间体1-4;1-4与1-5在金属催化的条件下,进行偶联反应,得到中间体1-6;在强酸作用下,1-6脱去保护基,形成中间体1-7;1-7与1-8在碱性条件下,通过取代反应得到1-9。其中,Z
1、Z
2、X
1、X
4、W、R
1、R
2、R
3、R
4、R
5、n、m和n1均具有本发明所述定义;PG是保护基团。
合成方案2
中间体2-1与2-2在强碱作用下,通过取代反应,生成中间体2-3;中间体2-3在金属催化的条件下,与2-4进行偶联反应,得到中间体2-5;在强酸作用下,2-5脱去保护基,形成中间体2-6;2-6与2-7在碱性条件下,通过取代反应得到2-8。其中,Z
1、Z
2、X
1、X
2、X
3、W、R
1、R
2、R
3、R
4、R
5、n、m和n1均具有本发明所述定义;PG是保护基团。
实施例
中间体的合成
中间体1 3-氟-4-((6-(哌啶-4-基)吡啶-2-基)氧甲基)苯甲腈 盐酸盐
步骤1)N-叔丁基氧羰基-4-(6-氯吡啶-2-基)哌啶-4-甲酸甲酯
将二异丙基胺(1.47ml,10.0mmol)溶于四氢呋喃(10mL)中,置于-30℃低温冷浴下,向其中缓慢滴加2.5M的正丁基锂(4.2mL,10.5mmol)。然后将N-叔丁基氧羰基-4-哌啶甲酸甲酯(2.43g,10.0mmol)的四氢呋喃(10mL)溶液慢慢滴加进反应瓶中,滴加完后搅拌10分钟。将2,6-二氯吡啶(1.48g,10.0mmol)的四氢呋喃(10mL)溶液滴加进反应瓶中,混合物自然升温至室温搅拌3小时。待TLC显示反应无变化时,用饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取,收集有机相,干燥后减压浓缩,残余物经柱层析纯化,得到产物350mg,收率10%。LC-MS[M+H]
+:356.8。
步骤2)N-叔丁基氧羰基-4-(6-氯吡啶-2-基)哌啶-4-甲酸
将中间体N-叔丁基氧羰基-4-(6-氯吡啶-2-基)哌啶-4-甲酸甲酯(350mg,1.0mmol)溶于甲醇(5.0mL)中,并置于冰水浴中,向其中加入水(1.0mL)和氢氧化钠固体(460mg,11.5mmol),然后移至室温下搅拌1h。TLC监测原料消失后,用1.0N盐酸调至pH=6,混合物用乙酸乙酯萃取,减压浓缩得到标题化合物为淡黄色固体320mg,收率94%,直接用于下一步骤。LC-MS[M+H]
+:341.6。
步骤3)4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯
将N-叔丁基氧羰基-4-(6-氯吡啶-2-基)哌啶-4-甲酸(320mg)溶于1,2-二氯乙烷(10mL)中,混合物加热到80℃下搅拌。LC-MS监控反应完全后,减压浓缩除去溶剂,得到产物260mg,收率100%。LCMS[M+H]
+:297.8。
步骤4)4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯
将4-氰基-2-氟苄醇(101mg,0.67mmol)和4-(6-氯吡啶-2-基)哌啶-1-甲酸叔丁酯(166mg,0.56mmol)溶于1,4-二氧六环(15mL)中,然后加入三(二亚苄基丙酮)二钯(26mg,0.035mmol)、2-二环己基磷-2,4,6-三异丙基联苯(28mg,0.07mmol)和碳酸铯(293mg,1.07mmol),混合物加热到100℃并搅拌反应。TLC监测反应完全后,用饱和氯化铵水溶液淬灭,乙酸乙酯萃取,减压浓缩,残余物经柱层析纯化,得到产物200mg,收率81%。
步骤5)3-氟-4-((6-(哌啶-4-基)吡啶-2-基)氧甲基)苯甲腈 盐酸盐
将4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(200mg,0.49mmol)溶于甲醇(3mL)中,然后滴加盐酸乙醇溶液(1.2mL,4.9mmol,4mol/L),混合物于室温下搅拌反应。原料消失后,减压浓缩,得到标题化合物为油状物(161mg,收率95%)。LCMS[M+H]
+:312.2。
中间体2 1-(6-(4-氯-2-苄氧基)吡啶-2-基)哌嗪 三氟乙酸盐
步骤1)4-(6-氯吡啶-2-基)哌嗪-1-甲酸叔丁酯
将2,6–二氯吡啶(2g,13.5mmol)和哌嗪-1-甲酸叔丁酯(3.02g,16.2mmol)置于100mL单口瓶中,然后加入碳酸铯(8.8g,27mmol)和乙腈(30mL),混合物于85℃下搅拌12小时。冷却至室温,过滤除去不溶物,混合物减压浓缩,残余物经柱层析纯化,得到产物500mg,收率12%。
步骤2)4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-(6-氯吡啶-2-基)哌嗪-1-甲酸叔丁酯(450mg,1.51mmol)、4-氯-2-氟苄醇(243mg,1.51mmol)、碳酸铯(984mg,3.02mmol)、三(二亚苄基丙酮)二钯(138mg,0.15mmol)、1,1'-联萘-2,2'-双二苯膦(188mg,0.30mmol)和甲苯(10mL)置于50mL单口瓶中,氮气保护,混合物于110℃下反应12小时。冷却至室温,过滤除去不溶物,减压浓缩,所得残余物经柱层析纯化,得到目标产物330mg,收率52%。
步骤3)1-(6-(4-氯-2-苄氧基)吡啶-2-基)哌嗪 三氟乙酸盐
将4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(200mg,0.47mmol)溶于二氯甲烷(5mL),加入三氟乙酸(1mL),混合物于室温下搅拌4小时。停止反应,减压浓缩得到粗品245mg。LCMS[M+H]
+:322.7。
中间体3 3-氟-4-((6-(哌嗪-1-基)吡啶-2-基)氧甲基)苯甲腈 盐酸盐
步骤1)4-((6-氯吡啶-2-基)氧甲基)-3-氟苯甲腈
将3-氟-4-羟甲基苯甲腈(6g,39.7mmol)溶于四氢呋喃(120mL),降温至0℃,加入氢化钠(3.18g,79.4mmol,60%),将混合物搅拌0.5小时。然后加入二氯吡啶(11.75g,79.4mmol),混合物于室温下搅拌0.5小时。升温50℃再反应1小时。停止反应,降至室温,将反应液倒入冰水中(150mL),乙酸乙酯(150mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩后,所得残余物经柱层析纯化,得到目标化合物为白色固体(7.19g,收率69%)。LCMS[M+H]
+:263.6。
步骤2)4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯
将4-((6-氯吡啶-2-基)氧甲基)-3-氟苯甲腈(4g,15.18mmol)、哌嗪-1-甲酸叔丁酯(3.68g,19.73mmol)、三(二亚苄基丙酮)二钯(0.7g,0.76mmol)、1,1'-联萘-2,2'-双二苯膦(0.95g,1.52mmol)和碳酸铯(9.9g,30.36mmol)置于250mL单口瓶中,加入甲苯(80mL),混合物在氮气保护下升温至100℃反应过夜。停止反应,冷却至室温,加入水(50mL)洗,水相再用乙酸乙酯(50mL×2)萃取,合并有机相,饱和食盐水洗,经无水硫酸钠干燥,柱层析纯化得到产物3.9g,收率62%。LCMS[M+H]
+:413.5。
步骤3)3-氟-4-((6-(哌嗪-1-基)吡啶-2-基)氧甲基)苯甲腈 盐酸盐
将4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(500mg,1.21mmol)溶于乙醇(5mL),加入盐酸乙醇(1mL,4mmol,4mol/L),混合物于室温下搅拌4.5小时。停止反应,减压浓缩得到产物550mg。
中间体4 (S)-1-(6-(4-氯-2-氟苄氧基)-3,5-二氟吡啶-2-基)-3-甲基哌嗪 盐酸盐
步骤1)2-(4-氯-2-氟苄基)氧基)-3,5,6-三氟吡啶
向2,3,5,6-四氟吡啶(4.5g,30mmol),2-氟-4-氯苄醇(4.8g,30mmol)及碳酸钾(12.3g,90mmol)的混合样品中,加入N-甲基吡咯(30mL),上述混合液于100℃搅拌反应过夜;TLC检测原料基本反应完全后,将体系降至室温,加入饱和食盐水/乙酸乙酯(60mL,v/v=1:1),分离出有机相,水相用乙酸乙酯(30mL*2)萃取,有机相合并后,用无水硫酸钠干燥,减压浓缩至干,残余物经柱层析纯化(PE),得产物4.67g,收率53%。
步骤2)(S)-4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯
将2-(4-氯-2-氟苄基)氧基)-3,5,6-三氟吡啶(511mg,1.75mmol),2S-N-Boc-哌嗪(387mg,1.93mmol)及碳酸钾(266mg,1.93mmol)溶于N,N-二甲基甲酰胺(10mL)中,加热至110℃反应过夜;TLC检测原料反应完全后,将反应液倒入水(10mL)中,二氯甲烷(10mL*3)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩至干,残余物经柱层析纯化(PE:EA=10:1),得无色油283mg,收率58%。
步骤3)(S)-1-(6-(4-氯-2-氟苄氧基)-3,5-二氟吡啶-2-基)-3-甲基哌嗪 盐酸盐
将(S)-4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)-2-甲基哌嗪-1-甲酸叔丁酯(283mg,0.6mmol)溶于乙醇(6mL)中,加入30%盐酸乙醇溶液(2.8mL),室温搅拌反应2小时;TLC检测原料反应完全后,直接浓缩,得白色固体244mg,收率99%。
中间体5 1-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪 盐酸盐
步骤1)2-((4-氯-2-氟苄基)氧基)-3,5,6-三氟吡啶
向2,3,5,6-四氟吡啶(4.5g,30mmol),2-氟-4-氯苄醇(4.8g,30mmol)及碳酸钾(12.3g,90mmol)的混合物中,加入N-甲基吡咯(30mL),上述混合液在100℃下搅拌反应过夜;TLC检测原料基本反应完全后,将体系降至室温,加入饱和食盐水/乙酸乙酯(60mL,v/v=1:1),分离出有机相,水相用乙酸乙酯(30mL*2)萃取,有机相合并后,用无水硫酸钠干燥,减压浓缩至干,残余物经柱层析纯化(PE),得产物4.67g,收率53%。
步骤2)4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪-1-甲酸叔丁酯
将2-((4-氯-2-氟苄基)氧基)-3,5,6-三氟吡啶(265mg,0.91mmol),N-Boc-哌嗪(188mg,1.01mmol)及碳酸钾(139mg,1.01mmol)溶于N,N-二甲基甲酰胺(4mL)中,加热至110℃反应过夜;TLC检测原料反应完全后,将反应液倒入水(5mL)中,二氯甲烷(5mL*3)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩至干,残余物经柱层析纯化(PE:EA=15:1),得无色油状物236mg,收率57%。
步骤3)1-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪盐酸盐
将4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪-1-甲酸叔丁酯(236mg,0.51mmol)溶于乙醇(6mL)中,加入30%盐酸乙醇溶液(2.0mL),室温搅拌反应2小时;TLC检测原料反应完全后,直接浓缩,得白色固体174mg,收率95%。
中间体6 4-((4-氯-2-氟苄基)氧基)-5-氟-2-(哌嗪-1-基)吡啶 盐酸盐
步骤1)2,4-二氯-5-氟嘧啶
将5-氟尿嘧啶(30g,230.6mmol),三氯氧磷(105.8g,690.2mmol)置于500mL三口瓶中,升温 至95℃搅拌,滴加二甲基苯胺(55.9g,461.2mmol),滴加完毕后保持该温度反应过夜。冷却至室温,缓慢倒入-10℃的稀盐酸(122mL,3N)中搅拌1小时,加入二氯甲烷(300mL)萃取,有机相用水洗至中性,无水硫酸钠干燥,过滤,减压浓缩得浅黄色固体产物31.5g,收率83%。
步骤2)2-氯-4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶
将4-氯-2-氟苄醇(5.29g,32.93mmol)溶于四氢呋喃(75mL),降温至0℃,加入氢化钠(790mg,32.93mmol,60%),混合物搅拌30分钟,滴加2,4-二氯-5-氟嘧啶(5g,29.94mmol)的四氢呋喃(25mL)溶液,室温搅拌过夜。将反应液倒入饱和氯化铵(200mL)中,乙酸乙酯(200mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,柱层析纯化得类白色固体产物3.65g,收率38%。
步骤3)4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-甲酸叔丁酯
将2-氯-4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶(0.5g,1.72mmol),1-Boc-哌嗪(352mg,1.89mmol)溶于DMF(10mL),加入三乙胺(348mg,3.44mmol),混合物升温至100℃反应过夜。冷却至室温,加入水(15mL),乙酸乙酯(20mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,柱层析纯化得黄色油状产物326mg,收率43%。
步骤4)4-((4-氯-2-氟苄基)氧基)-5-氟-2-(哌嗪-1-基)吡啶 盐酸盐
将4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-甲酸叔丁酯(326mg,0.74mmol)溶于乙醇(2mL),加入盐酸的乙醇溶液(2mL,30%),混合物在室温下搅拌过夜。减压浓缩,得到灰白色固体产物285mg,收率>99%。
中间体7 2-((4-氯-2-氟苄基)氧基)-5-氟-4-(哌嗪-1-基)吡啶 盐酸盐
步骤1)4-(2-氯-5-氟嘧啶-4-基)哌嗪-1-甲酸叔丁酯
将2,4-二氯-5-氟嘧啶(3g,17.96mmol)溶于二氯甲烷(50mL),加入三乙胺(3.64g,35.92mmol),1-Boc-哌嗪(3.51g,18.86mmol),混合物于室温反应过夜。TLC检测反应完全后,加入水(50mL)洗,无水硫酸钠干燥,乙酸乙酯打浆得类白色固体产物5g,收率88%。
步骤2)4-(2-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-4-基)哌嗪-1-甲酸叔丁酯
将4-氯-2-氟苄醇(608mg,3.79mmol),4-(2-氯-5-氟嘧啶-4-基)哌嗪-1-甲酸叔丁酯(1g,3.16mmol),x-phos(2-二环己基磷-2',4',6'-三异丙基联苯,300mg,0.63mmol),醋酸钯(70mg,0.32mmol),碳酸铯(2.57g,7.9mmol)和甲苯(20mL)置于50mL单口瓶中,氮气排气3次,升温至110℃反应过夜。冷却至室温,加入水(20mL),用乙酸乙酯(25mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,残余物经柱层析纯化,得黄色油状产物900mg,收率65%。
步骤3)2-((4-氯-2-氟苄基)氧基)-5-氟-4-(哌嗪-1-基)吡啶 盐酸盐
将4-(2-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-4-基)哌嗪-1-甲酸叔丁酯(900mg,2.04)溶于乙醇(9mL),加入盐酸乙醇溶液(9mL,35%),混合物在室温搅拌过夜。减压浓缩蒸除乙醇,得无色油状产物220mg,收率32%。
中间体8 2-((4-氯-2-氟苄基)氧基)-4-(哌啶-4-基)嘧啶 盐酸盐
步骤1)1-叔丁基-4-甲基4-(2-(甲硫基)嘧啶-4-基)哌啶-1,4-二甲酸酯
将N-Boc-4-哌啶甲酸甲酯(5.0g,19.3mmol)溶于干燥四氢呋喃(50mL)中,混合物在氮气保护下,置于-40℃搅拌,将HMDSLi(23mL,23mmol,1.0M)缓慢滴入上述体系中,滴加完成后,在-40℃下搅拌反应0.5小时;2-甲硫基-4-氯嘧啶(3.0g,18.7mmol)溶于干燥四氢呋喃(15mL)中,然后缓慢滴入 上述混合体系内,滴加完成后,混合物自然升至室温反应1小时;TLC检测原料基本反应完全后,将反应体系置于冰水浴中,使体系内温度低于10℃,加入5%柠檬酸水溶液(75mL)和饱和食盐水(30mL),然后用乙酸乙酯(100mL*3)萃取,有机相合并,用无水硫酸钠干燥,减压浓缩至干,残余物经柱层析纯化(PE:EA=3:1),得黄色油状产物7.2g,收率>99%。
步骤2)4-(2-(甲硫基)嘧啶-4-基)哌啶-1-甲酸叔丁酯
将1-叔丁基-4-甲基4-(2-(甲硫基)嘧啶-4-基)哌啶-1,4-二甲酸酯(7.2g,18.6mmol)溶于甲醇/四氢呋喃(69mL,v/v=2:1)中,加入2M氢氧化钠溶液(18mL,36mmol),混合物于室温搅拌反应2小时;TLC检测原料剩余较多,升温至40℃反应2小时;TLC检测原料反应完全后,用1M柠檬酸水溶液调节PH至4,混合液用乙酸乙酯(50mL*2)萃取,有机相合并,用无水硫酸钠干燥,减压浓缩至干,得黄色油状粗产物,5.95g,收率>99%。
步骤3)4-(2-(甲基砜基)嘧啶-4-基)哌啶-1-甲酸叔丁酯
将4-(2-(甲硫基)嘧啶-4-基)哌啶-1-甲酸叔丁酯(5.95g,18.6mmol)溶于二氯甲烷(140mL)中,0℃下,将间氯过氧苯甲酸(7.55g,37.2mmol)加入体系中,自然升至室温反应过夜;LC-MS检测原料基本反应完全后,将反应液过一层硅藻土,滤渣用二氯甲烷洗,有机相合并,用无水硫酸钠干燥,减压浓缩至干,残余物经柱层析纯化(PE:EA=1:1),得白色固体4.9g,收率77%。
步骤4)4-(2-((4-氯-2-氟苄基)氧基)嘧啶-4-基)哌啶-1-甲酸叔丁酯
将2-氟-4-氯苄醇(2.2g,13.68mmol)溶于无水四氢呋喃(140mL)中,氮气保护下,滴加HMDSNa(13.7mL,27.3mmol,2.0M),混合液搅拌15分钟,将4-(2-(甲基砜基)嘧啶-4-基)哌啶-1-甲酸叔丁酯(4.9g,14.37mmol)的四氢呋喃(100mL)溶液滴入上述体系内,完成后继续搅拌反应2小时,TLC检测原料反应完全后,加入水(50mL)和饱和食盐水(50mL),分离出有机相,有机相用无水硫酸钠干燥,减压浓缩至干,柱层析纯化(PE:EA=2:1),得黄色油状产物,4.94g,收率86%。
步骤5)2-((4-氯-2-氟苄基)氧基)-4-(哌啶-4-基)嘧啶 盐酸盐
将4-(2-((4-氯-2-氟苄基)氧基)嘧啶-4-基)哌啶-1-甲酸叔丁酯(4.94g,11.76mmol)溶于乙醇(20mL)中,加入30%盐酸乙醇溶液(49mL),混合物于室温搅拌反应1小时,LC-MS检测原料反应完全后,直接减压浓缩备用,得标题化合物3.08g,收率82%。
中间体9 4-(3-((4-氯-2-氟苄基)氧基)苯基)-1,2,3,6-四氢哌啶 盐酸盐
步骤1)4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
将4-(3-羟基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(850mg,3.1mmol)溶于乙腈(15mL),加入碳酸钾(1.16g,8.4mmol),混合物于室温搅拌10分钟,加入4-氯-2-氟苄溴(628mg,2.8mmol),然后升温至60℃反应过夜。过滤除去不溶物,减压浓缩,残余物经柱层析纯化得无色油状产物500mg,收率43%。
步骤2)4-(3-((4-氯-2-氟苄基)氧基)苯基)-1,2,3,6-四氢哌啶 盐酸盐
将4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(500mg,1.19mmol)溶于乙醇(5mL),加入盐酸乙醇溶液(5mL,30%),混合物于室温下搅拌3小时。减压浓缩,加入甲基叔丁基醚打浆得白色固体产物190mg,收率45%。
中间体10 4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶 盐酸盐
步骤1)4-(3-羟基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯
将3-溴苯酚(3g,17.34mmol),N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯(5.9g,19.07mmol),碳酸铯(11.3g,34.68mmol)和Pd(dppf)Cl
2(1.25g,1.73mmol)置于250mL两口瓶中,加入1,4-二氧六环 (150mL),混合物于氮气保护下,升温至88℃反应过夜。过滤除去不溶物,减压浓缩,残余物经柱层析纯化得类白色固体产物3.9g,收率82%。
步骤2)4-(3-羟基苯基)哌啶-1-甲酸叔丁酯
将4-(3-羟基苯基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(1g,3.64mmol)溶于四氢呋喃(10mL),加入湿钯碳(0.2g,10%),混合物用氢气置换3次,室温搅拌过夜。过滤除去不溶物,减压浓缩得无色油状产物1.05g,收率>99%。
步骤3)4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶-1-甲酸叔丁酯
将4-(3-羟基苯基)哌啶-1-甲酸叔丁酯(1.05g,3.64mmol)溶于乙腈(15mL),加入碳酸钾(1.51g,10.92mmol),混合物于室温搅拌10分钟,加入4-氯-2-氟苄溴(853mg,3.82mmol),升温至60℃反应3.5小时。过滤除去不溶物,减压浓缩,残余物经柱层析纯化得无色油状产物1.48g,收率97%。
步骤4)4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶 盐酸盐
将4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶-1-甲酸叔丁酯(1.48g,3.52mmol)溶于乙醇(10mL),加入盐酸乙醇溶液(5mL,30%),混合物于室温搅拌过夜。减压浓缩,加入甲基叔丁基醚打浆得白色固体产物1.15g,>99%。
中间体11 2-((4-氯-2-氟苄基)氧基)-6-(哌啶-4-基)吡啶 盐酸盐
步骤1)4-(甲氧羰基)-4-(6-溴吡啶-2-基)哌啶-1-甲酸叔丁酯
将4-(甲氧羰基)-哌啶-1-甲酸叔丁酯(20g,82.3mmol)溶于四氢呋喃(200mL)中,置于-40℃下搅拌10分钟,将LDA(49mL,98mmol,2.0M的THF溶液)缓慢滴入上述体系中,滴加完成后,混合物于-40℃下继续搅拌0.5小时,随后将2,6-二溴吡啶(23.5g,98.7mmol)溶于四氢呋喃(200mL)后,缓慢滴入上述混合体系,滴加完成后,自然升至室温,继续反应3小时;然后将反应体系重新降温至0℃,将水(50mL)缓慢滴加进反应体系中,升至室温,分离出有机层,水层用乙酸乙酯(50mL*3)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,残余物经柱层析纯化(PE:EA=20:1),得淡黄色固体,23g,收率70%。
步骤2)4-(6-溴吡啶-2-基)-1-(叔丁氧羰基)哌啶-4-甲酸
将4-(甲氧羰基)-4-(6-溴吡啶-2-基)哌啶-1-甲酸叔丁酯(23g,58mmol)溶于四氢呋喃(200mL)中,加入1.0M氢氧化钠溶液(116mL,116mmol),混合物升温至50℃搅拌反应过夜;反应完成后,分离出有机相,水相用1.0M盐酸水溶液调节pH至4-5,再用二氯甲烷(100mL*3)萃取,有机相合并,用无水硫酸钠干燥,减压浓缩蒸除溶剂,得白色固体,粗产物19g,粗品收率85%。
步骤3)4-(6-溴吡啶-2-基)哌啶-1-甲酸叔丁酯
将4-(6-溴吡啶-2-基)-1-(叔丁氧羰基)哌啶-4-甲酸(19g,49mmol)溶于1,2-二氯乙烷(150mL)中,混合物升温至80℃反应12小时,反应完成后,减压浓缩蒸除溶剂,所得残余物经柱层析纯化(PE:EA=20:1),得白色固体14g,收率84%。
步骤4)4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯
将4-(6-溴吡啶-2-基)哌啶-1-甲酸叔丁酯(6.5g,19mmol),2-氟-4-氯苄醇(3.5g,22mmol),Pd
2(dba)
3(0.87g,0.95mmol),BINAP(1.18g,1.9mmol)及碳酸铯(12.3g,38mmol)溶于甲苯(65mL)中,混合物在氮气保护下,于100℃搅拌反应10小时,反应完成后,直接减压浓缩蒸除溶剂,残余物经柱层析纯化(PE:EA=8:1),得白色固体6.8g,收率85%。
步骤5)2-((4-氯-2-氟苄基)氧基)-6-(哌啶-4-基)吡啶 盐酸盐
将4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯(2.1g,5mmol)溶于30%盐酸乙醇溶液(20mL)中,混合物于室温搅拌反应,TLC检测原料反应完全后,直接减压浓缩蒸除溶剂,得黄色固体1.6g,收率>99%,LC-MS[M+H]
+:321.1。
中间体12 4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶盐酸盐
步骤1)1,5-二氟-2-碘-4-苯甲醚
将2,4-二氟-1-苯甲醚(3g,20.8mmol)溶于三氟乙酸(50mL),加入N-碘代丁二酰亚胺(5.15g,22.9mmol),混合物于室温反应过夜。反应完全后,将反应体系冷却至室温,倒入200g碎冰中,冰块完全融化后,过滤收集固体。将所得固体重新溶于二氯甲烷中,无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析(PE)分离纯化,得到目标产物(4.52g,80%)为淡黄色固体。
步骤2)2,4-二氟-5-碘苯酚
将1,5-二氟-2-碘-4-苯甲醚(4.52g,16.7mmol)溶于二氯甲烷(75mL)。冰浴下向反应体系中缓慢滴加三溴化硼(12.5g,50.2mmol)。将反应体系缓慢升温至室温,搅拌反应2h。TLC监测转化完全后,向反应体系中加入甲醇(10mL)淬灭反应(注意HBr尾气吸收)。反应淬灭完成后,用二氯甲烷萃取,有机相用水(3*100mL)洗,然后用饱和食盐水(100mL)洗。有机相经无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析(PE:EA=10:1)分离纯化,得到目标产物(4.54g,>99%)为淡黄色透明油状液体。
步骤3)1-((4-氯-2-氟苄基)氧基)-2,4-二氟-5-碘苯
将2,4-二氟-5-碘苯酚(4.54g,17.7mmol)溶于乙腈(120mL)。向反应体系中依次加入碳酸钾(7.34g,53.1mmol)和1-(溴甲基)-4-氯-2-氟苯(4.35g,19.5mmol)。将反应体系升温至60℃搅拌过夜。TLC监测转化完全后,过滤除去不溶物,滤液减压浓缩除去反应溶剂,残余物经柱层析(PE)分离纯化,得到目标产物(6.06g,86%)为白色固体。
步骤4)4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶-1-甲酸叔丁酯
将新鲜活化的Zn粉(262mg,4.02mmol)装入圆底烧瓶中。N
2氛下,向圆底烧瓶加入N,N-二甲基乙酰胺(1.5mL),再向体系中缓慢滴加三甲基氯硅烷(70μL)和1,2-二溴乙烷(50μL)的混合物,搅拌反应直至体系中不再产生气体。将4-碘哌啶-1-甲酸叔丁酯(1g,3.21mmol)溶于无水N,N-二甲基乙酰胺中,然后将其缓慢滴加至反应体系中。滴加完毕后,将反应置于55℃金属砂浴中加热2h,直至体系中的Zn粉完全溶解,溶液体系澄清,冷却到室温后,氮气保护保存制得的Zn试剂(浓度:0.6mol/L。
向圆底烧瓶中加入Pd(dppf)
2Cl
2(46.8mg,0.064mmol),碘化亚铜(24.4mg,0.128mmol),1-((4-氯-2-氟苄基)氧基)-2,4-二氟-5-碘苯(853mg,2.14mmol)。氮气氛下,加入N,N-二甲基乙酰胺(10mL),和上一步制备的Zn试剂(0.6mol/L)。加毕后,将反应体系置于80℃金属砂浴中加热反应过夜。反应毕,加入水(30mL),用乙酸乙酯萃取,有机相用水(3*20mL)洗,然后用饱和氯化钠溶液(50mL)洗。有机相经无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析(PE:EA=10:1)分离纯化,得到目标产物(420mg,43%)为无色透明油状液体。
步骤5)4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶盐酸盐
将4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶-1-甲酸叔丁酯(420mg,0.92mmol)溶于甲醇(10mL)中。向反应体系中加入30%盐酸甲醇溶液(10mL),混合物于室温搅拌3h。反应毕,将溶剂减压浓缩除去,所得白色固体用乙醚打浆,过滤,油泵真空干燥,得到目标产物(291mg,81%)为白色固体。LCMS[M+H]
+:356)。
实施例1 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(环丁-2-基甲基)-1H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸
步骤1)2-((叔丁氧羰基)氨基)-1H-咪唑-5-甲酸乙酯
将2-氨基咪唑-5-甲酸乙酯(3.1g,20mmol)溶于二氯甲烷(100mL)中,加入三乙胺(4.18mL,30mmol),置于冰水浴下搅拌,然后缓慢加入二碳酸二叔丁酯(4.8g,22mmol),混合物于室温下搅拌过夜。TLC检测反应完全后,将反应混合物倒入饱和碳酸氢钠溶液中,分离出有机层,水层用二氯甲烷(100mL×2)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化,得到产物4.5g,收 率88%。LCMS[M+H]
+:256.2。
步骤2)1-氨基-2-((叔丁氧羰基)氨基)-1H-咪唑-5-甲酸乙酯
将2-((叔丁氧羰基)氨基)-1H-咪唑-5-甲酸乙酯(3.8g,15mmol)溶于干燥N,N-二甲基甲酰胺(40mL)中,混合物于-10℃下搅拌,将双(三甲基硅基)氨基锂(16.5mL,16.5mmoL,1.0mol/L)缓慢滴加至上述体系中,搅拌反应10分钟后,将O-(二苯基膦酰)羟胺(4.2g,18mmol)的N,N-二甲基甲酰胺(5mL)溶液滴加至上述反应体系,然后缓慢升至室温搅拌反应6小时。TLC检测反应完全后,加入适量水至体系溶清,减压浓缩,残余物加入乙酸乙酯(20mL)溶解,重新减压浓缩至干,所得残余物经柱层析纯化,得产物2.8g,收率70%。LCMS[M+H]
+:271.1。
步骤3)2-((叔丁氧羰基)氨基)-1-((氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯
将1-氨基-2-((叔丁氧羰基)氨基)-1H-咪唑-5-甲酸乙酯(2.7g,10mmol)溶于乙腈(30mL)中,加入碳酸钾(2.7g,20mmol)和甲磺酸-(氧杂环丁-2-基)甲酯(2.0g,12mmol),混合物于50℃下搅拌反应6小时。TLC检测反应完全后,降至室温,加入饱和食盐水(30mL),二氯甲烷(30mL),分离出有机层,水层用二氯甲烷(30mL×2)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得到产物2.7g,收率80%。LCMS[M+H]
+:341.2。
步骤4)2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑[1,2-b][1,2,4]三氮唑-6-甲酸乙酯
将2-((叔丁氧羰基)氨基)-1-((氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯(1.5g,4.4mmol)溶于四氢呋喃(30mL),加入乙酸(0.26g,4.4mmol),并通入氮气鼓气1分钟,随后加入2-氯-1,1,1-三甲氧基乙烷(1.4g,8.8mmol),混合物于100℃下封管反应12小时。然后向反应混合物中加入对甲苯磺酸一水合物(84mg,0.44mmol),于75℃下反应1小时。停止反应,加入水(15mL),用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩得粗品1.3g,直接用于下一步反应。
步骤5)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸乙酯
将3-氟-4-((6-(哌啶-4-基)吡啶-2-基)氧甲基)苯甲腈盐酸盐(108mg,0.31mmol)溶于乙腈(3mL),加入碳酸钾(83mg,0.6mmol),混合物在室温下搅拌10分钟后,加入2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑[1,2-b][1,2,4]三氮唑-6-甲酸乙酯(130mg,0.44mmol),升温至50℃反应过夜。停止反应,混合物冷却至室温,加入水(5mL)淬灭,乙酸乙酯(10mL×3)萃取,饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化得到产物89mg,收率50%。LCMS[M+H]
+:574.7。
步骤6)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(环丁-2-基甲基)-1H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸乙酯(89mg,0.155mmol)溶于乙醇(1mL),然后加入氢氧化钠溶液(1.0mL,1.0mmol,1mol/L),混合物于50℃下反应过夜。停止反应,减压浓缩除去乙醇,加入1N HCl调节pH约等于5,然后用乙酸乙酯萃取(3mL×3),经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(二氯甲烷:甲醇=10:1),得到标题化合物(40mg,收率47%)。LCMS[M+H]
+:546.6。
1H NMR(500MHz,DMSO-d
6)δ7.90(s,1H),7.64(t,J=8.2Hz,1H),7.54(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.50(s,2H),5.25(m,1H),4.75(m,2H),4.68–4.60(m,1H),4.43(m,1H),3.98(s,2H),3.05–2.93(m,2H),2.82–2.71(m,1H),2.62(m,1H),2.49(m,1H),2.29(m,2H),1.85–1.82(m,2H).1.71–1.63(m,2H)。
实施例2 2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)5-溴-4-硝基噻吩-2-甲酸乙酯
将5-溴噻吩-2-甲酸乙酯(4.5g,19.14mmol)置于50mL两口瓶中,加入H
2SO
4,冰水浴降温至0℃,滴加硝酸(6.3mL,65%),滴加完全后将混合物缓慢升至室温,反应1小时。TLC检测显示原料反应完全,停止反应。将反应液倒入冰水(50mL)中,乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得到目标化合物3.36g,收率63%。LCMS[M+H]
+:279.2。
步骤2)5-((2,4-二甲氧基苄基)氨基)-4-消极噻吩-2-甲酸乙酯
将5-溴-4-硝基噻吩-2-甲酸乙酯(2g,7.14mmol),2,4-二甲氧基苄胺(1.55g,9.28mmol)置于单口瓶中,加入碳酸钾(3.95g,28.56mmol)和乙腈(45mL),混合物于室温下搅拌2.5小时。停止反应,反应液倒入冰水(50mL)中,乙酸乙酯萃取(60mL×3),合并有机相,用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得到产物2.7g,收率79%。LCMS[M+H]
+:367.2。
步骤3)5-氨基-4-硝基噻吩-2-甲酸乙酯
将5-((2,4-二甲氧基苄基)氨基)-4-消极噻吩-2-甲酸乙酯(2.7g,7.4mmol)溶于二氯甲烷(30mL),加入三氟乙酸(3mL),混合物于室温下搅拌过夜。TLC显示原料反应完全后,停止反应,倒入冰水(100mL)中,加入乙酸乙酯(150mL×3)萃取,合并有机相,用饱和食盐水洗,经无水硫酸钠干燥,过滤,减压浓缩得产物1.9g。LCMS[M+H]
+:217.2。
步骤4)5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-甲酸乙酯
将5-氨基-4-硝基噻吩-2-甲酸乙酯(1.9g,8.79mmol)溶于四氢呋喃(40mL),加入三乙胺(1.34g,13.2mmol)和二碳酸二叔丁酯(2.3g,10.55mmol),混合物于室温下搅拌过夜。TLC检测原料反应完全后停止反应,减压浓缩,残余物经柱层析纯化得到产物1.45g,收率52%。LCMS[M+H]
+:317.3。
步骤5)4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-甲酸乙酯(1.18g,3.73mmol)溶于甲醇(7.5mL),加入水(2.5mL)、铁粉(1.04g,18.65mmol)、和氯化铵(400mg,7.46mmol),混合物于60℃下反应2小时。TLC检测反应完全后,停止反应,冷却至室温,过滤除去不溶物,减压浓缩除去甲醇,加入水(10mL),用乙酸乙酯(20mL×3)萃取,合并有机相,饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得到产物800mg,收率75%。LCMS[M+H]
+:287.1。
步骤6)5-((叔丁氧羰基)氨基)-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯(632mg,2.2mmol)溶于二氯甲烷(18mL),向所得混合物中加入氧杂环丁基-2-甲醛(228mg,2.65mmol),然后加入3滴乙酸,混合物于室温下搅拌20分钟。向反应混合物中加入三乙酰氧基硼氢化钠(933mg,4.4mmol),室温搅拌1小时。然后向反应混合物中加入二氯甲烷(30mL)稀释,加入水(20mL)洗,然后饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得到产物330mg,收率42%。LCMS[M+H]
+:357.1。
步骤7)2-(氯乙基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯(130mg,0.365mmol)溶于四氢呋喃(6.5mL),然后加入乙酸(22mg,0.365mmol),并通入氮气鼓气1分钟,加入2-氯-1,1,1-甲氧基乙烷(113mg,0.733mmol),所得混合物于100℃下封管反应12小时。向混合物中加入对甲苯磺酸一水合物(7mg,0.036mmol),于75℃下反应1小时。停止反应,加入水(15mL),乙酸乙酯(20mL×3)萃取,合并有机相,用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩得粗品140mg,直接用于下一步反应。
步骤8)2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将1-(6-(4-氯-2-苄氧基)吡啶-2-基)哌嗪三氟乙酸盐(112mg,0.255mmol)溶于乙腈(3mL),加入碳酸钾(202mg,1.46mmol),混合物于室温下搅拌10分钟。然后向混合物中加入2-(氯乙基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(140mg,0.365mmol),升温至50℃反应过夜。停止反应,冷却至室温,加入水(5mL)淬灭,乙酸乙酯(10mL×3)萃取,用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析纯化得到产物40mg,收率26%。LCMS[M+H]
+:601.1。
步骤9)2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(40mg,0.067mmol)溶于乙醇(1.0mL),加入氢氧化钠溶液(1mL,1mmol,1mol/L),混合物于50℃下反应过夜。TLC检测原料反应完全后,停止反应,减压浓缩除去乙醇,然后加入1N HCl调节pH约等于5,混合物用乙酸乙酯(3mL×3)萃取,有机层经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(二氯甲烷:甲醇=10:1)得到产物(10.7mg,产率:28%)。LCMS[M+H]
+:573.0。
1H NMR(500MHz,DMSO-d
6)δ7.79(s,1H),7.52(t,J=8.2Hz,1H),7.45(d,J=8.7Hz,2H),7.30(d,J=8.3Hz,1H),6.33(d,J=8.0Hz,1H),6.09(d,J=7.7Hz,1H),5.30(s,2H),5.09(d,J=7.5Hz,1H),4.65(dd,J=15.1,6.8Hz,1H),4.58–4.45(m,2H),4.41–4.33(m,1H),3.83(d,J=13.6Hz,1H),3.73(d,J=13.6Hz,1H),3.55–3.41(m,8H),2.69(t,J=9.1Hz,1H),2.42–2.35(m,1H)。
实施例3 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-噻唑并[2,3-d]咪唑-5-甲酸
步骤1)4-硝基-5-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯
将5-溴-4-硝基噻吩-2-甲酸乙酯(2.0g,7.14mmol)加入到氧杂环丁-2-基甲胺(0.93g,10.71mmol)的N,N-二甲基甲酰胺(20mL)溶液中,然后加入三乙胺(3.0mL,21.4mmol),混合物于45℃下搅拌反应过夜。TLC检测原料反应完全后,减压浓缩除去溶剂,残余物经柱层析纯化,得到产物1.6g,产率:80%。LCMS[M+H]
+:287.0。
步骤2)5-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)-4-硝基噻吩-2-甲酸乙酯
将4-硝基-5-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯(1.6g,5.6mmol)溶于四氢呋喃(30mL)中,混合物置于冰水浴中搅拌,然后加入二碳酸二叔丁酯(1.46g,6.72mmol)和三乙胺(1.56mL,11.2mmol),然后自然升至室温搅拌反应8小时。TLC检测原料反应完全后,将反应液倒入饱和碳酸氢钠(30mL)中,用二氯甲烷(30mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析纯化,得到产物1.9g,产率:88%。LCMS[M+H]
+:387.0。
步骤3)4-氨基-5-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-甲酸乙酯(1.9g,4.9mmol)溶于甲醇(7.5mL),向其中加入水(2.5mL)、铁粉(1.38g,24.6mmol)和氯化铵(524mg,9.8mmol),混合物于60℃下反应2小时。TLC检测反应完全后,停止反应,冷却至室温,过滤除去不溶物,减压浓缩除去甲醇,加入水(10mL),用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得产物1.22g,收率70%。LCMS[M+H]
+:357.1。
步骤4)2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯(356mg,1.0mmol)溶于四氢呋喃(10mL),向其中加入乙酸(60mg,1.0mmol)并用氮气鼓气1分钟,然后加入2-氯-1,1,1-甲氧基乙烷(309mg,2.0mmol),混合物于100℃下封管反应12小时。然后向反应混合物中加入对甲苯磺酸一水合物(19mg,0.1mmol),于75℃下反应1小时。停止反应,加入水(15mL),用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩得粗品310mg,直接用于下一步反应。
步骤5)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将1-(6-(4-氯-2-苄氧基)吡啶-2-基)哌嗪三氟乙酸盐(243mg,0.7mmol)溶于乙腈(3mL),向其中加入碳酸钾(483mg,3.5mmol),混合物于室温下搅拌10分钟,加入2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(310mg,0.98mmol),升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭反应,反应混合物用乙酸乙酯(10mL×3)萃取,饱和食盐水洗,经无水硫酸钠干燥,减压浓缩除去溶剂,所得残余物经柱层析纯化得产物124mg,收率30%。LCMS[M+H]
+:589.6。
步骤6)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(100mg,0.17mmol)溶于乙醇(1.0mL),向其中加入氢氧化钠溶液(1mL,1mmol,1mol/L),混合物于50℃反应过夜。TLC检测原料反应完全后,停止反应,减压浓缩除去乙醇,加入1N HCl调节pH约等于5,反应混合物用乙酸乙酯(3mL×3)萃取,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=10:1),得到产物(24mg,产率25%)。LCMS[M+H]
+:562.6。
1H NMR(500MHz,DMSO-d
6)δ7.80(s,1H),7.64(t,J=8.2Hz,1H),7.54(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.48(s,2H),5.12(m,1H),4.79(m,1H),4.65(m,1H),4.49(m,1H),4.40(m,1H),3.94(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.98(d,J=11.3Hz,1H),2.85(d,J=11.3Hz,1H),2.71(p,J=7.8Hz,1H),2.64–2.55(m,2H),2.31–2.10(m,2H),1.77–1.64(m,4H)。
实施例4 5-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-4-(氧杂环丁-2-基甲基)-4H-咪唑并[4,5-d]噻唑-2-甲酸
步骤1)4-硝基-5-((2,4-二甲氧基苄基)氨基)噻唑-2-甲酸乙酯
将5-溴-4-硝基噻唑-2-甲酸乙酯(2.0g,7.14mmol,Ref.Eur.J.Inorg.Chem.,2011,539)和2,4-二甲氧基苄胺(1.55g,8.28mmol)溶于乙腈(45mL)中,向其中加入碳酸钾(3.95g,28.56mmol),混合物于室温下搅拌反应3小时。TLC检测原料反应完全后,减压浓缩除去溶剂,残余物经柱层析纯化,得到产物2.4g,产率:92%。LCMS[M+H]
+:368.4。
步骤2)5-氨基-4-硝基噻唑-2-甲酸乙酯
将4-硝基-5-((2,4-二甲氧基苄基)氨基)噻唑-2-甲酸乙酯(2.4g,6.53mmol)溶于二氯甲烷(24mL)中,然后加入三氟乙酸(2.4mL),混合物于室温下搅拌反应8小时。TLC检测原料反应完全后,将反应混合物倒入冰水(100mL)中,加入乙酸乙酯(100mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,过滤,减压浓缩得粗品1.5g。LCMS[M+H]
+:218.0。
步骤3)5-((叔丁氧羰基)氨基)-4-硝基噻唑-2-甲酸乙酯
将5-氨基-4-硝基噻唑-2-甲酸乙酯(1.4g,6.53mmol)溶于四氢呋喃(30mL),然后加入三乙胺(1.36mL,9.8mmol)和二碳酸二叔丁酯(1.7g,7.84mmol),混合物于室温下搅拌过夜。TLC检测原料反应完全后,减压浓缩除去溶剂,所得残余物经柱层析纯化得产物1.5g,收率72%。LCMS[M+H]
+:318.0。
步骤4)4-氨基-5-((叔丁氧羰基)氨基)噻唑-2-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-硝基噻唑-2-甲酸乙酯(1.5g,4.73mmol)溶于甲醇(7.5mL),然后加入水(2.5mL)、铁粉(1.04g、18.65mmol)和氯化铵(400mg,7.46mmol),混合物于60℃下反应2小时。停止反应,冷却至室温,过滤除去不溶物,减压浓缩除去溶剂,加入水(10mL),混合物用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化,得到产物817mg,收率60%。LCMS[M+H]
+:288.0。
步骤5)5-((叔丁氧羰基)氨基)-4-((氧杂环丁-2-基甲基)氨基)噻唑-2-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)氨基)噻唑-2-甲酸乙酯(800mg,2.79mmol)溶于二氯甲烷(16mL)中,向所得混合物中加入氧杂环丁基-2-甲醛(288mg,3.35mmol),然后加入5滴乙酸,室温搅拌20分钟。向反应混合物中加入三乙酰氧基硼氢化钠(1.17g,5.5mmol),室温搅拌1小时。然后加入二氯甲烷(30mL)稀释,混合物用水(20mL)和饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得产物498mg,收率50%。LCMS[M+H]
+:358.1。
步骤6)5-(氯甲基)-4-(氧杂环丁-2-基甲基)-4H-咪唑并[4,5-d]噻唑-2-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)噻唑-2-甲酸乙酯(358mg,1.0mmol)溶于四氢呋喃(10mL),然后加入乙酸(60mg,1.0mmol),并用氮气鼓气1分钟,随后加入2-氯-1,1,1-甲氧基乙烷(309mg,2.0mmol),混合物于100℃下封管反应12小时。向反应混合物中加入对甲苯磺酸一水合物(19mg,0.1mmol),混合物于75℃下反应1小时。停止反应,加入水(15mL),混合物用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩得粗品320mg,直接用于下一步反应。
步骤7)5-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-4-(氧杂环丁-2-基甲基)-4H-咪唑并[4,5-d]噻唑-2-甲酸乙酯
将1-(6-(4-氯-2-苄氧基)吡啶-2-基)哌嗪三氟乙酸盐(243mg,0.7mmol)溶于乙腈(3mL),然后加入碳酸钾(483mg,3.5mmol),混合物于室温下搅拌10分钟,然后加入2-(氯甲基)-3-(氧杂环丁-2-基甲基)-3H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(320mg,1.0mmol),混合物升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭反应,然后用乙酸乙酯(10mL×3)萃取,经饱和食盐水洗,无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析纯化得产物140mg,收率34%。LCMS[M+H]
+:591.0。
步骤8)5-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-4-(氧杂环丁-2-基甲基)-4H-咪唑并[4,5-d]噻唑-2-甲酸
将5-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-4-(氧杂环丁-2-基甲基)-4H-咪唑并[4,5-d]噻唑-2-甲酸乙酯(120mg,0.20mmol)溶于乙醇(1.0mL),然后加入氢氧化钠溶液(1mL,1mmol,1mol/L),混合物于50℃下反应过夜。TLC检测原料反应完全后,停止反应,减压浓缩除去乙醇,向混合物中加入1N HCl调节pH约等于5,用乙酸乙酯(3mL×3)萃取,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化(二氯甲烷:甲醇=10:1),得到产物(35mg,产率31%)。LCMS[M+H]
+:563.4。
1H NMR(500MHz,DMSO-d
6)δ7.64(t,J=8.2Hz,1H),7.54(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.48(s,2H),5.12(m,1H),4.79(m,1H),4.65(m,1H),4.49(m,1H),4.40(m,1H),3.94(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.98(d,J=11.3Hz,1H),2.85(d,J=11.3Hz,1H),2.71(p,J=7.8Hz,1H),2.64–2.55(m,2H),2.30–2.11(m,2H),1.76–1.62(m,4H)。
实施例5 (2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)膦酸
步骤1)(5-((2,4-二甲氧基苄基)氨基)-4-硝基噻吩-2-基)膦酸二甲酯
将(5-溴-4-硝基噻吩-2-基)膦酸二甲酯(2g,6.33mmol,Ref.Chem.Commun.,2014,50,10622.)和2,4-二甲氧基苄胺(1.48g,8.86mmol)置于单口瓶中,然后加入碳酸钾(3.49g,25.32mmol)和乙腈(40mL),混合物于室温下搅拌2.5小时。停止反应,反应液倒入冰水(50mL)中,用乙酸乙酯萃取(50mL×3),合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化得产物2.29g,收率90%。LCMS[M+H]
+:403.4。
步骤2)(5-氨基-4-硝基噻吩-2-基)膦酸二甲酯
将(5-((2,4-二甲氧基苄基)氨基)-4-硝基噻吩-2-基)膦酸二甲酯(2.2g,5.47mmol)溶于二氯甲烷(22mL)中,然后加入三氟乙酸(2.2mL),混合物于室温下搅拌反应8小时。TLC检测原料反应完全后,将反应混合物倒入冰水(100mL)中,用乙酸乙酯(100mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,过滤,减压浓缩,残余物经柱层析纯化得产物1.24g,收率90%。LCMS[M+H]
+:253.2。
步骤3)(3-硝基-5-(二甲氧基膦酰基)噻吩-2-基)胺基甲酸叔丁酯
将(5-氨基-4-硝基噻吩-2-基)膦酸二甲酯(1.2g,4.76mmol)溶于四氢呋喃(24mL)中,然后加入三乙胺(1.0mL,7.2mmol),混合物置于冰水浴下搅拌,然后加入二碳酸二叔丁酯(1.24g,5.71mmol),所得混合物在室温下搅拌8小时。TLC检测反应完全后,减压浓缩,残余物经柱层析纯化,得到产物1.5g,收率90%。LCMS[M+H]
+:353.2。
步骤4)(3-氨基-5-(二甲氧基膦酰基)噻吩-2-基)胺基甲酸叔丁酯
将(3-硝基-5-(二甲氧基膦酰基)噻吩-2-基)胺基甲酸叔丁酯(1.5g,4.26mmol)溶于甲醇/水(10mL,v/v=1:1)中,然后加入铁粉(1.19g,21.3mmol)和氯化铵(451mg,8.52mmol),混合物于60℃下反应2小时。TLC检测原料反应完全后,冷却至室温,过滤除去不溶物,减压浓缩,向残余物中加入水(10mL),用乙酸乙酯(10mL×3)萃取。合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化,得到产物0.89g,收率65%。LCMS[M+H]
+:323.2。
步骤5)(5-(二甲氧基膦酰基-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-基)胺基甲酸叔丁酯
将(3-氨基-5-(二甲氧基膦酰基)噻吩-2-基)胺基甲酸叔丁酯(0.89g,2.76mmol)溶于四氢呋喃(5mL)中,然后加入甲磺酸-(1-乙基-1H-咪唑-5-基)甲酯(0.84g,4.14mmol)和碳酸钾(0.76g,5.52mmol),混合物于室温下搅拌反应6小时。TLC检测反应完全后,降至室温,倒入水(20mL)中,用乙酸乙酯(20mL×3)萃取,有机相合并,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(水:甲醇=5:1),得产物0.83g,收率70%。LCMS[M+H]
+:431.4。
步骤6)(2-(氯甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)膦酸二甲酯
将(5-(二甲氧基膦酰基-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-基)胺基甲酸叔丁酯(0.7g,1.6mmol)溶于四氢呋喃(10mL),然后加入乙酸(96mg,1.6mmol),并通入氮气鼓气5分钟,然后加入2-氯-1,1,1-三甲氧基乙烷(495mg,3.2mmol),混合物于100℃下封管反应12小时。加入对甲苯磺酸一水合物(30mg,0.16mmol),混合物于75℃下反应1小时。停止反应,加入水(20mL),乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩得粗品590mg,直接用于下一步反应。
步骤7)(2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)膦酸二甲酯的合成
将1-(6-(4-氯-2-苄氧基)吡啶-2-基)哌嗪三氟乙酸盐(387mg,0.92mmol)溶于乙腈(5mL),然后加入碳酸钾(635mg,4.6mmol),混合物于室温下搅拌30分钟,然后加入(2-(氯甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)膦酸二甲酯(500mg,1.29mmol),将混合物升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭,乙酸乙酯(10mL×3)萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,减压浓缩除去溶剂,所得残余物经柱层析纯化得到产物186mg,收率30%。LCMS[M+H]
+:675.1。
步骤8)(2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)膦酸
将(2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)膦酸二甲酯(150mg,0.22mmol)溶于二氯甲烷(5mL)中,混合物置于冰水浴下搅拌,将三甲基溴硅烷(0.11mL,0.88mmol)滴入上述反应体系,自然升至室温搅拌反应12小时。TLC检测原料基本反应完全后,将反应液倒入饱和食盐水(20mL)中,二氯甲烷(20mL×3)萃取,合并的有机相经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化,得到产物(85.2mg,收率60%)。LCMS[M+H]
+。647.0。
1H NMR(500MHz,DMSO-d
6)δ9.10(s,1H),8.20(s,1H),8.11(s,1H),7.63(t,J=8.2Hz,1H),7.55(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.88(s,2H)5.15(s,2H),4.79(s,2H),4.36(q,J=8Hz,2H),3.55–3.41(m,8H),1.58(t,J=8Hz,3H)。
实施例6 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(环丁-2-基甲基)-3H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸
步骤1)2-((氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯
将2-氨基-1H-咪唑-5-甲酸乙酯(2.0g,12.9mmol)溶于乙腈(30mL)中,然后加入碳酸钾(3.6g,25.8mmol)和甲磺酸-(氧杂环丁-2-基)甲酯(2.58g,15.5mmol),混合物于50℃下搅拌反应6小时。TLC检测 反应完全后,降至室温,向混合物中加入饱和食盐水(30mL)和二氯甲烷(30mL),分离出有机层,水层用二氯甲烷(30mL×2)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得到产物2.38g,收率82%。LCMS[M+H]
+:226.2。
步骤2)2-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯
将2-((氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯(2.3g,10.2mmol)溶于二氯甲烷(50mL)中,然后加入三乙胺(2.84mL,20.4mmol),混合物置于冰水浴下搅拌,然后缓慢加入二碳酸二叔丁酯(2.67g,12.2mmol),将反应混合物室温搅拌过夜。TLC检测反应完全后,将混合物倒入饱和碳酸氢钠溶液中,分离出有机层,水层用二氯甲烷(50mL×2)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得产物2.82g,收率85%。LCMS[M+H]
+:326.2。
步骤3)1-氨基-2-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯
将2-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯(2.8g,8.6mmol)溶于干燥N,N-二甲基甲酰胺(50mL)中,混合物于-10℃下搅拌,然后将双(三甲基硅基)氨基锂(9.5mL,9.5mmoL,1.0mol/L)缓慢滴入上述体系中,混合物搅拌反应10分钟后,将O-(二苯基膦酰)羟胺(2.4g,10.3mmol)的N,N-二甲基甲酰胺(5mL)溶液滴入上述体系,然后缓慢升至室温搅拌反应6小时。TLC检测反应完全后,加入适量水至体系溶清,减压浓缩,残余物用乙酸乙酯(30mL)溶解,重新减压浓缩至干,所得残余物经柱层析纯化,得产物2.05g,收率70%。LCMS[M+H]
+:341.1。
步骤4)2-氯甲基-3-(氧杂环丁-2-基甲基)-3H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸乙酯
将1-氨基-2-((叔丁氧羰基)(氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯(2.0g,5.88mmol)溶于四氢呋喃(40mL),然后加入乙酸(0.35g,5.88mmol),并通入氮气鼓气5分钟,然后加入2-氯-1,1,1-三甲氧基乙烷(1.87g,11.76mmol),混合物于100℃封管反应12小时。向反应混合物中加入对甲苯磺酸一水合物(112mg,0.59mmol),于75℃下反应1小时。停止反应,加入水(20mL),乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩得粗品1.7g,直接用于下一步反应。
步骤5)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸乙酯
将3-氟-4-((6-(哌嗪-4-基)吡啶-2-基)氧甲基)苯甲腈盐酸盐(417mg,1.2mmol)溶于乙腈(5mL),然后加入碳酸钾(331mg,2.4mmol),混合物于室温下搅拌10分钟,加入2-氯甲基-3-(氧杂环丁-2-基甲基)-3H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸乙酯(500mg,1.67mmol),升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭,混合物用乙酸乙酯(10mL×3)萃取,有机层用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化得到产物330mg,收率48%。LCMS[M+H]
+:575.7。
步骤6)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(环丁-2-基甲基)-3H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(氧杂环丁-2-基甲基)-3H-咪唑并[1,2-b][1,2,4]三氮唑-6-甲酸乙酯(150mg,0.26mmol)溶于乙醇(1mL),然后加入氢氧化钠溶液(1.0mL,1.0mmol,1mol/L),混合物于50℃下反应过夜。停止反应,减压浓缩除去乙醇,然后加入1N HCl调节pH约等于5,混合物用乙酸乙酯(3mL×3)萃取,有机层经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(二氯甲烷:甲醇=10:1),得到标题化合物(43mg,收率30%)。LCMS[M+H]
+:547.5。
1H NMR(500MHz,DMSO-d
6)7.95(s,1H),7.63(t,J=8.2Hz,1H),7.55(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.50(s,2H),5.12(m,1H),4.79(m,1H),4.65(m,1H),4.49(m,1H),4.40(m,1H),3.94(d,J=13.5Hz,1H),3.83(d,J=13.6Hz,1H),3.55–3.41(m,8H),2.69(t,J=9.1Hz,1H),2.42–2.35(m,1H)。
实施例7 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-a]咪唑-5-甲酸
步骤1)2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-a]咪唑-5-甲酸乙酯
将2-((氧杂环丁-2-基甲基)氨基)-1H-咪唑-5-甲酸乙酯(1.0g,4.4mmol)溶于乙二醇二甲醚(10mL)中,然后加入1,3-二氯丙酮(1.12g,8.8mmol),混合物于室温下搅拌反应2小时,然后回流搅拌反应过夜。TLC检测原料基本反应完全后,将反应混合物降至室温,加入饱和碳酸钠(10mL),用二氯甲烷(20mL×3)萃取,合并的有机相经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得到产物0.78g,收率60%。LCMS[M+H]
+:298.6。
步骤2)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-a]咪唑-5-甲酸乙酯
将3-氟-4-((6-(哌嗪-4-基)吡啶-2-基)氧甲基)苯甲腈盐酸盐(417mg,1.2mmol)溶于乙腈(5mL),然后加入碳酸钾(331mg,2.4mmol),混合物于室温下搅拌10分钟,然后加入2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-a]咪唑-5-甲酸乙酯(500mg,1.68mmol),混合物升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭,反应混合物用乙酸乙酯(10mL×3)萃取,有机层用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得到产物379mg,收率55%。LCMS[M+H]
+:574.6。
步骤3)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-a]咪唑-5-甲酸的合成
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-咪唑并[1,2-a]咪唑-5-甲酸乙酯(200mg,0.34mmol)溶于乙醇(1mL),然后加入氢氧化钠溶液(1.0mL,1.0mmol,1mol/L),混合物于50℃下反应过夜。停止反应,减压浓缩除去乙醇,然后加入1N HCl调节pH约等于5,混合物用乙酸乙酯萃取(3mL×3),有机层经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(二氯甲烷:甲醇=10:1),得到标题化合物(48mg,收率25%)。LCMS[M+H]
+:546.5。
1H NMR(500MHz,DMSO-d
6)7.95(s,1H),7.70(s,1H),7.63(t,J=8.2Hz,1H),7.55(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.50(s,2H),5.09(m,1H),4.77(m,1H),4.63(m,1H),4.45(m,1H),4.39(m,1H),3.95(d,J=13.5Hz,1H),3.85(d,J=13.6Hz,1H),3.55–3.41(m,8H),2.68(t,J=9.1Hz,1H),2.41–2.34(m,1H)。
实施例8 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-5-基)哌啶-1-基)甲基)-3-((1-乙基-1H-咪唑-2-基)甲基)吡唑并[1,5-a]吡啶-5-甲酸
步骤1)1-氨基-4-(甲氧基羰基)吡啶-2,4-二硝基苯酚复合盐
将4-吡啶甲酸甲酯(2.0g,14.58mmol)溶于乙腈(20mL)中,然后加入O-(2,4-二硝基苯基)羟胺(2.90g,14.58mmol),混合物于40℃下搅拌反应24小时。TLC检测反应基本完全后,降至室温,将样品减压浓缩至干,得到粗品4.9g,无需纯化直接使用。
步骤2)3-(1-乙基-1H-咪唑-2-羰基)-2-((4-甲氧基苄氧基)甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯
将1-氨基-4-(甲氧基羰基)吡啶-2,4-二硝基苯酚复合盐(3.3g,9.8mmol)溶于四氢呋喃(50mL)中,然后加入1,8-二氮杂二环十一碳-7-烯(2.2g,14.7mmol)和1-(1-乙基-1H-咪唑-5-基)-4-(4-甲氧基苄氧基)丁-2-炔-1-酮(3.5g,11.76mmol),混合物于室温下搅拌反应8小时,将反应液倒入饱和食盐水(30mL)中,用二氯甲烷(30mL×3)萃取,有机相合并,减压浓缩,所得残余物经柱层析纯化,得到产物1.98g,收率45%。LCMS[M+H]
+:449.5。
步骤3)3-(1-乙基-1H-咪唑-5-甲基)-2-((4-甲氧基苄氧基)甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯
将3-(1-乙基-1H-咪唑-5-羰基)-2-((4-甲氧基苄氧基)甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯(1.98g,4.4mmol)溶于四氢呋喃(20mL)中,然后加入对甲苯磺酸一水合物(84mg,0.44mmol)和对甲基苯磺酰肼(0.98g,5.28mmol),混合物于室温下搅拌反应2小时。TLC检测原料反应完全后,过滤,滤渣用四氢呋喃(5.0mL)洗。向合并的有机相中加入Pd/C(0.2g),混合物在氢气氛围下搅拌反应过夜。TLC检测中间体基本反应完全后,过滤,滤渣用二氯甲烷(5.0mL×2)洗,合并的有机相减压浓缩,所得残留样品直接用于下一步反应。
步骤4)3-(1-乙基-1H-咪唑-5-甲基)-2-(羟甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯
将上一步得到的残留样品重新溶于二氯甲烷(20mL),然后加入三氟乙酸(2.0mL),混合物于室温下搅拌反应8小时,LCMS检测反应完全后,将反应液倒入饱和碳酸氢钠(20mL)中,分离出有机层,水层用二氯甲烷(20mL×2)萃取,合并的有机相经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得到产物0.69g,收率50%。LCMS[M+H]
+:315.1。
步骤5)3-((1-乙基-1H-咪唑-5-基)甲基)-2-((甲磺酰基)氧甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯
将3-(1-乙基-1H-咪唑-5-甲基)-2-((4-甲氧基苄氧基)甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯(0.69g,2.2mmol)溶于二氯甲烷(5mL)中,然后加入三乙胺(0.61mL,4.4mmol),混合物置于冰水浴中搅拌,接着滴入甲磺酰氯(0.20mL,2.64mmol),将反应混合物缓慢升至室温搅拌反应。TLC检测原料反应完全后,加入水(10mL),分离出有机层,水层用二氯甲烷(10mL×3)萃取,有机层合并,减压浓缩,残余物经柱层析纯化,得到产物0.73g,收率85%。LCMS[M+H]
+:393.4。
步骤6)2-((4-(6-(4-氰基-2-氟苄基)吡啶-2-基)哌啶-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯
将3-氟-4-((6-(哌啶-4-基)吡啶-2-基)氧甲基)苯甲腈盐酸盐(317mg,0.91mmol)溶于乙腈(5.0mL)中,然后加入碳酸钾(251mg,1.82mmol),混合物于室温下搅拌10分钟,然后加入3-((1-乙基-1H-咪唑-5-基)甲基)-2-((甲磺酰基)氧甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯(500mg,1.27mmol),混合物升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭,反应混合物用乙酸乙酯(10mL×3)萃取,有机层用饱和食盐水洗,经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得到产物276mg,收率50%。LCMS[M+H]
+:608.3。
步骤7)2-((4-(6-(4-氰基-2-氟苄基)吡啶-2-基)哌啶-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)甲基)吡唑并[1,5-a]吡啶-5-甲酸
将2-((4-(6-(4-氰基-2-氟苄基)吡啶-2-基)哌啶-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)甲基)吡唑并[1,5-a]吡啶-5-甲酸甲酯(200mg,0.33mmol)溶于乙醇(1mL),然后加入氢氧化钠溶液(1.0mL,1.0mmol,1mol/L),混合物于50℃下反应过夜。停止反应,减压浓缩除去乙醇,然后加入1N HCl调节pH约等于5,混合物用乙酸乙酯萃取(3mL×3),有机层经无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(二氯甲烷:甲醇=10:1),得到标题化合物(43mg,收率22%)。LCMS[M+H]
+:694.7。
1H NMR(500MHz,DMSO-d
6)δ9.10(s,1H),8.20(s,1H),8.25(s,1H),8.07(t,J=8.2Hz,1H),7.55(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),7.28–7.21(m,2H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.88(s,2H)5.15(s,2H),4.79(s,2H),4.36(q,J=8Hz,2H),2.71(m,1H),2.64–2.55(m,2H),2.30–2.11(m,2H),1.76–1.62(m,4H).1.58(t,J=8Hz,3H)。
实施例9 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-5-甲基-1-(氧杂环丁-2-基甲基)-4-氧代-1,4-二氢噻吩并[2,3-d]嘧啶-6-甲酸
步骤1)4-氰基-3-甲基-5-((氧杂丁-2-基甲基)氨基)噻吩-2-甲酸甲酯
将5-氨基-4-氰基-3-甲基噻吩-2-甲酸甲酯(1.96g,10mmol)溶于乙腈(20mL)中,加入甲磺酸-(氧杂 环丁-2-基)甲酯(2.0g,12mmol)和碳酸钾(2.7g,20mmol),混合物于50℃下搅拌反应6小时,停止反应,降至室温,向反应混合物中加入饱和食盐水(30mL),随后加入二氯甲烷(30mL),分离出有机层,水层用二氯甲烷(30mL×2)萃取,合并的有机相用无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化,得产物2.14g,收率80%。LCMS[M+H]
+:267.2。
步骤2)4-胺甲酰基-3-甲基-5-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸甲酯
将4-氰基-3-甲基-5-((氧杂丁-2-基甲基)氨基)噻吩-2-甲酸甲酯(2.14g,8.0mmol)溶于甲醇(40mL)中,加入甲醇钠(432mg,8.0mmol),混合物于50℃下搅拌反应6小时,停止反应,降至室温,减压浓缩除去甲醇,加入二氯甲烷/水(40mL,v/v=1:1),分离出有机层,水层用二氯甲烷(20mL×2)萃取,合并的有机相用无水硫酸钠干燥,减压浓缩,得粗产品,直接用于下一步反应。
步骤3)2-(氯甲基)-5-甲基-1-(氧杂环丁-2-基甲基)-4-氧代-1,4-二氢噻吩并[2,3-d]嘧啶-6-甲酸甲酯
将4-胺甲酰基-3-甲基-5-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸甲酯的粗产品溶于1,4-二氧六环(20mL)中,加入2-氯-1,1,1-三甲氧基乙烷(1.4g,8.8mmol),氮气保护,120℃封管反应12小时。停止反应,加入水(15mL),乙酸乙酯(20mL×3)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得粗品1.0g,直接用于下一步反应。
步骤4)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-yl)哌啶-1-基)甲基)-5-甲基-1-(氧杂环丁-2-基甲基)-4-氧代-1,4-二氢噻吩并[2,3-d]嘧啶-6-甲酸甲酯
将3-氟-4-((6-(哌啶-4-基)吡啶-2-基)氧甲基)苯甲腈盐酸盐(0.36g,1.0mmol)溶于乙腈(10mL),加入碳酸钾(276mg,2.0mmol),混合物于室温下搅拌10分钟,然后加入2-(氯甲基)-5-甲基-1-(氧杂环丁-2-基甲基)-4-氧代-1,4-二氢噻吩并[2,3-d]嘧啶-6-甲酸甲酯的粗产品(500mg),升温至50℃反应过夜。停止反应,冷却至室温,加入水(10mL)淬灭,乙酸乙酯(10mL×3)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,所得残余物经柱层析纯化得产物308mg,收率50%。LCMS[M+H]
+:618.7。
步骤5)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-5-甲基-1-(氧杂环丁-2-基甲基)-4-氧代-1,4-二氢噻吩并[2,3-d]嘧啶-6-甲酸
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-yl)哌啶-1-基)甲基)-5-甲基-1-(氧杂环丁-2-基甲基)-4-氧代-1,4-二氢噻吩并[2,3-d]嘧啶-6-甲酸甲酯(200mg,0.32mmol)溶于甲醇(2mL)中,加入氢氧化钠溶液(1.0mL,1.0mmol,1mol/L),混合物于50℃下反应过夜。停止反应,减压浓缩除去乙醇,然后加入1N HCl调节pH约等于5,混合物用乙酸乙酯萃取(5mL×3),无水硫酸钠干燥,减压浓缩,残余物经纯化得到产物(58mg,收率30%)。LCMS[M+H]
+:604.7。
1H NMR(500MHz,DMSO-d
6)δ7.64(t,J=8.2Hz,1H),7.54(d,J=8.7Hz,1H),7.46(d,J=8.3Hz,1H),7.37(d,J=8.3Hz,1H),6.76(d,J=8.0Hz,1H),6.66(d,J=7.7Hz,1H),5.51(s,2H),5.25(m,1H),4.75(m,2H),4.68–4.60(m,1H),4.43(m,1H),3.98(s,2H),3.05–2.93(m,2H),2.82–2.71(m,1H),2.63(m,1H),2.52(s,3H),2.48(m,1H),2.31(m,2H),1.85–1.63(m,4H)。
实施例10 2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-6-甲酸
步骤1)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-溴咪唑并[1,2-a]吡啶-6-甲酸甲酯
将3-氟-4-((6-(哌嗪-1-基)吡啶-2-基)氧甲基)苯甲腈盐酸盐(1.05g,2.89mmol)溶于二氯甲烷(10mL)中,加入足量三乙胺搅拌至体系澄清后,加入饱和氯化钠(10mL),分离出有机相,水相用二氯甲烷(10mL)萃取,有机相合并,然后减压浓缩,得游离样品(905mg,2.89mmol);将游离样品重新溶于乙腈(20mL)中,加入3-溴-2-(氯甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(800mg,2.63mmol),碳酸钾(727mg,5.26mmol)以及催化量碘化钾,加热至50℃反应过夜;将反应冷却至室温,倒入饱和氯化钠(20mL)中,用乙酸乙酯(20mL×3)萃取,有机相合并后用无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化(PE:EA=1:1 to EA),得产物,为淡黄色固体895mg,收率79%。
步骤2)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-溴咪唑并[1,2-a]吡啶-6-甲酸甲酯(250mg,0.43mmol),4-甲氧基苯硼酸(98mg,0.65mmol),醋酸钯(9.6mg,0.043mmol),三苯基膦(33.8mg,0.129mmol)及碳酸钾(118.6mg,0.86mmol)溶于甲苯(5mL)中,在氮气保护下,70℃反应过夜;LC-MS检测原料反应完全后,直接减压浓缩,所得残留物经柱层析纯化(PE:EA=1:2 to 1:3),得产物,为白色固体212mg,收率81%。
1H NMR(500MHz,CDCl
3)δ8.79(s,1H),7.74(d,J=10.0Hz,1H),7.65–7.60(m,2H),7.49(s,1H),7.47(s,1H),7.45–7.40(m,2H),7.36(d,J=10.0Hz,1H),7.13(s,1H),7.11(s,1H),6.16(dd,J=10.0,5.0Hz,2H),5.43(s,2H),3.93(d,J=3.5Hz,6H),3.79(s,2H),3.70(s,2H),3.48(s,4H),2.60(s,4H)。
步骤3)2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-6-甲酸
将2-((4-(6-(4-氰基-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-(4-甲氧基苯基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(200mg,0.33mmol),碳酸铯(538mg,1.65mmol)溶于1,4-二氧六环/水(2.0mL,v/v=4:1)中,混合物在100℃下搅拌反应;TLC检测原料转化完全后,直接使用厚制备版分离纯化(DCM:MeOH=15:1),得产物,为类白色固体18mg,收率9%。HPLC P>94.7%,LCMS[M+H]
+:593.2。
1H NMR(500MHz,DMSO-D
6)δ8.67(s,1H),7.88(d,J=10.0Hz,1H),7.70(m,1H),7.66(m,3H),7.63(s,1H),7.61(s,1H),7.46(t,J=10.0Hz,1H),7.20(s,1H),7.18(s,1H),6.31(d,J=8.5Hz,1H),6.11(d,J=8.5Hz,1H),5.39(s,2H),3.86(s,3H),2.03–1.97(m,4H)。
实施例11 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)1-乙基-1H-咪唑-5-甲醛
向250mL单口瓶中加入4-咪唑甲醛(5g,52.03mmol),碳酸钾(14.3g,104.6mmol)和乙腈(60mL),冰浴降温至0℃,滴加碘乙烷(12.2g,78.04mmol),滴加完毕后,升至室温搅拌30min,然后升温至60℃反应过夜。TLC检测原料反应完全后,停止反应,加入二氯甲烷(100mL)稀释,加入水(100mL),分离出有机相,水相用二氯甲烷(100mL)萃取,合并有机相,经无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残留物经柱层析纯化(PE:EA=1:1),得产物1.2g,收率18%。
步骤2)(1-乙基-1H-咪唑-5-基)甲醇
将1-乙基-1H-咪唑-5-甲醛(1g,8.06mmol)溶于甲醇(10mL)中,冰浴下加入硼氢化钠(613mg,16.1mmol),室温搅拌1小时。TLC检测原料反应完全后,加入冰水(3mL)淬灭,减压浓缩除去甲醇,加入乙酸乙酯(15mL*3)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩蒸除溶剂,得无色油状产物500mg,收率49%。
步骤3)5-(氯甲基)-1-乙基-1H-咪唑盐酸盐
将(1-乙基-1H-咪唑-5-基)甲醇(500mg,3.97mmol)置于50mL单口瓶中,加入二氯亚砜(5mL),室温反应4h。停止反应,减压浓缩,得类粗产物为白色固体(800mg)。
步骤4)5-((叔丁氧羰基)氨基)-4-(((1-乙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-甲酸乙酯
将5-(氯甲基)-1-乙基-1H-咪唑盐酸盐(380mg,2.10mmol)溶于乙腈(20mL),加入4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯(500mg,1.75mmol)和DIPEA(903mg,7.00mmol),室温搅拌反应12h。TLC检测反应完全后,停止反应,减压浓缩除去乙腈,加入水(10mL),用乙酸乙酯(20mL*3)萃取, 合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残留物经柱层析纯化,得黄色泡沫状产物250mg,收率36%。
步骤5)2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-(((1-乙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-甲酸乙酯(250mg,0.63mmol)置于100mL单口瓶中,加入二氯甲烷(25mL),三氟乙酸(0.5mL)和2-氯-1,1,1-三甲氧基乙烷(294mg,1.90mmol),混合物于室温搅拌反应1h。TLC检测反应完全后,减压浓缩得粗品,经制备型TLC纯化得粗品产物260mg。
步骤6)2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体2的盐酸盐(182mg,0.51mmol)溶于乙腈(5mL),加入碳酸钾(235mg,1.7mmol)和2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(150mg,0.425mmol),升温至50℃搅拌反应12h。TLC检测反应完全后,加入水(5mL),用乙酸乙酯(15mL*3)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,然后经制备型TLC纯化得浅黄色油状产物30mg。
步骤7)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(30mg,0.047mmol)溶于乙醇(2mL),加入氢氧化钠(1mL,1M)溶液,室温搅拌反应15h。TLC检测反应完全后,减压浓缩除去乙醇,加入水(2mL),用乙酸乙酯(2mL*2)萃取,分离出水相,将水相调节pH约等于5,然后用乙酸乙酯(3mL*3)萃取,有机相经无水硫酸钠干燥,过滤,减压浓缩,冻干得类白色固体产物14.3mg,收率50%。纯度:97.0%。
1H NMR(500MHz,DMSO-d
6)δ7.77(s,1H),7.52(t,J=8.2Hz,1H),7.45(d,J=9.4Hz,2H),7.29(d,J=8.3Hz,1H),7.06(s,1H),7.01(s,1H),6.32(d,J=8.1Hz,1H),6.09(d,J=7.8Hz,1H),5.58(s,2H),5.30(s,2H),3.88(q,J=7.4Hz,2H),3.80(s,2H),3.50(s,4H),2.52(s,4H),0.99(t,J=7.2Hz,3H)。
实施例12 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(136mg,0.43mmol)置于25mL单口瓶中,加入碳酸钾(147mg,1.06mmol),乙腈(5mL)和中间体2盐酸盐(140mg,粗品,0.35mmol),升温60℃反应2.5h。冷却至室温,加入水(5mL),用乙酸乙酯(10mL*3)萃取,合并有机相,然后用饱和食盐水洗,无水硫酸钠干燥,经制备型TLC纯化得标题化合物为无色透明油状物60mg,收率22%。
步骤2)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(75mg,0.12mmol)溶于乙醇(3mL),加入氢氧化钠(1.5mL,1M)溶液,室温搅拌反应15h。TLC检测原料反应完全后,减压浓缩除去乙醇,加入水(2mL),用乙酸乙酯(2mL*2)萃取,分离出水相,水相调节pH约等于5,然后用乙酸乙酯(3mL*3)萃取,有机相经无水硫酸钠干燥,过滤, 减压浓缩,加入乙腈、水和两滴三氟乙酸,冻干得类白色固体产物28mg,收率38%,纯度:85.7%。
1H NMR(500MHz,MeOH-d
4)δ8.94(s,1H),7.72–7.63(m,1H),7.56–7.48(m,2H),7.36(s,1H),7.29–7.20(m,2H),6.93(d,J=7.3Hz,1H),6.74(dd,J=8.4,2.2Hz,1H),5.80(s,2H),5.45(s,2H),4.77–4.70(m,2H),4.24(q,J=7.7Hz,2H),3.92–3.81(m,2H),3.37–3.33(m,2H),3.03(s,1H),2.20(d,J=10.5Hz,4H),2.20(td,J=7.5Hz,2.3Hz,3H)。
实施例13 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-4-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-4-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体2的盐酸盐(30mg,0.085mmol)溶于乙腈(1.5mL),加入K
2CO
3(30mg,0.213mmol)和2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(25mg,0.071mmol),升温至60℃搅拌反应12h。TLC检测反应完全后,加入水(5mL),用乙酸乙酯(15mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,经制备型TLC纯化得浅黄色油状产物30mg,收率66%。
步骤2)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-4-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-4-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(30mg,0.047mmol)溶于乙醇(4mL),加入氢氧化钠(1.5mL,1M)溶液,室温反应8.5h。TLC检测反应完全后,减压浓缩除去乙醇。加入水(2mL),乙酸乙酯萃取(2mL*2),有机相弃去,水相调节pH约等于5,乙酸乙酯萃取(3mL*3),有机相经无水硫酸钠干燥,过滤,减压浓缩,冻干得类白色固体产物14.3mg,收率50%。纯度:97.7%。
1H NMR(500MHz,MeOH-d
4)δ7.79(s,1H),7.54–7.44(m,3H),7.33(s,1H),7.21(t,J=8.7Hz,2H),6.34(d,J=8.1Hz,1H),6.17(d,J=7.9Hz,1H),5.52(s,2H),5.36(s,2H),4.18(s,2H),4.06(q,J=7.5Hz,2H),3.63(s,4H),2.89(d,J=5.6Hz,4H),1.43(t,J=7.4Hz,3H)。
实施例14 (S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)(S)-氧杂环丁-2-基甲醛
将(S)-氧杂环丁-2-基甲醇(760mg,8.64mmol)溶于二氯甲烷(10mL)中,加入Dess-martin(5.5g,12.96mmol),混合物室温搅拌过夜。停止反应,过滤,得滤液60mL,无需纯化直接用于下一步反应。
步骤2)5-溴-4-硝基噻吩-2-甲酸乙酯
将5-溴噻吩-2-甲酸乙酯(4.5g,19.14mmol)置于50mL两口瓶中,加入H
2SO
4,然后将反应体系置于冰水浴中降温至0℃,滴加65%HNO
3(6.3mL),滴加完全后缓慢升至室温,反应1h。TLC检测反应完全后,停止反应。将反应液倒入冰水(50mL)中,用乙酸乙酯(30mL×3)萃取,合并有机相,用饱 和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得浅黄色固体产物,3.36g,收率63%。
步骤3)5-((2,4-二甲氧基苄基)氨基)-4-硝基噻吩-2-甲酸乙酯
将5-溴-4-硝基噻吩-2-甲酸乙酯(2g,7.14mmol)和2,4-二甲氧基苄胺(1.55g,9.28mmol)置于单口瓶中,加入碳酸钾(3.95g,28.56mmol)和乙腈(45mL),室温搅拌2.5h。TLC检测反应完全后,停止反应,将反应液倒入冰水(50mL)中,用乙酸乙酯(60mL×3)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得浅黄色固体产物,2.7g,收率>99%。
步骤4)5-氨基-4-硝基噻吩-2-甲酸乙酯
将5-((2,4-二甲氧基苄基)氨基)-4-硝基噻吩-2-甲酸乙酯(2.7g,7.1mmol)溶于二氯甲烷(30mL)中,加入三氟乙酸(3mL),混合物室温搅拌过夜。TLC检测反应完全后,停止反应,倒入冰水(100mL)中,用乙酸乙酯(150mL×3)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,得浅黄色固体产物,1.9g,>99%。
步骤5)5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-甲酸乙酯
将5-氨基-4-硝基噻吩-2-甲酸乙酯(1.9g,8.79mmol)溶于四氢呋喃(40mL),加入三乙胺(1.34g,13.2mmol)和(Boc)
2O(2.3g,10.55mmol),室温搅拌过夜。TLC检测反应完全后,停止反应,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得产物1.45g,收率64%。
步骤6)4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-硝基噻吩-2-甲酸乙酯(1.18g,3.73mmol)溶于甲醇(7.5mL),加入水(2.5mL)、铁粉(1.04g,18.65mmol)和氯化铵(400mg,7.46mmol),升温至60℃反应2h。TLC检测反应完全后,停止反应,冷却至室温,减压浓缩蒸除甲醇,过滤除去不溶物,加入水(10mL),用乙酸乙酯萃取(20mL×3),合并有机相,用饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得黄棕色油状产物800mg,75%。
步骤7)(S)-5-((叔丁氧羰基)氨基)-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯(632mg,2.2mmol)溶于二氯甲烷(18mL)中,加入(S)-氧杂环丁基-2-甲醛(228mg,2.65mmol),滴入3滴乙酸,室温搅拌反应20分钟。加入三乙酰氧基硼氢化钠(933mg,4.4mmol),室温再搅拌反应1h。加入二氯甲烷(30mL)稀释,加入水(20mL)洗,分离出有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得深棕色油状产物330mg,38%。
步骤8)(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将(S)-5-((叔丁氧羰基)氨基)-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-甲酸乙酯(130mg,0.365mmol)溶于四氢呋喃(6.5mL),加入乙酸(22mg,0.365mmol)氮气鼓气1分钟,加入2-氯-1,1,1-三甲氧基乙烷(113mg,0.733mmol),100℃封管反应12h。12h后,加入对甲苯磺酸一水合物(7mg,0.036mmol),然后在75℃反应1h。停止反应,加入水(15mL),用乙酸乙酯(20mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,得深棕色油状粗品140mg,直接用于下一步反应。
步骤9)(S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体2(112mg,0.255mmol)溶于乙腈(3mL),加入碳酸钾(202mg,1.46mmol)室温搅拌10分钟,加入(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(140mg,0.365mmol),混合样升温50℃反应过夜。TLC检测到原料反应完全后,停止反应,冷却至室温,加入水(5mL)淬灭,用乙酸乙酯(10mL*3)萃取,有机相用饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得黄棕色油状产物40mg,26%。
步骤10)(S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将(S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌嗪-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(40mg,0.067mmol)溶于乙醇(1mL),加入1N氢氧化钠溶液(1mL),混合物在50℃反应过夜。TLC检测原料反应完全后,停止反应,减压浓缩蒸除乙醇,用1N HCl调节pH约等于5,乙酸 乙酯(3mL*3)萃取,无水硫酸钠干燥,减压浓缩蒸除溶剂,所得残余物柱层析纯化,得类白色固体产物10.7mg,产率:28%。纯度:88.9%,LCMS[M+H]
+:572.1。
1H NMR(500MHz,DMSO-d
6)δ7.79(s,1H),7.52(t,J=8.2Hz,1H),7.45(d,J=8.7Hz,2H),7.30(d,J=8.3Hz,1H),6.33(d,J=8.0Hz,1H),6.09(d,J=7.7Hz,1H),5.30(s,2H),5.09(d,J=7.5Hz,1H),4.65(dd,J=15.1,6.8Hz,1H),4.58–4.45(m,2H),4.41–4.33(m,1H),3.83(d,J=13.6Hz,1H),3.73(d,J=13.6Hz,1H),3.55–3.41(m,8H),2.69(t,J=9.1Hz,1H),2.42–2.35(m,1H)。
实施例15 (S)-2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)-2-甲基哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)(S)-2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)-2-甲基哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将(S)-1-(6-(4-氯-2-氟苄氧基)-3,5-二氟吡啶-2-基)-3-甲基哌嗪盐酸盐(155mg,0.38mmol)溶于乙腈(3mL),加入碳酸钾(158mg,1.14mmol),升温至70℃搅拌20分钟,加入2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(134mg,0.38mmol),反应过夜。停止反应,冷却至室温,加入水(5mL),用乙酸乙酯(3*5mL)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经制备型TLC纯化分离得浅黄色油状产物60mg,7%。
步骤2)(S)-2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)-2-甲基哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将(S)-2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)-2-甲基哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(60mg,0.087mmol)溶于乙醇(2mL),加入氢氧化锂(1mL,1M),室温下搅拌过夜。减压浓缩除去乙醇,加入水(3mL),用乙酸乙酯(3mL)萃取,有机相弃去,水相调节pH约等于5,乙酸乙酯(3*5mL)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,冻干得类白色固体产物42.0mg,73%。纯度:98%。
1H NMR(500MHz,MeOH-d
4)δ8.03(s,1H),7.47(t,J=8.1Hz,1H),7.40(t,J=10.2Hz,1H),7.27–7.19(m,2H),7.12(s,1H),7.06(s,1H),5.80–5.60(m,2H),5.43(s,2H),4.36(d,J=14.0Hz,1H),4.03(q,J=7.5Hz,2H),3.63(d,J=14.0Hz,1H),3.54(t,J=15.3Hz,2H),3.09(t,J=10.8Hz,1H),2.97(d,J=11.1Hz,1H),2.78(d,J=12.1Hz,1H),2.70(d,J=8.6Hz,1H),2.45(t,J=10.4Hz,1H),1.28–1.20(m,6H)。
实施例16 2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将1-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪盐酸盐(112mg,0.283mmol),2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(100mg,0.283mmol),碳酸钾(156mg,1.132mmol)和乙腈(3mL)置于15毫升密封管中,升温至70℃反应过夜。冷却至室温,过滤除去不溶物,经制备型TLC纯化得黄色油状产物60mg,31%。
实施例17 2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸三氟乙酸盐复合物
将2-((4-(6-((4-氯-2-氟苄基)氧基)-3,5-二氟吡啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(60mg,0.089mmol)溶于乙醇(2mL),加入氢氧化锂(1mL,1M)室温搅拌过夜。减压浓缩除去乙醇,加入水(2mL),乙酸乙酯(2mL)萃取,有机相弃去,水相调节pH约等于5,乙酸乙酯(5mL*3)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,加入2滴三氟乙酸,冻干得类白色固体产物36.0mg,63%。纯度:98%。
1H NMR(500MHz,MeOH-d
4)δ9.08(s,1H),7.58(d,J=2.1Hz,1H),7.52–7.45(m,2H),7.43(s,1H),7.26(d,J=8.0Hz,2H),5.83(s,2H),5.44(s,2H),4.29(dd,J=14.9,7.2Hz,4H),3.50(s,4H),3.09(s,4H),1.49–1.43(m,3H)。
实施例18 2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将4-((4-氯-2-氟苄基)氧基)-5-氟-2-(哌嗪-1-基)吡啶盐酸盐(107mg,0.283mmol),碳酸钾(156mg,1.132mmol)和乙腈(3mL)置于15毫升的密封管中,升温至70℃搅拌40分钟,加入2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(100mg,0.283mmol),混合物于70℃反应过夜。过滤除去不溶物,浓缩,残余物经制备型TLC纯化得黄色油状产物50mg,收率27%。
实施例19 2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸三氟乙酸盐复合物
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(50mg,0.076mmol)溶于乙醇(2mL),加入氢氧化锂(1mL,1M)室温搅拌过夜。减压浓缩除去乙醇,加入水(2mL),用乙酸乙酯(2mL)萃取,有机相弃去,水相调节pH约等于5,乙酸乙酯(5mL*3)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,加入2滴三氟乙酸,冻干得类白色固体产物32mg,67%。纯度:94%。
1H NMR(500MHz,MeOH-d
4)δ9.08(s,1H),8.08(s,1H),7.59(s,1H),7.53(t,J=8.3Hz,1H),7.42(s,1H),7.28(t,J=7.8Hz,2H),5.83(s,2H),5.51(s,2H),4.35(s,2H),4.29(d,J=7.5Hz,2H),3.88(s,4H),3.07(s,4H),1.46(td,J=7.4,2.1Hz,3H)。
实施例20 6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[2,1-b]噻唑-2-甲酸乙酯
步骤1)6-(氯甲基)-5-咪唑并[2,1-b]噻唑-2-甲酸乙酯
将2-氨基噻唑-5羧酸乙酯(1.72g,10mmol)和二氯丙酮(2.54mg,20mmol)置于30mL密封管中,加入氯苯(20mL),混合物在130℃搅拌2小时,冷却至室温,减压浓缩蒸除溶剂,所得残余物经柱层析纯化,得淡黄色固体产物1.02g,收率42%。
步骤2)6-(氯甲基)-5-碘咪唑并[2,1-b]噻唑-2-甲酸乙酯
将6-(氯甲基)-5-咪唑并[2,1-b]噻唑-2-甲酸乙酯(0.6g,2.45mmol)和碘代丁二酰亚胺(0.6g,2.7mmol)溶于乙腈(20mL)中,室温下搅拌反应过夜,减压浓缩蒸除溶剂,所得残余物经柱层析纯化,得白色固体产物0.6g,收率66%。
步骤3)6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-碘咪唑并[2,1-b]噻唑-2-甲酸乙酯
将中间体2的盐酸盐(1.07g,3mmol)和6-(氯甲基)-5-碘咪唑并[2,1-b]噻唑-2-甲酸乙酯(1.22g,3.3mmol)溶于乙腈(30mL),加入三乙胺(0.9g,9mmol),在60℃下反应14h。冷却至室温,减压浓缩蒸除溶剂,所得残余物经柱层析纯化,得淡黄色固体产物1.3g,收率66%。
步骤4)6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[2,1-b]噻唑-2-甲酸乙酯
将6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-碘咪唑并[2,1-b]噻唑-2-甲酸乙酯(129mg,0.2mmol)溶于无水四氢呋喃(5mL),混合物冷却至-40℃,滴入异丙基氯化镁(0.3mL,1.3M),搅拌反应0.5h,然后加入1-乙基-5-咪唑甲醛。继续于-40℃下搅拌1h后,缓慢升至室温并搅拌反应过夜,加入饱和氯化铵溶液(5mL)淬灭反应,分液,有机相干燥,减压浓缩蒸除溶剂,所得残余物经柱层析纯化,得浅黄色油状产物70mg,收率54%。
实施例21 6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[2,1-b]噻唑-2-甲酸
将6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[2,1-b]噻唑-2-甲酸乙酯(26mg,0.04mmol)溶于甲醇(1.2mL),加入氢氧化锂(8.4mg,0.2mmol)和水(0.4mL),混合物在室温反应3h。停止反应,用1N HCl调节pH约等于5,经制备型TLC提纯,冻干得白色固体12.1mg,收率48%。纯度:90.4%。
1H NMR(500MHz,CD
3OD)δ8.02(s,1H),7.82(s,1H),7.45(dd,J=12.9,7.3Hz,2H),7.20(t,J=9.6Hz,2H),6.61(s,1H),6.42(s,1H),6.26(d,J=7.8Hz,1H),6.13(d,J=7.8Hz,1H),5.33(s,2H),4.27–4.12(m,2H),3.74(dd,J=55.7,13.6Hz,2H),3.47–3.38(m,4H),2.71–2.58(m,4H),1.44(t,J=7.2Hz,3H)。
实施例22 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
步骤1)2-(氯甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-氨基吡啶-5羧酸甲酯(4.08g,27mmol)和二氯丙酮(6.81g,54mmol)置于60mL密封管中,加入氯苯(50mL),混合物在130℃下搅拌3小时,冷却至室温,减压浓缩蒸除溶剂,残余物经柱层析纯化,得白色固体产物3.02g,收率50%。
步骤2)2-(氯甲基)-3-碘咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-(氯甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(3.18g,14.2mmol)和碘代丁二酰亚胺(3.52g,15.7mmol)溶于乙腈(40mL)中,室温下搅拌反应过夜,减压浓缩蒸除溶剂,残余物经柱层析纯化,得白色固体产 物4.4g,收率89%。
步骤3)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-碘咪唑并[1,2-a]吡啶-6-甲酸甲酯
将中间体2的盐酸盐(0.54g,1.5mmol)和2-(氯甲基)-3-碘咪唑并[1,2-a]吡啶-6-甲酸甲酯(0.63g,1.8mmol)溶于乙腈(15mL),加入三乙胺(530mg,5.3mmol),在60℃下反应14h。冷却至室温,减压浓缩蒸除溶剂,残余物经柱层析纯化,得白色固体产物0.6g,收率63%。
步骤4)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-碘咪唑并[1,2-a]吡啶-6-甲酸甲酯(635mg,1mmol)溶于无水THF(15mL),混合物冷却至-40℃,滴入异丙基氯化镁(1.2mL,1.3M),搅拌反应0.5h,然后加入1-乙基-5-咪唑甲醛。继续于-40℃下搅拌1h后,缓慢升至室温并搅拌反应过夜,加入饱和氯化铵溶液(15mL)淬灭反应,分离出有机相,有机相用无水硫酸钠干燥,减压浓缩蒸除溶剂,残余物经柱层析纯化,得浅黄色固体产物308mg,收率49%。
实施例23 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[1,2-a]吡啶-6-甲酸
将2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌嗪-1-基)甲基)-3-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(63mg,0.1mmol)溶于甲醇(3.6mL),加入氢氧化锂(21mg,0.5mmol)和水(1.2mL),混合物在室温反应3h。停止反应,用1N HCl调节pH约等于5,经制备型TLC提纯,冻干得白色固体10.8mg,17%。纯度:92.3%。
1H NMR(500MHz,CD
3OD)δ8.91(s,1H),7.91(d,J=9.3Hz,1H),7.80(s,1H),7.54(d,J=9.1Hz,1H),7.44(q,J=7.8Hz,2H),7.20(t,J=9.9Hz,2H),6.59(s,1H),6.38(s,1H),6.24(d,J=7.9Hz,1H),6.12(d,J=7.7Hz,1H),5.32(s,2H),4.29(qd,J=14.3,7.1Hz,2H),3.85(dd,J=35.3,13.8Hz,2H),3.37(s,4H),2.62(dd,J=35.3,11.1Hz,4H),1.52(t,J=7.0Hz,3H)。
实施例24 6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-(1-乙基-1H-咪唑-5-羰基)咪唑并[2,1-b]噻唑-2-甲酸乙酯
将6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-((1-乙基-1H-咪唑-5-基)(羟基)甲基)咪唑并[2,1-b]噻唑-2-甲酸乙酯(26mg,0.04mmol)和Dess Martin高碘烷(25mg,0.06mmol)置于25mL单口瓶中,加入DCM(5mL),室温下搅拌反应过夜,减压浓缩蒸除溶剂,所得残余物经柱层析纯化,得白色固体产物18mg,收率69%。
实施例25 6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-(1-乙基-1H-咪唑-5-羰基)咪唑并[2,1-b]噻唑-2-甲酸
将6-((4-(6-((4-氯-2-氟苄基)氧基)哌啶-2-基)哌嗪-1-基)甲基)-5-(1-乙基-1H-咪唑-5-羰基)咪唑并[2,1-b]噻唑-2-甲酸(50mg,0.08mmol)溶于甲醇(2.4mL),加入LiOH(16.8mg,0.4mmol)和水(0.6mL), 混合物在室温反应3h。停止反应,用1N HCl调节pH约等于5,经制备型TLC提纯,冻干得白色固体13.3mg,收率27%。纯度:87.3%。
1H NMR(500MHz,CD
3OD)δ8.54(s,1H),8.04(s,1H),7.97(s,1H),7.49–7.40(m,2H),7.21(t,J=10.5Hz,2H),6.25(d,J=8.1Hz,1H),6.10(d,J=7.8Hz,1H),5.33(s,2H),4.43(q,J=7.0Hz,2H),3.67(s,2H),3.42(s,4H),2.47(s,4H),1.49(t,J=7.1Hz,3H)。
实施例26 2-((4-(2-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-4-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻唑并[2,3-d]咪唑-5-甲酸
步骤1)2-((4-(2-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-4-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻唑并[2,3-d]咪唑-5-甲酸乙酯
将2-((4-氯-2-氟苄基)氧基)-5-氟-4-(哌嗪-1-基)吡啶盐酸盐(220mg,0.58mmol),碳酸钾(321mg,2.32mmol)和乙腈(5mL)置于15毫升的密封管中,升温至60℃搅拌40分钟,加入2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(180mg,0.51mmol),混合物于60℃下反应过夜。过滤除去不溶物,浓缩,经制备型TLC纯化得无色油状产物140mg,收率42%。
步骤2)2-((4-(2-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-4-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻唑并[2,3-d]咪唑-5-甲酸
将2-((4-(2-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-4-基)哌嗪-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻唑并[2,3-d]咪唑-5-甲酸乙酯(140mg,0.213mmol)溶于乙醇(3mL),加入氢氧化锂(1.5mL,1M),混合物于室温搅拌过夜。减压浓缩除去乙醇,加入水(3mL),乙酸乙酯(3mL)萃取,有机相弃去,水相用1M稀盐酸调节pH约等于6,析出大量固体,过滤,用水洗两次,干燥得类白色固体产物97mg,收率72%。纯度:93.8%。
1H NMR(500MHz,MeOH-d
4)δ9.11(s,1H),8.10(d,J=6.9Hz,1H),7.58(d,J=2.1Hz,1H),7.52(t,J=8.1Hz,1H),7.46(s,1H),7.27(t,J=8.7Hz,2H),5.84(s,2H),5.45(s,2H),4.29(d,J=7.4Hz,2H),4.21(s,2H),3.97(s,4H),3.00(s,4H),1.45(td,J=7.4,2.1Hz,3H)。
实施例27 2-((4-(2-((4-氯-2-氟苄基)氧基)嘧啶-4-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)2-((4-(2-((4-氯-2-氟苄基)氧基)嘧啶-4-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-((4-氯-2-氟苄基)氧基)-4-(哌啶-4-基)嘧啶盐酸盐(180g,0.5mmol),碳酸钾(276mg,2.0mmol),乙腈(3mL)置于15mL密封管中,混合物加热至70℃搅拌30分钟,加入2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(250mg,0.51mmol)反应过夜。冷却至室温,过滤除去不溶物,减压浓缩蒸除溶剂,残留物经柱层析纯化,得黄色油状产物30mg,收率9%。
步骤2)2-((4-(2-((4-氯-2-氟苄基)氧基)嘧啶-4-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(2-((4-氯-2-氟苄基)氧基)嘧啶-4-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(60mg,0.094mmol)溶于乙醇(2mL),加入氢氧化锂(1mL,1M),混合物于室温搅拌过夜。减压浓缩除去乙醇,加入水(3mL),乙酸乙酯(3mL)萃取,有机相弃去,水相调节 pH约等于5,乙酸乙酯(5mL*3)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩蒸除溶剂,加入2滴三氟乙酸,冻干得类白色固体产物45mg,收率79%。纯度:97.8%。
1H NMR(500MHz,MeOH-d
4)δ9.05(s,1H),8.54(d,J=5.1Hz,1H),7.62–7.53(m,2H),7.39(s,1H),7.27(t,J=10.3Hz,2H),7.11(d,J=5.1Hz,1H),5.81(s,2H),5.51(s,2H),4.65(s,2H),4.27(q,J=7.3Hz,2H),3.77(d,J=12.0Hz,2H),3.22(s,2H),3.06(s,1H),2.17(d,J=23.1Hz,4H),1.48(t,J=7.3Hz,3H)。
实施例28 6-((1-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-4-基)((1-乙基-1H-咪唑-5-基)甲基)氨基)苯并[d]异噻唑-3-甲酸
步骤1)2-氯-6-((4-氯-2-氟苄基)氧基)吡啶
将4-氯-2-氟苄醇(3g,18.7mmol)溶于THF(30mL),冰水浴下加入氢化钠(1.12g,28.05mmol,60%),将混合物搅拌0.5小时后加入2,6-二氯吡啶(3.32g,22.4mmol),室温搅拌12h。停止反应,加入冰水(30mL),乙酸乙酯(30mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,残余物经柱层析纯化,得白色固体产物2g,85%。
步骤2)6-溴苯并[d]异噻唑-3-甲酸甲酯
将6-溴苯并[d]异噻唑-3-甲酸(10g,38.75mmol)溶于甲醇(100mL),加入浓硫酸(2.5mL),混合物升温70℃反应过夜。停止反应,减压浓缩除去甲醇,加入乙酸乙酯(200mL),依次用水(100mL)、饱和碳酸氢钠溶液(100mL)、饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩,得浅黄色固体产物7.4g,收率70%。
步骤3)6-((1-(叔丁氧羰基)哌啶-4-基)氨基)苯并[d]异噻唑-3-甲酸甲酯
将6-溴苯并[d]异噻唑-3-甲酸甲酯(2g,7.36mmol),1-Boc-4-氨基哌啶(1.77g,8.84mmol),碳酸铯(4.8g,14.72mmol),x-phos(702mg,1.47mmol),Pd
2(dba)
3(674mg,0.74mmol)置于100mL单口瓶中,加入甲苯(50mL),混合物在氮气环境下升温110℃反应过夜。停止反应,冷却至室温,过滤,滤液浓缩,残余物经柱层析纯化,得浅黄色固体产物1.8g,收率63%。
步骤4)6-(哌啶-4-基氨基)苯并[d]异噻唑-3-甲酸甲酯的三氟乙酸盐
将6-((1-(叔丁氧羰基)哌啶-4-基)氨基)苯并[d]异噻唑-3-甲酸甲酯(1.55g,3.96mmol)溶于二氯甲烷(20mL),加入三氟乙酸(4mL),混合物于室温搅拌过夜。浓缩得2.0g,收率>99%。
步骤5)6-((1-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-4-基)氨基)苯并[d]异噻唑-3-甲酸甲酯
将6-(哌啶-4-基氨基)苯并[d]异噻唑-3-甲酸甲酯的三氟乙酸盐(2.0g,3.96mmol),2-氯-6-((4-氯-2-氟苄基)氧基)吡啶(1.08g,3.96mmol),碳酸铯(5.4g,46.63mmol),x-phos(189mg,0.396mmol),Pd
2(dba)
3(181mg,0.198mmol)置于100mL单口瓶中,加入甲苯(50mL),混合物在氮气环境下升温至110℃反应过夜。停止反应,冷却至室温,过滤,滤液浓缩,残余物经柱层析纯化,得无色透明油状产物260mg,12%。
步骤6)6-((1-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-4-基)((1-乙基-1H-咪唑-5-基)甲基)氨基)苯并[d]异噻唑-3-甲酸甲酯
将6-((1-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-4-基)氨基)苯并[d]异噻唑-3-甲酸甲酯(260mg,0.49mmol),1-氧基-5-氯甲基咪唑盐酸盐(98mg,0.54mmol),碳酸钾(271mg,1.96mmol)置于48毫升的密封管中,加入乙腈(5mL),混合物升温至70℃反应过夜。过滤除去不溶物,经制备型TLC纯化得黄色油状产物60mg,19%。
步骤7)6-((1-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-4-基)((1-乙基-1H-咪唑-5-基)甲基)氨基)苯并[d]异噻唑-3-甲酸
将6-((1-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-4-基)((1-乙基-1H-咪唑-5-基)甲基)氨基)苯并[d]异噻唑-3-甲酸甲酯(60mg,0.094mmol)溶于乙醇(3mL)中,加入1M的氢氧化锂的水溶液(1.5mL),混合物在室温下搅拌过夜。减压浓缩除去乙醇,调节pH约等于5,乙酸乙酯(3*5mL)萃取,合并有机相,无水硫酸钠干燥,浓缩,残余物经制备型TLC纯化,冻干得米黄色产物18mg,30%。纯度:95.8%。
1H NMR(500MHz,DMSO-d
6)δ9.11(s,1H),8.37(d,J=9.3Hz,1H),7.57(s,1H),7.51(t,J=8.2Hz,1H),7.45(d,J=9.2Hz,2H),7.35(s,1H),7.28(d,J=8.4Hz,1H),7.18(d,J=9.4Hz,1H),6.39(d,J=8.2Hz,1H),6.06(d,J=7.8Hz,1H),5.31(s,2H),4.65(s,2H),4.41(d,J=12.8Hz,2H),4.26(q,J=7.6Hz,3H),2.97(t,J=12.6Hz,2H),1.88(d,J=11.9Hz,2H),1.70(dd,J=12.0,3.9Hz,2H),1.48(t,J=7.3Hz,3H)。
实施例29 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3,6-二甲酸
步骤1)6-氯烟酸叔丁酯
将6-氯盐酸(4.9g,31mmol)溶于氯化亚砜(27mL)中,回流反应过夜;原料反应完全后,减压浓缩至干,往残余物中加入二氯甲烷(10mL),将叔丁醇(28mL,310mmol)的二氯甲烷(10mL)溶液滴入上述体系中,再加入三乙胺(43mL,310mmol)及催化量的4-二甲氨基吡啶(244mg,2mmol),继续反应,TLC监测,待转化完全后,用二氯甲烷(83mL)稀释,所得溶液用饱和碳酸氢钠(100mL*3)洗,然后再用水(100mL*3)洗,有机相用无水硫酸钠干燥,减压浓缩,得棕色固体3.04g,收率46%;
1H NMR(500MHz,CDCl
3)δ8.94(s,1H),8.19(d,J=8.0Hz,1H),7.39(d,J=8.0Hz,1H),1.61(s,9H)。
步骤2)6-氨基烟酸叔丁酯
将6-氯烟酸叔丁酯(3.04g,14.09mmol)、叠氮化钠(1.83g,28.15mmol)、三苯基膦(14.38g,28.15mmol)溶于二甲基亚砜(80mL),混合物于120℃反应过夜,然后于100℃下过周末,TLC检测原料转化完全后,降温,加入1.0M盐酸溶液(20mL),混合物继续在120℃下反应1小时;冷却至室温,加入1.0M盐酸溶液(20mL),加入水(100mL),用乙酸乙酯(100mL*3)萃取,水层调节PH至中偏碱性后,再用乙酸乙酯(100mL*3)萃取,得到的乙酸乙酯层用水(100mL)洗,饱和食盐水(100mL)洗,无水硫酸钠干燥,浓缩至干,得黄色油状物2.15g,收率79%。
1H NMR(500MHz,CDCl
3)δ8.67(s,1H),7.96(d,J=8.5Hz,1H),6.46(d,J=8.5Hz,1H),5.04(br,2H),1.57(s,9H)。
步骤3)2-(氯甲基)-3-(乙氧基羰基)-咪唑并[1,2-a]吡啶-6-甲酸叔丁酯
将6-氨基烟酸叔丁酯(2.15g,11mmol)溶于甲苯(40mL)中,加入2,4-二氯乙酰乙酸乙酯(3.07g,15.4mmol),回流反应过夜;TLC监测原料基本转化完全后,直接减压浓缩至干,残余物经柱层析纯化(PE:EA=1:0 to 2:1),得白色固体920mg,收率25%。
1H NMR(500MHz,CDCl
3)δ9.95(s,1H),7.99(d,J=9.0Hz,1H),7.72(d,J=9.0Hz,1H),5.08(s,2H),4.54(q,J=7.0Hz,2H),1.66(s,9H),1.52(t,J=7.0Hz,3H)。
步骤4)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3-(乙氧基羰基)-6-甲酸叔丁酯
将2-(4-氯-2-氟苄氧基)-6-(哌啶-4-基)吡啶盐酸盐(1.0g,2.8mmol)溶于乙腈(20mL)中,加入碳酸钾(1.5g,10.88mmol),混合物于室温搅拌5分钟,然后再加入6-(叔丁基)3-乙基2-(氯甲基)咪唑并[1,2-a]吡啶-3,6-二甲酸酯(0.62g,1.83mmol),于50℃反应过夜;TLC监测原料转化完全后,冷却至室温,加入乙酸乙酯(20mL)稀释,加入水(20mL),分离出有机层,水层用乙酸乙酯(20mL)萃取,有机层合并后用无水硫酸钠干燥,浓缩,残余物经柱层析纯化(PE:EA=1:2),得黄色油状物1.03g,收率90%。
1H NMR(500MHz,CDCl
3)δ9.98(s,1H),7.94(d,J=9.0Hz,1H),7.72(d,J=9.0Hz,1H),7.53-7.43(m,2H),7.12(m,2H),6.75(d,J=7.5Hz,1H),6.60(d,J=7.5Hz,1H),5.41(s,2H),4.51(q,J=7.0Hz,2H),4.12(s,2H),3.24(d,J=10.5Hz,2H),2.60(t,J=10.0Hz,1H),2.34(t,J=11.5Hz,2H),1.99(q,J=12.5Hz,1H),1.89(d,J=12.0Hz,2H),1.65(s,9H),1.52(t,J=7.0Hz,3H)。
步骤5)6-(叔丁氧羰基)-2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3-甲酸
将6-(叔丁基)3-乙基2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3,6-二 甲酸酯(255mg,0.41mmol)溶于乙醇/水(10mL,v/v=3:1)中,加入氢氧化锂一水合物(28mg,0.61mmol),混合物于室温反应过夜;LC-MS监测原料反应完全后,调节pH至4左右,用二氯甲烷(15mL*3)萃取,无水硫酸钠干燥,浓缩至干,得泡沫状固体151mg,收率62%。LC-MS ESI[M+H]
+:595.2。
步骤6)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3,6-二甲酸
将6-(叔丁氧羰基)-2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3-甲酸(30mg,0.05mmol)溶于20%三氟乙酸的二氯甲烷(1.2mL)溶液中,混合物于室温搅拌过夜;LC-MS监测原料转化完全后,直接浓缩,然后加入乙腈,冻干,得黄色固体28.1mg,收率>99%。
1H NMR(500MHz,DMSO-d
6)δ9.96(s,1H),8.01(d,J=10.0Hz,1H),7.91(d,J=9.5Hz,1H),7.70(t,J=7.5Hz,1H),7.62(t,J=8.5Hz,1H),7.50(d,J=10.0Hz,1H),7.34(d,J=7.5Hz,1H),6.91(d,J=7.0Hz,1H),6.75(d,J=9.0Hz,1H),5.41(s,2H),4.84(s,2H),3.30(br,4H),2.93(br,1H),2.01(br,4H)。
实施例30 5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4-((1-乙基-1H-咪唑-5-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸
步骤1)5-甲基噻吩-2-甲酸甲酯
将5-甲基-2-噻吩甲酸(15g,105.6mmol)溶于甲醇(150mL),加入硫酸(3mL),混合物升温至90℃反应过夜。停止反应,冷却至室温,减压浓缩除去甲醇,加入水(100mL),乙酸乙酯萃取(50mL*3),合并有机相,依次用5%氢氧化钠溶液(50mL*2),饱和食盐水洗,无水硫酸干燥,过滤,减压浓缩得黄色油状产物15.2g,收率92%。
步骤2)5-甲基-4-硝基噻吩-2-甲酸甲酯
将5-甲基噻吩-2-甲酸甲酯(15.2g,97.4mmol)溶于硫酸(34mL),混合物降温至0℃,滴加硝酸的硫酸溶液(8.2mL硝酸溶于23mL硫酸),反应1小时,将反应液缓慢倒入冰水(400mL)中,乙酸乙酯(3*200mL)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得浅黄色固体产物8.3g,收率39%。
步骤3)5-(2-(二甲氨基)丙-1-烯-1-基)-4-硝基噻吩-2-甲酸甲酯
将5-甲基-4-硝基噻吩-2-甲酸甲酯(7.1g,35.3mmol)溶于N,N-二甲基乙酰胺(35mL),加入1,1-二甲氧基-N,N-二甲基乙胺(7.05g,52.95mmol),混合物升温100℃反应1小时。停止反应,冷却至室温,析出大量固体,过滤,滤渣用乙酸乙酯洗,干燥,得砖红色固体产物5.1g,收率53%。
步骤4)5-甲基-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯
将5-(2-(二甲氨基)丙-1-烯-1-基)-4-硝基噻吩-2-甲酸甲酯(5.1g,18.87mmol)溶于甲醇(100mL),加入铁粉(5.27g,94.35mmol),氯化铵(2.02g,37.74mmol)和水(30mL),混合物升温至60℃,反应过夜。停止反应,冷却至室温,过滤除去不溶物,减压浓缩除去甲醇,加入乙酸乙酯萃取(3*50mL),合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得浅黄色固体产物1.66g,收率45%。
步骤5)4-(叔丁氧羰基)-5-甲基-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯
将5-甲基-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯(500mg,2.56mmol)溶于THF(10mL),加入三乙胺(518mg,5.12mmol),(Boc)
2O(1.12g,5.12mmol)和DMAP(312mg,2.56mmol),混合物升温至50℃反应4小时,停止反应,减压浓缩,残余物经柱层析纯化得浅黄色固体产物530mg,收率70%。
步骤6)4-(叔丁氧羰基)-5-(溴甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯
将4-(叔丁氧羰基)-5-甲基-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯(200mg,0.68mmol)溶于四氯化碳(4mL),加入N-溴代丁二酰亚胺(145mg,0.81mmol)和偶氮二异丁腈(11mg,0.068mmol),混合物升温至50℃反应2.5小时。停止反应,减压浓缩,得黄色固体粗品产物400mg,直接用于下一步反应。
步骤7)4-(叔丁氧羰基)-5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯
将4-(叔丁氧羰基)-5-(溴甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯(400mg,粗品,0.68mmol),中间体11的三氟乙酸盐(600mg,0.75mmol),碳酸钾(376mg,2.72mmol)置于48毫升的密封管中,加入乙腈(15mL),升温60℃反应过夜。停止反应,加入水(15mL),乙酸乙酯(15mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,柱层析纯化得浅棕色油状产物200mg,收率48%。
步骤8)5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯
将4-(叔丁氧羰基)-5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯(200mg,0.326mmol)溶于二氯甲烷(10mL),加入三氟乙酸(3mL),混合物于室温搅拌过夜。停止反应,减压浓缩,加入乙酸乙酯(10mL)溶解,饱和碳酸氢钠(10mL)洗,水相再用乙酸乙酯萃取(2*10mL),合并有机相,饱和食盐水洗,无水硫酸钠干燥,过滤,减压浓缩,得浅棕色油状产物189mg,收率>99%。
步骤9)5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4-((1-乙基-1H-咪唑-5-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯
将5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯(180mg,0.35mmol)溶于N,N-二甲基甲酰胺(5mL),加入碳酸铯(342mg,1.05mmol)和1-乙基-5氯甲基咪唑(82.4mg,0.455mmol),混合物升温至100℃,反应过夜。停止反应,减压浓缩,残余物经柱层析纯化得产物25mg,收率11%。
步骤10)5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4-((1-乙基-1H-咪唑-5-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸
将5-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-4-((1-乙基-1H-咪唑-5-基)甲基)-4H-噻吩并[3,2-b]吡咯-2-甲酸甲酯(25mg,0.04mmol)溶于MeOH(1.5mL),加入1N的氢氧化钠水溶液(0.5mL)反应过夜。停止反应,减压浓缩除去溶剂,加入水(2mL),1N稀盐酸调节pH约6,乙酸乙酯(5mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,再加入乙酸乙酯(5mL)使其溶解,过滤除去不溶物,减压浓缩,冻干得类白色固体产物14mg,收率58%。LCMS[M+H]
+:608.2。
1H NMR(500MHz,MeOH-d
4)δ7.83(s,1H),7.60(t,J=7.8Hz,1H),7.48(t,J=8.0Hz,1H),7.31(s,1H),7.20(ddd,J=11.0,9.1,2.0Hz,2H),6.85(d,J=7.3Hz,1H),6.81(s,1H),6.67(d,J=8.2Hz,1H),6.55(s,1H),5.56(s,2H),5.40(s,2H),4.00(s,2H),3.97(q,J=7.3Hz,2H),3.32(s,0H),2.78(p,J=7.7Hz,1H),2.57(s,2H),1.98(q,J=7.4,6.7Hz,4H),1.15(t,J=7.3Hz,3H)。
实施例31 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-3-(氧杂环丁烷-3-基氨基甲酰基)咪唑并[1,2-a]吡啶-6-羧酸
将6-(叔丁氧羰基)-2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)咪唑并[1,2-a]吡啶-3-甲酸(60mg,0.1mmol),3-氮杂环丁胺(14.6mg,0.2mmol),HATU(42mg,0.11mmol),三乙胺(20mg,0.2mmol)和二氯甲烷(2mL)置于5mL样品瓶中,混合物于室温下搅拌反应过夜。减压浓缩蒸除溶剂,所得残余物经柱层析纯化,得中间产物35mg。随后将该中间产物溶于甲醇(3mL)和水(1mL)的混合液中,加入氢氧化锂(20mg),混合物于60℃下搅拌反应过夜,减压除去大部分甲醇,加入5mL水,调pH值到5-6之间,析出沉淀,过滤,干燥,得白色固体产物30mg,两步收率50%。LCMS[M+H]
+:594.2。纯度95%.
1H NMR(500MHz,CD
3OD)δ11.62(s,1H),10.11(s,1H),7.85–7.83(m,1H),7.73(d,J=3.0Hz,1H),7.65(t,J=6.0Hz,1H),7.55(t,J=8.0Hz,1H),7.48–7.46(m,2H),7.23–7.30(m,1H),6.90(d,J=5.0 Hz,1H),6.68(d,J=5.0Hz,1H),5.34(s,2H),5.22–5.18(m,1H),4.90(t,J=5.0Hz,2H),4.63(t,J=5.0Hz,2H),4.06–4.02(m,1H),3.95(s,2H),3.08(d,J=5.8Hz,2H),2.77–2.73(m,1H),2.34–2.29(m,2H),1.95–1.89(m,4H)。
实施例32 2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(3-羟基氮杂环丁基-1-羰基)咪唑并[1,2-a]吡啶-6-甲酸
步骤1)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(乙氧羰基)咪唑并[1,2-a]吡啶-6-甲酸叔丁酯
将2-(氯甲基)-3-(乙氧基羰基)-咪唑并[1,2-a]吡啶-6-甲酸叔丁酯(50mg,0.15mmol)和中间体6(0.6g,2.7mmol)溶于乙腈(2mL)中,加入三乙胺(45mg,0.4mmol),混合物于60℃下搅拌反应过夜,停止反应,残余物直接经柱层析纯化,得白色固体产物60mg,收率4%。
步骤2)6-(叔丁氧羰基)-2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(乙氧羰基)咪唑并[1,2-a]吡啶-3-甲酸
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(乙氧羰基)咪唑并[1,2-a]吡啶-6-甲酸叔丁酯(90mg,0.14mmol)溶于乙醇(4mL)和水(1mL)的混合液中,混合物于60℃下搅拌24h。冷却至室温,减压浓缩,残余物经柱层析纯化,得白色固体产物50mg,收率57%。
步骤3)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(3-羟基氮杂环丁基-1-羰基)咪唑并[1,2-a]吡啶-6-甲酸
将6-(叔丁氧羰基)-2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(乙氧羰基)咪唑并[1,2-a]吡啶-3-甲酸(40mg,0.065mmol),氮杂环丁烷-3-醇盐酸盐(11mg,0.1mmol),HATU(38mg,0.1mmol),三乙胺和二氯甲烷(2mL)置于5mL样品瓶中,混合物于室温下搅拌反应过夜。停止反应后,残余物直接经柱层析纯化,得中间产物35mg。随后将该中间产物溶于甲醇(3mL)和水(1mL)的混合液中,加入氢氧化锂(11mg),混合物于60℃下搅拌反应过夜,减压浓缩,加入水(5mL),调节PH值至5-6之间,析出沉淀,过滤,干燥,得白色固体产物15mg,收率38%。LCMS[M+H]
+:614.2。纯度95%。
1H NMR(500MHz,CD
3OD)δ9.21(s,1H),8.04(d,J=3.0Hz,1H),8.01–7.99(m,1H),7.67(d,J=9.4Hz,1H),7.52(t,J=8.1Hz,1H),7.29–7.25(m,2H),5.49(s,2H),4.72–4.67(m,1H),4.46–4.43(m,2H),4.10(s,2H),4.05–4.02(m,2H),3.87–3.84(m,4H),2.85–2.84(m,4H)。
实施例33 (2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸单乙酯
步骤1)5-溴噻吩-2-磷酸二乙酯
将乙酸钯(231mg,0.987mmol),1,1'-双(二苯基膦)二茂铁(1.09g,1.97mmol),乙酸钾(426mg,4.41mmol)置于25毫升两口瓶中,加入四氢呋喃(100mL)和三乙胺(4.79g,47.46mmol),混合物在氮气保护,升温至68℃反应25分钟,加入2,5-二溴噻吩(10.5g,43.47mmol)和亚磷酸二乙酯(5.46g, 39.48mmol),混合物反应过夜。停止反应,冷却至室温,加入水(100mL),用乙酸乙酯(100mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得黄色浑浊液产物3.7g,收率11%。
步骤2)5-溴-4-硝基噻吩-2-磷酸二乙酯
将5-溴噻吩-2-磷酸二乙酯(3.7g,12.32mmol)溶于浓硫酸(16.5mL),混合物降温至0℃,滴加硝酸(5.5mL,65%),反应0.5小时,TLC显示原料消失,停止反应。将反应液倒入冰水(50mL)中,乙酸乙酯(50mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得浅黄色油状产物3.24g,收率77%。
步骤3)5-((2,4-二甲氧基苄基)氨基)-4-硝基噻吩-2-磷酸二乙酯
将5-溴-4-硝基噻吩-2-磷酸二乙酯(3.24g,9.42mmol)溶于乙腈(40mL),加入碳酸钾(3.9g,28.26mmol)和2,4-二甲氧基苄胺(2.05g,12.24mmol),混合物升温至50℃反应4小时,然后室温下反应过夜。TLC显示原料消失,停止反应,加入水(30mL),乙酸乙酯(30mL*3)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得黄棕色油状粗品产物5g。
步骤4)5-(二乙氧基膦酰基)-3-硝基噻吩-2-氨基甲酸叔丁酯
将5-((2,4-二甲氧基苄基)氨基)-4-硝基噻吩-2-磷酸二乙酯(5g,9.42mmol)溶于二氯甲烷(20mL),加入三氟乙酸(3mL),混合物于室温反应7小时,TLC显示原料消失,减压浓缩得粗品,加入(Boc)
2O(4.1g,18.84mmol),三乙胺(4.76g,47.1mmol),DMAP(346mg,2.83mmol)和四氢呋喃(50mL),混合物于室温搅拌过夜。停止反应,加入水(50mL),用乙酸乙酯(50mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化,得浅黄色固体产物3.42g,收率>99%。
步骤5)3-氨基-5-(二乙氧基)膦酰基噻吩-2-氨基甲酸叔丁酯
将5-(二乙氧基膦酰基)-3-硝基噻吩-2-氨基甲酸叔丁酯(1.4g,3.68mmol)溶于乙醇,加入雷尼镍(200mg),用氢气置换3次,混合物于氢气球保护下反应4.5小时。停止反应,过滤除去不溶物,减压浓缩,得棕色固体产物1.2g,收率93%。
步骤6)5-(二乙氧基膦酰基)-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-氨基甲酸叔丁酯
将3-氨基-5-(二乙氧基)膦酰基噻吩-2-氨基甲酸叔丁酯(1.2g,3.42mmol)溶于乙腈,加入1-乙基-5-氯甲基咪唑盐酸盐(744mg,4.11mmol)和二异丙基乙胺(1.76g,13.68mmol),混合物于室温下反应过夜。停止反应,加入水(20mL),乙酸乙酯(20mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩溶剂,残余物经柱层析纯化得浅黄色油状粗品产物1.4g,收率89%。
步骤7)(2-(氯甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸二乙酯
将5-(二乙氧基膦酰基)-3-(((1-乙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-氨基甲酸叔丁酯(700mg,1.53mmol)溶于二氯甲烷(70mL),加入三氟乙酸(3mL)和2-氯-1,1,1-三甲氧基乙烷(945mg,6.11mmol),混合物于室温下搅拌过夜。减压浓缩得粗品,经柱层析纯化,得产物300mg,收率47%。
步骤8)(2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸二乙酯
将(2-(氯甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸二乙酯(190mg,0.45mmol)溶于乙腈(5mL),加入碳酸钾(248mg,1.8mmol)和中间体11的三氟乙酸盐(236mg,0.54mmol),混合物升温至70℃反应过夜。停止反应,过滤除去不溶物,减压浓缩,残余物经柱层析纯化得产物100mg,收率32%。
步骤9)(2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸单乙酯
将(2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸二乙酯(30mg,0.043mmol)溶于乙醇(1.5mL),加入1N氢氧化钠(1mL),混合物于室温反应2天,升温至70℃反应过夜。TLC显示原料消失,停止反应,减压浓缩除去溶剂,加入水(2mL),用1N稀盐酸调节pH约等于5,乙酸乙酯(2mL*3)萃取,合并有机相,无水硫酸钠干燥,减压浓缩得粗品,加入乙酸乙酯(10mL)使其溶解,过滤除去不溶物,减压浓缩,冻干得米黄色固体产物13.6mg,收率43%。纯度:94%。LCMS[M+H]
+:673.1。
1H NMR(500MHz,MeOH-d
4)δ7.78(s,1H),7.59(t,J=7.8Hz,1H),7.50(t,J=8.0Hz,1H),7.30–7.16(m,2H),7.04(s,1H),6.96(d,J=8.1Hz,1H),6.83(d,J =7.3Hz,1H),6.65(d,J=8.2Hz,1H),5.67(s,2H),5.43(s,2H),4.01(q,J=7.3Hz,2H),3.81(q,J=7.3Hz,4H),3.02(d,J=11.3Hz,2H),2.66(s,1H),2.32–2.24(m,2H),1.91–1.77(m,4H),1.16(dt,J=12.6,7.1Hz,6H)。
实施例34 (S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体11的三氟乙酸盐(360mg,1.01mmol)溶于乙腈(10mL),加入碳酸钾(558mg,1.46mmol),混合物于室温下搅拌10分钟,加入(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(400mg,1.01mmol),升温50℃反应过夜。停止反应,冷却至室温,加入5mL水,用乙酸乙酯(10mL*3)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经柱层析纯化得浅棕色油状产物230mg,收率38%。
1H NMR(500MHz,MeOH-d
4)δ7.89(s,1H),7.59(t,J=7.8Hz,1H),7.51(t,J=8.1Hz,1H),7.22(ddd,J=15.1,8.9,2.0Hz,2H),6.84(d,J=7.4Hz,1H),6.65(d,J=8.2Hz,1H),5.44(s,2H),5.30–5.22(m,1H),4.74(dd,J=15.1,6.9Hz,1H),4.63(td,J=15.1,13.3,4.8Hz,2H),4.46(dt,J=9.4,6.0Hz,1H),4.37(q,J=7.1Hz,2H),3.94–3.75(m,2H),3.04(d,J=11.3Hz,1H),2.95(d,J=11.4Hz,1H),2.80(dq,J=11.8,7.7Hz,1H),2.70–2.61(m,1H),2.57–2.47(m,1H),2.33–2.20(m,2H),1.91–1.82(m,4H),1.39(t,J=7.1Hz,3H)。
实施例35 (S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将(S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(230mg,0.384mmol)溶于乙醇(3mL),加入1N氢氧化钠(1mL),混合物于室温反应过夜。停止反应,减压浓缩除去乙醇,加入1N三氟乙酸调节pH约等于6,乙酸乙酯萃取(5mL*3),无水硫酸钠干燥,减压浓缩得粗品,加入乙酸乙酯(10mL)溶解产物,过滤除去不溶物,减压浓缩,冻干得类白色固体产物152mg,收率69%。纯度:97%,LCMS[M+H]
+:571.0。
1H NMR(500MHz,MeOH-d
4)δ7.64–7.58(m,2H),7.50(t,J=8.0Hz,1H),7.21(ddd,J=12.2,8.8,2.0Hz,2H),6.87(d,J=7.3Hz,1H),6.68(d,J=8.2Hz,1H),5.42(s,2H),5.22(dd,J=7.2,2.6Hz,1H),4.73–4.62(m,2H),4.59(dd,J=15.3,2.7Hz,1H),4.43(dt,J=9.3,5.9Hz,1H),4.27(d,J=2.6Hz,2H),3.46(dd,J=27.6,11.9Hz,2H),2.88–2.75(m,4H),2.56–2.45(m,1H),2.03(q,J=8.4,6.9Hz,4H)。
实施例36 (2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸二铵盐
将(2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-基)磷酸二乙酯(30mg,0.043mmol)溶于氢溴酸-乙酸(1.5mL,33%),混合物于室温反应2天。停止反应,减压浓缩除去溶剂,加入水(1mL)使其溶解,制备分离纯化,浓缩,加入0.5毫升氨水,冻干得类白色固体产物10.0mg,收率34%。纯度:94%,LCMS[M-H]
-:677.2。
实施例37 (S)-2-((4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)(S)-2-((4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体1的三氟乙酸盐(68mg,0.197mmol)溶于乙腈(5mL),加入碳酸钾(110mg,0.8mmol),然后加入(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(100mg,0.197mmol),混合物升温至70℃反应4h。停止反应,冷却至室温,加入5mL水,用乙酸乙酯(3*10mL)萃取,饱和食盐水洗,无水硫酸钠干燥,减压浓缩,残余物经制备型TLC纯化得浅棕色油状产物37mg,收率32%。
步骤2)(S)-2-((4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将(S)-2-((4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(37mg,0.063mmol)溶于乙腈(1mL),加入DBU(19.2mg,0.126mmol),混合物升温反应过夜。停止反应,减压浓缩除去乙腈,加入10%的三氟乙酸调节pH约等于5~6,乙酸乙酯(5mL*3)萃取,合并有机相,无水硫酸钠干燥,减压浓缩得粗品,残余物经制备型TLC纯化,冻干得类白色固体产物15mg,收率42%。纯度:91%,LCMS[M+H]
+:562.2。
1H NMR(500MHz,MeOH-d
4)δ7.69(t,J=7.6Hz,1H),7.65–7.60(m,2H),7.59–7.54(m,2H),6.88(d,J=7.3Hz,1H),6.72(d,J=8.2Hz,1H),5.54(s,2H),5.28–5.21(m,1H),4.68(td,J=16.6,16.0,6.9Hz,2H),4.60(dd,J=15.2,2.7Hz,1H),4.45(q,J=6.8,6.4Hz,1H),4.13(d,J=3.9Hz,2H),3.37(d,J=8.0Hz,1H),3.26(d,J=11.9Hz,1H),2.79(dd,J=17.5,9.3Hz,2H),2.65(d,J=26.0Hz,2H),2.55–2.48(m,1H),1.94(s,4H)。
实施例38 2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((3-羟基氮杂环丁-1-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸
步骤1)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-(氯甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(0.9g,4mmol)和中间体6(1.5g,4mmol)溶于无水乙腈(25ml)中,加入三乙胺(2mL),随后将混合物于115℃下搅拌反应3小时,减压浓缩蒸除溶剂,残余物经柱层析纯化,得黄色固体产物1.5g,收率71%。
步骤2)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(羟甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(1.5g,2.8mmol)溶于甲醛水溶液(20mL)和乙酸(2mL)中,混合物于100℃下搅拌反应过夜,减压浓缩蒸除溶剂,残余物经柱层析纯化,分离得黄色油状产物800m g,收率51%。
步骤3)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(((甲磺酰基)氧基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(羟甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(800mg,1.4mmol)与三乙胺(0.4mL,2.8mmol)溶于无水二氯甲烷(20mL)中,冷却至-40℃,滴加入甲磺酰氯(220mg,2.0mmol),滴完后将混合物缓慢升至室温并搅拌反应过夜。减压浓缩蒸除溶剂,残余物经柱层析纯化,得产物280mg,收率31%。
步骤4)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((3-羟基氮杂环丁-1-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(((甲磺酰基)氧基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(64mg,0.1mmol)和氮杂环丁烷-3-醇(22mg,0.3mmol)溶于乙腈(2mL)中, 加入三乙胺(40mg,0.4mmol),然后混合物于90℃下搅拌反应2.5h。减压浓缩蒸除溶剂,残余物经柱层析纯化,得产物38mg,收率62%。
步骤5)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((3-羟基氮杂环丁-1-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((3-羟基氮杂环丁-1-基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(35mg,0.057mmol)溶于甲醇(3mL)和水(1mL)中,加入氢氧化锂(6.3mg,0.22mmol),混合物于30℃下搅拌反应2h。用稀盐酸调pH 6左右,减压蒸除大部分甲醇,析出大量沉淀,加入水(2mL),过滤,抽干得白色固体产物20mg,收率66%。纯度98%,LCMS[M+H]
+:600.3。
1H NMR(500MHz,CDCl
3)δ9.46(s,1H),7.96–7.91(m,2H),7.51(d,J=5.0Hz,1H),7.41–7.37(m,1H),7.15–7.08(m,2H),5.40(s,2H),4.87(s,2H),4.67–4.65(m,1H),4.41(s,2H),4.16–4.05(m,4H),3.86(s,4H),3.67(s,1H),2.95(s,4H)。
实施例39 2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((氧杂环丁-3-基氨基)甲基)咪唑并[1,2-a]吡啶-6-甲酸
步骤1)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((氧杂环丁-3-基氨基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-(((甲磺酰基)氧基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(64mg,0.1mmol)和3-氧杂环丁胺(14.6mg,0.2mmol)溶于乙腈(2mL)中,加入三乙胺(20mg,0.4mmol),然后混合物于90℃下搅拌反应2.5h。冷却至室温,减压浓缩蒸除溶剂,残余物经柱层析纯化,得产物35mg,收率57%。
步骤2)2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((氧杂环丁-3-基氨基)甲基)咪唑并[1,2-a]吡啶-6-甲酸
将2-((4-(4-((4-氯-2-氟苄基)氧基)-5-氟嘧啶-2-基)哌嗪-1-基)甲基)-3-((氧杂环丁-3-基氨基)甲基)咪唑并[1,2-a]吡啶-6-甲酸甲酯(35mg,0.058mmol)溶于甲醇(3mL)和水(1mL)中,加入氢氧化锂(6.3mg,0.22mmol),混合物于30℃下搅拌反应过夜。用稀盐酸调pH6左右,减压浓缩大部分甲醇,析出大量沉淀,加入水(2mL),过滤,抽干得白色固体产物13.8mg,收率40%。纯度97%,LCMS[M+H]
+:600.3。
1H NMR(500MHz,CDCl
3)δ9.04(s,1H),8.01(d,J=5.0Hz,1H),7.60(d,J=5.0Hz,1H),7.50(d,J=5.0Hz,1H),7.44(t,J=5.0Hz,1H),7.18–7.14(m,2H),5.45(s,2H),4.97(t,J=5.0Hz,2H),4.66(t,J=5.0Hz,2H),4.30(d,J=5.0Hz,4H),3.92–3.87(m,6H),2.79–2.77(m,4H)。
实施例40(S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将(S)-2-((4-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(40mg,0.07mmol)溶于二氯甲烷(1.5mL),加入EDCI(24mg,0.126mmol)、HOBt(9mg,0.07mol)和氨水(3滴),混合物于室温搅拌4小时。停止反应,减压浓缩,残余物经制备型TLC纯化,冻干得类白色固体产物15mg,收率38%。LCMS[M+H]
+:570.2。
1H NMR(500MHz,MeOH-d
4)δ7.81(s,1H),7.59(t,J=7.8Hz,1H),7.52(d,J=8.1Hz,1H),7.22(ddd,J=14.5,9.0,2.0Hz,2H),6.84(d,J=7.3Hz,1H),6.65(d,J=8.2Hz,1H),5.44(d,J=2.5Hz,2H),5.27(dd,J=7.2,2.8Hz,1H),4.76–4.58(m,3H),4.48(dt,J=9.4,6.0Hz,1H),3.94–3.73(m,2H),3.05(d,J=11.4Hz,1H),2.96(d,J=11.6Hz,1H),2.82(ddd,J=11.9,5.9,2.9Hz,1H),2.65(p,J=8.0Hz,1H),2.53(dq,J=11.3,7.5Hz,1H),2.34–2.22(m,2H),1.90–1.80(m,4H)。
实施例41 (S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲 基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)(S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体9(100mg,0.28mmol),(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(137mg,0.28mmol),碳酸钾(155mg,1.12mmol)和乙腈(5mL)置于15毫升密封管中,升温至60℃反应过夜。冷却至室温,过滤除去不溶物,经制备型TLC纯化得黄色油状产物36mg,收率22%。
步骤2)(S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将(S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(36mg,0.06mmol)溶于乙醇(2mL)中,加入1M的氢氧化钠的水溶液(1mL),混合物于室温搅拌过夜。减压浓缩除去乙醇,用1N的稀盐酸调节pH约等于6,乙酸乙酯(5mL*3)萃取,合并有机相,加入无水硫酸钠干燥,浓缩,再加入乙酸乙酯(10mL)过滤,浓缩冻干得类白色固体产物30mg,收率88%。纯度:99%,LCMS[M+H]+:568.2。
1H NMR(500MHz,CD
3OD)δ7.77(s,1H),7.53(t,J=8.2Hz,1H),7.30–7.22(m,3H),7.06(t,J=5.4Hz,2H),6.93(dd,J=8.1,2.1Hz,1H),6.14(s,1H),5.21(ddd,J=14.4,7.0,2.6Hz,1H),5.14(s,2H),4.71(dd,J=15.2,6.8Hz,1H),4.67–4.62(m,1H),4.60(dd,J=15.2,2.7Hz,1H),4.43(dt,J=9.2,6.0Hz,1H),4.19(q,J=14.2Hz,2H),3.53–3.40(m,2H),3.12–3.00(m,2H),2.81–2.72(m,1H),2.66(s,2H),2.53–2.45(m,1H)。
实施例42 (S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)(S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体10(100mg,0.28mmol)、(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(137mg,0.28mmol)、碳酸钾(155mg,1.12mmol)和乙腈(4mL)置于15毫升密封管中,升温至60℃反应过夜。冷却至室温,过滤除去不溶物,减压浓缩蒸除溶剂,残余物经制备型TLC纯化得黄色油状产物80mg,收率48%。
步骤2)(S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将(S)-2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(80mg,0.134mmol)溶于乙醇(3mL)中,加入1M的氢氧化钠的水溶液(1.5mL),混合物于室温下搅拌过夜。减压浓缩除去乙醇,用1N的稀盐酸调节pH约等于6,乙酸乙酯(5mL*3)萃取,合并有机相,加入无水硫酸钠干燥,浓缩,再加入乙酸乙酯(10mL)过滤,浓缩冻干得类白色固体产物57mg,收率74。纯度:98%,LCMS[M+H]+:570.2。
1H NMR(500MHz,CD
3OD)δ7.69(s,1H),7.53(t,J=8.2Hz,1H),7.25(ddd,J=8.5,5.0,2.2Hz,3H),6.87(dd,J=12.6,4.5Hz,3H),5.23(qd,J=7.0,2.6Hz,1H),5.12(s,2H),4.70(dt,J=14.2,7.3Hz,2H),4.60(dd,J=15.3,2.6Hz,1H),4.44(dt,J=9.2,6.0Hz,1H),4.25(s,2H),3.42(dd,J=31.1,12.3Hz,2H),2.86–2.68(m,4H),2.52(ddd,J=16.4,11.5,7.3Hz,1H),2.04–1.96(m,2H),1.93–1.80(m,2H)。
实施例43 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸异丙酯
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(100mg,0.134mmol)置于5mL单口瓶中,加入K
2CO
3(41mg,0.295mmol)、乙腈(2mL)和2-溴丙烷(18mg,0.147mmol),混合物升温至70℃反应过夜。冷却至室温,加入水(5mL),乙酸乙酯(3*10mL)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,残余物经制备型TLC纯化,冻干得类白色固体产物30mg,收率34%。纯度:99%,LCMS[M+H]
+:651.2。
1H NMR(500MHz,CD
3OD)δ7.84(s,1H),7.62–7.58(m,1H),7.50(t,J=8.0Hz,1H),7.26–7.17(m,2H),7.16–7.08(m,2H),6.84(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.69(s,2H),5.43(s,2H),5.16(dt,J=12.5,6.2Hz,1H),4.00(q,J=7.3Hz,2H),3.86(s,2H),3.04(d,J=11.5Hz,2H),2.72–2.63(m,1H),2.30(dd,J=11.5,9.2Hz,2H),1.84(dt,J=21.4,11.1Hz,4H),1.40–1.28(m,6H),1.21–1.12(m,3H)。
实施例44 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸异丁酯
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(100mg,0.134mmol)置于5mL单口瓶中,加入K
2CO
3(41mg,0.295mmol)、乙腈(2mL)和溴代异丁烷(20mg,0.147mmol),混合物升温至70℃反应过夜。冷却至室温,加入水(5mL),用乙酸乙酯(10mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩蒸除溶剂,残余物经制备型TLC纯化,冻干得类白色固体产物40mg,收率45%。纯度:99%,LCMS[M+H]
+:664.1。
1H NMR(500MHz,CD
3OD)δ7.83(s,1H),7.63–7.57(m,1H),7.50(t,J=8.1Hz,1H),7.25–7.18(m,2H),7.12(d,J=3.5Hz,2H),6.84(d,J=7.3Hz,1H),6.66(d,J=8.1Hz,1H),5.70(s,2H),5.42(s,2H),4.06(d,J=6.5Hz,2H),4.00(q,J=7.3Hz,2H),3.86(s,2H),3.04(d,J=11.6Hz,2H),2.73–2.62(m,1H),2.30(td,J=11.6,2.6Hz,2H),2.03(dp,J=13.4,6.7Hz,1H),1.91–1.77(m,4H),1.17(t,J=7.3Hz,3H),1.01(d,J=6.7Hz,6H)。
实施例45 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸-2-(吗啉-1-基)乙酯
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(100mg,0.164mmol)置于25mL单口瓶中,加入HATU(94mg,0.246mmol),吗啉乙醇(32mg,0.246mmol),四氢呋喃(5mL)和二异丙基乙胺(42mg,0.328mmol),混合物升温至70℃反应过夜。冷却至室温,加入水(5mL),用乙酸乙酯(10mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩溶剂,残余物经制备型TLC纯化,冻干得类白色固体产物11mg,收率9%。纯度:98%,LCMS[M+H]
+:722.2。
1H NMR(500MHz,CD
3OD)δ7.82(s,1H),7.62–7.57(m,1H),7.50(t,J=8.2Hz,1H),7.24–7.18(m,2H),7.16(s,1H),7.11(s,1H),6.84(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.70(s,2H),5.43(s,2H),4.43(t,J=5.6Hz,2H),4.00(q,J=7.3Hz,2H),3.86(s,2H),3.75–3.67(m,4H),3.04(d,J=11.5Hz,2H),2.76(t,J=5.6Hz,2H),2.71–2.63(m,1H),2.64–2.55(m,4H),2.30(dd,J=12.5,10.1Hz,2H),1.93–1.77(m,4H),1.16(t,J=7.3Hz,3H)。
实施例46 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(135mg,0.38mmol)置于25mL单口瓶中,加入碳酸钾(210mg,1.52mmol),乙腈(5mL)和中间体11(300mg,0.38mmol),混合物升温至60℃反应2.5h。冷却至室温,加入水(5mL),乙酸乙酯(10mL*3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,残余物经制备型TLC纯化得无色透明油状物60mg,收率22%。
1H NMR(500MHz,氯仿-d)δ7.62(s,1H),7.53(t,J=7.7Hz,1H),7.46(d,J=7.9Hz,1H),7.18–7.10(m,4H),6.75(d,J=7.3Hz,1H),6.65(d,J=8.1Hz,1H),5.55(s,2H),5.42(s,2H),4.35(q,J=7.1Hz,2H),3.86(dd,J=12.8,5.3Hz,4H),3.07(s,2H),2.68(t,J=11.8Hz,1H),2.35(s,2H),1.95(d,J=12.9Hz,2H),1.84(d,J=12.6Hz,2H),1.38(t,J=7.1Hz,3H),1.20(t,J=7.3Hz,3H)。
实施例47 2-((6-((4-氯-2-氟苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸
步骤1)6-氯-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯
向2,6-二氯吡啶(1.48g,10mmol)的二氧六环(50mL)和水(10mL)溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-5,6-二氢吡啶-1(2H)-甲酸叔丁酯(3.09g,10mmol),碳酸铯(7.15g,22mmol)和1,1'-双二苯基膦二茂铁二氯化钯(0.7g,1mmol),混合物于90℃搅拌过夜。反应完全后,加入乙酸乙酯(50mL),用饱和氯化钠洗,有机相经硫酸钠干燥,减压浓缩除去溶剂,所得残余物经柱层析纯化(PE:EA=10:1),得产物(1.8g,61%)。
步骤2)6-(((4-氯-2-氟苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯
向6-氯-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯(1.8g,6.1mmol)的甲苯(60mL)溶液中加入(4-氯-2-氟苯基)甲醇(1g,6.25mmol),碳酸铯(4g,12.3mmol),三二亚苄基丙酮二钯(0.28g,0.3mmol)和(±)-2,2'-双-(二苯膦基)-1,1'-联萘(0.38g,0.6mmol),混合物于100℃下搅拌过夜。反应完全后,加入乙酸乙酯(50mL),用饱和氯化钠洗,有机相经硫酸钠干燥,减压浓缩除去溶剂,所得残余物经柱层析纯化(PE:EA=10:1),得产物(1g,39%)。
步骤3)6-((4-氯-2-氟苄基)氧基)-1',2',3',6'-四氢-2,4'-联吡啶盐酸盐
向6-(((4-氯-2-氟苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-甲酸叔丁酯(1g,6.75mmol)的乙醇(5mL)溶液中加入盐酸乙醇(5mL),混合物搅拌过夜。反应完全后,过滤,烘干,得产物(0.56g,74%)。
步骤4)2-((6-((4-氯-2-氟苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
向6-((4-氯-2-氟苄基)氧基)-1',2',3',6'-四氢-2,4'-联吡啶盐酸盐(156mg,0.44mmol)的乙腈(1mL)和水(1mL)溶液中加入2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸乙酯(135mg,0.44mmol)和碳酸钾(210mg,1.76mmol),混合物于60℃下搅拌过夜。反应完全后,加入乙酸乙酯(5mL),用饱和氯化钠洗,有机相经硫酸钠干燥,减压浓缩除去溶剂,所得残余物经柱层析纯化(DCM:MeOH=20:1),得产物(141mg,15%)。
步骤5)2-((6-((4-氯-2-氟苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-羧酸
向2-((6-((4-氯-2-氟苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1'(2'H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(141mg,0.23mmol)的乙醇(2mL)溶液中加入1M盐酸(0.5mL),混合物搅拌过夜。反应完全后,用1M盐酸将混合物调至中性,减压浓缩除去溶剂,所得残余物经柱层析纯化(DCM:MeOH=10:1),得产物(25.1mg,18.9%)。LCMS[M+H]+:569.33。
1H NMR(500MHz,CD
3OD)δ7.79(s,1H),7.68–7.63(m,1H),7.50(t,J=8.1Hz,1H),7.26–7.18(m,2H),7.10(d,J=7.5Hz,1H),6.73(d,J=8.3Hz,2H),5.47(d,J=17.0Hz,2H),5.25–5.15(m,1H),4.76–4.54(m,3H),4.43(dt,J=9.2,5.9Hz,1H),4.33–4.17(m,2H),3.57(s,2H),3.19–3.04(m,2H),2.76(dd,J=29.2,11.8Hz,3H),2.56–2.41(m,1H)。
实施例48 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-N-羟基-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
步骤1)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(136mg,0.43mmol)置于25mL单口瓶中,加入碳酸钾(147mg,1.06mmol),乙腈(5mL)和中间体11(140mg,粗品,0.35mmol),混合物升温至60℃反应2.5h。冷却至室温,加入水(5mL),用乙酸乙酯(10mL X 3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,经制备型TLC纯化得无色透明油状物60mg,收率22%。
步骤2)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-N-羟基-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(100mg,0.157mmol)溶于1,4-二氧六环(1mL),加入水(2mL),50%羟胺水溶液(22mg,0.33mmol),然后加入氢氧化钠(38mg,0.95mmol),混合物于室温搅拌反应1h。TLC检测原料反应完全后,稀盐酸调节pH约等于6,乙酸乙酯(10mL X 3)萃取,有机相经无水硫酸钠干燥,过滤,减压浓缩,残余物经制备型TLC(DCM:MeOH=10:1)纯化,冻干,得类白色固体产物32mg,收率32.6%,纯度:95%。
1H NMR(500MHz,CD
3OD)δ7.81(s,1H),7.60(t,J=7.8Hz,1H),7.50(t,J=8.2Hz,1H),7.22(t,J=8.3Hz,2H),7.09(s,1H),7.07(s,1H),6.84(d,J=7.3Hz,1H),6.66(d,J=8.2Hz,1H),5.67(s,2H),5.43(s,2H),4.02(q,J=7.2Hz,2H),3.85(s,2H),3.04(d,J=11.5Hz,2H),2.67(t,J=11.5Hz,1H),2.29(t,J=10.6Hz,2H),1.83(dt,J=21.5,10.9Hz,4H),1.17(t,J=7.3Hz,3H)。
实施例49 2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-N-(甲磺酰基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
步骤1)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(136mg,0.43mmol) 置于25mL单口瓶中,加入碳酸钾(147mg,1.06mmol),乙腈(5mL)和中间体11(140mg,粗品,0.35mmol),混合物升温至60℃反应2.5h。冷却至室温,加入水(5mL),乙酸乙酯(10mL X 3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,经制备型TLC纯化得无色透明油状物60mg,收率22%。
步骤2)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(75mg,0.12mmol)溶于乙醇(3mL),加入氢氧化钠(1.5mL,1M)溶液,混合物于室温搅拌反应15h。TLC检测原料反应完全后,减压浓缩除去乙醇,加入水(2mL),乙酸乙酯(2mL X 2)萃取,分离出水相,水相调节pH约等于5,乙酸乙酯(3mL X 3)萃取,有机相经无水硫酸钠干燥,过滤,减压浓缩,加入乙腈、水和两滴三氟乙酸,冻干,得类白色固体产物28mg,收率38%,纯度:85.7%。
1H NMR(500MHz,MeOH-d
4)δ8.94(s,1H),7.72–7.63(m,1H),7.56–7.48(m,2H),7.36(s,1H),7.29–7.20(m,2H),6.93(d,J=7.3Hz,1H),6.74(dd,J=8.4,2.2Hz,1H),5.80(s,2H),5.45(s,2H),4.77–4.70(m,2H),4.24(q,J=7.7Hz,2H),3.92–3.81(m,2H),3.37–3.33(m,2H),3.03(s,1H),2.20(d,J=10.5Hz,4H),2.20(td,J=7.5Hz,2.3Hz,3H)。
步骤3)2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-N-(甲磺酰基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(150mg,0.25mmol)溶于二氯甲烷(5mL),加入甲基磺酰胺(42mg,0.44mmol),1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(94mg,0.49mmol)和4-二甲氨基吡啶(90mg,0.74mmol),混合物于室温搅拌过夜。LCMS显示原料少量剩余,产物生成,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,取1/4制备分离纯化得产物(14.8mg),收率:35%,纯度:97%。LCMS[M+H]
+:686.29。
1H NMR(500MHz,CD
3OD)δ9.00(s,1H),7.71–7.63(m,1H),7.52(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.26(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.28(s,3H),3.04(s,1H),2.27(dt,J=29.6,13.3Hz,4H),1.48(t,J=7.3Hz,3H)。
实施例50 2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(24mg,0.095mmol),中间体9(34mg,0.095mmol)置于25mL单口瓶中,加入碳酸甲(66mg,0.475mmol)和乙腈(3mL),混合物升温至60℃反应过夜。LCMS显示产物生成,停止反应,冷却至室温。加入水(5mL),乙酸乙酯(3X 5mL)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩得粗品,经柱层析纯化得浅黄色油状产物(36mg,0.057mmol),收率:59.7%。
步骤2)2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(3-((4-氯-2-氟苄基)氧基)苯基)-3,6-二氢吡啶-1(2H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(36mg,0.057mmol)溶于乙醇(2.5mL),加入氢氧化钠水溶液(1mL,1M),混合物于室温搅拌过夜。LCMS显示反应完全,停止反应,减压浓缩除去乙醇,加入水(2mL) 使其溶解,用1N稀盐酸调节pH约等于6,乙酸乙酯(3X 5mL)萃取,合并有机相,无水硫酸钠干燥,过滤除去不溶物,减压浓缩得粗品,加入乙酸乙酯(10mL)使其溶解,过滤除去不溶物,减压浓缩,冻干,得类白色固体产物(17.8mg,0.029mmol),收率:51.5%,纯度:98%。LCMS[M+H]
+:606.19。
1H NMR(500MHz,CD
3OD)δ9.14(s,1H),7.63(s,1H),7.54(t,J=8.2Hz,1H),7.42(s,1H),7.35(t,J=7.9Hz,1H),7.27(t,J=7.2Hz,2H),7.14(d,J=8.8Hz,2H),7.03(d,J=8.2Hz,1H),6.20(s,1H),5.81(s,2H),5.17(s,2H),4.90(s,2H),4.28(q,J=7.3Hz,2H),4.21(s,2H),3.82(s,2H),2.99(s,2H),1.50(t,J=7.3Hz,3H)。
实施例51 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-异丙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)5-((叔丁氧羰基)氨基)-4-(((1-异丙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯(500mg,1.75mmol)溶于乙腈(10mL),加入N,N-二异丙基乙胺(903mg,7.00mmol)和1-异丙基-1H-5-氯甲基咪唑盐酸盐(511mg,2.62mmol),混合物于室温搅拌过夜。TLC显示原料剩余,新产物生成,停止反应。减压浓缩除去乙腈,加入水(10mL),乙酸乙酯(10mL X 3)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩得粗品,经柱层析纯化得黄色油状产物(365mg,0.89mmol),收率:51%。
步骤2)2-(氯甲基)-1-((1-异丙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-(((1-异丙基-1H-咪唑-5-基)甲基)氨基)噻吩-2-甲酸乙酯(200mg,0.49mmol)溶于二氯甲烷(20mL),加入三氟乙酸(0.4mL)和2-氯-1,1,1-三甲氧基乙烷(227mg,1.47mmol),混合物于室温下搅拌过夜。LCMS显示产物生成,停止反应。经减压浓缩,残余物经柱层析纯化得黄色油状产物(100mg,0.27mmol),收率:55.6%。
步骤3)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-异丙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-异丙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(107mg,0.27mmol)置于单口瓶中,加入碳酸钾(150mg,1.09mmol),中间体11(100mg,0.27mmol)和乙腈(5mL),混合物升温至60℃反应5h。LCMS显示反应完全,停止反应,冷却至室温。减压浓缩除去乙腈,加入水(10mL),乙酸乙酯(3X 15mL)萃取,合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压浓缩得粗品,经柱层析纯化得浅黄色油状产物(110mg,0.17mmol),收率:63%。
步骤4)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-异丙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-异丙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(110mg,0.17mmol)溶于乙醇(4mL),加入1M的氢氧化钠水溶液(2mL),混合物于室温搅拌过夜。LCMS显示反应完全,减压浓缩除去乙醇,加入水(2mL)使其溶解,1M稀盐酸调节pH约等于6,析出大量固体,过滤,滤渣用水洗三次,干燥,得类白色固体产物(53.8mg,0.086mmol),收率:50.8%,纯度:97%。LCMS[M+H]
+:623.23。
1H NMR(500MHz,CD
3OD)δ9.27(d,J=1.3Hz,1H),7.73–7.65(m,1H),7.59(s,1H),7.52(t,J=8.2Hz,1H),7.40(s,1H),7.24(dd,J=12.3,4.3Hz,2H),6.94(d,J=7.3Hz,1H),6.76(d,J=8.2Hz,1H),5.85(s,2H),5.45(s,2H),4.82(s,2H),4.67(dt,J=13.2,6.6Hz,1H),3.95(s,2H),3.41(s,2H),3.07(s,1H),2.26(dd,J=30.5,11.8Hz,4H),1.55(d,J=6.7Hz,6H)。
实施例52 2-((6-((4-氯-2-氟苄基)氧基)-3',6'-二氢-[2,4'-吡啶]-1'(2'H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸三氟乙酸盐
步骤1)2-((6-((4-氯-2-氟苄基)氧基)-3',6'-二氢-[2,4'-吡啶]-1'(2'H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(36mg,0.143mmol)和中间体9(60mg,0.143mmol,粗品)置于50毫升单口瓶中,加入碳酸钾(99mg,0.715mmol)和乙腈(4mL),混合物升温至60℃反应过夜。停止反应,减压浓缩,残余物经柱层析纯化,得浅黄色油状产物18mg。
步骤2)2-((6-((4-氯-2-氟苄基)氧基)-3',6'-二氢-[2,4'-吡啶]-1'(2'H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸三氟乙酸盐
将2-((6-((4-氯-2-氟苄基)氧基)-3',6'-二氢-[2,4'-吡啶]-1'(2'H)-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(18mg,0.028mmol)溶于乙醇(2mL),加入1M的氢氧化钠水溶液(1mL),混合物于室温反应过夜。停止反应,减压浓缩除去乙醇,1N稀盐酸调节至中性,加入乙腈使其溶解,过滤除去不溶物,滤液经制备分离(0.1%CF
3COOH的水溶液:MeCN=90:10~10:90),得黄色油状产物,1.8mg,收率:11%,LC-MS[M+H]
+:607.1。
1H NMR(500MHz,CD
3OD)δ8.93(s,1H),7.69(t,J=7.7Hz,1H),7.55(s,1H),7.51(t,J=7.9Hz,1H),7.42(s,1H),7.29–7.19(m,2H),7.14(d,J=7.6Hz,1H),6.84–6.71(m,2H),5.79(s,2H),5.46(s,2H),4.57–4.48(m,2H),4.27–4.18(m,2H),3.83(s,2H),3.38(s,2H),2.82(s,2H),1.40(t,J=7.1Hz,3H)。
实施例53 2-((4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)2-((4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将中间体12(61.1mg,0.16mmol)溶于乙腈(2mL)。向反应体系中依次加入K
2CO
3(97mg,0.7mmol)和2-(氯甲基)-1-((1-乙基-1H-咪唑5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(50mg,0.14mmol),将混合物置于金属砂浴中加热反应(50℃)过夜。反应完成后,过滤除去体系中无机盐,减压浓缩除去溶剂,残余物经薄层层析色谱(DCM:MeOH=20:1)分离,得到目标产物(13mg,14%)为淡黄色固体。LCMS[M+H]
+:672。
步骤2)2-((4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(5-((4-氯-2-氟苄基)氧基)-2,4-二氟苯基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(13mg,0.02mmol)溶于四氢呋喃(2mL)。向反应体系中加入水(1mL),和氢氧化钠(1.6mg,0.04mmol),将混合物置于金属砂浴中加热反应(50℃)过夜。TLC监测转化完全后,用1N盐酸调节体系pH=6,此时体系中有大量白色固体析出,用滴管将上清液吸除。将所得固体粗产品用制备型HPLC进行制备分离,冻干,得到目标产物(4.4mg,35%)为淡黄色固体。HPLC纯度=95%,LCMS[M+H]
+:644。
1H NMR(500MHz,MeOH-d
4)δ9.01(s,1H),7.57(s,1H),7.53(t,J=8.1Hz,1H),7.41–7.35(m,1H),7.28(s,1H),7.26(s,1H),7.10–7.05(m,1H),7.02(t,J=10.6Hz,1H),5.81(s,2H),5.18(s,2H),4.62(s,2H),4.26(q,J=7.1Hz,2H),3.81–3.67(m,2H),3.24–3.05(m,3H),2.15–2.01(m,4H),1.47(t,J=7.3Hz, 3H)。
实施例54 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸
步骤1)5-硝基-1H-吡唑-3-甲酸甲酯
将5-硝基-1H-吡唑-3-甲酸(2g,12.73mmol)溶于甲醇(10mL)。冰浴下向反应体系中缓慢滴加氯化亚砜(2.68g,20mmol)。滴加完毕后,将反应体系置于金属砂浴中回流(80℃)。回流2h后,将反应体系冷却至室温,减压浓缩除去溶剂,真空干燥,得到目标产物(2.18g,98%)为白色固体。
步骤2)叔丁基二甲基(氧杂环丁-2-基甲氧基)硅烷
将(氧杂环丁-2-基)甲醇(5g,67.5mmol)溶于二氯甲烷(200mL)。冰浴下向反应体系中依次加入1H-咪唑(9.2g,135mmol)和TBSCl(15.26g,101.2mmol)。将反应体系缓慢升温至室温并搅拌过夜,TLC监测转化完全后,向反应体系中加入100mL水,分液,得到的有机相用水(3*100mL)洗,然后用饱和食盐水(100mL)洗。有机相经Na
2SO
4干燥,减压浓缩除去溶剂,残余物经柱层析(PE:EA=50:1)分离,得到目标产物(11.1g,87%)为无色油状液体。
步骤3)1-(3-((叔丁基二甲基硅基)氧基)-2-羟基丙基)-5-硝基-1H-吡唑-3-甲酸甲酯
将5-硝基-1H-吡唑-3-甲酸甲酯(500mg,2.92mmol)溶于甲苯(12mL)。向反应体系中依次加入2,6-二甲基吡啶(47mg,0.44mmol)和叔丁基二甲基(氧杂环丁-2-基甲氧基)硅烷(824mg,4.38mmol)。将反应体系升温至70℃反应48h。TLC监测转化完全后,减压浓缩除去反应溶剂,残余物经柱层析(PE:EA=3:1)分离,得到目标产物(920mg,粗混合物,79%)为无色油状液体。
步骤4)1-(3-((叔丁基二甲基硅基)氧基)-2-氧代丙基)-5-硝基-1H-吡唑-3-甲酸甲酯
将1-(3-((叔丁基二甲基硅基)氧基)-2-氧代丙基)-5-硝基-1H-吡唑-3-甲酸甲酯(4.02g,11.2mmol)溶于二氯甲烷(120mL)。向反应体系中加入Dess-Martin试剂(7.13g,16.8mmol),混合物于室温搅拌反应。LC-MS监测转化完全后,向反应中加入100mL饱和碳酸氢钠溶液和15g硫代硫酸钠,剧烈搅拌至反应体系澄清。反应水相使用DCM萃取,将合并的有机相用饱和食盐水(100mL)洗,无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析(PE:EA=20:1至10:1)分离,得到目标产物(760mg,19%)为无色油状液体。
步骤5)2-(((叔丁基二甲基硅基)氧基)甲基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯
将1-(3-((叔丁基二甲基硅基)氧基)-2-氧代丙基)-5-硝基-1H-吡唑-3-甲酸甲酯(760mg,2.13mmol)溶于10mL MeOH。向反应体系中加入10%Pd/C(222mg,0.21mmol),将体系内用氢气置换三次,于室温下搅拌。TLC监测转化完全后(2h),混合物通过硅藻土过滤除去体系中Pd/C,向所得滤液中加入醋酸(200μL),然后置于金属砂浴中回流(80℃)过夜。LC-MS监测转化完全后,减压浓缩除去溶剂,残余物经柱层析(PE:EA=2:1)分离,得到目标产物(466mg,71%)为白色固体。LCMS[M+H]
+:310。
步骤6)2-(((叔丁基二甲基硅基)氧基)甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯
将2-(((叔丁基二甲基硅基)氧基)甲基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯(271mg,0.88mmol)溶于乙腈(11mL)。向反应体系中依次加入碳酸钾(363mg,2.64mmol)和1-溴-2-甲氧乙基(181mg,1.31mmol),将混合物置于金属砂浴中加热反应(50℃)。TLC监测转化完全后,过滤除去体系中无机盐,减压浓缩除去溶剂,残余物经柱层析(PE:EA=4:1)分离,得到目标产物(240mg,72%)为白色固体。LCMS[M+H]
+:368。
步骤7)2-(羟甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯
将2-(((叔丁基二甲基硅基)氧基)甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯(240mg,0.65mmol)溶于四氢呋喃(6mL)。向反应体系中加入TBAF(185mg,0.71mmol),混合物于室温搅拌。TLC监测转化完全后(5min),加入水(50mL),用乙酸乙酯萃取,合并的有机相用饱和食盐水(30mL)洗,经Na
2SO
4干燥,减压浓缩除去溶剂,残余物经薄层层析(DCM:MeOH=20:1)分离,得到目标产物(146mg,89%)为黄色油状液体。
步骤8)2-甲酰基-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯
将2-(羟甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯(146mg,0.58mmol)溶于二氯甲烷(6mL)。向反应体系中加入Dess-Martin试剂(294mg,0.7mmol),混合物于室温搅拌反应。TLC监测转化完全后,向反应中加入10mL饱和碳酸氢钠溶液和1.5g硫代硫酸钠,剧烈搅拌至反应体系澄清。反应水相使用二氯甲烷萃取,将合并的有机相用饱和食盐水(10mL)洗,无水硫酸钠干燥,减压浓缩除去溶剂,残余物经柱层析(EA)分离,得到目标产物(64mg,44%)为黄色固体。LCMS[M+H]
+:252。
步骤9)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯
将中间体11(135mg,0.38mmol)溶于水(2mL)中,向反应体系中加入1,2-二氯乙烷(2mL)和碳酸氢钠(84mg,1.0mmol),混合物于室温下搅拌3h后,用二氯甲烷萃取,合并的有机相用饱和食盐水(10mL)洗,无水硫酸钠干燥,减压浓缩除去溶剂,得到2-((4-氯-2-氟苄基)氧基)-6-(哌啶-4-基)吡啶。将所得游离化合物溶于1,2-二氯乙烷(1mL)中,依次向反应体系中加入2-甲酰基-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯(64mg,0.25mmol),三(乙酰氧基)硼氢化钠(159mg,0.75mmol),混合物于室温搅拌2h。TLC监测转化完全后,向反应中加入10mL水。水相使用DCM萃取,将合并的有机相用饱和NaCl溶液(10mL)洗,Na
2SO
4干燥,减压浓缩除去溶剂,残余物经薄层层析(DCM:MeOH=20:1)分离得,到目标产物(92mg,66%)为黄色油状物。LCMS[M+H]
+:556。
步骤10)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸
将2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(2-甲氧乙基)-1H-咪唑并[1,2-b]吡唑-6-甲酸甲酯(92mg,0.165mmol)溶于2mL THF,向反应体系中加入1mL水和LiOH(8mg,0.331mmol),将反应体系置于金属砂浴中加热(50℃)。TLC监测转化完全后,将反应冷却至室温,用1N HCl调节水相pH值约为6,用EtOAc萃取,将合并的有机相用饱和NaCl溶液(10mL)洗,经Na
2SO
4干燥,真空除去溶剂,残余物经薄层层析(DCM:MeOH=10:1)分离,得到目标产物(37mg,41%)为白色粉末。LCMS[M+H]
+:542。
1H NMR(500MHz,CH
3OH-d
4/TFA)δ7.89(s,1H),7.68(t,J=7.8Hz,1H),7.50(t,J=8.2Hz,1H),7.31(s,1H)7.24(t,J=8.1Hz,2H),6.94(d,J=6.8Hz,1H),6.76(d,J=8.2Hz,1H),5.43(s,2H),4.64(s,2H),4.43(s,2H),3.89–3.71(m,4H),3.42(s,3H),3.29(s,1H),3.05(s,1H),2.28–2.05(m,4H),1.66–1.56(m,1H)。
实施例55 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-2-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
步骤1)1-乙基-1H-咪唑-2-甲醛
将1H-咪唑-2-甲醛(2g,20.82mmol)溶于120mL CH
3CN中,向反应体系中滴加碘乙烷(4.87g,31.2mmol)。滴加完毕后,将反应体系置于金属砂浴中加热(60℃)。反应过夜后,将反应体系冷却至室温,过滤除去无机盐,减压浓缩除去滤液中溶剂,残余物经柱层析(PE:EA=1:1)纯化,得到目标产物(2.27g,88%)为淡黄色油状液体。
步骤2)(1-乙基-1H-咪唑-2-基)甲醇
将1-乙基-1H-咪唑-2-甲醛(2.27g,18.31mmol)溶于75mL MeOH中。冰浴下向反应体系中缓慢加入硼氢化钠(831mg,21.97mmol)。将反应体系缓慢升温至室温并搅拌1h。TLC监测转化完全后,减压浓缩除去反应液,然后加入100mL EA和100mL水萃取。有机相用水(3*50mL)洗,然后用饱和NaCl溶液(100mL)洗。有机相经Na
2SO
4干燥,减压浓缩除去溶剂,得到目标产物(1.27g,56%)为无色油状液体。
步骤3)2-(氯甲基)-1-乙基-1H-咪唑盐酸盐
将(1-乙基-1H-咪唑-2-基)甲醇(1.27g,10.07mmol)在冰浴冷却的条件下溶于30mL SOCl
2中,将反应体系回流(金属砂浴80℃)反应2h。反应完毕后,减压浓缩除去SOCl
2,油泵真空干燥,得到目标产物(920mg, 56%)为白色固体。
步骤4)5-((叔丁氧羰基)氨基)-4-(((1-乙基-1H-咪唑-2-基)甲基)氨基)噻吩-2-甲酸乙酯
将4-氨基-5-((叔丁氧羰基)氨基)噻吩-2-甲酸乙酯(500mg,1.75mmol)溶于CH
3CN(20mL)。向反应体系中加入2-(氯甲基)-1-乙基-1H-咪唑盐酸盐(217mg,2.1mmol)和二异丙基乙胺(1.35g,10.5mmol),混合物于室温下搅拌过夜。反应完成后,将反应溶剂真空除去,残余物经柱层析(PE:EA=1:1至DCM:MeOH=20:1)分离,得到目标产物(320mg,46%)为棕黑色油状物。LCMS[M+H]
+:395。
步骤5)2-(氯甲基)-1-((1-乙基-1H-咪唑-2-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将5-((叔丁氧羰基)氨基)-4-(((1-乙基-1H-咪唑-2-基)甲基)氨基)噻吩-2-甲酸乙酯(200mg,0.51mmol)溶于二氯甲烷(20mL)。向反应体系中加入三氟乙酸(0.4mL),和2-氯-1,1,1-三甲氧基乙烷(235mg,1.53mmol),混合物于室温反应过夜。反应完毕后,减压浓缩除去溶剂,残余物经柱层析(DCM:MeOH=15:1)分离,得到粗产物(180mg)为棕黑色油状物。LCMS[M+H]
+:353。
步骤6)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-2-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯
将2-(氯甲基)-1-((1-乙基-1H-咪唑-2-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(180mg,粗混合物)溶于乙腈(6mL)。向反应体系中依次加入碳酸钾(415mg,0.6mmol)和中间体11(214mg,3.0mmol),将混合物置于金属砂浴中加热反应(50℃)过夜。LCMS监测原料转化完全后,过滤除去体系中无机盐,减压浓缩除去溶剂,残余物经薄层色谱层析柱(DCM:MeOH=20:1)分离,得到目标产物(32mg,9.8%)为淡黄色油状物。LCMS[M+H]
+:637。
步骤7)2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-2-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸
将2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-2-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸乙酯(32mg,0.05mmol)溶于2mL THF中,向反应体系中加入1mL水和LiOH(2.4mg,0.1mmol),将反应体系置于金属砂浴中加热(50℃)。TLC监测转化完全后,将反应冷却至室温,用1N HCl调节水相pH值约为6,然后用EtOAc萃取,合并的有机相用饱和NaCl溶液(10mL)洗,经Na
2SO
4干燥,减压浓缩除去溶剂,半制备液相分离得到目标产物(25mg,83%)为淡黄色粉末。LCMS[M+H]
+:609。
1H NMR(500MHz,MeOH-d
4)δ7.83(s,1H),7.69(t,J=7.7Hz,1H),7.51(t,J=8.1Hz,1H),7.26(dd,J=22.1,10.2Hz,3H),7.10(s,1H),6.97(d,J=7.4Hz,1H),6.78(d,J=8.1Hz,1H),5.87(s,2H),5.51(s,2H),4.74(s,2H),4.39(dd,J=14.7,7.2Hz,2H),3.73(d,J=12.1Hz,2H),3.34(s,2H),3.10(s,1H),2.21(s,4H),1.52(t,J=7.2Hz,3H)。
进一步,根据与实施例49类似的方法,合成得到表A所示化合物。
表A.本发明实施例56-60
实施例61 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-N-氨磺酰基-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(122mg,0.2mmol)溶于二氯甲烷(5mL),加入N,N'-羰基二咪唑(42mg,0.3mmol),混合物于室温搅拌反应2小时,然后加入氨基磺酰胺(19mg,0.2mmol),混合物于室温搅拌过夜。LCMS显示原料基本反应完全,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(11mg),收率:8%,纯度:98%。LCMS[M+H]
+:687.15。
1H NMR(500MHz,CD
3OD)δ9.00(s,1H),7.71–7.63(m,1H),7.52(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.18(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),2.10(s,3H),1.35(t,J=7.3Hz,3H)。
实施例62 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-N-(N- 甲胺基磺酰基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(122mg,0.2mmol)溶于二氯甲烷(5mL),加入N,N'-羰基二咪唑(42mg,0.3mmol),混合物于室温搅拌反应2小时,然后加入N-甲基磺酰胺(22mg,0.2mmol),混合物于室温搅拌过夜。LCMS显示原料基本反应完全,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(8mg),收率:6%,纯度:98%。LCMS[M+H]
+:701.21。
1H NMR(500MHz,CD
3OD)δ9.00(s,1H),7.71–7.63(m,1H),7.52(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.19(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.79(s,3H),2.27(m,4H),2.10(s,3H),1.35(t,J=7.3Hz,3H)。
实施例63 N-乙酰基-2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(150mg,0.25mmol)溶于二氯甲烷(5mL),加入乙酰胺(26mg,0.44mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(94mg,0.49mmol)和4-二甲氨基吡啶(90mg,0.74mmol),混合物于室温搅拌过夜。LCMS显示原料少量剩余,产物生成,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(48mg,30%),纯度:98%。LCMS[M+H]
+:650.20。
1H NMR(500MHz,CD
3OD)δ8.99(s,1H),7.71–7.63(m,1H),7.52(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.26(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),2.10(s,3H),1.48(t,J=7.3Hz,3H)。
实施例64 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-N-(2,2,2-三氟乙酰基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(150mg,0.25mmol)溶于二氯甲烷(5mL),加入三氟乙酰胺(26mg,0.44mmol),1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(94mg,0.49mmol)和4-二甲氨基吡啶(90mg,0.74mmol),混合物于室温搅拌过夜。LCMS显示原料少量剩余,产物生成,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(21mg,12%),纯度:97%。LCMS[M+H]
+:704.10。
1H NMR(500MHz,CD
3OD)δ9.11(s,1H),7.70–7.63(m,1H),7.52(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.26(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),1.39(t,J=7.3Hz,3H)。
实施例65 N-氨甲酰基-2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(150mg,0.25mmol)溶于甲苯(5mL),加入3,4,5-三氟苯硼酸(2.2mg,0.0125mmol),脲(17mg,0.28mmol),4A分子筛(50mg),将混合物回流搅拌过夜。LCMS显示原料少量剩余,产物生成,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(24mg,15%),纯度:98%。LCMS[M+H]
+:651.2。
1H NMR(500MHz,CD
3OD)δ8.89(s,1H),7.70–7.63(m,1H),7.50(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.22(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),1.38(t,J=7.3Hz,3H)。
实施例66 N-硫代氨甲酰基-2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(150mg,0.25mmol)溶于甲苯(5mL),加入3,4,5-三氟苯硼酸(2.2mg,0.0125mmol),硫脲(21mg,0.28mmol),4A分子筛(50mg),将混合物回流搅拌过夜。LCMS显示原料反应完全,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(18mg,11%),纯度:98%。LCMS[M+H]
+:667.2。
1H NMR(500MHz,CD
3OD)δ8.88(s,1H),7.70–7.63(m,1H),7.50(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.19(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),2.27(m,4H),1.35(t,J=7.3Hz,3H)。
实施例67 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-N-(N-甲基胺甲酰基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(150mg,0.25mmol)溶于甲苯(5mL),加入3,4,5-三氟苯硼酸(2.2mg,0.0125mmol),N-甲基脲(21mg,0.28mmol),4A分子筛(50mg),将混合物回流搅拌过夜。LCMS显示原料反应完全,停止反应。反应液经水(5mL)洗,减压浓缩得粗品产物,制备分离纯化得产物(17mg,10%),纯度:98%。LCMS[M+H]
+:665.2。
1H NMR(500MHz,CD
3OD)δ8.90(s,1H),7.70–7.63(m,1H),7.50(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.19(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.04(s,1H),3.02(s,3H),2.27(m,4H),1.38(t,J=7.3Hz,3H)。
实施例68 2-((4-(6-((4-氯-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-((1-乙基-1H-咪唑-5-基)甲基)-N-(S-甲基砜亚胺基)-1H-噻吩并[2,3-d]咪唑-5-甲酰胺(含其互变异构体)
将2-((1-(6-(4-氯-2-氟苄氧基)吡啶-2-基)哌啶-4-基)基)-1-((1-基-1H-咪唑-5-基)甲基)-1H-噻吩并[2,3-d]咪唑-5-甲酸(122mg,0.2mmol)溶于二氯亚砜(5mL),混合物于60℃搅拌反应1小时,减压浓缩除去溶剂,将所得残余物溶于乙腈(5mL),将0.5M哒嗪的乙腈(2mL)溶液滴加入上述体系中,搅拌1分钟,然后再加入N-(叔丁基二甲基硅基)甲基砜亚胺[Ref.Chen,Y.;Gibson,J.A convenient synthetic route to sulfonimidamides from sulfonamides.RSC Adv.2015,5,4171-4174.](19mg,0.2mmol)的乙腈(1mL)溶液,混合物于室温搅拌过夜。LCMS显示原料基本反应完全,停止反应。反应液减压浓缩得粗品产物,制备分离纯化得产物(35mg,13%,含其互变异构体),纯度:98%。LCMS[M+H]
+:685.20。
1H NMR(500MHz,CD
3OD)δ9.00(br,1H),7.71–7.63(m,1H),7.52(t,J=8.2Hz,1H),7.43(s,1H),7.33(s,1H),7.26–7.19(m,2H),6.94(d,J=7.4Hz,1H),6.75(d,J=8.3Hz,1H),5.80(s,2H),5.45(s,2H),4.66(s,2H),4.20(q,J=7.3Hz,2H),3.94(s,2H),3.35(s,2H),3.10(d,J=0.5Hz,3H)3.04(s,1H),2.27(m,4H),1.38(t,J=7.3Hz,3H)。
生物试验
试验A:GLP-1R激动剂活性测试
GLP-1R激动剂活性检测是一种竞争性免疫检测方法,通过对比细胞产生的内源性cAMP和标记了d2染色剂的外源cAMP来计算得来的。穴状化合物(cryptate)偶联的抗-cAMP抗体可用于检测cAMP的含量,检测出的信号强度与cAMP含量成反比。
该实验使用能在细胞表面表达人GLP-1R的HEK/GLP1R/CRE/Luc细胞株。将人GLP-1 R基因克隆至HEK细胞中表达,在进行实验之前制备细胞悬液。根据板型布置,配制稀释1000倍浓度的本发明受试化合物工作液,将全部10nl体积工作液加入检测板中。每孔加入细胞悬液10μL。密封板,于37℃,5%CO
2孵育30分钟。每孔加5μL的cAMP-d2工作液,然后加入5μL抗-cAMP标记抗体工作液检测cAMP的生成水平。用盖子把板子盖上。室温孵育1小时。用荧光酶标仪在665和615/620nm读取荧光,保存数据。通过化合物浓度和相应的cAMP水平拟合的效应曲线来计算本发明受试化合物激活GLP-1 R的EC
50值。
本发明受试化合物的GLP-1R激动活性(EC
50)测试结果在表1中列出,其中,+:>100nM;++:50-100nM;+++:10-50nM;++++:<10nM
表1.化合物GLP-1R激动活性
受试化合物 | EC 50(nM) | 受试化合物 | EC 50(nM) |
实施例2 | ++++ | 实施例10 | + |
实施例11 | ++++ | 实施例12 | ++++ |
实施例13 | + | 实施例14 | ++++ |
实施例15 | ++++ | 实施例17 | ++++ |
实施例19 | ++++ | 实施例21 | + |
实施例23 | + | 实施例25 | ++++ |
实施例26 | ++++ | 实施例27 | ++++ |
实施例28 | + | 实施例29 | +++ |
实施例30 | + | 实施例31 | +++ |
实施例32 | + | 实施例33 | +++ |
实施例34 | ++ | 实施例35 | ++++ |
实施例36 | + | 实施例37 | ++++ |
实施例38 | + | 实施例39 | + |
实施例40 | + | 实施例41 | +++ |
实施例42 | +++ | 实施例46 | ++++ |
受试化合物 | EC 50(nM) | 受试化合物 | EC 50(nM) |
实施例47 | ++++ | 实施例48 | +++ |
实施例49 | ++++ | 实施例50 | ++++ |
实施例51 | ++++ | 实施例53 | +++ |
实施例56 | ++++ | 实施例57 | ++++ |
实施例58 | ++++ | 实施例59 | ++++ |
实施例61 | ++++ | 实施例62 | ++++ |
实施例63 | ++++ | 实施例67 | +++ |
试验B:药代动力学研究
肝微粒体稳定性实验
将本发明受试化合物与人和大鼠肝微粒体孵化后,通过测定本发明受试化合物在不同孵化时间的减少量,评价其代谢稳定性。
大鼠吸收药动学研究
本实验通过对SD大鼠1mg/kg单次静脉注射(i.v.)和5mg/kg口服灌胃(i.g.)给药研究后,于不同时间点获得大鼠血浆样品;用LC-MS/MS方法检测SD大鼠血浆中本发明受试化合物的浓度,从而评估本发明化合物在SD大鼠体内的药代动力学特征。
6只SD大鼠随机分为2组,A组动物静脉注射给予1mg/kg的本发明受试化合物溶液,分别在给药前及给药后0.083、0.25、0.5、1、2、4、8和24h于静脉采血;B组动物灌胃给予5mg/kg的本发明受试化合物制剂,分别在给药前及给药后0.25、0.5、1、2、4、8和24h于静脉采血。
运用LC-MS/MS方法检测SD大鼠血浆中本发明受试化合物的浓度,所得血药浓度数据采用WinNonlin非房室模型计算相关药代动力学参数。
试验表明,本发明化合物在人和大鼠中具有较好的肝微粒体稳定性,且具有较好的药代动力学性质,口服吸收较快,生物利用度较好。
总之,本发明化合物对GLP-1受体具有很好的激动作用,具有优异的体内外药效、药代性质,具备较佳的临床应用前景。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明/实用新型的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明/实用新型专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明/实用新型构思的前提下,还可以做出若干变形和改进,这些都属于本发明/实用新型的保护范围。因此,本发明/实用新型专利的保护范围应以所附权利要求为准。
Claims (25)
- 式(I)所示化合物:或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、区域异构体、氮氧化物、或混合物,其中,L 1是O、S、-N(R c)-、-C(=O)-、或-C(R a)(R b)-;L 2是O、S、-N(R c)-、-C(=O)-、-(C(R a)(R b)) t1-、-X-(C(R a)(R b)) t1-、或-(C(R a)(R b)) t1-X-(C(R a)(R b)) t2-;Z 1和Z 2各自独立地为N或CH;Ar 1是C 6-10芳基、C 1-9杂芳基、C 3-8环烷基、C 2-9杂环基、C 5-12稠合双环基、或C 5-12稠合杂双环基,其中所述Ar 1任选地被0、1、2、3或4个R 2取代;Cy是C 3-8环烷基、C 2-9杂环基、C 5-12螺双环基、C 5-12螺杂双环基、C 5-12稠合双环基、C 5-12稠合杂双环基、C 5-12桥环基、或C 5-12桥杂环基,其中所述Cy任选地被0、1、2、3或4个R 3取代;Ar 2是8个环原子组成的稠合杂芳基、并且所述环原子包含1、2、3、或4个独立地选自O、S和/或N的杂原子,所述Ar 2任选地被0、1、2、3或4个R 6取代;或者Ar 2是:X是O、S、-N(R d)-、或-C(=O)-;X 1、X 2和X 3分别独立地为N或-C(R 6)-;X 5是O或S;W是-C(=O)OR 7a、-S(=O) 1-2OR 7a、-P(=O)(OR 7a)(OR 7b)、-P(=O)(OR 7a)(R 7c)、-S(=O) 1-2R 7d、-C(=O)R 7d、-C(=O)N(R 7c)R 7d、-S(=O) 1-2N(R 7c)R 7d、-C(=O)N(R 7c)S(=O) 1-2R 7d、-C(=O)N(R 7c)S(=O) 1-2N(R 7c)R 7d、-C(=O)N(R 7c)C(=O)R 7d、-C(=O)N(R 7c)C(=O)N(R 7c)R 7d、-C(=O)N(R 7c)C(=S)N(R 7c)R 7d、-C(=O)N(R 7c)S(=NR 7a) 1-2R 7d、-C(=O)N(R 7c)S(=O)(=NR 7a)R 7d、各R 1分别独立地为H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 3-8环烷基C 2-6烯基、C 3-8环烷基C 2-6炔基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基、-S(=O) 1-2R 1a、-C(=O)R 1a、-C(=O)OR 1b、-OS(=O) 1-2R 1a、-OC(=O)R 1a、-N(R 1b)C(=O)R 1a、-OC(=O)NR 1bR 1c、-NR 1bR 1c、-N(R 1b)S(=O) 1-2R 1a、或-N(R 1b)C(=O)NR 1bR 1c;R 5是H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、C 1-6氨基烷基、C 1-6烷氧基C 1-6烷基、C 3-10环烷基、C 2-9杂环基、C 6-10芳基、C 1-9杂芳基、R 5c-C(=O)-、R 5c-OC(=O)-、R 5c-C(=O)O-、R 5c-NHC(=O)-、R 5c-C(=O)NH-、R 5c-L 3-C 1-6烷基-、R 5a-C 1-6烷基、或R 5a-C 1-6羟基烷基-,其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6氰基烷基、C 1-6氨基烷基、C 3-10环烷基、C 2-9杂环基、C 6-10芳基、C 1-9杂芳基、R 5c-C(=O)-、R 5c-OC(=O)-、R 5c-NHC(=O)-、R 5c-L 3-C 1-6烷基-、R 5a-C 1-6烷基-和R 5a-C 1-6羟基烷基-独立任选地被0、1、2、3或4个R 5b取代;R 5a是C 3-10环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基,其中所述R 5a任选地被0、1、2、3或4个R 5b取代;R 5c是H、C 1-6烷基、C 3-10环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基,其中所述R 5c任选地被0、1、2、3或4个R 5b取代;L 3是O、S、-N(R d)-、或-C(=O)-;各R 1a、R 2、R 3、R 4、R 5b、R 6、R a和R b分别独立地为H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、-NR 1bR 1c、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基;其中C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基和C 1-6卤代烷氧基的取代基取代;各R 1b、R 1c、R c、R d、R 7c和R 7d分别独立地为H、D、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基;其中C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基和C 1-6卤代烷氧基的取代基取代;R 7a和R 7b各自独立地为H、碱金属离子、碱土金属离子、-OH、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基;其中C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基和C 1-6卤代烷氧基的取代基取代;n是0、1、2、3、4或5;和各t1和t2分别独立地为1、2、3或4。
- 根据权利要求1所述的化合物,其中,L 1是O、NH、或CH 2;L 2是O、S、-N(R c)-、或-CH 2-。
- 根据权利要求1-3任一项所述的化合物,其中,Ar 1是其中,Y 1和Y 2分别独立地为N或-C(R 2)-;Y 3和Y 4分别独立地为-C(=O)-、O、S、-N(R 2a)-、-(C(R 2) 2) t3-、或-W 1-(C(R 2) 2) t3-;W 1是-C(=O)-、O、S、或-N(R 2a)-;各R 2a分别独立地为H、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基;和t3是1、2、或3。
- 其中,X 1、X 2和X 3分别独立地为N或-C(R 6)-;X 4为O、S、-N(R 6a)-、或-C(R 6) 2-;X 5是O或S;和各R 6a独立地为H、C 1-6烷基、C 1-6羟基烷基、C 1-6卤代烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷硫基、C 1-6烷氨基、C 1-6卤代烷氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,W是-COOH、-COOCH 3、-COOCH 2CH 3、-COOCH 2CH 2CH 3、-COOCH(CH 3) 2、-COOCH 2CH(CH 3) 2、-P(=O)(OH) 2、-P(=O)(OCH 3)(OCH 3)、-P(=O)(ONa +)(ONa +)、-P(=O)(ONH 4 +)(ONH 4 +)、-P(=O)(OH)(OCH 3)、-P(=O)(OH)(OPh)、-P(=O)(OH)(OCH 2CH 3)、-P(=O)(OCH 2CH 3)(OCH 2CH 3)、其中R 7d是H、甲基、乙基、丙基、异丙基、丁基、叔丁基、-CF 3、-CH 2CF 3、-CH 2CN、-CH 2CH 2CN、-CH 2OH、-CH 2CH 2OH、环丙基、环丁基、环戊基、苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、吡唑基、三唑基、或四唑基,其中R 7d任选地被0、1、2、3或4个独立选自H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基和C 1-4卤代烷氧基的取代基取代。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,各R 1分别独立地为H、D、F、Cl、Br、-OH、-NH 2、-NO 2、-CN、甲基、乙基、-CF 3、-CH 2CF 3、-CH 2CN、-CH 2CH 2CN、-CH 2OH、或-CH 2CH 2OH;n是0、1、2、3或4。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,R 5是H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 1-4卤代烷基、C 1-4氰基烷基、C 1-4烷氧基C 1-4烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 1-9杂芳基、R 5c-C(=O)-、R 5c-OC(=O)-、R 5c-C(=O)O-、R 5c-NHC(=O)-、R 5c-C(=O)NH-、R 5c-L 3-C 1-4烷基-、R 5a-C 1-4烷基-、或R 5a-C 1-4羟基烷基-,其中所述C 1-4烷基、C 1-4卤代烷基、C 1-4氰基烷基、C 1-4烷氧基C 1-4烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 1-9杂芳基、R 5c-C(=O)-、R 5c-OC(=O)-、R 5c-C(=O)O-、R 5c-NHC(=O)-、R 5c-C(=O)NH-、R 5c-L 3-C 1-4烷基-、R 5a-C 1-4烷基-和R 5a-C 1-4羟基烷基-独立任选地被0、1、2、3或4个R 5b取代;R 5a是C 3-6环烷基、C 3-6杂环基、C 6-10芳基、或C 1-9杂芳基,其中所述R 5a任选地被0、1、2、3或4个R 5b取代;R 5c是H、C 1-4烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、或C 1-9杂芳基,其中所述R 5c任选地被0、1、2、3或4个R 5b取代;和L 3是O、S、-NH-、或-C(=O)-。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,R 5是H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、甲氧基甲基、甲氧基乙基、-CF 3、-CH 2CF 3、-CH 2CH 2CN、-CH 2CH 2OH、-COOH、H 2NC(=O)-、R 5c-C(=O)-、R 5c-OC(=O)-、R 5c-NHC(=O)-、R 5c-L 3-C 1-3烷基-、R 5a、R 5a-C 1-3羟基烷基-、或R 5a-C 1-3烷基-;L 3是O、S、-NH-、或-C(=O)-;和R 5a和R 5c各自独立地为其中所述R 5a和R 5c各自任选地被0、1、2或3个独立地选自由H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 1-4卤代烷基、C 1-4氰基烷基、C 1-4羟基烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基和C 3-6环烷基组成的组的基团取代。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,各R 1a、R 2、R 3、R 4、R 5b、R 6、R a和R b分别独立地为H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 1-4卤代烷氨基、-NR 1bR 1c、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基;其中C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基和C 1-4卤代烷氧基的取代基取代。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,各R 5b分别独立地为H、D、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、-CF 3、-CH 2CF 3、-CH 2CHF 2、甲氧基、乙氧基、丙氧基、甲氧基甲基、环丙基、环丙基甲基、或环丁基。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,各R 1b、R 1c、R c、R d、R 2a、R 6a、R 7c和R 7d分别独立地为H、OH、D、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷硫基、C 1-4烷氨基、C 1-4卤代烷氨基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基;其中C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基和C 1-4卤代烷氧基的取代基取代。
- 根据权利要求1-3和6-7任一项所述的化合物,其中,R 7a和R 7b各自独立地为H、Li +、Na +、K +、NH 4 +、Mg 2+、Ca 2+、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基;其中C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基任选地被0、1、2、3或4个独立选自H、F、Cl、Br、I、-OH、-NH 2、-NO 2、-CN、氧代(=O)、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4羟基烷基、C 1-4卤代烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 1-4烷氧基和C 1-4卤代烷氧基的取代基取代。
- 药物组合物,所述药物组合物包含权利要求1-21中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的辅料、稀释剂或载体。
- 根据权利要求22所述的药物组合物,其进一步包含附加治疗剂。
- 使用权利要求1-21任一项所述的化合物或权利要求22-23任一项所述的药物组合物在制备用于预防和/或治疗哺乳动物心血管代谢性疾病和相关病症的药物中的用途。
- 根据权利要求24所述的用途,其中,所述心血管代谢性疾病和相关病症是T1D、T2DM、糖尿病前期、特发性T1D、LADA、EOD、YOAD、MODY、营养不良相关性糖尿病、妊娠糖尿病、高血糖症、胰岛素抗性、肝脏胰岛素抗性、葡萄糖耐受不良、糖尿病神经病变、糖尿病肾病变、肾疾病、糖尿病视网膜病变、脂肪细胞功能障碍、内脏脂肪细胞囤积、睡眠窒息症、肥胖症、进食障碍、使用其它药剂导致的体重增加、过度嗜糖、血脂异常症、高胰岛素血症、NAFLD、NASH、纤维变性、硬化、肝细胞癌、心血管疾病、动脉粥样硬化、冠状动脉疾病、外周血管疾病、高血压、内皮功能障碍、受损的血管顺应性、充血性心力衰竭、心肌梗塞、中风、出血性中风、缺血性中风、创伤性脑损伤、肺性高血压、血管成形术后再狭窄、间歇性跛行、餐后脂血症、代谢性酸中毒、酮体症、关节炎、骨质疏松症、帕金森病、左心室肥大、外周动脉疾病、黄斑变性、白内障、肾小球硬化、慢性肾衰竭、代谢综合征、综合征X、经前综合征、心绞痛、血栓症、动脉粥样硬化、短暂性脑缺血发作、血管再狭窄、葡萄糖代谢不良、受损的空腹血糖病况、高尿酸血症、痛风、勃起功能障碍、皮肤和结缔组织异常、牛皮癣、足部溃窃、溃病性结肠炎、高apo B脂蛋白血症、阿尔茨海默病、精神分裂症、认知功能受损、炎性肠病、短肠综合征、克隆病、结肠炎、肠易激综合征、多囊性卵巢综合征、或成瘾。
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