WO2022134837A1 - 一种吡咯衍生物及其制备方法和用途 - Google Patents
一种吡咯衍生物及其制备方法和用途 Download PDFInfo
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- WO2022134837A1 WO2022134837A1 PCT/CN2021/126634 CN2021126634W WO2022134837A1 WO 2022134837 A1 WO2022134837 A1 WO 2022134837A1 CN 2021126634 W CN2021126634 W CN 2021126634W WO 2022134837 A1 WO2022134837 A1 WO 2022134837A1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/16—Peri-condensed systems
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Definitions
- the invention relates to the technical field of medicine, in particular to a compound used as a fungal dihydroorotate dehydrogenase (DHODH) inhibitor and a preparation method and application thereof.
- DHODH fungal dihydroorotate dehydrogenase
- DHODH catalyzes the fourth step in the de novo synthesis of pyrimidine nucleotides and is a flavin-dependent mitochondrial enzyme.
- Pyrimidine is a key component of RNA and DNA biosynthesis, and DHODH inhibitors inhibit cell growth by inhibiting the activity of DHODH to deplete pyrimidine nucleotides in cells.
- hDHODH human dihydroorotate dehydrogenase
- Dihydroorotate dehydrogenase against viruses or fungi The inhibitors can be used to treat viral or fungal infection-related diseases, respectively.
- Invasive fungal infections are known as hidden killers and are an important cause of final death in patients with tumors, AIDS, organ transplants, etc.
- Species that cause fungal infections include Aspergillus, Sporozoites, etc.
- therapies that can combat drug-resistant infections as well as infections with refractory pathogens.
- the prevalence of pulmonary aspergillosis is approximately 3 million worldwide and approximately 240,000 in Europe. Without timely diagnosis and long-term antifungal treatment, the 5-year mortality rate is as high as nearly 80%.
- the main technical problem solved by the present invention is to provide a compound that can effectively inhibit fungi.
- the present invention provides a compound having the structure shown in formula I or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, which is pharmaceutically Acceptable Hydrates, Solvates or Salts:
- Ring A is a 5- to 10-membered ring, and the selected from alkyl, heteroalkyl, acyl, ester, amide, sulfonyl, sulfonamido, sulfinyl, sulfinamide;
- Ring B is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;
- the any two R 1 include two R 1 of two adjacent substitution sites, or two R 1 of two non-adjacent substitution sites, or two R 1 of the same substitution site ; other similar situations The same is true.
- R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, -NH 2 , substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10-membered heteroalkane base, substituted or unsubstituted 3-12-membered cycloalkyl, substituted or unsubstituted 3-12-membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl, ester, amide, sulfonyl, sulfonamide, boronic acid, boronic ester, phosphoryl, or R 2 , R 3 together form a substituted or unsubstituted C1-C6 alkyl group,
- R 5 is selected from substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10-membered heteroalkyl, substituted or unsubstituted 3-12-membered cycloalkyl, substituted or unsubstituted 3-12-membered Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
- R 6 is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10-membered heteroalkyl, substituted or unsubstituted 3-12-membered cycloalkyl, substituted or unsubstituted 3- 12-membered heterocycloalkyl, substituted or unsubstituted alkenyl;
- Z 1 , Z 2 , Z 3 are independently selected from N or CR 8 ;
- R 8 is independently selected from hydrogen, halogen, nitro, cyano, hydroxyl, -NH 2 , substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10 membered heteroalkyl, Substituted or unsubstituted 3-12-membered cycloalkyl, substituted or unsubstituted 3-12-membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, acyl, ester, amido, sulfonyl, sulfonamide, boronic acid, boronic ester, phosphoryl, or any two R 8 and its The connected atoms form a substituted or unsubstituted 5- to 9-
- R 8 and R 9 together form a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 2-6 membered heteroalkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted ester group, substituted or unsubstituted amido, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfonamido, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfinamide;
- n 1, n 2, n 3 are independently selected from 0, 1, 2, 3, 4, 5, 6; n 4, n 9 are independently selected from 1, 2, 3;
- n 5 is selected from 1, 2, 3, 4; n 6, n 7 are independently selected from 0, 1, 2;
- R 10 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 are independently selected from hydrogen, acyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10-membered heteroalkane group, substituted or unsubstituted 3- to 12-membered cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocycloalkyl, substituted or unsubstituted alkenyl;
- R 11 and R 12 are independently selected from hydrogen, halogen, hydroxyl, C1-C10 alkyl at each occurrence;
- the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, -NH 2 , nitro, carboxyl, acyl, ester, Amido, aryl, heteroaryl, sulfinyl, sulfonyl, sulfonamido, sulfinamide.
- R 9 is not fixed, which means that R 9 can be in any substitutable position in the ring structure where it is located; the same is true for the other substituents whose positions are not fixed.
- R 2 and R 3 together form a substituted or unsubstituted C1-C6 alkyl group
- the two substituents R 2 and R 3 are connected together to form an alkyl group consisting of two connecting ends, such as -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc., and the same applies to other similar situations.
- adjacent R 8 and R 9 refers to the closest R 8 and R 9 in the compound of the present invention in space, that is, situation shown.
- Z 2 is CR 8
- Z 1 and Z 3 are independently selected from N or CR 8 .
- Z 2 and Z 3 are CR 8 , and Z 1 is selected from N or CR 8 .
- ring A is a substituted or unsubstituted 5- to 7-membered ring, and the heteroatom in ring A is selected from O, N, and S.
- the two R 1 of the substitution site and the atoms to which they are connected constitute a substituted or unsubstituted 3-6 membered cycloalkyl group.
- the two R1 atoms of the point to which they are attached form a substituted or unsubstituted cyclopropyl group.
- n 1 is selected from 0, 1, 2, 3, 4; further selected from 0, 1, 2.
- the compound of the present invention has the structure shown in formula II or its tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof.
- R 21 , R 22 , R 23 and R 24 are independently selected from hydrogen, halogen, hydroxyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkenyl, or R 21 , R 22 and The connected atoms form a substituted or unsubstituted 3-6 membered cycloalkyl; the substituents in R 21 , R 22 , R 23 and R 24 are independently selected from halogen, hydroxyl, -NH 2 , ester group, acyl group, C1 ⁇ C4 alkyl, 3-6 membered cycloalkyl;
- Z 1 is selected from N or CR 8 ;
- R 8 is selected from hydrogen, halogen, nitro, cyano, hydroxyl, -NH 2 , substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted 2-10-membered heteroalkyl, substituted or unsubstituted 3 ⁇ 12-membered cycloalkyl, substituted or unsubstituted 3-12-membered heterocycloalkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted phenyl , substituted or unsubstituted 5- to 9-membered heteroaryl, acyl, ester, amide, sulfonyl, sulfonamide, boronic acid, boronic ester, phosphoryl, or R 8 and R 24 and their connected Atoms constitute a substituted or unsubstituted 5-7-membered al
- R 8 and R 19 together form a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted 2-6 membered heteroalkyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted ester group, a substituted or unsubstituted substituted amido, substituted or unsubstituted sulfonyl, substituted or unsubstituted sulfonamido, substituted or unsubstituted sulfinyl, substituted or unsubstituted sulfinamide;
- R 8 , R 19 , R 20 , R 25 , R 26 , R 27 , and R 28 are independently selected from halogen, C1-C10 alkyl, 3-12-membered cycloalkyl, and 2-10-membered heteroalkane base, 3-6 membered heterocycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, hydroxyl, cyano, -NH 2 , carboxyl, acyl, ester, amido, phenyl, 5-9 membered hetero Aryl, sulfinyl, sulfonyl, sulfonamido, sulfinamide;
- R 21 and R 22 are independently selected from hydrogen, halogen, hydroxyl, C1-C4 alkyl substituted or unsubstituted by halogen, or R 21 , R 22 and the connected atoms form a substituted or unsubstituted cyclopropyl group ;
- R 23 is selected from hydrogen, C1-C4 alkyl.
- ring A is selected from the following groups substituted or unsubstituted:
- ring A is selected from the following groups substituted or unsubstituted:
- Ring A is selected from the following groups, substituted or unsubstituted:
- ring A is selected from the following groups substituted or unsubstituted:
- L is selected from a bond, C2-C4 alkynylene.
- L is selected from a bond.
- the compound of the present invention has the structure shown in formula III or formula IV or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof Forms, pharmaceutically acceptable hydrates, solvates or salts:
- W 1 and W 2 are independently selected from O, CH 2 , CHF, CF 2 , NH and NCH 3 , preferably O, CF 2 and CH 2 ;
- Z 1 is selected from N or CR 8 ;
- R 8 is selected from hydrogen, halogen, cyano, hydroxyl, -NH 2 , substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2-5 membered alkoxy, substituted or unsubstituted 2-5 membered Azaalkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted C2-C4 alkenyl, acyl, ester, amide, boronic acid, boronic ester, or R 8 and R 19 together form substituted or unsubstituted C1-C2 alkyl, substituted or unsubstituted 2-membered heteroalkyl, substituted or unsubstituted ester group;
- R 8 is selected from H, F, -OH, -B(OH) 2 , or R 8 and R 19 and their connected atoms form the following groups:
- R 8 is selected from H, F.
- R 24 is selected from hydrogen, halogen, preferably H, F, Cl; more preferably H.
- R 25 , R 26 , R 27 , and R 28 are independently selected from halogen, C1-C6 alkyl, 3-6 membered cycloalkyl, 2-6 membered heteroalkyl, and 3-6 membered heterocycloalkane group, hydroxyl group, cyano group, -NH 2 , carboxyl group, acyl group, ester group, amido group, sulfinyl group, sulfonyl group, sulfonamido group, sulfinamide group.
- each occurrence of R 25 and R 27 is independently selected from hydrogen, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted 3 ⁇ 6-membered cycloalkyl, acyl, ester group, R 26 and R 28 are H;
- R 25 , R 26 , R 27 , and R 28 are H.
- R 19 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-7-membered heteroalkyl, acyl, and ester group;
- R 19 and R 20 are H.
- ring B is selected from phenyl, naphthyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 3-9 membered cycloalkyl, substituted or unsubstituted 3-9 membered heterocycle alkyl.
- ring B is selected from substituted or unsubstituted 5-6 membered heteroaryl groups.
- Ring B is selected from the group consisting of substituted or unsubstituted: phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, Triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl.
- Ring B is selected from pyrimidinyl, pyridyl, pyridazinyl, thiazolyl, triazolyl, oxadiazolyl; preferably pyrimidinyl, pyridyl, pyridazinyl, thiazolyl; Pyrimidyl is more preferred.
- each occurrence of R 7 is selected from hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-7 membered heteroalkyl, substituted or unsubstituted 3 ⁇ 6-membered cycloalkyl, substituted or unsubstituted 3-6-membered heterocycloalkyl, acyl, ester, amide, sulfonyl, sulfonamide, or two adjacent R 7 and their connected atoms Substituted or unsubstituted 3- to 6-membered hydrocarbon rings, substituted or unsubstituted 3- to 6-membered heterohydrocarbon rings; heteroatoms in the heteroalkyl, heterocycloalkyl, heteroaryl, and heterohydrocarbon rings described in R 7 One or more selected from N, O, S; further, R 7 is independently selected from hydrogen, halogen, cyano, substituted or unsubstitute
- the substituent in R 7 is selected from halogen, C1-C6 alkyl, 3-6 membered cycloalkyl, 2-6 membered heteroalkyl, 3-6 membered heterocycloalkyl, hydroxyl, cyano, -NH 2 , acyl group, ester group.
- each occurrence of R 7 is independently selected from F, -OCH 3 , -CF 3 , -CH 3 , -OH, cyano; further, n 2 is 1.
- R 5 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3 ⁇ 6-membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; the substituent in R 5 is selected from halogen, C1-C6 alkyl, 3-6 membered ring Alkyl, 2-6 membered heteroalkyl, 3-6 membered heterocycloalkyl, hydroxyl, cyano, amino, acyl, ester, amido, sulfinyl, sulfonyl, sulfonamido, sulfinamide .
- R 5 is selected from substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted Pyridyl, substituted or unsubstituted pyrimidinyl, preferably substituted or unsubstituted phenyl, the substituent in R 5 is selected from halogen or C1-C6 alkyl; further, the substituent in R 5 is selected from F, Cl , C1 ⁇ C4 alkyl.
- R 2 and R 3 are independently selected from hydrogen, halogen, cyano, hydroxyl, -NH 2 , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2-6 membered heteroalkyl, substituted or unsubstituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C2-C6 alkenyl, acyl, ester, amido, sulfonyl, sulfonamide group, or R 2 and R 3 together form a substituted or unsubstituted C3-C4 alkyl group, a substituted or unsubstituted 3- to 4-membered heteroalkyl group; the substituents in R 2 and R 3 are independently selected from halogen, C1 ⁇ C6 alkyl, 3 ⁇ 6 membered cycloalkyl, 2
- R 4 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C2-C4 alkenyl.
- R 2 and R 3 are independently selected from hydrogen, cyano group, substituted or unsubstituted C1-C4 alkyl group, substituted or unsubstituted 2-4 membered heteroalkyl group, or R 2 and R 3 together form a substituted or unsubstituted C3-C4 alkyl, substituted or unsubstituted 3-4 membered heteroalkyl; the substituents in R 2 and R 3 are independently selected from halogen, hydroxyl, C1-C4 alkyl, 3-6 membered Cycloalkyl, 2-4 membered heteroalkyl, 3-6 membered heterocycloalkyl, C2-C4 alkenyl;
- R 4 is selected from hydrogen, methyl.
- R 2 and R 3 are independently selected from hydrogen, cyano, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted substituted or unsubstituted Or R 2 and R 3 together form a substituted or unsubstituted substituted or unsubstituted
- R 2 and R 3 are independently selected from hydrogen, cyano, substituted or unsubstituted methyl, substituted or unsubstituted methyl Or R 2 and R 3 together form a substituted or unsubstituted substituted or unsubstituted
- R 2 and R 3 are independently selected from hydrogen, cyano, and substituted or unsubstituted methyl groups; and R 4 is selected from hydrogen.
- R 2 and R 3 are independently selected from F, Cl and hydroxyl.
- R 6 is selected from hydrogen, halogen-substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 3-6 membered cycloalkyl.
- R 6 is selected from hydrogen, fluorine substituted or unsubstituted C1-C4 alkyl, preferably H.
- the compound is selected from the following structures, or its R or S configuration:
- the present invention also provides a pharmaceutical composition, the active ingredient of which is any compound of the present invention or its stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, ester, co-crystal, N- One or a combination of two or more of oxides, isotopically labeled compounds, metabolites, and prodrugs.
- the present invention also provides the use of a compound of the present invention or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a DHODH inhibitor.
- the present invention also provides the use of the compound of the present invention or its stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal in the preparation of a medicament for the treatment or prevention of fungal infections or diseases caused by fungal infections .
- the present invention also provides the use of a compound of the present invention or a stereoisomer, solvate, hydrate, pharmaceutically acceptable salt or co-crystal thereof in the preparation of a fungicide.
- the fungi are selected from one or more organisms of the following genera: Absidia, Acremonium, Alternaria, Aspergillus, Bipolaris, Blastomyces, Blumeria, Cladosporium, Coccidioides, Colletotrichium, Curvularia, Encephalitozoon, Epicoccum, Epidermophyton, Exophiala, Exserohilum, Fusarium, Histoplasma, Leptosphaeria, Microsporum, Mycosphaerella, Neurospora, Paecilomyces, Penicillium, Phytophthora, Plasmopara, Pneumocystis, Pyricularia, Pythium, Puccinia, Rhizoctonia, Rhizomucor, Scedosporium, Scopula riopsis, Trichophyton, Trichosporon, Ustilago;
- the fungi are selected from one or more organisms of the following genera: Aspergillus, Scedosporium, Fusarium, preferably Aspergillus and/or Scedosporium, more preferably Aspergillus.
- the fungi are selected from one or more of A.fumigatus, A.flavus, A.terreus, A.niger, A.lentulus, S.apiospermum, S.prolificans, and S.species.
- the fungi are selected from one or more of A. fumigatus, A. flavus, A. terreus, A. niger and S. prolificans.
- the disease caused by the fungal infection is selected from systemic fungal infection disease and surface fungal infection disease.
- the disease of the systemic fungal infection is selected from pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, systemic aspergillosis, asthma, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis, chromoblastosis disease, rhinocerebral mucormycosis, blastomycosis, histoplasmosis, keloid blastomycosis, chromothricosis, disseminated sporotrichosis, fungal colonization of cystic fibrosis, sinusitis .
- the surface-infected fungal disease is selected from the group consisting of ringworm, onychomycosis, and athlete's foot.
- the present invention also provides the following intermediates for preparing the aforementioned compounds, such as M-9, IM2, IM3 and the like.
- the above-mentioned compounds or their analogs can be further synthesized through the above-mentioned intermediates.
- the present invention also provides the preparation method of the compound of the present invention: including the preparation of intermediate M-9:
- M-7, M-8 react to generate M-9 compound, and the type of reaction is selected from one or more of substitution reaction, condensation reaction, reduction reaction, free radical reaction, and metal-catalyzed coupling reaction;
- R T4 is selected from halogen, aldehyde group, C1-C6 alkyl sulfonate group substituted by halogen (such as trifluoromethanesulfonate group);
- R F1 , R F2 represent functional groups capable of forming a cyclic structure together with the atoms to which they are attached by themselves or through transformation, each independently selected from hydrogen, halogen, nitro, cyano, aldehyde, hydroxyl, carboxyl, substituted C1-C6 alkyl, substituted C1-C6 alkoxy, or, substituted or unsubstituted following groups: mercapto, sulfone, sulfoxide, ketone, amino, ester, amide, hydroxymethyl, Aminomethyl, wherein the substituent is selected from halogen, hydroxyl, carboxyl, ester group;
- R N is selected from amino group or a group that can be converted into amino group, preferably amino group, nitro group, carboxyl group, ester group, halogen, more preferably amino group, nitro group;
- R B is selected from the protecting group of hydrogen or amino, further selected from hydrogen, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB) and 2,4-and methoxybenzyl (DMB);
- R 1 , R 9 , Z 1 , Z 2 , Z 3 , n 1 , n 3 , n 4 , n 9 are as defined in the compounds of the present invention.
- R T4 is selected from halogen
- R F1 is selected from halogen, aldehyde group, ester group, sulfonyl chloride group, hydroxymethyl group
- R F2 is selected from hydrogen, hydroxymethyl group.
- M-7 and M-8 are first coupled with NH in M-8 through RT4 , and then M-9 is obtained through cyclization reaction;
- R T4 is selected from F, Cl
- R F1 is selected from aldehyde group, ester group, sulfonyl chloride group, hydroxymethyl
- R F2 is hydrogen, hydroxymethyl
- reaction conditions of R T4 and the NH coupling in M-8 are: M-7, M-8, alkali and solvent are mixed and reacted;
- the base is selected from inorganic bases, preferably sodium carbonate and/or potassium carbonate, more preferably potassium carbonate;
- described solvent is selected from one or more in DMSO, DMF, toluene;
- reaction temperature is 80-120°C, preferably 100°C.
- R F1 is an aldehyde group
- R F2 is hydrogen
- the cyclization reaction process is:
- the aldehyde group in M-9' is first The reaction generates an imine structure, and then closes the ring under the action of NaH to generate M-9-1.
- R F1 is hydroxymethyl
- R F2 is hydroxymethyl
- the cyclization reaction process is:
- M-9" generates M-9 through dehydration condensation reaction; further, M-9" generates M-9-2 through dehydration condensation of concentrated sulfuric acid.
- M-7 and M-8 are coupled and cyclized simultaneously, and M-9 is obtained by one-step reaction.
- R F1 is F
- R F2 is hydroxymethyl
- R T4 is selected from F
- reaction process is:
- M-7', M-8' react under the action of alkali to generate M-9-3; further, the alkali is selected from KOH and/or NaOH.
- the preparation of the compound of the present invention also includes the preparation of intermediate IM-2, and the synthetic route is as follows:
- Compound M-11 and S-5 are subjected to the action of a base (such as NaH, etc.) or a reducing agent (such as sodium borohydride, etc.) to generate IM-2 (when R 6 in the compound is H, it should be understood as such step is omitted).
- a base such as NaH, etc.
- a reducing agent such as sodium borohydride, etc.
- R T1 and R T5 are independently selected from halogen, aldehyde group, C1-C6 alkyl sulfonate group substituted by halogen;
- R 6 , R 7 and n 2 are as defined in the compounds of the present invention.
- nitro group is converted into amino group by reduction reaction, and the condition of reduction reaction can be palladium-carbon catalyzed hydrogenation reaction in the presence of hydrogen, or carry out in the presence of iron powder or zinc powder.
- the alkali in the step (1) is an inorganic base, preferably potassium carbonate and/or sodium carbonate;
- the transition metal catalyst in the step (1) is a palladium catalyst, further selected from tetrakistriphenylphosphine palladium, palladium acetate, triphenylphosphine (dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, bis(triphenylphosphine)palladium dichloride, t-BuXPhos-Pd -One or more of G3.
- compound IM-2 and IM-1 are subjected to the action of a base to generate the compound described in any one of claims 1 to 26, and the structure of compound IM-1 is as follows:
- Lg 3 is selected from leaving groups, preferably halogen, C1-C6 alkoxy group, C1-C6 alkyl sulfonate group substituted by halogen; R 2 , R 3 , R 4 , R 5 , L are the same as the present as defined in Invention Compounds.
- the preparation of the compound of the present invention also includes the preparation of intermediate IM-3, and the synthetic route is as follows:
- R N in M-9 is converted into -NH 2 ;
- M-12 and S-5 are formed under the action of a base (such as NaH, etc.) or a reducing agent (such as sodium borohydride, etc.) to generate M-13 (when R 6 in the compound is H, it should be understood as this step omitted);
- a base such as NaH, etc.
- a reducing agent such as sodium borohydride, etc.
- Lg 3 is selected from leaving groups, preferably halogen, C1-C6 alkoxy, C1-C6 alkyl sulfonate group substituted by halogen;
- R 2 , R 3 , R 4 , R 5 , L are as defined in the compounds of the present invention.
- the base in step (3) is N,N-diisopropylethylamine (DIEA); the condensing agent in step (3) is selected from 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide (EDCI) or in O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) one or more.
- DIEA N,N-diisopropylethylamine
- EDCI 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
- compound IM-3 and IM-4 are subjected to the action of a base to generate the compound described in any one of claims 1 to 26, and the structure of compound IM-4 is as follows:
- R T1 is selected from halogen, C1-C6 alkoxy group, and C1-C6 alkyl sulfonate group substituted by halogen.
- connection mode is not limited.
- the atoms connected to them can form a substituted or unsubstituted ester group.
- the "sinusitis” includes, but is not limited to, sinusitis, maxillary sinusitis, frontal sinusitis, gastritis, sphenoid sinusitis, and the like.
- compositions containing the compounds of the present invention or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or co-crystals may contain pharmaceutically acceptable excipients.
- “Pharmaceutically acceptable” as used herein is meant to include any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.
- the pharmaceutically acceptable adjuvant of the present invention is a general term for all additional materials in the drug except the main drug, and the adjuvant should have the following properties: (1) it has no toxic effect on the human body, and has almost no side effects; (2) its chemical properties are stable , not easily affected by temperature, pH, storage time, etc.; (3) It has no incompatibility with the main drug, and does not affect the efficacy and quality inspection of the main drug; (4) It does not interact with packaging materials.
- the adjuvants in the present invention include but are not limited to fillers (diluents), lubricants (glidants or anti-adherents), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, bacteriostatic agents , emulsifier, disintegrant, etc.
- Binders include syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.) , gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone, etc.; fillers include lactose, sugar powder, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, phosphoric acid Calcium hydrogen, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowder silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and Its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatin
- salts refers to a salt of a compound of the present invention with an acid or base suitable for use as a medicament.
- the above acids and bases are Lewis acids and bases in a broad sense.
- Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.
- the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, parenteral (intravenous, intramuscular or subcutaneous), and topical.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
- Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances and the like.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially
- compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
- the compounds of the present invention may likewise be used in the preparation of injections.
- the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (referring to a molded tablet or a machine-compressed tablet made by aseptic operation of a drug, and used for temporary use). Dissolved in water for injection for subcutaneous or intramuscular injection).
- the powder for injection also contains at least an excipient.
- the excipients described in the present invention are ingredients that are intentionally added to the drug and should not have pharmacological properties in the amount used, however, the excipients can aid in the processing, dissolution or dissolution of the drug, through the target Delivery to the route of administration may contribute to stability.
- substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
- Member means the number of skeleton atoms constituting the ring.
- the "one key” mentioned in the present invention means that there is only one connecting key, which can also be understood as “no”.
- Alkyl means an aliphatic hydrocarbon group and means a saturated hydrocarbon group.
- the alkyl moiety may be a straight chain alkyl group or a branched chain alkyl group.
- Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
- C1-Cn used in the present invention includes C1-C2, C1-C3... C1-Cn, and n is an integer greater than one; the prefix as a substituent indicates the minimum and maximum number of carbon atoms in the substituent, for example , "C1-C6 alkyl” refers to a straight-chain or branched alkyl group containing one to six carbon atoms.
- Hydrocarbon ring refers to a ring structure with carbon atoms on the ring skeleton, and the carbon atoms can be connected by single bonds or double bonds, and hydrocarbon rings include saturated hydrocarbon rings, alkene rings, and aromatic ring structures.
- Alkenyl ring refers to a group containing a carbon-carbon double bond on the ring skeleton.
- Heteroalkyl refers to an alkyl group containing a heteroatom, wherein the heteroatom includes but is not limited to O, S, N, P, etc.; alkoxy, sulfanyl, aminoalkyl, etc. all belong to heteroalkyl.
- alkenyl means an aliphatic hydrocarbon group having at least one carbon-carbon double bond.
- the alkenyl groups can be straight or branched.
- Alkynyl means an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
- the alkynyl group may be straight or branched.
- Alkynylene a straight-chain or branched divalent hydrocarbon group containing one or more carbon-carbon triple bonds, such as Wait.
- “Amido” is a chemical structure having the formula -C(O)NHR or -NHC(O)R, when having two attached ends, the structure -C(O)NH( CH2 )a- or -NHC( O)( CH2 )a-, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.
- Ester refers to a chemical structure having the formula -C(O)OR or -OC(O)R, when having two attached ends, the structure is -C(O)O( CH2 )a- or -OC (O)( CH2 )a-, wherein R can be selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., and a is a natural number.
- Acyl refers to a chemical structure having the formula -C(O)R, when having two attached ends, the structure is -C(O)( CH2 )a-, where R can be selected from alkyl, heteroalkyl , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc., a is a natural number.
- Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon substituent.
- C3-C6 cycloalkyl refers to a cycloalkyl with 3 to 6 carbon atoms; in the present invention, cycloalkyl may also include A non-aryl structure with unsaturated bonds on the ring skeleton.
- Heterocycloalkyl refers to a cycloalkyl group containing at least one heteroatom in the ring backbone.
- Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.
- Ring refers to any covalently closed structure, including, for example, carbocyclic (eg, aryl or cycloalkyl), heterocycle (eg, heteroaryl or heterocycloalkyl), aryl (eg, aryl or heteroaryl) ), non-aromatic groups (such as cycloalkyl or heterocycloalkyl).
- the "ring” in the present invention may be a single ring or a polycyclic ring, and may be a combined ring, a spiro ring or a bridged ring.
- Typical heterocycloalkyl groups include, but are not limited to:
- Aryl means that a planar ring has a delocalized pi electron system and contains 4n+2 pi electrons, where n is an integer.
- Aryl rings may consist of five, six, seven, eight, nine or more than nine atoms.
- Aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracenyl, fluorenyl, indenyl, and the like.
- Typical heteroaryl groups include, but are not limited to:
- Halogen or halo refers to fluorine, chlorine, bromine or iodine.
- Alkyl, heteroalkyl, cyclic, heterocyclyl, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, boronic ester, guanidino, acylguanidino, aryl described herein , heteroaryl, imino, etc. can be unsubstituted alkyl, heteroalkyl, cyclic, heterocyclic, amino, ester, carbonyl, amide, sulfonyl, phosphoryl, boronic acid, boronic ester group, guanidino group, acylguanidino group, aryl group, heteroaryl group, imino group, or substituted alkyl group, heteroalkyl group, cyclic group, heterocyclic group, amino group, ester group, carbonyl group, amide group, sulfonic acid group Acyl, phosphoryl, boronic acid, boronic ester, guanidino, acylguani
- the present invention provides a series of compounds with obvious inhibitory effect on DHODH activity, provides a new solution for the treatment of diseases with DHODH as the target of treatment, such as fungal infections, and can be used to prepare and treat related diseases It can also be used to prepare agricultural fungicides and has broad application prospects.
- the reaction was monitored by thin layer chromatography (TLC) or liquid phase-mass spectrometry (LC-MS).
- the developing solvent systems used in silica gel column or thin-layer preparation plate purification include but are not limited to: dichloromethane/methanol system, n-hexane/ethyl acetate system and petroleum ether/ethyl acetate system, and the volume ratio of the solvent is based on the polarity of the compound Adjust according to the difference, or add ammonia, triethylamine, etc. to adjust.
- the developing solvent system used in the reverse-phase preparation and purification includes but is not limited to: (a) Phase A: water, Phase B: acetonitrile; (b) Phase A: water, Phase B: methanol.
- reaction temperature is room temperature (20°C to 30°C).
- the structure of the compound is determined by mass spectrometry (MS) and/or nuclear magnetic resonance (1HNMR) equipment.
- MS mass spectrometry
- 1HNMR nuclear magnetic resonance
- PE petroleum ether
- HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
- t-BuXPhos-Pd-G3 Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl)palladium(II)
- the first step preparation of (Z)-2-(hydroxyimino)-3-oxo-3-phenylpropionic acid ethyl ester (A-2)
- the second step the preparation of 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate diethyl ester (A-3)
- Zinc powder (7.4g, 113.2mmol), anhydrous sodium acetate (7.7g, 93.9mmol) ethyl acetoacetate (5.5g, 42.3mmol) and glacial acetic acid (2mL) were added to the reaction flask, put into an oil bath and heated to 60 °C, and then the solution of compound A-2 (8.1 g, 36.7 mmol) and glacial acetic acid (3 mL) was added to the reaction system three times. After 1 h, the addition was completed, and the temperature was raised to 70 °C for 3 h, and then added Zinc powder (3.7 g, 56.6 mmol) was reacted for 1 h, and TLC showed that the reaction of the starting material was complete.
- reaction solution was cooled to room temperature and filtered with suction.
- the filtrate was evaporated in vacuo and taken with toluene (1 mL) twice.
- the residual liquid was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and anhydrous Na 2 SO 4 After drying and vacuum evaporation, the crude product was purified by silica gel column to obtain 7.0 g of light pink solid product A-3, yield: 62%.
- the third step preparation of 1,5-dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate diethyl ester (A-4)
- reaction solution was quenched with water, 1N hydrochloric acid solution (14 mL) was added, extracted twice with ethyl acetate, the organic phases were combined, washed with water, washed with saturated brine, dried over anhydrous Na 2 SO 4 , and evaporated in vacuo to obtain 6.5 g of a yellow solid Crude product A-4, yield: 89%.
- the fourth step preparation of 1,5-dimethyl-3-phenyl-1H-pyrrole-2,4-dicarboxylic acid (A-5)
- reaction solution was evaporated in vacuo to remove ethanol, the obtained residue was dissolved in water (10 mL), cooled to 0 °C, and the pH of the solution was adjusted to about 2 with concentrated hydrochloric acid, kept below 10 °C and stirred for 1 h, then suction filtered, and the filter cake was successively water (10 mL) , washed with petroleum ether (10 mL), evaporated and dried under vacuum below 60° C. to obtain 4.8 g of gray solid product A-5, yield: 90%.
- the sixth step preparation of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (A)
- the seventh step the preparation of 2-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)-5-nitrobenzaldehyde (1-3)
- Step 11 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-1,2, Preparation of 3,4,10,10a-Hexahydropyrazine[1,2-a]indol-8-yl)-2-oxoacetamide (T-1)
- the first step the preparation of 4-(2-formyl-4-nitrophenyl)-1,4-diazepine-1-carboxylic acid tert-butyl ester (2-2)
- the third step 9-nitro-4,5,11,11a-tetrahydro-1H-[1,4]diaza[1,2-a]indole-2(3H)-carboxylate tert-butyl ester (2-4-a) and 9-nitro1,2,4,5,11,11a-hexahydro-3H-[1,4]diaza[1,7-a]indole-3-carboxylate Preparation of tert-butyl acid (2-4-b)
- Step 6 2-(5-Fluoropyrimidin-2-yl)-2,3,4,5,11,11a-hexahydro-1H-[1,4]diaza[1,2-a]indol Preparation of indol-9-amine (2-7-a)
- Step 7 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidin-2-yl)-2,3,4 Preparation of ,5,11,11a-hexahydro-1H-[1,4]diaza[1,2-a]indol-9-yl)-2-oxoacetamide (T-2-a)
- Compound T-2-b was synthesized by a method similar to that described in the fourth step to the seventh step in Example 2.
- the first step 8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tertiary Preparation of Butyl Ester (3-3)
- Step 5 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3 Preparation of ,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (T-3)
- the first step 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoro-6-methoxy-1,6-di Hydropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)- Preparation of 2-Oxyacetamide (16-1)
- Step 2 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoro-6-oxo-1,6-dihydro) pyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2 - Preparation of oxyacetamide (T-16)
- the first step the preparation of 3-(hydroxymethyl)-4-(2-(methoxycarbonyl)-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (18-2)
- the second step the preparation of 3-(hydroxymethyl)-4-(2-(hydroxymethyl)-4-nitrophenyl)piperazine-1-carboxylate tert-butyl ester (18-3)
- Step 5 3-(5-Fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][ Preparation of 1,4]oxazepan-9-amine (18-6)
- Step 6 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-1,2,3 ,4,4a,5-hexahydro-7H-benzo[e]pyrazino[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide (T-18 ) preparation
- Compound T-18 was synthesized using a method similar to that described in the eleventh step in Example 1.
- the first step the preparation of 2-(allylsulfonyl)-1-chloro-4-nitrobenzene (19-2)
- reaction system was cooled to room temperature, water was added to it, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 . After vacuum evaporation, the obtained crude product was separated and purified by column chromatography to obtain 260 mg of product 19-2, 51% yield.
- the second step the preparation of 1-chloro-2-((2,3-dibromopropyl)sulfonyl)-4-nitrobenzene (19-3)
- the third step 8-nitro1,2,3,4,4a,5,6a,7-octahydrobenzo[b]pyrazino[1,2-d][1,4]thiazine6, Preparation of 6-dioxide (19-4)
- Step 4 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6,6-di Oxide-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]thiazin-8-yl)-2-oxoacetamide
- the first step the preparation of 2-chloropyrimidine-5-sulfonamide (20-2)
- Step 2 (R)-2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(3-(5-sulfamoylpyrimidine- 2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)acetamide (T -20) preparation
- the first step the preparation of 4-(tert-butoxycarbonyl)-1-(2-cyano-4-nitrophenyl)piperazine-2-carboxylic acid (21-3)
- the second step the preparation of 1-(tert-butyl) 3-methyl 4-(2-cyano-4-nitrophenyl) piperazine-1,3-dicarboxylic acid (21-4)
- Step 5 3-(5-Fluoropyrimidin-2-yl)-9-nitro-2,3,4,4a,6,7-hexahydrobenzo[f]pyrazine[1,2-a] Preparation of [1,4]diaza-5(1H)-one (21-7)
- the sixth step 9-amino-3-(5-fluoropyrimidin-2-yl)-2,3,4,4a,6,7-hexahydrobenzo[f]pyrazine[1,2-a][ Preparation of 1,4]diaza-5(1H)-one (21-8)
- Step 7 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-5-oxo-1 ,2,3,4,4a,5,6,7-Octahydrobenzo[f]pyrazino[1,2-a][1,4]diaza-9-yl)-2-oxoethyl
- Amide (T-21) 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-5-oxo-1 ,2,3,4,4a,5,6,7-Octahydrobenzo[f]pyrazino[1,2-a][1,4]diaza-9-yl)-2-oxoethyl
- Step 2 3-Nitro-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetri Preparation of Fluoroacetate (22-3)
- the third step 8-(5-fluoropyrimidin-2-yl)-3-nitro-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3 Preparation of ,2-b][1,4]oxazine(22-4)
- the fourth step 8-(5-fluoropyrimidin-2-yl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] Preparation of [1,4]oxazin-3-amine (22-5)
- Step 5 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(8-(5-fluoropyrimidin-2-yl)-6,6a,7 ,8,9,10-Hexahydropyrazine[1,2-d]pyridyl[3,2-b][1,4]oxazin-3-yl)-2-oxoacetamide (T-22) preparation
- the first step (R)-N-(3-(5-bromopyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2 -d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (23-2 ) preparation
- the first step (R)-N-(3-(4,6-dichloro-1,3,5-triazin-2-yl)-1,2,3,4,4a,5-hexahydrobenzene [b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl )-2-oxyacetamide (28-2) preparation
- Step 2 (R)-2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxo-N-(3-(5-vinylpyrimidine- 2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)acetamide (29 -3)
- the solvent in the reaction system was spin-dried, water was added to the reaction system, extracted three times with ethyl acetate, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the obtained crude product was purified by silica gel column after vacuum evaporation 75 mg of the target product 29-3 was obtained, yield: 50%.
- the third step N-((R)-3-(5-((R)-1,2-dihydroxyethyl)pyrimidin-2-yl)-1,2,3,4,4a,5-hexa Hydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrole-2- yl)-2-oxoacetamide (T-29) preparation
- the first step preparation of (S)-2-chloro-5-((2,2-dimethyl-1,3-dioxan-4-yl)methoxy)pyrimidine (30-3)
- Step 2 N-((R)-3-(5-((((S)-2,2-dimethyl-1,3-dioxan-4-yl)methoxy)pyrimidine- 2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1 Preparation of ,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-2-oxoacetamide (30-4)
- the third step N-((R)-3-(5-((R)-2,3-dihydroxypropoxy)pyrimidin-2-yl)-1,2,3,4,4a,5- Hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl)-2-(1,5-dimethyl-3-phenyl-1H-pyrrole-2 -yl)-2-oxoacetamide (T-30) preparation
- Step 2 3-(5-Fluoropyrimidin-2-yl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4 ] Preparation of oxazine-8-amine (31-2)
- Step 6 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6-methyl- 1,2,3,4,4a,5,6,7-Octahydrobenzo[f]pyrazino[1,2-a][1,4]diaza-9-yl)-2-oxo
- Acetamide (T-31) 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-6-methyl- 1,2,3,4,4a,5,6,7-Octahydrobenzo[f]pyrazino[1,2-a][1,4]diaza-9-yl)-2-oxo
- the first step the preparation of 4-(2-fluoro-5-nitrophenyl)-4-hydroxybutan-2-acid ethyl ester (32-2)
- Diisopropylamine (6.6g, 65.2mmol) was added to a dry three-necked flask, nitrogen was replaced, anhydrous THF (80mL) was added, the system was cooled to about -10°C, and n-butyllithium (2.5M in hexane) was added dropwise.
- the third step preparation of 8-nitro-2,3,4a,5-tetrahydro-1H-pyrazino[1,2-a]quinoline-4,6-dione (32-4)
- the fourth step the preparation of 8-nitro-2,3,5,6-tetrahydro-1H-pyrazino[1,2-a]quinolin-4(4aH)-one (32-5)
- the fifth step the preparation of 8-nitro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline (32-6)
- Step 7 3-(5-Fluoropyrimidin-2-yl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-amine Preparation of (32-8)
- Step 8 2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)-2,3,4 Preparation of ,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)-2-oxoacetamide (T-32)
- reaction solution was poured into water, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , evaporated in vacuo and the crude product was purified by thin-layer preparative plate to obtain 38 mg of product T-32, yield : 62%.
- the first step the preparation of (S)-indoline-2-carboxylate methyl ester (33-2)
- the second step the preparation of (S)-1-acetylindoline-2-carboxylate methyl ester (33-3)
- the third step the preparation of (S)-1-acetyl-5-nitroindole-2-carboxylate methyl ester (33-4)
- the fifth step the preparation of (S)-N-(2-hydroxyethyl)-5-nitroindole-2-carboxamide (33-6)
- the seventh step preparation of (S)-(2-hydroxyethyl)((5-nitroindol-2-yl)methyl)carbamic acid tert-butyl ester (33-8)
- the first step preparation of (Z)-3-(2-fluorophenyl)-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (35-2)
- the second step preparation of 3-(2-fluorophenyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate diethyl ester (35-3)
- Zinc powder (863 mg, 13.2 mmol), anhydrous sodium acetate (902 mg, 11.0 mmol), ethyl acetoacetate (640 mg, 4.9 mmol) and glacial acetic acid (4 mL) were added to the reaction flask, and the mixture was heated to 60°C in an oil bath. , and then the solution prepared by compound 35-2 (1.0 g, 4.2 mmol) and glacial acetic acid (6 mL) was added to the reaction system three times. Zinc powder (431 mg, 6.6 mmol) was continued to react for 1 h, and TLC showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature and filtered with suction.
- the third step preparation of 3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid (35-4)
- the fourth step the preparation of 4-(2-fluorophenyl)-1,2-dimethyl-1H-pyrrole (35-5)
- the fifth step the preparation of 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (35-6)
- reaction solution was poured into water, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , evaporated in vacuo and the crude product was purified by thin-layer preparative plate to obtain 24 mg of product T-35, yield : 38%.
- the first step preparation of (Z)-3-(3-fluorophenyl)-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (36-2)
- the second step the preparation of 3-(3-fluorophenyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate diethyl ester (36-3)
- Zinc powder (896 mg, 13.7 mmol), anhydrous sodium acetate (935 mg, 11.4 mmol), ethyl acetoacetate (664 mg, 5.1 mmol) and glacial acetic acid (4 mL) were added to the reaction flask, and the solution was heated to 60° C. in an oil bath. , and then the solution prepared by compound 36-2 (1.1 g, 4.6 mmol) and glacial acetic acid (6 mL) was added to the reaction system three times. Zinc powder (447 mg, 6.8 mmol) continued to react for 1 h, and TLC showed that the reaction of the starting material was complete. The reaction solution was cooled to room temperature and filtered with suction.
- the third step the preparation of 3-(3-fluorophenyl)-1,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid (36-4)
- the fourth step the preparation of 4-(3-fluorophenyl)-1,2-dimethyl-1H-pyrrole (36-5)
- the fifth step the preparation of 2-(3-(3-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (36-6)
- reaction solution was poured into water, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , evaporated in vacuo and the crude product was purified by thin-layer preparative plate to obtain 18 mg of product T-36, yield : 30%.
- the first step preparation of (Z)-3-(4-fluorophenyl)-2-(hydroxyimino)-3-oxopropionic acid ethyl ester (37-2)
- the second step preparation of 3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2,4-dicarboxylate diethyl ester (37-3)
- Zinc powder (1.3g, 19.9mmol), anhydrous sodium acetate (1.4g, 17.1mmol), ethyl acetoacetate (1.1g, 8.5mmol) and glacial acetic acid (5mL) were added to the reaction flask, and heated in an oil bath To 60°C, a solution of compound 37-2 (1.6g, 6.7mmol) and glacial acetic acid (5mL) was added to the reaction system in three portions. After the dropwise addition, the temperature was raised to 70°C and the reaction was stirred for 3h. Then, zinc powder (661 mg, 10.1 mmol) was added to continue the reaction for 1 h. TLC showed that the reaction of the starting materials was complete.
- reaction solution was cooled to room temperature and filtered with suction. After the filtrate was evaporated in vacuo, the residual liquid was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous Na 2 SO 4 . After evaporation in vacuo, the crude product was passed through silica gel Column purification gave 1.2 g of product 37-3, two-step yield: 56%.
- the third step preparation of 3-(4-fluorophenyl)-1,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid (37-4)
- the fourth step the preparation of 4-(4-fluorophenyl)-1,2-dimethyl-1H-pyrrole (37-5)
- the fifth step the preparation of 2-(4-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-2-oxoacetyl chloride (37-6)
- the first step (S)-2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(2-(5-fluoropyrimidine-2) -yl)-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-8-yl)-2-oxoacetamide (T-38) preparation
- reaction solution was poured into water, extracted twice with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , evaporated in vacuo and the crude product was purified by thin-layer preparative plate to obtain 80 mg of product T-38, yield : 76%.
- the first step 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)- 1,2,3,4,4a,5-Hexahydro-7H-benzo[e]pyrazine[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide
- T-39 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl)- 1,2,3,4,4a,5-Hexahydro-7H-benzo[e]pyrazine[2,1-c][1,4]oxazolin-9-yl)-2-oxoacetamide
- the first step 2-(3-(2-fluorophenyl)-1,5-dimethyl-1H-pyrrol-2-yl)-N-(8-(5-fluoropyrimidin-2-yl)- 6,6a,7,8,9,10-Hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-3-yl)-2-oxoethyl
- reaction solution was poured into water, extracted three times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous Na 2 SO 4 , evaporated in vacuo and the crude product was purified by thin-layer preparative plate to obtain 30 mg of product T-40, yield: 33%.
- the first step the preparation of 4-bromo-1-methyl-1H-pyrrole-2-carbonitrile (41-2)
- the third step the preparation of 5-bromo-1-methyl-4-phenyl-1H-pyrrole-2-carbonitrile (41-4)
- the fourth step the preparation of 2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxyacetic acid methyl ester (41-5)
- the fifth step the preparation of 2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-2-oxyacetic acid (41-6)
- Step 6 (R)-2-(5-cyano-1-methyl-3-phenyl-1H-pyrrol-2-yl)-N-(3-(5-fluoropyrimidin-2-yl) -1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)-2-oxoacetamide (T -41)
- T -41 Preparation
- RPMI1640 Dissolve a packet of RPMI1640 powder in 1L of purified water and mix well, add 0.165M MOPS, adjust pH to 7.0, and filter and sterilize with 0.22um membrane. Store at 4°C for no more than 3 months.
- Physiological saline Dissolve 9 g of sodium chloride powder in 1 L of purified water, mix well, and autoclave at 121°C for 30 minutes. Store at room temperature (RT) for no more than 1 week.
- each compound was 0.8 mg/mL (eg 150 ⁇ L of dimethyl sulfoxide + 10 uL of 12.8 mg/mL compound/control).
- a magnifying glass device was used. The tested 96-well microplate was photographed, and the optical density at 530 nm was read with a microplate reader (Tecan Spark).
- the structure of the positive control compound F901318 is:
- the compounds of the present invention showed strong inhibition against Aspergillus fumigatus (ATCC MYA-4609/AF293/CBS 101355, ATCC-204305) and Aspergillus flavus (ATCC 204304, ATCC MYA-1004) in the minimum inhibitory concentration (MIC) test active.
- MIC minimum inhibitory concentration
- test compound and F901318 were mixed orally (both 10 mg/kg, 3 rats in each group) and administered to SD rats for pharmacokinetic study.
- the test compound and F901318 used 5% DMSO+10% solutol +85% saline is dissolved, and is formulated into a colorless, transparent and clear dosing solution after vortexing for 1-2 min and sonicating for 5-10 min. Animals were fasted overnight before oral dosing and resumed feeding 4 hours after dosing. After oral administration of SD rats, the pharmacokinetic samples were collected through orbital blood collection. Three whole blood samples were collected at time points, and the collection volume was about 0.2-0.3 mL.
- the blood samples were immediately placed on ice after collection, and centrifuged within 15 minutes to separate the plasma (centrifugation conditions: 8000 rpm, 1 minute, room temperature). The collected plasma was stored at –20°C until analysis. Take 20 ⁇ L of plasma sample into a 0.5mL EP tube, add 200 ⁇ L of working internal standard solution (blank without internal standard and add the same volume of solvent), vortex for 3min, centrifuge at 13,500 rpm for 10min, and take 100 ⁇ L of supernatant , and analyzed by LC-MS/MS injection.
- Cmax maximum compound concentration
- AUC exposure
- T1/2 half-life
- Tmax time to reach Cmax.
- the compounds of the present invention have better exposure and maximum compound concentration in pharmacokinetic assays.
- liver microsome stability of some compounds of the present invention are shown in Table 6 below:
- some compounds of the present invention have better liver microsome stability for human or/and rat two species.
- Test Example 5 Experiment 1 of the survival rate of Aspergillus fumigatus bloodstream infection model in mice
- mice male CD-1 mice, 6-8 weeks old, 10 in each group;
- Microbial pathogen Aspergillus fumigatus ATCCMYA-4690 (AF293);
- Inoculum collection conditions SDA culture plate, 25 degrees Celsius incubator for at least 7 days, PBS+0.1% Tween 20 collection, count under microscope;
- Inoculation level, inoculation route and inoculation volume 3.60E+05CFU/mouse, tail vein injection, injection volume 100 ⁇ L/mouse;
- Treatment The treatment started 24 hours after infection.
- the test compound was dissolved in PEG400 (0.3 mg/mL) and administered orally at 3 mg/kg twice a day for 6 consecutive days and observed for 8 hours.
- T-5, T-33 and F901318 all play a role in prolonging the survival time of mice.
- day 7 survival was 40% for T-33, compared to 0% for both reference compounds F901318 and T-5.
- the in vivo efficacy of T-33 was significantly better than that of F901318 and T-5 in this model.
- Test Example 6 Survival rate experiment 2 of mouse Aspergillus fumigatus bloodstream infection model
- mice male CD-1 mice, 6-8 weeks old, 10 in each group;
- Microbial pathogen Aspergillus fumigatus ATCCMYA-4690 (AF293);
- Inoculum collection conditions SDA culture plate, 25 degrees Celsius incubator for at least 7 days, PBS+0.1% Tween 20 collection, count under microscope;
- Inoculation level, inoculation route and inoculation volume 3.90E+05CFU/mouse, tail vein injection, injection volume 100 ⁇ L/mouse;
- Treatment The treatment started 24 hours after infection.
- the test compound was dissolved in PEG400 (0.3 mg/mL), and the corresponding dose was orally administered twice a day for 6 consecutive days and observed for 8 hours.
- T-33, T-38 and F901318 all play a role in prolonging the survival time of mice.
- day 7 survival was 30% for T-33, 50% for T-38, and 0% for the reference compound F901318.
- T-33 showed a dose-dependent relationship at three doses of 1 mg/kg, 3 mg/kg and 10 mg/kg, and the survival rate of T-33 mice reached 80% at the dose of 10 mg/kg (bid).
- the in vivo efficacy of T-33 and T-38 was significantly better than that of F901318 in this model.
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Abstract
Description
Claims (34)
- 一种化合物,其特征在于,具有式I所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:环B选自取代或非取代的芳基、取代或非取代的杂芳基、取代或非取代的环烷基、取代或非取代的杂环烷基;R 1每次出现时独立地选自氢、卤素、氰基、=O、羟基、-NH 2、羧基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、取代或非取代的芳基、取代或非取代的杂芳基、酯基、酰基、酰胺基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基,或任意两个R 1及其相连的原子组成取代或非取代的3~12元烃环、取代或非取代的3~12元杂烃环;R 2、R 3、R 4分别独立选自氢、卤素、硝基、氰基、羟基、-NH 2、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、取代或非取代的C2~C10炔基、取代或非取代的芳基、取代或非取代的杂芳基、酰基、酯基、酰胺基、磺酰基、磺酰胺基、硼酸基、硼酸酯基、磷酰基,或R 2、R 3共同组成取代或非取代的C1~C6烷基、取代或非取代的3~10元杂烷基,或R 2、R 3及其相连的原子组成取代或非取代杂芳基;R 5选自取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的芳基、取代或非取代的杂芳基;R 6选自氢、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的烯基;R 7每次出现时独立地选自氢、卤素、氰基、=O、羟基、-NH 2、羧基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、取代或非取代的芳基、取代或非取代的杂芳基、酰基、酯基、酰胺基,磺酰基、磺酰胺基、硼酸基、硼酸酯基,或任意两个R 7及其相连的原子组成取代或非取代的3~12元烃环、取代或非取代的3~12元杂烃环;R 9每次出现时独立地选自氢、卤素、硝基、氰基、羟基、-NH 2、=O、羧基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、取代或非取代的C2~C10炔基、取代或非取代的芳基、取代或非取代的杂芳基、酰基、酯基、酰胺基、磺酰基、磺酰胺基、硼酸基、硼酸酯基、磷酰基,或任意两个R 9及其相连的原子组成取代或非取代的烃环、取代或非取代的杂烃环;Z 1、Z 2、Z 3分别独立选自N或CR 8;R 8每次出现时独立地选自氢、卤素、硝基、氰基、羟基、-NH 2、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、取代或非取代的C2~C10炔基、取代或非取代的芳基、取代或非取代的杂芳基、酰基、酯基、酰胺基、磺酰基、磺酰胺基、硼酸基、硼酸酯基、磷酰基,或任意两个R 8及其相连的原子组成取代或非取代的5~9元烯环、取代或非取代的5~9元杂烯环、取代或非取代的苯环、取代或非取代的5~9元杂芳环;或相邻的R 8和R 9共同组成取代或非取代的C1~C6烷基、取代或非取代的2~6元杂烷基、取代或非取代的酰基、取代或非取代的酯基、取代或非取代的酰胺基、取代或非取代的磺酰基、取代或非取代的磺酰胺基、取代或非取代的亚磺酰基、取代或非取代的亚磺酰胺基;n 1、n 2、n 3分别独立选自0、1、2、3、4、5、6;n 4、n 9分别独立选自1、2、3;L选自一键、O、S、S(=O)、S(=O) 2、C(=O)、NR 10、-(CR 11R 12)n 5-、-S(=O)n 6NR 13-、-NR 14S(=O)n 7NR 15-、-C(=O)NR 16-、-NR 17C(=O)NR 18-、C2~C4亚烯基、C2~C4亚炔基;n 5选自1、2、3、4;n 6、n 7分别独立选自0、1、2;R 10、R 13、R 14、R 15、R 16、R 17、R 18分别独立选自氢、酰基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的烯基;或R 11、R 12每次出现时独立地选自氢、卤素、羟基、C1~C10烷基;其中,R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 13、R 14、R 15、R 16、R 17、R 18中的取代基分别独立选自卤素、烷基、环烷基、杂烷基、杂环烷基、烯基、炔基、羟基、氰基、-NH 2、硝基、羧基、酰基、酯基、酰胺基、芳基、杂芳基、亚磺酰基、磺酰基、 磺酰胺基、亚磺酰胺基。
- 根据权利要求1所述的化合物,其特征在于,Z 2为CR 8,Z 1、Z 3分别独立选自N或CR 8;进一步地,Z 2、Z 3为CR 8,Z 1选自N或CR 8。
- 根据权利要求1或2所述的化合物,其特征在于,环A为取代或非取代的5~7元环,环A中的杂原子选自O、N、S。
- 根据权利要求1~3任一项所述的化合物,其特征在于,R 1每次出现时独立地选自氢、卤素、氰基、=O、羟基、-NH 2、羧基、取代或非取代的C1~C6烷基、取代或非取代的2~7元杂烷基、取代或非取代的3~9元环烷基、取代或非取代的3~9元杂环烷基、取代或非取代的C2~C6烯基、取代或非取代的苯基、取代或非取代的5~10元杂芳基、酯基、酰基、酰胺基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基,或任意两个R 1及其相连的原子组成取代或非取代的3~6元烃环,其中R 1的取代基选自卤素、烷基、环烷基、杂烷基、杂环烷基、烯基、炔基、羟基、氰基、氨基、羧基、酰基、酯基、酰胺基、芳基、杂芳基;进一步地,R 1每次出现时独立地选自氢、卤素、氰基、=O、取代或非取代的C1~C6烷基、取代或非取代的2~7元杂烷基、取代或非取代的3~9元环烷基、取代或非取代的3~9元杂环烷基,或同一取代位点的两个R 1与其相连的原子组成取代或非取代的3~6元烃环,其中R 1的取代基选自卤素、烷基、环烷基、杂烷基、杂环烷基、羟基、氰基、氨基。
- 根据权利要求4所述的化合物,其特征在于,R 1每次出现时独立地选自氢、卤素、=O、取代或非取代的C1~C4烷基、取代或非取代的2~5元烷氧基、取代或非取代的3~6元环烷基、取代或非取代的3~6元杂环烷基,或同一取代位点的两个R 1与其相连的原子组成取代或非取代的3~6元环烷基,其中R 1的取代基选自卤素、烷基、环烷基、杂烷基、杂环烷基、羟基、氰基、氨基;进一步地,R 1每次出现时独立地选自氢、卤素、=O、被卤素取代或非取代的C1~C4烷基、被卤素取代或非取代的3~6元环烷基,或同一取代位点的两个R 1与其相连的原子组成取代或非取代的3~6元环烷基;进一步地,R 1每次出现时独立地选自氢、F、Cl、=O、被F取代或非取代的C1~C4烷基、被卤素取代或非取代的环丙基、或同一取代位点的两个R 1与其相连的原子组成取代或非取代的环丙基。
- 根据权利要求1~5任一项所述的化合物,其特征在于,n 1选自0、1、2、3、4;进一步选自0、1、2。
- 根据权利要求1~6任一项所述的化合物,其特征在于,具有式II所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:J、Y、T分别独立选自一键、O、S、S(=O)、S(=O) 2、CR 21R 22、C=O、NR 23;R 21、R 22、R 23、R 24分别独立选自氢、卤素、羟基、取代或非取代的C1~C4烷基、取代或非取代的C1~C4烯基,或R 21、R 22及相连的原子组成取代或非取代的3~6元环烷基;R 21、R 22、R 23、R 24中的取代基分别独立选自卤素、羟基、-NH 2、酯基、酰基、C1~C4烷基、3~6元环烷基;Z 1选自N或CR 8;R 8选自氢、卤素、硝基、氰基、羟基、-NH 2、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、取代或非取代的C2~C10炔基、取代或非取代的苯基、取代或非取代的5~9元杂芳基、酰基、酯基、酰胺基、磺酰基、磺酰胺基、硼酸基、硼酸酯基、磷酰基,或R 8与R 24及其相连的原子组成取代或非取代的5~7元烯环、取代或非取代的5~7元杂烯环、取代或非取代的苯环、取代或非取代的5~7元杂芳环;R 19、R 20分别独立选自氢、卤素、氰基、羧基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、酰基、酯基、酰胺基、磺酰基、磺酰胺基,或R 19、R 20共同组成=O,或R 19、R 20与其相连的原子组成取代或非取代的3~6元环烷基;或R 8和R 19共同组成取代或非取代的C1~C6烷基、取代或非取代的2~6元杂烷基、取代或非取代的酰基、取代或非取代的酯基、取代或非取代的酰胺基、取代或非取代的磺酰基、取代或非取代的磺酰胺基、取代或非取代的亚磺酰基、取代或非取代的亚磺酰胺基;R 25、R 26、R 27、R 28每次出现时独立地选自氢、卤素、氰基、羟基、-NH 2、羧基、取代或非取代的C1~C10烷基、取代或非取代的2~10元杂烷基、取代或非取代的3~12元环烷基、取代或非取代的3~12元杂环烷基、取代或非取代的C2~C10烯基、酰基、酯基、酰胺基、磺酰基、磺酰胺基,或R 25、R 26共同组成=O,或R 27、R 28共同组成=O,或R 25、R 26与其相连的原子组成取代或非取代的3~6元环烷基,或R 27、R 28与其相连的 原子组成取代或非取代的3~6元环烷基;R 8、R 19、R 20、R 25、R 26、R 27、R 28中的取代基分别独立选自卤素、C1~C10烷基、3~12元环烷基、2~10元杂烷基、3~9元杂环烷基、C2~C10烯基、C2~C10炔基、羟基、氰基、-NH 2、羧基、酰基、酯基、酰胺基、苯基、5~9元杂芳基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基;进一步地,R 21、R 22分别独立选自氢、卤素、羟基、被卤素取代或非取代的C1~C4烷基,或R 21、R 22及相连的原子组成取代或非取代的环丙基;R 23选自氢、C1~C4烷基。
- 根据权利要求1~10任一项所述的化合物,其特征在于,L选自一键、S、S(=O)、S(=O) 2、C(=O)、-(CR 11R 12)n 5-、-C(=O)NR 16-、C2~C4亚炔基;进一步地,L选自一键、C2~C4亚炔基;更进一步地,L选自一键。
- 根据权利要求1~11任一项所述的化合物,其特征在于,具有式III或式IV所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐:W 1、W 2分别独立选自O、CH 2、CHF、CF 2、NH、NCH 3,优选O、CF 2、CH 2;Z 1选自N或CR 8;R 8选自氢、卤素、氰基、羟基、-NH 2、取代或非取代的C1~C4烷基、取代或非取代的2~5元烷氧基、取代或非取代的2~5元氮杂烷基、取代或非取代的3~6元环烷基、取代或非取代的C2~C4烯基、酰基、酯基、酰胺基、硼酸基、硼酸酯基,或R 8和R 19共同组成取代或非取代的C1~C2烷基、取代或非取代的2元杂烷基、取代或非取代的酯基;
- 根据权利要求7~13任一项所述的化合物,其特征在于,R 24选自氢、卤素,优选H、F、Cl;更优选H。
- 根据权利要求7~14任一项所述的化合物,其特征在于,R 25、R 26、R 27、R 28每次出现时独立地选自氢、卤素、氰基、羟基、-NH 2、羧基、取代或非取代的C1~C6烷基、取代或非取代的2~6元杂烷基、取代或非取代的3~6元环烷基、取代或非取代的3~6元杂环烷基、取代或非取代的C2~C6烯基、酰基、酯基、酰胺基、磺酰基、磺酰胺基,或R 25、R 26共同组成=O,或R 27、R 28共同组成=O,或R 25、R 26与其相连的原子组成取代或非取代的3~6元环烷基,或R 27、R 28与其相连的原子组成取代或非取代的3~6元环烷基;进一步地,R 25、R 26、R 27、R 28每次出现时独立地选自氢、卤素、取代或非取代的C1~C6烷基、取代或非取代的2~6元杂烷基、取代或非取代的3~6元环烷基、3~6元杂 环烷基、酰基、酯基,或R 25、R 26共同组成=O,或R 27、R 28共同组成=O,或R 25、R 26与其相连的原子组成取代或非取代的3~6元环烷基,或R 27、R 28与其相连的原子组成取代或非取代的3~6元环烷基;R 25、R 26、R 27、R 28中的取代基分别独立选自卤素、C1~C6烷基、3~6元环烷基、2~6元杂烷基、3~6元杂环烷基、羟基、氰基、-NH 2、羧基、酰基、酯基、酰胺基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基;进一步地,R 25、R 27每次出现时独立地选自氢、卤素、取代或非取代的C1~C6烷基、取代或非取代的2~6元杂烷基、取代或非取代的3~6元环烷基、酰基、酯基,R 26、R 28为H;或R 25、R 26共同组成=O,或R 27、R 28共同组成=O,或R 25、R 26与其相连的原子组成取代或非取代的3~6元环烷基,或R 27、R 28与其相连的原子组成取代或非取代的3~6元环烷基;更进一步地,R 25、R 26、R 27、R 28为H。
- 根据权利要求7~15任一项所述的化合物,其特征在于,R 19选自氢、卤素、氰基、取代或非取代的C1~C6烷基、取代或非取代的2~7元杂烷基、酰基、酯基;R 20为H,或R 19、R 20共同组成=O,或R 19、R 20与其相连的原子组成取代或非取代的3~6元环烷基;或R 19和R 8共同组成其引用的权利要求中的限定的基团;进一步地,R 19、R 20均为H,或R 19、R 20共同组成=O,或R 19、R 20与其相连的原子组成取代或非取代的环丙基;或R 19和R 8共同组成其引用的权利要求中的限定的基团;进一步地,R 19、R 20均为H。
- 根据权利要求1~16任一项所述的化合物,其特征在于,环B选自苯基、萘基、取代或非取代的5~10元杂芳基、取代或非取代的3~9元环烷基、取代或非取代的3~9元杂环烷基;进一步地,环B选自取代或非取代的5~6元杂芳基;进一步地,环B选自取代或非取代的如下基团:苯基、嘧啶基、吡啶基、吡嗪基、哒嗪基、噻吩基、吡唑基、咪唑基、噁唑基、噻唑基、三氮唑基、四氮唑基、噻二唑基、噁二唑基。
- 根据权利要求17所述的化合物,其特征在于,环B选自嘧啶基、吡啶基、哒嗪基、噻唑基、三氮唑基、噁二唑基;优选嘧啶基、吡啶基、哒嗪基、噻唑基;更优选嘧啶基。
- 根据权利要求1~18任一项所述的化合物,其特征在于,R 7每次出现时选自氢、卤素、氰基、羟基、取代或非取代的C1~C6烷基、取代或非取代的2~7元杂烷基、取代或非取代的3~6元环烷基、取代或非取代的3~6元杂环烷 基、酰基、酯基、酰胺基、磺酰基、磺酰胺基,或相邻的两个R 7及其相连的原子组成取代或非取代的3~6元烃环、取代或非取代的3~6元杂烃环;R 7中所述杂烷基、杂环烷基、杂芳基、杂烃环中的杂原子选自N、O、S中的一种或几种;进一步地,R 7每次出现时独立选自氢、卤素、氰基、取代或非取代的C1~C6烷基、取代或非取代的2~7元氧杂烷基、取代或非取代的2~7元氮杂烷基、取代或非取代的3~6元环烷基、取代或非取代的3~6元杂环烷基、磺酰胺基,或相邻的两个R 7及其相连的原子取代或非取代的3~6元杂烃环,R 7中的取代基选自卤素、C1~C6烷基、3~6元环烷基、2~7元杂烷基、3~6元杂环烷基、羟基、氰基、-NH 2、酰基、酯基、酰胺基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基;n 2选自0、1、2、3、4、5;进一步地,R 7每次出现时独立选自氢、卤素、氰基、-OH、-N(CH 3) 2、-N(CH 2CH 3) 2、-S(=O) 2NH 2、-CH 3、-CH 2CH 3、-CH(CH 3) 2、 吗啉基、哌啶基、哌嗪基、氮杂环丁烷基、吡咯烷基、-(CH 2)n 8-OH、-CH(OH)-CH 2OH、-C(CH 3) 2OH、-OCH 2CH(OH)-CH 2OH、-OCH 2CH 2OCH 3、-OCH 2CH 2OCH 2CH 3、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-CF 3、-CHF 2、-CF 2CF 3,或相邻的两个R 7及其相连的原子取代或非取代的3~6元氮杂烃环、3~6元氧杂烃环,n 8选自1、2、3、4;n 2选自0、1、2、3。
- 根据权利要求1~20任一项所述的化合物,其特征在于,R 5选自取代或非取代的C1~C4烷基、取代或非取代的2~6元杂烷基、取代或非取代的3~6元环烷基、取代或非取代的3~6元杂环烷基、取代或非取代的苯基、取代或非取代的5~6元杂芳基;R 5中的取代基选自卤素、C1~C6烷基、3~6元环烷基、2~6元杂烷基、3~6元杂环烷基、羟基、氰基、氨基、酰基、酯基、酰胺基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基;进一步地,R 5选自取代或非取代的四氢吡喃基、取代或非取代的C1~C4烷基、取代或非取代的苯基、取代或非取代的噻吩基、取代或非取代的吡啶基、取代或非取代的嘧啶基,优选取代或非取代的苯基,R 5中的取代基选自卤素或C1~C6烷基;进一步地,R 5中的取代基选自F、Cl、C1~C4烷基。
- 根据权利要求1~21任一项所述的化合物,其特征在于R 2、R 3分别独立选自氢、卤素、氰基、羟基、-NH 2、取代或非取代的C1~C6烷基、取代或非取代的2~6元杂烷 基、取代或非取代的3~6元环烷基、取代或非取代的3~6元杂环烷基、取代或非取代的C2~C6烯基、酰基、酯基、酰胺基、磺酰基、磺酰胺基,或R 2、R 3共同组成取代或非取代的C3~C4烷基、取代或非取代的3~4元杂烷基;R 2、R 3中的取代基分别独立选自卤素、C1~C6烷基、3~6元环烷基、2~6元杂烷基、3~6元杂环烷基、C2~C4烯基、C2~C4炔基、羟基、氰基、-NH 2、硝基、羧基、酰基、酯基、酰胺基、亚磺酰基、磺酰基、磺酰胺基、亚磺酰胺基;R 4选自氢、C1~C4烷基、C1~C4卤代烷基、C1~C4烷氧基、C2~C4烯基;进一步地,R 2、R 3分别独立选自氢、氰基、取代或非取代的C1~C4烷基、取代或非取代的2~5元杂烷基,或R 2、R 3共同组成取代或非取代的C3~C4烷基、取代或非取代的3~4元杂烷基;R 2、R 3中的取代基分别独立选自卤素、羟基、C1~C4烷基、3~6元环烷基、2~4元杂烷基、3~6元杂环烷基、C2~C4烯基;R 4选自氢、甲基;进一步地,R 2、R 3分别独立选自氢、氰基、取代或非取代的甲基、取代或非取代的乙基、取代或非取代的 取代或非取代的 或R 2、R 3共同组成取代或非取代的 取代或非取代的 优选R 2、R 3分别独立选自氢、氰基、取代或非取代的甲基、取代或非取代的 或R 2、R 3共同组成取代或非取代的 取代或非取代的 更优选R 2、R 3分别独立选自氢、氰基、取代或非取代的甲基;R 4选自氢;更进一步地,R 2、R 3中的取代基分别独立选自F、Cl、羟基。
- 根据权利要求1~22任一项所述的化合物,其特征在于,R 6选自氢、卤素取代或非取代的C1~C6烷基、取代或非取代的3~6元环烷基;进一步地,R 6选自氢、氟取代或非取代的C1~C4烷基,优选H。
- 一种药用组合物,其特征在于,该药用组合物活性成份选自权利要求1~28任一权利要求所述的化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐、酯、共晶、N-氧化物、同位素标记化合物、代谢物、前药的中的一种或两种以上的组合。
- 权利要求1~26任意一项所述化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备DHODH抑制剂中的用途。
- 权利要求1~26任意一项所述化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备用于治疗或预防真菌感染或真菌感染所致疾病的药物中的用途。
- 权利要求1~26任意一项所述化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶在制备杀真菌剂中的用途。
- 根据权利要求29或30所述的用途,其特征在于,所述真菌选自以下属的一种或几种生物:Absidia、Acremonium、Alternaria、Aspergillus、Bipolaris、Blastomyces、Blumeria、Cladosporium、Coccidioides、Colletotrichium、Curvularia、Encephalitozoon、Epicoccum、Epidermophyton、Exophiala、Exserohilum、Fusarium、Histoplasma、Leptosphaeria、Microsporum、Mycosphaerella、Neurospora、Paecilomyces、Penicillium、Phytophthora、Plasmopara、Pneumocystis、Pyricularia、Pythium、Puccinia、Rhizoctonia、Rhizomucor、Scedosporium、Scopulariopsis、Trichophyton、Trichosporon、Ustilago;进一步地,所述真菌选自以下属的一种或几种生物:Aspergillus、Scedosporium、Fusarium,优选Aspergillus和/或Scedosporium,更优选Aspergillus。
- 根据权利要求31所述的用途,其特征在于,所述真菌选自A.fumigatus、A.flavus、A.terreus、A.niger、A.lentulus、S.apiospermum、S.prolificans、S.species中的一种或几种;进一步地,所述真菌选自A.fumigatus、A.flavus、A.terreus、A.niger、S.prolificans中的一种或几种。
- 根据权利要求29所述的用途,其特征在于,所述真菌感染所致疾病选自全身性感染真菌的疾病、表面感染真菌的疾病;进一步地,所述全身性感染真菌的疾病选自肺曲霉病、过敏性支气管肺曲霉病、系统性曲霉病、哮喘、球孢子菌病、副球孢子菌病、孢子丝菌病、着色芽生菌病、暗鼻脑毛霉菌病、芽生菌病、组织胞浆菌病、瘢痕疙瘩性芽生菌病、色丝孢霉病、播散性孢子丝菌病、囊性纤维化的真菌定植、窦炎;所述表面感染真菌的疾病选自癣菌病、甲癣、脚癣。
- 权利要求1~26任一项所述的化合物的制备方法,其特征在于,还包括中间体IM-2或IM-3的制备;IM-2的合成路线如下:(1)将化合物M-9与IM-4在碱或过渡金属催化剂的作用下生成M-10;(2)将化合物M-10中的R N转化为-NH 2;(3)将化合物M-11与S-5在碱或还原剂的作用下生成IM-2;R T1、R T5独立选自卤素、醛基、被卤素取代的C1~C6烷基磺酸酯基;进一步地,步骤(1)中的碱为无机碱,优选碳酸钾和/或碳酸钠;步骤(1)中的过渡金属催化剂为钯催化剂,进一步选自四三苯基膦钯、醋酸钯、三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、双(三苯基膦)二氯化钯、t-BuXPhos-Pd-G3中的一种或几种;进一步地,将化合物IM-2与IM-1在碱或缩合剂的作用下生成权利要求1~26任一项所述的化合物,化合物IM-1的结构如下:IM-3的合成路线如下:(a)将M-9中的R N转化为-NH 2;(b)将M-12与S-5在碱或还原剂的作用下生成M-13;(c)将M-13与IM-1在碱或缩合剂的作用下生成IM-3;Lg 3选自离去基团,优选卤素、C1~C6烷氧基、被卤素取代的C1~C6烷基磺酸酯基;进一步地,步骤(c)中的碱为N,N-二异丙基乙胺;步骤(c)中的缩合剂选自1-(3-二甲基氨基丙基)-3-乙基碳二亚胺和/或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐;进一步地,将化合物IM-3与IM-4在碱或过渡金属催化剂的作用下生成权利要求1~26任一项所述的化合物;其中,R N选自氨基或能转化为氨基的基团,优选氨基、硝基、羧基、酯基、卤素,更优选氨基、硝基;R B选自氢或氨基的保护基团,进一步选自氢、叔丁氧羰基、苄氧羰基、9-芴基甲氧基羰基、苄基、对甲氧基苄基和2,4-而甲氧基苄基;R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 9、L、Z 1、Z 2、Z 3、环A、环B、n 1、n 2、n 3、n 4、n 9同权利要求1~26任一项所述的化合物中所定义。
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