WO2022161416A1 - 一种芳香化合物、其制备方法及应用 - Google Patents
一种芳香化合物、其制备方法及应用 Download PDFInfo
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- WO2022161416A1 WO2022161416A1 PCT/CN2022/074136 CN2022074136W WO2022161416A1 WO 2022161416 A1 WO2022161416 A1 WO 2022161416A1 CN 2022074136 W CN2022074136 W CN 2022074136W WO 2022161416 A1 WO2022161416 A1 WO 2022161416A1
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- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N vinyl ethyl ether Natural products CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
- C07C311/46—Y being a hydrogen or a carbon atom
Definitions
- the present invention relates to an aromatic compound, its preparation method and application.
- ATP receptors are classified into two main families, P2Y- and P2X-purinoceptors, based on molecular structure, transduction mechanism, and pharmacological properties.
- P2X-purinoceptors are a family of ATP-gated cation channels, and several subtypes have been cloned, including: six homomeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors Receptors P2X2/3, P2X4/6, P2X1/5.
- the P2X4 receptor is the only subtype of the P2X family whose crystal structure has been solved, and its resolution is as high as And the study found that P2X4 is the P2X subtype with the strongest permeability to Ca 2+ .
- Cough is the main symptom of respiratory diseases. In respiratory outpatient clinics, 70% to 80% of patients have cough symptoms. With the increasing prevalence of COPD, IPF, etc., and cough as the main symptom of most respiratory diseases, the demand also increases. As the body's defensive nerve reflex, coughing is beneficial to clear respiratory secretions and harmful factors, but frequent and severe coughing will seriously affect the patient's work, life and social activities.
- the indications of drugs under development involving P2X4 targets are mostly neuropathic pain or inflammation, and there is no information about drugs under development for cough indications. And there is no drug marketed for P2X4 inhibitory pathway to treat many diseases including chronic cough. Therefore, the development of new compounds that can inhibit the activity of P2X4 has positive significance for the treatment of diseases.
- the invention provides an aromatic compound, its preparation method and application.
- the compound has higher P2X4 antagonistic activity, better safety and pharmacokinetic properties.
- the present invention provides a compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, its solvent compound or a solvate of a pharmaceutically acceptable salt thereof;
- R 2 is selected from
- R 2-1 is selected from the following groups unsubstituted or optionally substituted by one, two or more Ra: C 1 -C 20 alkyl, C 3 -C 20 cycloalkyl, 3-20 membered heterocycle base, C 6 -C 20 aryl, 5-20-membered heteroaryl;
- R 2-2 is selected from hydrogen, halogen, OH, CN, NO 2 , unsubstituted or optionally substituted by one, two or more Rb of the following groups: C 1 -C 20 alkyl, C 1 -C 20 alkoxy groups; each Rb is the same or different, independently selected from halogen, OH, CN, NO 2 ;
- R 3-1 is selected from halogen, OH, CN, NO 2 , the following groups unsubstituted or optionally substituted by one, two or more Rc: C 1 -C 20 alkyl, C 1 -C 20 alkane oxy or C 3 -C 20 cycloalkyl; each Rc is the same or different, independently selected from halogen, OH, CN, NO 2 ;
- n is selected from 0, 1, 2, 3 or 4.
- R 2 is selected from
- R 2-2 is selected from hydrogen, halogen, OH, CN, NO 2 , unsubstituted or optionally substituted by one, two or more Rb of the following groups: C 1 -C 12 alkyl, C 1 -C 12 alkoxy groups; each Rb is the same or different and independently selected from halogen, OH, CN, NO 2 ;
- R 3-1 is selected from halogen, OH, CN, NO 2 , the following groups unsubstituted or optionally substituted by one, two or more Rc: C 1 -C 12 alkyl, C 1 -C 12 alkane oxy or C 3 -C 12 cycloalkyl; each Rc is the same or different, independently selected from halogen, OH, CN, NO 2 ;
- n is selected from 0, 1, 2, 3 or 4.
- R 2 is or for Wherein, R 2-1 is as defined above, R 2-3 is selected from halogen, OH, CN, NO 2 , the following groups unsubstituted or optionally substituted by one, two or more Rb: C 1 ⁇ C 20 alkyl, C 1 -C 20 alkoxy; each Rb is the same or different, independently selected from halogen, OH, CN, NO 2 ;
- R 2 is or for
- One or more 5- to 10-membered heteroaryl groups or “the number of heteroatoms substituted by one or more R 2-1e is 1, 2 or 3, and the heteroatoms are selected from N, O and S One or more of the 5- to 10-membered heteroaryl groups";
- R 2-3 is halogen, OH, C 1 -C 10 alkyl, C 1 -C 10 alkoxy;
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen, hydroxyl, cyano, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 10 cycloalkyl .
- R 2 is
- One or more 5- to 6-membered heteroaryl groups or “the number of heteroatoms substituted by one or more R 2-1e is 1, 2 or 3, and the heteroatoms are selected from N, O and S One or more of the 5- to 6-membered heteroaryl groups";
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- R 2-1c-1 is independently NH 2 ;
- R 2-1c-2 and R 2-1c-3 are independently NH 2 or C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen, hydroxy, cyano, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl .
- R 2-2 is selected from hydrogen, halogen, OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- R 2-1c-1 is independently halogen, NH 2 , C 3 -C 6 cycloalkyl
- R 2-1c-2 and R 2-1c-3 are independently NH 2 or C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen, hydroxy, cyano, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl .
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- R 2-1c-1 is independently NH 2 ;
- R 2-1c-2 and R 2-1c-3 are independently NH 2 or C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen, hydroxy, cyano, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 6 cycloalkyl .
- R 2-1 is a C 1 -C 10 alkyl group, or a C 1 -C 10 alkyl group substituted by one or more R 2-1a , the C 1 -C 10 alkane
- the radicals can be C 1 -C 6 alkyl groups, and can also be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
- One or more of the 3- to 8-membered heterocycloalkyl such as oxetane, tetrahydrofuranyl, tetrahydropyranyl
- R 2-1 is a C 6 -C 10 aryl group, or a C 6 -C 10 aryl group substituted by one or more R 2-1d , the C 6 -C 10 aryl group
- the group can be phenyl.
- R 2-1 when R 2-1 is "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, a 5- to 6-membered heteroaryl group ”, or substituted by one or more R 2-1e “the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S.
- a 5- to 6-membered heteroatom "Aryl”, the "5- to 6-membered heteroaryl in which the number of heteroatoms is 1, 2 or 3, and the heteroatom is selected from one or more of N, O and S" can be " The number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S.
- a 5- to 6-membered heteroaryl group or "the number of heteroatoms is 1 or 2
- a 5- to 6-membered heteroaryl group whose heteroatom is N such as pyrazolyl, imidazolyl or pyridyl, and for example
- R 2-1a is independently C 3 -C 6 cycloalkyl
- the C 3 -C 6 cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclopentyl Hexyl, for example cyclopropyl, cyclobutyl or cyclopentyl.
- R 2-1a is independently "the number of heteroatoms is 1, 2 or 3, the heteroatoms are 3-6-membered heteroatoms selected from one or more of N, O and S.
- cycloalkyl the "3- to 6-membered heterocycloalkyl in which the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S” can be It can be "the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S.
- 3-6 membered heterocycloalkyl and it can also be "the number of heteroatoms is 1 or 2, 3-6 membered heterocycloalkyl whose heteroatom is O", such as oxetanyl or tetrahydrofuranyl, and for example
- the halogen can be fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.
- R 2-1c , R 2-1d and R 2-1e are independently C 1 -C 6 alkyl, or C 1 -C substituted with one or more R 2-1c-1
- the C 1 -C 6 alkyl groups can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.
- R 2-1c , R 2-1d and R 2-1e are independently C 3 -C 10 cycloalkyl
- the C 3 -C 10 cycloalkyl is cyclopropyl, Cyclobutyl, cyclopentyl.
- R 2-1c , R 2-1d and R 2-1e are independently C 1 -C 6 alkoxy
- the C 1 -C 6 alkoxy may be methoxy , ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example methoxy.
- R 2-1c-1 is a C 3 -C 6 alkyl group
- the C 3 -C 10 cycloalkyl group is cyclopropyl, cyclobutyl and cyclopentyl.
- R 2-1c-2 and R 2-1c-3 are independently C 1 -C 6 alkyl
- the C 1 -C 6 alkyl may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
- R 2-2 when R 2-2 is a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, eg methyl.
- the halogen when R 3-1 is independently halogen, or C 1 -C 6 alkyl substituted by halogen, the halogen can be fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.
- the C 1 -C 6 alkyl may be methyl , ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
- the C 1 -C 6 alkoxy may be methoxy, ethoxy, propoxy, iso- Propoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
- R 3-1 when R 3-1 is independently C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclopentyl hexyl.
- R 2-1 is C 1 -C 10 alkyl substituted by one or more R 2-1a
- the C 1 -C substituted by one or more R 2-1a 10 alkyl can be
- R 2-1 is C 6 -C 10 aryl substituted by one or more R 2-1d
- the C 6 -C substituted by one or more R 2-1d 10 Aryl can be as well as,
- R 2-1 when R 2-1 is substituted by one or more R 2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one of N, O and S. or multiple 5-6 membered heteroaryl groups", the number of "heteroatoms substituted by one or more R 2-1e is 1, 2 or 3, and the heteroatoms are selected from N, O and One or more of the 5- to 6-membered heteroaryl groups in S can be as well as
- R 2 can be as well as
- R 3-1 can be fluoro or chloro.
- R 2-1 is C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted by one or more R 2-1a , "the number of heteroatoms is 1, 2 or 3 3-10-membered heterocycloalkyl ", C 6 -C 10 aryl, surrounded by one or more R 2-1d- substituted C 6 -C 10 aryl group, "5- to 6-membered heteroaromatics with 1, 2 or 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S.
- base or "the number of heteroatoms substituted by one or more R 2-1e is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. 5-6-membered Heteroaryl".
- R 2-1 is C 1 -C 10 alkyl substituted with one or more R 2-1a , C 6 -C 10 aryl substituted with one R 2-1d , "heteroatom number" is 1, 2 or 3, and the heteroatom is selected from one or more of N, O and S. The number of atoms is 1, 2 or 3, and the heteroatom is selected from one or more of N, O and S.
- a 5- to 6-membered heteroaryl group is
- R 2-1 is a C 6 -C 10 aryl group substituted by one or more R 2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N, A 5- to 6-membered heteroaryl group of one or more of O and S", or "the number of heteroatoms substituted by one or more R 2-1e is 1, 2 or 3, and the heteroatoms are selected from A 5- to 6-membered heteroaryl group of one or more of N, O and S".
- R 2-2 is hydrogen, halogen, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy.
- R 2-1a is independently "a 3- to 6-membered heterocyclic ring in which the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S. alkyl".
- R 2-1c-1 is independently halogen, NH 2 , C 3 -C 6 cycloalkyl
- R 2-1c-2 and R 2-1c-3 are independently C 1 -C 6 alkyl.
- R 2-2 is hydrogen, C 1 -C 10 alkyl, or C 1 -C 10 alkoxy.
- R 3-1 is independently halogen.
- R 2-2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- R 2-1c-1 is independently halogen, NH 2 , C 3 -C 6 cycloalkyl
- R 2-1c-2 and R 2-1c-3 are independently NH 2 or C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen.
- R 2-2 is hydrogen, C 1 -C 6 alkyl
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- R 2-1c-1 is independently halogen, NH 2 , cyclopropyl
- R 2-1c-2 and R 2-1c-3 are independently NH 2 or C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen.
- R 2-2 is hydrogen, C 1 -C 6 alkyl
- R 2-1a is independently C 3 -C 6 cycloalkyl or "3 - 6 where the number of hetero atoms is 1, 2 or 3, and the hetero atoms are selected from one or more of N, O and S. membered heterocycloalkyl";
- R 2-1c-2 and R 2-1c-3 are independently NH 2 or C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen.
- R 2-1 is C 1 -C 10 alkyl substituted by one or more R 2-1a , C 6 -C 10 aryl substituted by one R 2-1d , "the number of heteroatoms is 1 or 2" Or 3, the heteroatom is selected from one or more of N, O and S in a 5- to 6-membered heteroaryl group", or substituted by one or more R 2-1e "the number of heteroatoms is 1, 5- to 6-membered heteroaryl group with 2 or 3 heteroatoms selected from one or more of N, O and S";
- R 2-2 is hydrogen, C 1 -C 3 alkyl
- R 2-1a is independently "a 3- to 6-membered heterocycloalkyl group in which the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S";
- R 2-1c-2 and R 2-1c-3 are independently C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen.
- R 2-1 is a C 6 -C 10 aryl group substituted by one or more R 2-1d , "the number of heteroatoms is 1, 2 or 3, and the heteroatom is selected from one of N, O and S.
- One or more 5- to 6-membered heteroaryl groups or substituted by one or more R 2-1e "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from N, O and S. one or more 5- to 6-membered heteroaryl groups";
- R 2-2 is hydrogen, methyl
- R 2-1c-2 and R 2-1c-3 are independently C 1 -C 6 alkyl
- n 0, 1, 2 or 3;
- R 3-1 is independently halogen.
- the compound shown in formula I can be any of the following structures,
- the compound shown in formula I can be any of the following compounds,
- Compound 2 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)- N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 3 2-(2-Chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 5 2-(2-Chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2- chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 7 2-(2-Chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2- chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 9 2-(2-Chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 10 2-(2-Chlorophenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chlorophenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide
- Compound 12 2-(2-Chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide
- Compound 13 2-(2-Chlorophenyl)-N-(4-(((1,1-dioxytetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl) Acetamide, 2-(2-chlorophenyl)-N-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 15 N-(4-((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide, N-( 4-((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
- Compound 16 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((p-tolyloxy)methyl)phenyl)acetamide, 2-(2-chlorophenyl)-N- (3-sulfamoyl-4-((p-tolyloxy)methyl)phenyl)acetamide,
- Compound 17 2-(2-Chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 18 2-(2-Chlorophenyl)-N-(4-((4-fluoro-3-methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chlorophenyl)-N-(4-((4-fluoro-3-methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 24 2-(2-Chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamate Acylphenyl)acetamide, 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 28 2-(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)- N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 30 2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-(2-chlorophenyl)- N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 33 2-(2-Chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl)acetamide, 2- (2-chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 35 2-(2-Chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 36 N-(4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide, N-( 4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
- Compound 42 N-(4-(((3-azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro Phenyl)acetamide, N-(4-(((3-azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
- Compound 49 2-(2-Chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 50 2-(2-Chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 51 2-(2-Chloro-4-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chloro-4-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 52 2-(2-Chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide, 2-( 2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 53 2-(2-Chloro-6-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl) Acetamide, 2-(2-chloro-6-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 56 2-(2-Chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl) Acetamide, 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 64 2-(2-Chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamic acid Acylphenyl)acetamide, 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
- Compound 65 2-(2-Chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)- 3-Sulfamoylphenyl)acetamide,
- the present invention provides a kind of preparation method of the above-mentioned compound shown in formula I, and it is method one or method two,
- the first method includes the following steps: in a solvent, in the presence of an acid, the compound shown in formula II is reacted with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) to generate the compound shown in formula IV , then the compound of formula IV is reacted with ammonia water to obtain the compound shown in the formula I;
- DCDMH 1,3-dichloro-5,5-dimethylhydantoin
- the second method comprises the following steps: in an organic solvent, the compound shown in formula III is reacted with hydrazine hydrate to obtain the compound shown in formula I;
- R 3-1 , n and R 2 in formulas I, II, III and IV are the same or different, and independently have the above-mentioned definitions.
- the compound represented by formula IV does not need to be separated, and the reaction solution of the previous step is directly reacted with ammonia water.
- the compound shown in formula II is reacted with 1,3-dichloro-5,5-dimethyl hydantoin (DCDMH), and then the reaction solution is reacted with ammonia water to obtain the described compound shown in formula I. compound.
- DCDMH 1,3-dichloro-5,5-dimethyl hydantoin
- the solvent may be a conventional solvent in the field, or may be a nitrile solvent, or a mixed solvent of a nitrile solvent and water, such as a mixed solvent of acetonitrile and water.
- the acid in the first method, can be a conventional acid in the art, an organic acid, or an organic carboxylic acid, such as acetic acid.
- the molar ratio of the DCDMH to the compound represented by formula II may be 1:1-5:1, for example, 2:1 or 3:1.
- the molar ratio of the acid and the compound represented by formula II may be 3:1-30:1, such as 5:1, 6:1, 8:1, 13:1, 17:1 or 25:1.
- the molar concentration of the compound represented by formula II in the solvent may be 0.01-0.3 mol/L, for example, 0.05 mol/L, 0.09 mol/L, 0.1 mol /L, 0.15mol/L, 0.18mol/L.
- the temperature during the reaction with the DCDMH may be 10-40°C.
- the reaction time with the DCDMH may be 5-120 min, such as 10 min, 15 min, 60 min.
- the molar volume ratio of the compound shown in formula II to the ammonia water can be 0.01-0.5mol/L, such as 0.015mol/L, 0.02mol/L, 0.08mol /L, 0.034mol/L, 0.2mol/L, 0.33mol/L or 0.39mol/L.
- the temperature during the reaction with the ammonia water may be 10-40°C.
- the reaction time with the ammonia water can be 5-60min, such as 10min, 30min.
- the post-treatment may include the following steps: removing the solvent in the reaction solution, and separating and purifying.
- the method for removing the solvent in the reaction solution can be a conventional method in the art, such as concentration under reduced pressure to dryness.
- the separation and purification methods can be conventional methods in the art, such as purification by preparative HPLC.
- the organic solvent can be a conventional organic solvent in the field, and can also be an alcohol solvent and/or an ether solvent, such as methanol and/or tetrahydrofuran.
- the molar ratio of the hydrazine hydrate and the compound represented by formula III may be 2:1-8:1, for example, 5:1.
- the molar concentration of the compound represented by the formula III in the organic solvent may be 0.01-0.3 mol/L, for example, 0.06 mol/L.
- the temperature of the reaction may be 10-40°C.
- the reaction time may be 0.5-3h, such as 1h.
- the post-treatment of the reaction may include the following steps: removing the solvent in the reaction solution, and separating and purifying.
- the method for removing the solvent in the reaction solution can be a conventional method in the art, such as concentration under reduced pressure to dryness.
- the separation and purification methods can be conventional methods in the art, such as purification by preparative HPLC.
- the present invention also provides an intermediate compound shown in formula II, III or IV, which can be used to prepare the compound shown in formula I:
- R 2 , R 3-1 and n are the same as those described in any of the previous schemes.
- the present invention also provides the following intermediate compounds, which can be used to prepare the compounds shown in formula I:
- the present invention provides a pharmaceutical composition, which comprises substance A and at least one pharmaceutical excipient;
- the substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, A solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the dosage of the substance A can be a therapeutically effective amount.
- the present invention also provides the application of a substance A in the preparation of P2X4 receptor antagonists or medicines;
- the substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, A solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the P2X4 receptor antagonist can be used in vitro.
- the medicament is used to treat or prevent urinary tract disease, respiratory disease, pain-related disease, autoimmune disease, inflammation, sleep disturbance, psychiatric disease, arthritis, neurological disease in animals (eg, humans).
- Degenerative disease traumatic brain injury, thrombosis, digestive tract disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer or eye disease.
- Said urinary tract disorders such as urinary incontinence, overactive bladder, dysuria or cystitis.
- respiratory diseases, such as respiratory disorders include respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (eg, chronic cough).
- Such pain-related conditions are, for example, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine, cluster headache, chronic pain or pruritus.
- Said neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, epilepsy or stroke.
- Said cardiovascular system diseases such as myocardial infarction, atherosclerosis, heart failure, hypertension or blood diseases.
- diseases of the digestive tract are eg colon syndrome, inflammatory bowel disease or gastrointestinal disorders.
- Such autoimmune diseases are, for example, arthritis (eg, rheumatoid arthritis).
- Said ophthalmic diseases such as dry eye syndrome, dry eye syndrome, ocular nerve pain, ocular trauma and postoperative ocular pain.
- the medicament can be used to prevent or treat a disease mediated at least in part by P2X4 in an animal (eg, a human).
- P2X4 Diseases mediated at least in part by P2X4 such as urinary tract diseases, respiratory diseases, pain-related diseases, autoimmune diseases, inflammation, sleep disorders, psychiatric diseases, arthritis, neurodegenerative diseases, traumatic brain injury, Thrombosis, digestive tract disease, sexual dysfunction, cardiovascular system disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer or eye disease.
- Said urinary tract disorders such as urinary incontinence, overactive bladder, dysuria or cystitis.
- respiratory diseases such as respiratory disorders, include respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (eg, chronic cough).
- Such pain-related conditions are, for example, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine, cluster headache, chronic pain or pruritus.
- Said neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, epilepsy or stroke.
- Said cardiovascular system diseases such as myocardial infarction, atherosclerosis, heart failure, hypertension or blood diseases.
- diseases of the digestive tract are eg colon syndrome, inflammatory bowel disease or gastrointestinal disorders.
- Such autoimmune diseases are, for example, arthritis (eg, rheumatoid arthritis).
- Said ophthalmic diseases such as dry eye syndrome, dry eye syndrome, ocular nerve pain, ocular trauma and postoperative ocular pain.
- the present invention also provides a method of treating or preventing a disease comprising administering to a patient (eg, a human) a therapeutically effective amount of Substance A;
- the diseases are urinary tract diseases, respiratory diseases, pain-related diseases, autoimmune diseases, inflammation, sleep disorders, mental diseases, arthritis, neurodegenerative diseases, traumatic brain injury, thrombosis, digestive tract diseases, sexual dysfunction, cardiovascular disease, endometriosis, musculoskeletal and connective tissue developmental disorders, cancer or eye disease;
- the substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, A solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the urinary tract disorder such as urinary incontinence, overactive bladder, dysuria or cystitis.
- the respiratory disease eg, a breathing disorder
- the respiratory disease includes respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (eg, chronic cough).
- the pain-related disorder such as inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain from burns, migraine, cluster headache, chronic pain, or itching.
- the neurodegenerative disease is eg Alzheimer's disease, Parkinson's disease, epilepsy or stroke.
- the cardiovascular system disease such as myocardial infarction, atherosclerosis, heart failure, hypertension or blood disease.
- the digestive tract disease such as colon syndrome, inflammatory bowel disease or gastrointestinal dysfunction.
- autoimmune diseases are, for example, arthritis (eg, rheumatoid arthritis).
- the ophthalmic disorder such as dry eye syndrome, dry eye, ocular nerve pain, ocular trauma and postoperative ocular pain.
- the present invention also provides a method of treating or preventing a disease mediated at least in part by P2X4, comprising administering to a patient (eg, a human) a therapeutically effective amount of Substance A;
- the substance A is the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its isotopic compound, its crystal form, its nitrogen oxide, A solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.
- the disease may be urinary tract disease, respiratory disease, pain-related disease, autoimmune disease, inflammation, sleep disturbance, psychiatric disease, arthritis, neurodegenerative disease, traumatic brain injury, Thrombosis, gastrointestinal disease, sexual dysfunction, cardiovascular disease, endometriosis, musculoskeletal and connective tissue developmental disorders, or cancer.
- the urinary tract disorder such as urinary incontinence, overactive bladder, dysuria or cystitis.
- the respiratory disease eg, a breathing disorder
- the respiratory disease includes respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (eg, chronic cough).
- the pain-related disorder such as inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain from burns, migraine, cluster headache, chronic pain, or itching.
- the neurodegenerative disease is eg Alzheimer's disease, Parkinson's disease, epilepsy or stroke.
- the cardiovascular system disease such as myocardial infarction, atherosclerosis, heart failure, hypertension or blood disease.
- the digestive tract disease such as colon syndrome, inflammatory bowel disease or gastrointestinal dysfunction.
- autoimmune diseases are, for example, arthritis (eg, rheumatoid arthritis).
- the ophthalmic disorder such as dry eye syndrome, dry eye, ocular nerve pain, ocular trauma and postoperative ocular pain.
- the aromatic compound of the present invention has higher P2X4 antagonistic activity, better safety and good pharmacokinetic properties.
- the numerical ranges recited in this specification and claims are equivalent to at least reciting each specific integer value therein.
- the numerical range "1-20” is equivalent to reciting each integer value in the numerical range “1-10", ie, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the numerical range
- Each integer value in "11-20” is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. It is to be understood that in the context of one, two or more used herein in describing a substituent, "more” shall refer to an integer > 3, such as 3, 4, 5, 6, 7, 8, 9 or 10 .
- the term “plurality” refers to an integer > 2, eg, 2, 3, 4, 5, etc.
- salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
- base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
- acids additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
- a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
- the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
- Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
- solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
- Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
- the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
- “Pharmaceutically acceptable salts” and “solvates” in the term “solvates of pharmaceutically acceptable salts” are as described above, and refer to compounds of the present invention in combination with 1, a relatively non-toxic, pharmaceutically acceptable compound. 2. A substance formed in combination with a stoichiometric or non-stoichiometric solvent.
- stereoisomer refers to the isomers caused by the atoms or atomic groups in the molecule being connected to each other in the same order, but with different spatial arrangements, such as cis-trans isomers, optical isomers or atropisomers.
- stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (physical bonding, etc.).
- tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. For example, acetone and 1-propen-2-ol can be interconverted by the rapid movement of hydrogen atoms on oxygen and ⁇ -carbon.
- isotopic compound refers to the substitution of one or more atoms in a compound with one or more atoms having the specified atomic mass or mass number.
- isotopes that may be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen , carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (eg, 2H, 3H , 13C , 14C , 15N , 18O , 17O , 18F , 35S and 36Cl ).
- Isotopic compounds of the present invention can generally be prepared according to the methods described herein by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
- crystal form means that the ions or molecules in it are arranged strictly periodically in three-dimensional space in a definite manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism.
- N-oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide.
- N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms.
- the corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
- oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
- oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
- variable eg R 2-1a
- the definition of the variable at each position has nothing to do with the definitions at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 R 2-1a groups, that is, the group may be substituted with up to 3 R 2-1a groups, the definition of R 2-1a at this position The definitions of the remaining positions R 2-1a are independent of each other. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- the present invention describes the group used in the structural formula It means that the corresponding group is connected with other fragments and groups in the compound through this site.
- linking substituents are described.
- the Markush variables listed for that group should be understood to be the linking group.
- C 1 -C 6 alkyl in the group "halo-C 1 -C 6 alkyl" should be understood as C 1 -C 6 alkylene.
- halogen refers to fluorine, chlorine, bromine or iodine.
- C 1 -C 20 alkyl is to be understood as a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms.
- C1 - C6 alkyl refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms.
- the alkyl group may be optionally substituted with one or more substituents described herein.
- the alkyl group contains 1-12 carbon atoms or 13-20 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; in still other embodiments , the alkyl group contains 1-4 carbon atoms.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2 -Dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomer.
- C 1 -C 20 alkoxy refers to a group -OC 1 -C 20 alkyl, such as C 1 -C 12 alkoxy or C 13 -C 20 alkoxy, preferably C 1 -C 6 alkoxy.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and similar alkoxy groups base.
- C 3 -C 20 cycloalkyl should be understood to mean a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably “C 3 -C 12 cycloalkyl", And its bicyclic and tricyclic hydrocarbon rings include bridged or spiro hydrocarbon rings.
- C 3 -C 12 cycloalkyl is understood to mean a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, and its bicyclic and tricyclic hydrocarbon rings include bridged or spiro hydrocarbon rings.
- the C 3-10 cycloalkyl group can be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic Hydrocarbyl such as decalin ring.
- 3-20 membered heterocyclyl is understood to mean a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring containing 1-5, preferably 1-3 independently selected from N, O, S and S
- the heterocyclic group is non-aromatic.
- the carbon atom on the 3-20-membered heterocyclic group can be connected with other groups, or it can be a 3-20-membered heterocyclic group Heterocyclic atoms on the ring are attached to other groups.
- the heterocyclic group may include, but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring such as diazepanyl.
- the heterocyclyl group can be benzo-fused.
- the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring, such as a hexahydropyrrole
- the [1,2-a]pyrazin-2(1H)-yl ring may be partially unsaturated, i.e.
- it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiene oxazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.
- C 6 -C 20 aryl should be understood to mean an aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6 -C 14 aryl”.
- the term “C 6 -C 14 aryl” is to be understood as preferably denoting an aromatic or partially aromatic monocyclic, bicyclic or tricyclic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms Cyclic hydrocarbon rings (“C 6 -C 14 aryl”), especially rings with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or with 9 carbon atoms a ring (“C 9 aryl”) such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (" C13
- 5-20 membered heteroaryl is understood to include aromatic or partially aromatic monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 independently selected from the group consisting of Heteroatoms of N, O and S, eg "5-14 membered heteroaryl".
- the term “5-14 membered heteroaryl” is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S. And, additionally in each case may be benzo-fused.
- heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxazolyl, thi-4H-pyrazolyl, etc.
- heteroaryl groups include, but are not limited to, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl , triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, etc.
- the carbon atoms on the 5-20-membered heteroaryl ring can be connected with other groups, or the 5-20-membered heteroaryl group can be connected with other groups.
- Heteroatoms on the aryl ring are attached to other groups.
- the 5-20 membered heteroaryl is substituted, it can be mono- or polysubstituted.
- the substitution site for example, the hydrogen attached to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen attached to the heteroatom on the heteroaryl ring may be substituted.
- a heterocyclyl, heteroaryl or heteroarylene group includes all possible isomeric forms thereof, such as positional isomers thereof.
- thienyl or thienylene includes thien-2-yl, thien-2-yl, thien-3-yl and thien-3 - base; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.
- pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)
- treatment refers to therapeutic therapy.
- treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
- prevention refers to a reduced risk of acquiring or developing a disease or disorder.
- terapéuticaally effective amount refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or disorder described herein.
- a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.
- patient refers to any animal, preferably a mammal, and most preferably a human, to whom the compound or composition is to be or has been administered according to embodiments of the present invention.
- mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
- the biological activity of the compounds of the present invention can be assessed using any conventionally known method. Suitable detection methods are well known in the art. For example, the compounds of the present invention can be tested for P2X4 inhibitory activity, pharmacokinetic activity, and/or liver microsomal stability, etc., by appropriate conventional methods.
- the detection methods provided by the present invention are presented only as examples and do not limit the present invention.
- the compounds of the present invention are active in at least one of the detection methods provided herein.
- room temperature in the present invention refers to 10-40°C.
- min refers to minutes.
- h refers to hours.
- the raw materials and reagents used in the following examples are commercially available products, or can be prepared by known methods.
- the experimental methods that do not specify specific conditions in the following examples are based on conventional methods and conditions, or according to commercial products. Manual selection. .
- B 2 pin 2 Bis(pinacolato) diboron
- DIAD diisopropyl azodiformate
- DIEA N,N-Diisopropylethylamine (N,N-Diisopropylethylamine)
- DCDMH 1,3-Dichloro-5,5-dimethylhydantoin
- HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea, (2-(7-azabenzotriazole) )-N,N,N',N'-tetramethylurea hexafluorophosphate)
- NBS N-Bromosuccinimide (N-Bromosuccinimide)
- Pd(dppf)Cl 2 1,1'-bisdiphenylphosphinoferrocene palladium dichloride
- Tween80 Tween80
- PE/EA Petroleum ether/ethyl acetate
- LAH Lithium Aluminum Hydride
- the intermediate 1-3 (2-chlorophenylacetic acid) (48.1 mg, 281 ⁇ mol), HATU (146 mg, 384 ⁇ mol), DIEA (99.3 mg, 768 ⁇ mol) was added to DMF (2.5 mL), and the reaction was performed at room temperature for 0.5 hours.
- Body 2-13 (90.0 mg, 256 ⁇ mol) was added to the reaction. The reaction was carried out at room temperature for 12h.
- intermediate 1-2 (9 g, 0.039 mol), intermediate 22-1 (2-chloro-5-fluorophenylacetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol), T 3 P (25 g, 0.078 mol) was dissolved in DCM (90 mL), and the reaction was stirred at room temperature for 0.5 h. Water and DCM were added to the reaction solution, the DCM phase was separated after fully stirring, the aqueous phase was extracted twice with DCM, the DCM phases were combined, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 22-2.
- LC-MS: [M+H] + 400.
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Abstract
公开了式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物。该化合物具有较高的P2X4拮抗活性、较好的安全性以及药代动力学性质。
Description
本发明要求享有于2021年1月27日向中国国家知识产权局提交的,专利申请号为202110113303.4,名称为“一种芳香化合物、其制备方法及应用”的在先申请和2021年6月08日向中国国家知识产权局提交的,专利申请号为202110638504.6,名称为“一种芳香化合物、其制备方法及应用”的在先申请的优先权以及2022年1月18日向中国国家知识产权局提交的,专利申请号为202210055268.X,名称为“一种芳香化合物、其制备方法及应用”的在先申请的优先权。三件在先申请的全文通过引用的方式结合于本发明中。
本发明涉及一种芳香化合物、其制备方法及应用。
ATP受体基于分子结构、转导机理和药理学特性被分类成两个主要家族,P2Y-和P2X-嘌呤受体。P2X-嘌呤受体是ATP-门控的阳离子通道的家族,已克隆数种亚型,包括:六种同聚受体,P2X1;P2X2;P2X3;P2X4;P2X5;和P2X7;和三种杂聚受体P2X2/3,P2X4/6,P2X1/5。P2X4受体是目前P2X家族唯一解出晶体结构的亚型,且其分辨率高达
并且研究发现,P2X4是对Ca
2+通透性最强的P2X亚型。
咳嗽是呼吸系统疾病的主要症状表现,呼吸科门诊中,70%~80%的患者都具有咳嗽症状。随着COPD、IPF等患病率逐渐升高,而咳嗽作为大多数呼气道疾病的主要表现症状,需求也随之增大。作为机体的防御性神经反射,咳嗽有利于清除呼吸道分泌物和有害因子,但频繁剧烈的咳嗽会对患者的工作、生活和社会活动造成严重影响。
目前涉及P2X4靶点相关的在研药物的适应症多为神经性疼痛或炎症,尚无咳嗽适应症相关药物在研信息。并且尚无P2X4抑制途径治疗包括慢性咳嗽在内的众多病症的药物上市。因此,开发新的可抑制P2X4活性的化合物对于疾病的治疗具有积极意义。
发明内容
本发明提供了一种芳香化合物、其制备方法及应用。该化合物具有较高的P2X4拮抗活性、较好的安全性以及药代动力学性质。
本发明提供了一种如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物;
R
2-1选自无取代或任选被一个、两个或更多个Ra取代的下列基团:C
1~C
20烷基、C
3~C
20环烷基、3-20元杂环基、C
6~C
20芳基、5-20元杂芳基;
每个Ra相同或不同,彼此独立地选自卤素、OH、CN、NO
2、氧代(=O)、COOH、
无取代或任选被一个、两个或更多个Ra1取代的下列基团:C
1~C
20烷基、C
3~C
20环烷基、C
1~C
20烷氧基、C
1~C
20烷硫基、-C(=O)-C
1~C
20烷基、-C(=O)-OC
1~C
20烷基、-O-C(=O)-C
1~C
20烷基、-SO
2-C
1~C
20烷基、-S(=O)-C
1~C
20烷基、3-20元杂环基、C
6~C
20芳基、5-20元杂芳基、NH
2;
每个Ra1相同或不同,彼此独立地选自卤素、OH、COOH、CN、NO
2、氧代(=O),无取代或任选被一个、两个或更多个Ra2取代的下列基团:C
1~C
20烷基、C
3~C
20环烷基、C
1~C
20烷氧基、NH
2;
每个Ra2相同或不同,彼此独立地选自卤素、OH、CN、NO
2、氧代(=O)、C
1~C
20烷基、C
1~C
20烷氧基;
R
2-2选自氢、卤素、OH、CN、NO
2,无取代或任选被一个、两个或更多个Rb取代的下列基团:C
1~C
20烷基、C
1~C
20烷氧基;每个Rb相同或不同,彼此独立地选自卤素、OH、CN、NO
2;
R
3-1选自卤素、OH、CN、NO
2,无取代或任选被一个、两个或更多个Rc取代的下列基团:C
1~C
20烷基、C
1~C
20烷氧基或C
3~C
20环烷基;每个Rc相同或不同,彼此独立地选自卤素、OH、CN、NO
2;
n选自0、1、2、3或4。
R
2-1选自无取代或任选被一个、两个或更多个Ra取代的下列基团:C
1~C
12烷基、C
3~C
12环烷基、3-12元杂环基、C
6~C
14芳基、5-14元杂芳基;每个Ra相同或不同,彼此独立地选自卤素、OH、CN、NO
2、氧代(=O)、
无取代或任选被一个、两个或更多个Ra1取代的下列基团:C
1~C
12烷基、C
3~C
12环烷基、C
1~C
12烷氧基、C
1~C
12烷硫基、-C(=O)-C
1~C
12烷基、-C(=O)-OC
1~C
12烷基、-O-C(=O)-C
1~C
12烷基、-SO
2-C
1~C
12烷基、-S(=O)-C
1~C
12烷基、3-12元杂环基、C
6~C
14芳基、5-14元杂芳基、NH
2;
每个Ra1相同或不同,彼此独立地选自卤素、OH、COOH、CN、NO
2、氧代(=O),无取代或任选被一个、两个或更多个Ra2取代的下列基团:C
1~C
12烷基、C
1~C
12烷氧基、C
3~C
12环烷基、NH
2;每个Ra2相同或不同,彼此独立地选自卤素、OH、CN、NO
2、氧代(=O)、C
1~C
12烷基、C
1~C
12烷氧基;
R
2-2选自氢、卤素、OH、CN、NO
2,无取代或任选被一个、两个或更多个Rb取代的下列基团:C
1~C
12烷基、C
1~C
12烷氧基;每个Rb相同或不同,彼此独立地选自卤素、OH、CN、NO
2;
R
3-1选自卤素、OH、CN、NO
2,无取代或任选被一个、两个或更多个Rc取代的下列基团:C
1~C
12烷基、C
1~C
12烷氧基或C
3~C
12环烷基;每个Rc相同或不同,彼此独立地选自卤素、OH、CN、NO
2;
n选自0、1、2、3或4。
根据本发明的实施方案,R
2为
或为
其中,R
2-1如上述所定义,R
2-3选自卤素、OH、CN、NO
2,无取代或任选被一个、两个或更多个Rb取代的下列基团:C
1~C
20烷基、C
1~C
20烷氧基;每个Rb相同或不同,彼此独立地选自卤素、OH、CN、NO
2;
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、C
3~C
10环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、被一个或多个R
2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~10元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~10元杂芳基”;
R
2-3为卤素、OH、C
1~C
10烷基、C
1~C
10烷氧基;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1c、R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3、
C
3~C
10环烷基,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基;
R
2-1c-1、R
2-1c-2和R
2-1c-3独立地为卤素、OH、COOH、CN、NO
2、氧代(=O),无取代或任选被一个、两个或更多个Ra2取代的下列基团:C
1~C
6烷基、C
1~C
6烷氧基、NH
2;
每个Ra2相同或不同,彼此独立地选自卤素、OH、CN、NO
2、氧代(=O)、C
1~C
6烷基、C
1~C
6烷氧基、C
3~C
6环烷基;
n为0、1、2或3;
R
3-1独立地为卤素、羟基、氰基、C
1~C
6烷基、卤素取代的C
1~C
6烷基、C
1~C
6烷氧基或C
3~C
10环烷基。
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、C
3~C
10环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、被一个或多个R
2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1c、R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3或
R
2-1c-1独立地为NH
2;
R
2-1c-2和R
2-1c-3独立地为NH
2或C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素、羟基、氰基、C
1~C
6烷基、卤素取代的C
1~C
6烷基、C
1~C
6烷氧基或C
3~C
6环烷基。
在某一方案中,上述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物中,某些基团的定义如下,未定义的基团同前任一方案所述(以下简称“在某一方案中”),
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、被一个或多个R
2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-2选自氢、卤素、OH、C
1~C
6烷基、C
1~C
6烷氧基;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1c、R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3、
C
3~C
6环烷基,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~6元杂环烷基;
R
2-1c-1独立地为卤素、NH
2、C
3~C
6环烷基;
R
2-1c-2和R
2-1c-3独立地为NH
2或C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素、羟基、氰基、C
1~C
6烷基、卤素取代的C
1~C
6烷基、C
1~C
6烷氧基或C
3~C
6环烷基。
在某一方案中
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、“杂原子数为1个、2个或3个,杂原子选 自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、被一个或多个R
2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1c、R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3或
R
2-1c-1独立地为NH
2;
R
2-1c-2和R
2-1c-3独立地为NH
2或C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素、羟基、氰基、C
1~C
6烷基、卤素取代的C
1~C
6烷基、C
1~C
6烷氧基或C
3~C
6环烷基。
在某一方案中,当R
2-1为C
1~C
10烷基、或被一个或多个R
2-1a取代的C
1~C
10烷基时,所述的C
1~C
10烷基可为C
1~C
6烷基,又可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基。
在某一方案中,当R
2-1为“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、或被一个或多个R
2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”可为“杂原子数为1个或2个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~8元杂环烷基”,例如氧杂环丁烷、四氢呋喃基、四氢吡喃基、吡咯烷基、哌啶基、2-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.1]庚烷基、3-氮杂双环[2.2.2]辛烷基或四氢噻吩-1,1-二氧化物,例如
在某一方案中,当R
2-1为C
6~C
10芳基、或被一个或多个R
2-1d取代的C
6~C
10芳基时,所述的C
6~C
10芳基可为苯基。
在某一方案中,当R
2-1为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”可为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”,又可为“杂原子数为1个或2个,杂原子为N的5~6元杂芳基”,例如吡唑基、咪唑基或吡啶基,又例如
在某一方案中,当R
2-1a独立地为C
3~C
6环烷基时,所述的C
3~C
6环烷基可为环丙基、环丁基、环戊基或环己基,例如环丙基、环丁基或环戊基。
在某一方案中,当R
2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”可为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”,又可为“杂原子数为1个或2个,杂原子为O的3~6元杂环烷基”,例如氧杂环丁烷基或四氢呋喃基,又例 如
在某一方案中,当R
2-1c、R
2-1d和R
2-1e独立地为卤素时,所述的卤素可为氟、氯、溴或碘,例如氟或氯。
在某一方案中,当R
2-1c、R
2-1d和R
2-1e独立地为C
1~C
6烷基、或被一个或多个R
2-1c-1取代的C
1~C
6烷基时,所述的C
1~C
6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基。
在某一方案中,当R
2-1c、R
2-1d和R
2-1e独立地为C
3~C
10环烷基时,所述的C
3~C
10环烷基为环丙基、环丁基、环戊基。
在某一方案中,当R
2-1c、R
2-1d和R
2-1e独立地为C
1~C
6烷氧基时,所述的C
1~C
6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基,例如甲氧基。
在某一方案中,当R
2-1c-1为C
3~C
6烷基时,所述的C
3~C
10环烷基为环丙基、环丁基、环戊基。
在某一方案中,当R
2-1c-2和R
2-1c-3独立地为C
1~C
6烷基时,所述的C
1~C
6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基。
在某一方案中,当R
2-2为C
1~C
6烷基时,所述的C
1~C
6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基。
在某一方案中,当R
3-1独立地为卤素、或被卤素取代的C
1~C
6烷基时,所述的卤素可为氟、氯、溴或碘,例如氟或氯。
在某一方案中,当R
3-1独立地为C
1~C
6烷基、或被卤素取代的C
1~C
6烷基时,所述的C
1~C
6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在某一方案中,当R
3-1独立地为C
1~C
6烷氧基时,所述的C
1~C
6烷氧基可为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基。
在某一方案中,当R
3-1独立地为C
3~C
6环烷基时,所述的C
3~C
6环烷基可为环丙基、环丁基、环戊基或环己基。
在某一方案中,当R
2-1为被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”可为
以及
在某一方案中,R
3-1可为氟或氯。
在某一方案中,R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、C
3~C
10环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”。
在某一方案中,R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”。
在某一方案中,R
2-1为被一个或多个R
2-1a取代的C
1~C
10烷基、被一个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”。
在某一方案中,R
2-1为被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”。
在某一方案中,R
2-2为氢、卤素、羟基、C
1~C
10烷基、C
1~C
10烷氧基。
在某一方案中,R
2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”。
在某一方案中,R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3、
C
3~C
6环烷基。
在某一方案中,R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、-C(=O)R
2-1c-2或-S(=O)
2R
2-1c-3。
在某一方案中,R
2-1c-1独立地为卤素、NH
2、C
3~C
6环烷基;
在某一方案中,R
2-1c-2和R
2-1c-3独立地为C
1~C
6烷基。
在某一方案中,R
2-2为氢、C
1~C
10烷基、C
1~C
10烷氧基。
在某一方案中,R
3-1独立地为卤素。
在某一方案中,
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、C
3~C
10环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-2为氢、C
1~C
6烷基、C
1~C
6烷氧基;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3、
C
3~C
6环烷基;
R
2-1c-1独立地为卤素、NH
2、C
3~C
6环烷基;
R
2-1c-2和R
2-1c-3独立地为NH
2或C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素。
在某一方案中,
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-2为氢、C
1~C
6烷基;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、被一个或多个R
2-1c-1取代的C
1~C
6烷基、C
1~C
6烷氧基、-C(=O)R
2-1c-2、-S(=O)
2R
2-1c-3、
C
3~C
6环烷基;
R
2-1c-1独立地为卤素、NH
2、环丙基;
R
2-1c-2和R
2-1c-3独立地为NH
2或C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素。
在某一方案中,
R
2-1为C
1~C
10烷基、被一个或多个R
2-1a取代的C
1~C
10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O)
2中的一种或多种的3~10元杂环烷基”、C
6~C
10芳基、被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-2为氢、C
1~C
6烷基;
R
2-1a独立地为C
3~C
6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1c-2和R
2-1c-3独立地为NH
2或C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素。
在某一方案中,
R
2-1为被一个或多个R
2-1a取代的C
1~C
10烷基、被一个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-2为氢、C
1~C
3烷基;
R
2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;
R
2-1c-2和R
2-1c-3独立地为C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素。
在某一方案中,
R
2-1为被一个或多个R
2-1d取代的C
6~C
10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R
2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;
R
2-2为氢、甲基;
R
2-1d和R
2-1e独立地为氰基、卤素、C
1~C
6烷基、-C(=O)R
2-1c-2或-S(=O)
2R
2-1c-3;
R
2-1c-2和R
2-1c-3独立地为C
1~C
6烷基;
n为0、1、2或3;
R
3-1独立地为卤素。
在某一方案中,所述的如式I所示的化合物可为以下任一结构,
根据本发明的实施方案,所述的如式I所示的化合物可为以下任一化合物,
化合物1:N-(4-((3-乙酰苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-((3-acetylphenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物2:2-(2-氯苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物3:2-(2-氯苯基)-N-(4-(((5-氟吡啶-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物4:N-(4-((4-氯苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物5:2-(2-氯苯基)-N-(4-((2,4-二氯苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物6:2-(2-氯苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物7:2-(2-氯苯基)-N-(4-((2,4-二氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物8:2-(2-氯苯基)-N-(4-(((4,5-二氯-1-甲基-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物9:2-(2-氯苯基)-N-(4-(((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物10:2-(2-氯苯基)-N-(4-((3-氰基-4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide
化合物11:N-(4-((3-氯-4-氟苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-((3-chloro-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物12:2-(2-氯苯基)-N-(4-((3-(甲基磺酰基)苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide
化合物13:2-(2-氯苯基)-N-(4-(((1,1-二氧化四氢噻吩-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物14:2-(2-氯苯基)-N-(3-氨磺酰基-4-((((四氢呋喃-3-基)氧基)甲基)苯基)乙酰胺,2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)acetamide,
化合物15:N-(4-((3-乙酰基-4-氟苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物16:2-(2-氯苯基)-N-(3-氨磺酰基-4-((对甲苯氧基)甲基)苯基)乙酰胺,2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((p-tolyloxy)methyl)phenyl)acetamide,
化合物17:2-(2-氯苯基)-N-(4-((4-氟-3-甲基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物18:2-(2-氯苯基)-N-(4-((4-氟-3-甲氧基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物19:2-(2-氯苯基)-N-(4-((4-氟-3-(2-氧代吡咯烷-1-基)苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidin-1-yl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物20:2-(2-氯-6-氟苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物21:2-(2-氯-4-氟苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-4-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物22:2-(2-氯-5-氟苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-5-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物23:2-(2-氯苯基)-N-(4-(((1-甲基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物24:2-(2-氯苯基)-N-(4-(((3-氟-1-甲基-1H-吡唑-5-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物25:2-(2-氯苯基)-N-(4-(((1-甲基-1H-咪唑-5-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物26:2-(2-氯苯基)-N-(4-(((1-甲基-1H-咪唑-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物27:2-(2-氯苯基)-N-(4-(((1-甲基-1H-咪唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物28:2-(2-氯苯基)-N-(4-((环丙基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物29:2-(2-氯苯基)-N-(4-((环丁基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物30:2-(2-氯苯基)-N-(4-((环戊基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物31:2-(2-氯苯基)-N-(4-(环丁氧基甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(cyclobutoxymethyl)-3-sulfamoylphenyl)acetamide,
化合物32:2-(2-氯苯基)-N-(3-氨磺酰基-4-((((四氢-2H-吡喃-4-基)氧基)甲基)苯基)乙酰胺,2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)acetamide,
化合物33:2-(2-氯苯基)-N-(4-((氧杂环丁烷-3-基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物34:2-(2-氯苯基)-N-(3-氨磺酰基-4-(((四氢呋喃-3-基)甲氧基)甲基)苯基)乙酰胺,2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)methoxy)methyl)phenyl)acetamide,
化合物35:2-(2-氯苯基)-N-(4-((氧杂环丁烷-3-基氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物36:N-(4-((氮杂环丁烷-3-基氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物37:2-(2-氯苯基)-N-(4-((吡咯烷-3-基氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物38:2-(2-氯苯基)-N-(4-((哌啶-4-基氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((piperidin-4-yloxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物39:2-(2-氯苯基)-N-(4-((哌啶-3-基氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((piperidin-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物40:2-(2-氯苯基)-N-(3-氨磺酰基-4-((((四氢-2H-吡喃-3-基)氧基)甲基)苯基)乙酰胺,2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)phenyl)acetamide,
化合物41:N-(4-(((2-氮杂双环[2.2.1]庚烷-5-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-(((2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物42:N-(4-(((3-氮杂双环[3.1.1]庚烷-6-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-(((3-azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物43:N-(4-(((2-氮杂双环[2.2.2]辛烷-5-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-(((2-azabicyclo[2.2.2]octan-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物44:2-(2-氯苯基)-N-(4-((3-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((3-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物45:N-(4-((3-(氨基甲基)苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-((3-(aminomethyl)phenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物46:2-(2-氯-6-氟苯基)-N-(4-(((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物47:2-(2-氯-5-氟苯基)-N-(4-(((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-5-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物48:2-(2-氯-4-氟苯基)-N-(4-(((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-4-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物49:2-(2-氯-6-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物50:2-(2-氯-5-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物51:2-(2-氯-4-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺, 2-(2-chloro-4-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物52:2-(2-氯-3-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物53:2-(2-氯-6-氟苯基)-N-(4-((((5-氟吡啶-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-6-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物54:2-(2-氯-5-氟苯基)-N-(4-(((5-氟吡啶-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-5-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物55:2-(2-氯-4-氟苯基)-N-(4-(((5-氟吡啶-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-4-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物56:2-(2-氯苯基)-N-(4-(((1-甲基-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物57:2-(2-氯苯基)-N-(4-(((1-环丙基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide.
化合物58:2-(2-氯苯基)-N-(4-((3-(S-甲基磺酰亚胺酰基)苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-((3-(S-methylsulfonimidoyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物59:2-(2-氯苯基)-N-(4-(1-((6-氟吡啶-3-基)氧基)乙基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(1-((6-fluoropyridin-3-yl)oxy)ethyl)-3-sulfamoylphenyl)acetamide,
化合物60:N-(4-(((4-氯-1H-吡唑-3-基)氧基)甲基)-3氨磺酰基苯基)-2-(2-氯苯基)乙酰胺,N-(4-(((4-chloro-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,
化合物61:2-(2-氯苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物62:2-(2-氯-4-氟苯基)-N-(4-(((1-甲基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物63:2-(2-氯苯基)-N-(4-(((1-(环丙基甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物64:2-(2-氯-5-氟苯基)-N-(4-(((1-甲基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物65:2-(2-氯-5-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物66:2-(2-氯苯基)-N-(4-(((1-(1,1-二氟丙基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chlorophenyl)-N-(4-(((1-(1,1-difluoropropyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物67:2-(2-氯-4-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物68:N-(4-(((4-氯-1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯-4-氟苯基)乙酰胺,
N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide,
化合物69:N-(4-(((4-氯-1-(二氟甲基)-1H-吡唑-5-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯-4-氟苯基)乙酰胺,
N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide,
化合物70:N-(4-(((4-氯-1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯-5-氟苯基)乙酰胺,
N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-5-fluorophenyl)acetamide,
化合物72:2-(2-氯苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物73:2-(2-氯苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-5-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物74:2-(2-氯-5-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
化合物75:2-(2-氯-4-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺,
2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,
本发明提供了一种上述的如式I所示的化合物的制备方法,其为方法一或方法二,
方法一包括以下步骤:溶剂中,在酸的存在下,将如式II所示化合物和1,3-二氯-5,5-二甲基海因(DCDMH)进行反应生成式IV所示化合物,再将式IV化合物与氨水进行反应,得所述的如式I所示的化合物;
方法二包括以下步骤:在有机溶剂中,将如式III所示化合物和水合肼进行反应,得所述的如式I所示的化合物;
其中,式I、II、III、IV中R
3-1、n、R
2相同或不同,彼此独立地具有上文所述的定义。
在某一方案中,方法一中,式IV所示化合物不需要分离,直接将上一步的反应液与氨水进行反应。即将如式II所示化合物和1,3-二氯-5,5-二甲基海因(DCDMH)进行反应,之后再将反应液与氨水进行反应,得到所述的如式I所示的化合物。
在某一方案中,方法一中,所述的溶剂可为本领域常规的溶剂,又可为腈类溶剂、或腈类溶剂和水的混合溶剂,例如乙腈和水的混合溶剂。
在某一方案中,方法一中,所述的酸可为本领域常规的酸,又可为有机酸,又可为有机羧酸,例如乙酸。
在某一方案中,方法一中,所述的DCDMH和所述的如式II所示化合物的摩尔比可为1:1-5:1,例如2:1或3:1。
在某一方案中,方法一中,所述的酸和所述的如式II所示化合物的摩尔比可为3:1-30:1,例如5:1、6:1、8:1、13:1、17:1或25:1。
在某一方案中,方法一中,所述的如式II所示化合物在所述的溶剂中的摩尔浓度可为0.01-0.3mol/L,例如0.05mol/L、0.09mol/L、0.1mol/L、0.15mol/L、0.18mol/L。
在某一方案中,方法一中,与所述的DCDMH反应时的温度可为10-40℃。
在某一方案中,方法一中,与所述的DCDMH反应的时间可为5-120min,例如10min、15min、60min。
在某一方案中,方法一中,所述的如式II所示化合物与所述的氨水的摩尔体积比可为0.01-0.5mol/L,例如0.015mol/L、0.02mol/L、0.08mol/L、0.034mol/L、0.2mol/L、0.33mol/L或0.39mol/L。
在某一方案中,方法一中,与所述的氨水反应时的温度可为10-40℃。
在某一方案中,方法一中,与所述的氨水反应的时间可为5-60min,例如10min、30min。
在某一方案中,方法一中,与所述的氨水反应后,其后处理可包括以下步骤:除去反应液中的溶剂,分离纯化,即可。所述的除去反应液中的溶剂的方式可为本领域常规的方式,例如减压浓缩至干。所述的分离纯化的方式可为本领域常规的方式,例如通过制备HPLC纯化。
在某一方案中,方法二中,所述的有机溶剂可为本领域常规的有机溶剂,又可为醇类溶剂和/或醚类溶剂,例如甲醇和/或四氢呋喃。
在某一方案中,方法二中,所述的水合肼和所述的如式III所示化合物的摩尔比可为2:1-8:1,例如5:1。
在某一方案中,方法二中,所述的如式III所示化合物在所述的有机溶剂中的摩尔浓度可为0.01-0.3mol/L,例如0.06mol/L。
在某一方案中,方法二中,所述的反应的温度可为10-40℃。
在某一方案中,方法二中,所述的反应的时间可为0.5-3h,例如1h。
在某一方案中,方法二中,所述的反应的后处理可包括以下步骤:除去反应液中的溶剂,分离纯化,即可。所述的除去反应液中的溶剂的方式可为本领域常规的方式,例如减压浓缩至干。所述的分离纯化的方式可为本领域常规的方式,例如通过制备HPLC纯化。
本发明还提供了一种如式II、III或IV所示的中间体化合物,所述中间体化合物可用于制备式I所示的化合物:
其中,R
2、R
3-1和n的定义同前任一方案所述。
本发明还提供如下所示的中间体化合物,所述中间体化合物可用于制备式I所示的化合物:
本发明提供了一种药物组合物,其包含物质A和至少一种药用辅料;
所述的物质A为上述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、 其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在所述的药物组合物中,所述的物质A的剂量可为治疗有效量。
本发明还提供了一种物质A在制备P2X4受体拮抗剂或药物中的应用;
所述的物质A为上述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某一方案中,所述的P2X4受体拮抗剂可在体外使用。
在某一方案中,所述的药物可用于治疗或预防动物(例如人类)的泌尿道疾病、呼吸系统疾病、疼痛相关的疾病、自身免疫病、炎症、睡眠障碍、精神疾病、关节炎、神经退行性疾病、外伤性脑损伤、血栓症、消化道疾病、性功能障碍、心血管系统疾病、子宫内膜异位、肌肉骨骼和结缔组织发育障碍、癌症或眼科疾病。所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。所述的呼吸系统疾病例如呼吸障碍,包括呼吸衰竭、特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。所述的疼痛相关的疾病例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛、慢性疼痛或瘙痒。所述的神经退行性疾病例如老年痴呆症、帕金森、癫痫或脑卒中。所述的心血管系统疾病例如心肌梗死、动脉粥样硬化、心衰、高血压或血液病。所述的消化道疾病例如结肠综合症、炎性肠病或胃肠功能紊乱。所述的自身免疫病例如关节炎(例如类风湿性关节炎)。所述眼科疾病如干眼综合症、干眼症、眼神经疼痛、眼外伤和术后眼部疼痛。
在某一方案中,所述的药物可用于预防或治疗动物(例如人类)的至少部分由P2X4介导的疾病。
所述的至少部分由P2X4介导的疾病例如泌尿道疾病、呼吸系统疾病、疼痛相关的疾病、自身免疫病、炎症、睡眠障碍、精神疾病、关节炎、神经退行性疾病、外伤性脑损伤、血栓症、消化道疾病、性功能障碍、心血管系统疾病、子宫内膜异位、肌肉骨骼和结缔组织发育障碍、癌症或眼科疾病。所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。所述的呼吸系统疾病例如呼吸障碍,包括呼吸衰竭、特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。所述的疼痛相关的疾病例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛、慢性疼痛或瘙痒。所述的神经退行性疾病例如老年痴呆症、帕金森、癫痫或脑卒中。所述的心血管系统疾病例如心肌梗死、动脉粥样硬化、心衰、高血压或血液病。所述的消化道疾病例如结肠综合症、炎性肠病或胃肠功能紊乱。所述的自身免疫病例如关节炎(例如类风湿性关节炎)。所述眼科疾病如干眼综合症、干眼症、眼神经疼痛、眼外伤和术后眼部疼痛。
本发明还提供了一种治疗或预防疾病的方法,其包括向患者(例如人类)施用治疗有效量的物质A;
所述的疾病为泌尿道疾病、呼吸系统疾病、疼痛相关的疾病、自身免疫病、炎症、睡眠障碍、精神疾病、关节炎、神经退行性疾病、外伤性脑损伤、血栓症、消化道疾病、性功能障碍、心血管系统疾病、子宫内膜异位、肌肉骨骼和结缔组织发育障碍、癌症或眼科疾病;
所述的物质A为上述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某一方案中,所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。
在某一方案中,所述的呼吸系统疾病例如呼吸障碍,包括呼吸衰竭、特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。
在某一方案中,所述的疼痛相关的疾病例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛、慢性疼痛或瘙痒。
在某一方案中,所述的神经退行性疾病例如老年痴呆症、帕金森、癫痫或脑卒中。
在某一方案中,所述的心血管系统疾病例如心肌梗死、动脉粥样硬化、心衰、高血压或血液病。
在某一方案中,所述的消化道疾病例如结肠综合症、炎性肠病或胃肠功能紊乱。所述的自身免疫病例如关节炎(例如类风湿性关节炎)。
在某一方案中,所述眼科疾病如干眼综合症、干眼症、眼神经疼痛、眼外伤和术后眼部疼痛。
本发明还提供了一种治疗或预防至少部分由P2X4介导的疾病的方法,其包括向患者(例如人类)施用治疗有效量的物质A;
所述的物质A为上述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
在某一方案中,所述的疾病可为泌尿道疾病、呼吸系统疾病、疼痛相关的疾病、自身免疫病、炎症、睡眠障碍、精神疾病、关节炎、神经退行性疾病、外伤性脑损伤、血栓症、消化道疾病、性功能障碍、心血管系统疾病、子宫内膜异位、肌肉骨骼和结缔组织发育障碍或癌症。
在某一方案中,所述的泌尿道疾病例如尿失禁、膀胱过度活动症、排尿困难或膀胱炎。
在某一方案中,所述的呼吸系统疾病例如呼吸障碍,包括呼吸衰竭、特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛或咳嗽(例如慢性咳嗽)。
在某一方案中,所述的疼痛相关的疾病例如炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛、慢性疼痛或瘙痒。
在某一方案中,所述的神经退行性疾病例如老年痴呆症、帕金森、癫痫或脑卒中。
在某一方案中,所述的心血管系统疾病例如心肌梗死、动脉粥样硬化、心衰、高血压或血液病。
在某一方案中,所述的消化道疾病例如结肠综合症、炎性肠病或胃肠功能紊乱。所述的自身免疫病例如关节炎(例如类风湿性关节炎)。
在某一方案中,所述眼科疾病如干眼综合症、干眼症、眼神经疼痛、眼外伤和术后眼部疼痛。
本发明的芳香化合物具有较高的P2X4拮抗活性、较好的安全性以及很好的药代动力学性质。
术语定义与说明
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。
有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
除非另外说明,本发明所使用的术语具有如下定义,下文中未涉及的术语的定义如本发明所属领域技术人员的通常理解。
除非另有说明,本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如,数值范围“1-20”相当于记载了数值范围“1-10”中的每一个整数数值即1、2、3、4、5、6、7、8、9、10,以及数值范围“11-20”中的每一个整数数值即11、12、13、14、15、16、17、18、19、20。应当理解,本文在描述取代基时使用的一个、两个或更多个中,“更多个”应当是指≥3的整数,例如3、4、5、6、7、8、9或10。术语“多个”是指≥2的整数,例如2个、3个、4个、5个等。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于:水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述,是指本发明化合物与1、与相对无毒的、药学上可接受的酸或碱制备得到的2、与化学计量或非化学计量的溶剂结合形成的物质。
术语“立体异构体”是指分子中原子或原子团相互连接次序相同,但空间排列不同而引起的异构体,例如顺反异构体、旋光异构体或阻转异构体等。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集,还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。例如,丙酮和1-丙烯-2-醇可以通过氢原子在氧上和α-碳上的迅速移动而互相转变。
术语“同位素化合物”是指化合物中的一个或多个原子被一个或多个具有特定原子质量或质量数的原子取代。可以掺入本发明化合物中的同位素的实例包括但不限于氢、碳、氮、氧、氟、硫和氯的同位素(例如
2H,
3H,
13C,
14C,
15N,
18O,
17O,
18F,
35S和
36Cl)。本发明的同位素化合物通常可以根据本文所述的方法通过用同位素标记的试剂取代非同位素标记的试剂来制备。
术语“晶型”是指其中的离子或分子是按照一种确定的方式在三维空间作严格周期性排列,并具有间隔一定距离周期重复出现规律;因上述周期性排列的不同,可存在多种晶型,也即多晶型现象。
术语“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂例如二氯甲烷中,使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
当任意变量(例如R
2-1a)在化合物的定义中多次出现时,该变量每一位置出现的定义与其余位置出现的定义无关,它们的含义互相独立、互不影响。因此,若某基团被1个、2个或3个R
2-1a基团取代,也就是说,该基团可能会被最多3个R
2-1a取代,该位置R
2-1a的定义与其余位置R
2-1a的定义是互相独立的。另外,取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,基团“卤代-C
1~C
6烷基”中的C
1~C
6烷基应当理解为C
1~C
6亚烷基。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写,除非另有说明,都以它们通常使用的、公认的缩写为准,或参照IUPAC-IUB Commissionon Biochemical Nomen clature(参见Biochem.1972,11:942-944)。
术语“氧代”是指取代基中的碳原子、氮原子或硫原子被氧化后形成的氧基取代(=O)。
术语“卤素”是指氟、氯、溴或碘。
术语“C
1~C
20烷基”应理解为具有1~20个碳原子的直链或支链饱和烃基。例如,“C
1~C
6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。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。在一些实施方案中,烷基基团含有1-12个碳原子或13-20个碳原子;在另一些实施方案中,烷基基团含有1-6个碳原子;在又一些实施方案中,烷基基团含有1-4个碳原子。所述烷基的实例包含,但并不限于,甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“C
1~C
20烷氧基”是指基团-O-C
1~C
20烷基,例如为C
1~C
12烷氧基或C
13~C
20烷氧基,优选C
1~C
6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基及其类似烷氧基。
术语“C
3~C
20环烷基”应理解为表示饱和的单环、双环烃环或三环烃环,其具有3~20个碳原子,优选“C
3~C
12环烷基”,且其双环和三环烃环包含桥环或螺环烃环。术语“C
3~C
12环烷基”应理解为表示饱和的单环、双环烃环或三环烃环,其具有3、4、5、6、7、8、9、10、11或12个碳原子,且其双环和三环烃环包含桥环或螺环烃环。所述C
3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”应理解为表示饱和的单环、双环烃环或三环烃环,其包含1-5个,优选1-3个独立选自N、O、S和S(=O)
2的杂原子的总成环原子数为3-20(如原子数为3、4、5、6、7、8、9、10等)的非芳族环状基团,且其双环和三环烃环包含桥环或螺环烃环,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的单环、双环烃环或三环烃环,其包含1-5个,优选1-3个独立选自N、O、S和S(=O)
2的杂原子,例如1、2、3个独立选自N、O、S和S(=O)
2的杂原子,且其双环和三环烃环包含桥环或螺环烃环。更优选“含有1个、2个或3个独立选自N、O、S和S(=O)
2的环杂原子的3-8元的饱和单环或双环体系”或含有1个、2个或3个独立选自N、O和S的环杂原子的3-6元的饱和单环。根据本发明,所述杂环基是无芳香性的。所述3-20元杂环基与其它基团相连构成本发明的化合物时,可以为3-20元杂环基上的碳原子与其它基团相连,也可以为3-20元杂环基环上杂环原子与其它基团相连。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、 吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢恶唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。
术语“C
6~C
20芳基”应理解为表示具有6~20个碳原子的芳香性或部分芳香性的单环、双环或三环烃环,优选“C
6~C
14芳基”。术语“C
6~C
14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的芳香性或部分芳香性的单环、双环或三环烃环(“C
6~C
14芳基”),特别是具有6个碳原子的环(“C
6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C
9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C
10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C
13芳基”),例如芴基,或者是具有14个碳原子的环(“C
14芳基”),例如蒽基。当所述C
6~C
20芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“5-20元杂芳基”应理解为包括芳香性或部分芳香性的单环、双环或三环芳族环系,其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3个独立选自N、O和S的杂原子。并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、恶唑基、噻唑基、咪唑基、吡唑基、异恶唑基、异噻唑基、恶二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并恶唑基、苯并异恶唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩恶嗪基等。杂芳基的实例包括但不限于呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基等。当所述5-20元杂芳基与其它基团相连构成本发明的化合物时,可以为5-20元杂芳基环上的碳原子与其它基团相连,也可以为5-20元杂芳基环上的杂原子与其它基团相连。当所述5-20元杂芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为杂芳基环上与碳原子相连的氢被取代,或者杂芳基环上与杂原子相连的氢被取代。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,可以包括在其1-、2-、3-、4-、5-、6-、7-、8-、9-、10-、11-、12-位等(如果存在)中的一个、两个或更多个位置上取代或与其他基团键合的形式,包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基;吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)缓解疾病或者病症的一种或多种生物学表现,(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,(3)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用,或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化,但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例,即将或已经接受了该化合物或组合物给药的任何动物,哺乳动物为优,人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人类为最优。
本发明化合物的生物活性可通过使用任何常规已知方法评定。适当的检测方法是本领域众所周知的。例如,可以通过适当的常规方法检测本发明化合物的P2X4抑制活性、药代动力学活性和/或肝微粒体稳定性等。本发明提供的检测方法仅作为实例呈现且不限制本发明。本发明化合物在至少一种本发明提供的检 测方法中具有活性。
除非特别说明,本发明中的“室温”是指10-40℃。“min”是指分钟。“h”是指小时。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备,下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。。
本发明实施例部分的缩略词示意如下:
ACN:乙腈(Acetonitrile)
AIBN:偶氮二异丁腈(2,2'-Azobis(2-methylpropionitrile))
Boc
2O:二碳酸二叔丁酯(Di-tert-butyl dicarbonate)
B
2pin
2:联硼酸频那醇酯(Bis(pinacolato)diboron)
CAN:硝酸铈铵(Ceric ammonium nitrate)
DIAD:偶氮二甲酸二异丙酯(diisopropyl azodiformate)
Dioxane:1,4-二氧六环
DCM:二氯甲烷(Methylene chloride)
DIEA:N,N-二异丙基乙胺(N,N-Diisopropylethylamine)
DCDMH:1,3-二氯-5,5-二甲基海因(1,3-Dichloro-5,5-dimethylhydantoin)
DME:乙二醇二甲醚(1,2-dimethoxy-ethan)
DMF:N,N-二甲基甲酰胺(N,N-Dimethylformamide)
DMF-DMA:N,N-二甲基甲酰胺二甲基缩醛(N,N-Dimethylformamide dimethyl acetal)
DMSO:二甲基亚砜(Dimethyl sulfoxide)
EA:乙酸乙酯(ethyl acetate)
FA:甲酸(Formic acid)
HATU:N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲,(2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)
NBS:N-溴代丁二酰亚胺(N-Bromosuccinimide)
NCS:N-氯代丁二酰亚胺
PPh
3:三苯基膦(triphenylphosphine)
Pd
2(dba)
3:三(二亚苄基丙酮)二钯(Tris(dibenzylideneacetone)dipalladium)
Pd(dppf)Cl
2:1,1'-双二苯基膦二茂铁二氯化钯(
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II))
PMBNH
2:对甲氧基苄胺(4-Methoxybenzylamine)
THF:四氢呋喃(Tetrahydrofuran)
Tween80:吐温80
T
3P:丙基磷酸三环酸酐溶液(Propyl phosphate tricyclic anhydride solution)
TEA:三乙胺(Triethylamine)
TFA:三氟乙酸(trifluoroacetic acid)
t-BuOK:叔丁醇钾(Potassium tert-butoxide)
t-Bu
3P:三叔丁基膦(Tri-tert-butylphosphine)
Xantphos:4,5-双二苯基膦-9,9-二甲基氧杂蒽
PE/EA:石油醚/乙酸乙酯
LAH:氢化铝锂(Lithium Aluminum Hydride)
对比例1
化合物D1:2-(2-氯苯基)-N-{4-[(4-氰苄基)氧基]-3-氨磺酰基苯基}乙酰胺的制备
合成路线
步骤(1)中间体D1-IN-01的制备
将称量好的中间体D1-SM-01(2.0g,9.012mmol)溶于150mL THF中,加入中间体D1-SM-02(1.0g,7.51mmol)和PPh
3(4.0g,15.02mmol),加完降温至0℃,滴加DIAD(4.5g,22.53mmol),加完后自然降温至室温反应3h,反应液加水,用EA萃取,有机相用饱和食盐水洗涤,硫酸钠干燥,反应液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=4/1)纯化,得到中间体D1-IN-01产物2.0g,为白色固体。
步骤(2)中间体D1-IN-02的制备
将称量好的中间体D1-IN-01(2.0g,6.003mmol)溶于80mL乙醇和20mL水中,加入铁粉(1.7g,30.017mmol)和氯化铵(1.6g,30.017mmol),加完后80℃反应2h,有产物生成,反应液降至室温,用饱和碳酸氢钠溶液淬灭并调节pH至8.0~10.0,用EA萃取,有机相用饱和食盐水洗,硫酸钠干燥,反应液减压浓缩得到中间体D1-IN-02产物1.7g,为淡黄色固体。LC-MS:[M+H]
+=305。
步骤(3)中间体D1-IN-03的制备
将称量好的中间体D1-IN-02(1.7g,5.608mmol)溶于80mL DCM中,加入2-氯苯乙酸(中间体1-3)(1.15g,6.729mmol),T
3P(7.1g,11.216mmol)和TEA(1.7g,16.824mmol),加完室温反应1h,反应液直接减压浓缩得粗品,粗品通过硅胶柱层析(PE/EA=3/1)纯化得到中间体D1-IN-03产物2.4g,为淡黄色固体。
步骤(4)中间体D1-IN-04的制备
将称量好的中间体D1-IN-03(1.2g,2.633mmol)溶于1,4-二氧六环(40mL)中,加入中间体1-9(苄硫醇)(655mg,5.266mmol),Pd
2(dba)
3(240mg,0.263mmol),Xantphos(153mg,0.263mmol),DIEA(982mg,7.899mmol)加完后,在氮气保护、100℃条件下反应过夜,将反应液降至室温加水,用EA萃取,有机相用饱和食盐水洗,硫酸钠干燥,反应液直接减压浓缩得粗品,粗品通过硅胶柱层析(PE/EA=3/1~1/1)纯化,得到中间体D1-IN-04产物900mg,为淡黄色固体。LC-MS:[M+H]
+=499.10。
步骤(5)化合物D1的制备
将中间体D1-IN-04(900mg,1.803mmol),溶于CH
3CN(40mL),AcOH(5mL)和H
2O(5mL)中,加入中间体1-11(DCDMH)(711mg,3.607mmol),在室温条件下反应10min将反应液加入到搅拌下的氨水(10mL)中,后室温下搅拌10min,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液直接减压浓缩得粗品,粗品通过Prep-HPLC纯化得到化合物D1产物365.3mg,为白色固体。LC-MS:[M+H]
+=456.10。
1H NMR(400MHz,DMSO-d
6)δ10.32(s,1H),8.07(d,J=2.6Hz,1H),7.85(d,J=8.3Hz,2H),7.70(dd,J =8.5,4.6Hz,3H),7.42(ddd,J=11.2,5.8,3.7Hz,2H),7.35–7.26(m,2H),7.22–7.08(m,3H),5.42(s,2H),3.80(s,2H).
对比例2
化合物D2:2-(2-氯苯基)-N-(4-((4-氟苄基)氧基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体D2-IN-01的制备
将称量好的中间体D1-SM-01(1.04g,4.757mmol)溶于75mL THF中,加入中间体D2-SM-01(500mg,3.964mmol)和PPh
3(2.08g,7.928mmol),加完降温至0℃,滴加DIAD(2.4g,11.892mmol),加完后室温反应3h,反应液加水,用EA萃取,有机相用饱和食盐水洗涤,后用硫酸钠干燥,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=20:1)纯化得到中间体D2-IN-01产物1.1g,为淡黄色固体。
步骤(2)中间体D2-IN-02的制备
将称量好的中间体D2-IN-01(1.1g,3.373mmol)溶于40mL乙醇和10mL水中,加入铁粉(945mg,16.865mmol)和氯化铵(902mg,16.865mmol),加完80℃反应2h,有产物生成,反应液降至室温,用饱和碳酸氢钠溶液淬灭并调节pH至8.0~10.0,用EA萃取,有机相饱和食盐水洗,硫酸钠干燥,减压浓缩得到中间体D2-IN-02产物1.0g,为淡黄色固体。
步骤(3)中间体D2-IN-03的制备
将称量好的中间体D2-IN-02(1.0g,3.377mmol)溶于40mL DCM中,加入2-氯苯乙酸(692g,4.052mmol),T
3P(4.3g,6.754mmol)和TEA(1.03g,10.131mmol),加完室温反应1h,反应液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=4/1~3/1)纯化得到中间体D2-IN-03产物900mg,为淡黄色固体。
步骤(4)中间体D2-IN-04的制备
将称量好的中间体D2-IN-03(900mg,2.202mmol)溶于1,4-二氧六环(30mL)中,加入中间体1-9(苄硫醇)(547mg,4.404mmol),Pd
2(dba)
3(201mg,0.221mmol),Xantphos(128mg,0.221mmol),DIEA(854mg,6.606mmol)加完氮气保护在100℃条件下反应过夜,将反应液降至室温加水,用EA萃取,有机相饱和食盐水洗,硫酸钠干燥,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=4/1~1/1)纯化,得到中间体D2-IN-04产物700mg,为淡黄色固体。
步骤(5)化合物D2的制备
将中间体D2-IN-04(700mg,1.422mmol),溶于CH
3CN(40mL),AcOH(5mL)和H
2O(5mL)中,加入中间体1-11(DCDMH)(561mg,2.845mmol),在室温条件下反应10min将反应液加入到搅拌下的氨水中(10mL),后室温搅拌10min,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤, 无水硫酸钠干燥后,减压浓缩通过Prep-HPLC纯化得到化合物D2产物256.6mg,为白色固体。LC-MS:[M+H]
+=449.00。
1H NMR(400MHz,DMSO-d
6)δ10.30(s,1H),8.05(d,J=2.7Hz,1H),7.70(dd,J=9.0,2.7Hz,1H),7.60–7.52(m,2H),7.47–7.36(m,2H),7.35–7.27(m,2H),7.24–7.13(m,3H),7.09(s,2H),5.30(s,2H),3.80(s,2H).
实施例1
化合物1:N-(4-((3-乙酰基苯氧基)甲基)-3-氨磺酰苯基)-2-(2-氯苯基)乙酰胺的制备
合成路线
步骤(1)中间体1-2的制备
将中间体1-1(10g,0.038mol)、铁粉(11g,0.196mol)、NH
4Cl(20g,0.38mol)溶于乙醇/水(100mL/20mL)中并升温至70℃搅拌反应2h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=10:1-5:1)纯化,得中间体1-2。LC-MS:[M+H]
+=230。
步骤(2)中间体1-4的制备
将中间体1-2(9g,0.039mol)、中间体1-3(2-氯苯乙酸)(8g,0.0468mol)、TEA(12g,0.117mol)、T
3P(25g,0.078mol)溶于DCM(90mL)中,室温搅拌反应0.5h。向反应液中加水和DCM,充分搅拌后分出DCM相,水相用DCM萃取两遍,合并DCM相,干燥后,减压浓缩即得产品。LC-MS:[M+H]
+=382。
步骤(3)中间体1-5的制备
将中间体1-4(14g,0.037mol)溶于THF(100mL)中并降温至0℃将LiAlH
4(4.22g,0.111mol)将其中室温搅拌反应10min。后处理,向反应液中加入1ml水和2M的NaOH水溶液3mL,再加大量的EA,然后过滤,滤液减压浓缩即得产品。LC-MS:[M+H]
+=354。
步骤(4)中间体1-6的制备
将中间体1-5(10g,0.028mol),溶于DCM(100mL)中并降温至0℃,将SOCl
2(6.61g,0.056mol)加入其中,升温至室温,搅拌反应1h。后处理,将反应液减压浓缩得中间体1-6(8.1g)。LC-MS:[M+H]
+=372。
步骤(5)中间体1-8的制备
将中间体1-6(500mg,1.34mmol)、中间体1-7(182mg,1.34mmol)、K
2CO
3(370mg,2.68mmol)溶于DMF(5mL)中,室温下搅拌1h。反应液加水(50mL)后用乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后得粗品,粗品经硅胶柱层析((PE/EA=4/1~1/1))纯化得到中间体1-8(385mg,收率60.9%)。LC-MS:[M+H]
+=472。
步骤(6)中间体1-10的制备
将中间体1-8(385mg,0.82mmol),中间体1-9(303mg,2.45mmol),Pd
2(dba)
3(116mg,0.164mmol),Xantphos(94mg,0.164mmol),DIEA(316mg,2.449mmol)溶于1,4-二氧六环(5mL)中,在115℃条件下反应16小时将反应液减压浓缩得到粗品。粗品经硅胶柱层析(PE/EA=5/1~3/1)纯化,得到中间体1-10(340mg,收率80.4%)。LC-MS:[M+H]
+=516。
步骤(7)化合物1的制备
将中间体1-10(340mg,0.6mmol),中间体1-11(DCDMH)(238mg,1.2mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.1mL),在室温条件下反应1小时,得到中间体1-12,TLC显示反应完毕,反应液不进行分离,直接将上述反应液滴加到搅拌下的氨水中(10mL),之后室温搅拌0.5小时,TLC显示反应完毕。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物1(2.5mg)。LC-MS:[M+H]
+=473。
1H NMR(400MHz,DMSO-d
6)δ10.56(s,1H),8.26(d,J=2.2Hz,1H),7.80(dd,J=8.5,2.2Hz,1H),7.66–7.52(m,5H),7.48–7.38(m,3H),7.34–7.24(m,3H),5.47(s,2H),3.84(s,2H),2.54(s,3H).
中间体1-12LC-MS:[M+H]
+=492。
以下实施例中与中间体1-12类似的酰氯中间体均未分离,直接与氨水反应。
实施例2
化合物2:2-(2-氯苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体2-2的制备
将中间体1-6(600mg,1.69mmol)、中间体2-1(228mg,2.03mmol)、K
2CO
3(467mg,3.384mmol)溶于DMF(15mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析PE/EA=10/1)纯化得到中间体2-2(360mg,为淡黄色固体)。
步骤(3)中间体2-4的制备
将中间体2-2(360mg,0.802mmol),中间体1-9(苄硫醇)(150mg,1.203mmol),Pd
2(dba)
3(74mg, 0.08mmol),Xantphos(47mg,0.08mmol),DIEA(312mg,2.407mmol)溶于1,4-二氧六环(10mL)中,氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=10/1~5/1)纯化得到中间体2-4(340mg,为黄色固体)。
步骤(4)化合物2的制备
将中间体2-4(340mg,0.691mmol),中间体1-11(DCDMH)(409mg,2.073mmol),溶于CH
3CN(8mL),AcOH(1mL)和H
2O(1mL),在室温条件下反应0.5小时。将反应液滴加到搅拌下的氨水中(2mL)后室温搅拌10min,将反应液加水,用EA萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥后,减压浓缩得粗品,粗品经过Prep-HPLC纯化,得到化合物2(29mg,为白色固体)。LC-MS:[M+H]
+=449.05。
1H NMR(600MHz,DMSO-d
6)δ10.58(s,1H),8.27(d,J=2.2Hz,1H),7.81(dd,J=8.5,2.2Hz,1H),7.62(d,J=8.5Hz,1H),7.58(s,2H),7.46–7.41(m,2H),7.33–7.29(m,2H),7.16–7.11(m,2H),7.05–7.01(m,2H),5.40(s,2H),3.86(s,2H).
实施例2-1
化合物2-1:2-(2-氯苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体2-8的制备
将中间体2-7(8g,33.9mmol),加入到氨水(100mL),THF(20mL)中,反应在室温条件下搅拌16小时。将反应液减压浓缩得到中间体2-8(11.0g,白色固体)。
步骤(2)中间体2-9的制备
将中间体2-8(11g,50.9mmol)和DMF-DMA(30.3g,254mmol)溶于DMF(150mL)中,室温反应1小时。用H
2O(200mL)稀释后。用EA(100mL)萃取二次。合并EA相,用饱和食盐水洗涤,无水 硫酸钠干燥后,过滤,滤液减压浓缩得到中间体2-9(10.0g,红色固体)。LC-MS:[M+H]
+=272.05。
1H NMR(400MHz,DMSO-d
6)8.09(s,1H),7.12(d,J=2.4Hz,1H),6.94(d,J=8.0Hz,1H),6.61(dd,J=8.0,2.4Hz,1H),5.28(s,2H),3.12(s,3H),2.92(s,3H),2.35(s,3H).
步骤(3)中间体2-10的制备
将中间体2-9(9g,33.2mmol),铁粉(18.5g,332mmol),NH
4Cl(26.6g,498mmol)溶于EtOH(120mL)和水(24mL)中,60℃反应1小时,将反应液中乙醇旋干,过滤,向滤液中加入水(200mL),用EA(80mL)萃取2次,有机相用饱和食盐水洗涤两次,无水硫酸钠干燥后,过滤,滤液减压浓缩得到中间体2-10(6.20g,纯度98.9%,黄色固体)。LC-MS:[M+H]
+=242.1。
1H NMR(400MHz,DMSO-d
6)δ8.09(s,1H),7.12(d,J=2.4Hz,1H),6.94(d,J=8.0Hz,1H),6.61(dd,J=8.0,2.4Hz,1H),5.28(s,2H),3.12(s,3H),2.92(s,3H),2.35(s,3H).
步骤(4)中间体2-11的制备
将中间体2-10(5.5g,22.8mmol),Boc
2O(7.45g,34.2mmol),DIEA(5.89g,45.6mmol)溶于DMF(51.5mL)中,60℃反应12小时。反应冷却至室温,向反应液加入H
2O(100mL)稀释后,再加EA(30mL)萃取三次。合并EA相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品,粗品经过硅胶柱层析(PE/EA=10/1-2/1)纯化得到中间体2-11(3.60g,纯度86.7%,白色固体)。LC-MS:[M+H]
+=342.1。
1H NMR(400MHz,CD
3OD-d
4)δ8.12(s,1H),8.04(d,J=2.4Hz,1H),7.43(dd,J=8.4,2.0Hz,1H),7.19(d,J=8.4Hz,1H),3.15(s,3H),3.03(t,J=2.0Hz,3H),2.56(s,3H),1.50(s,9H).
步骤(5)中间体2-12的制备
将中间体2-11(1.30g,3.81mmol),AIBN(0.187g,1.14mmol),NBS(0.881g,4.95mmol)加入到CCl
4(51.5mL)中,75℃反应2小时,LCMS检测反应完毕。将反应冷却至室温,该反应液滴加到含有中间体2-1(4-氟苯酚)(0.133g,1.19mmol),K
2CO
3(0.411g,2.97mmol)和DMF(6mL)的体系中。室温反应2h,LCMS显示反应完毕。向反应液中加入H
2O(100mL)稀释后,再加DCM(30mL)萃取两次,合并有机相,用饱和食盐水洗涤有机相两次,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品,粗品经过硅胶柱层析(PE/EA=10/1-5/1)纯化得到中间体2-12(150mg,80%纯度,黄色固体)。LC-MS:[M+H]
+=452.1。
1H NMR(400MHz,CD
3OD-d
4)8.13(d,J=7.2Hz,2H),7.54(d,J=2.4Hz,2H),7.02–6.94(m,4H),5.47(s,2H),3.09(s,3H),2.99(s,3H),1.52(s,9H).
步骤(6)中间体2-13的制备
将中间体2-12(150mg,332μmol)加入到HCl·EA(4M,2mL)中,室温反应2小时,LCMS检测反完毕,将反应液减压浓缩,得到中间体2-13(90.0mg,85.5%纯度,红色固体)。LC-MS:[M+H]
+=352.1。
步骤(7)中间体2-14的制备
将中间体1-3(2-氯苯乙酸)(48.1mg,281μmol),HATU(146mg,384μmol),DIEA(99.3mg,768μmol)加入到DMF(2.5mL)中,室温反应0.5小时后,中间体2-13(90.0mg,256μmol)加入到反应中。室温反应12h。向反应液中加入H
2O(10mL)稀释后,再加EA(5mL)萃取两次,用饱和食盐水洗涤有机相两次,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品,粗品经制备型薄层色谱(PE/EA=1/1)纯化,得到中间体2-14(30.0mg,85.0%纯度,黄色固体)。LC-MS:[M+H]
+=504.1。
1H NMR(400MHz,CD
3OD-d
4)8.05(s,1H),7.92(dd,J=8.4,2.0Hz,1H),7.83(d,J=2.0Hz,1H),7.60(d,J=8.4Hz,1H),7.47–7.38(m,3H),7.32–7.29(m,2H),6.95–6.86(m,4H),5.53(s,2H),3.87(s,2H),3.04(s,3H),2.96(s,3H).
步骤(8)化合物2的制备
将中间体2-14(30.0mg,59.5μmol),水合肼(15.0mg,298μmol)加入到MeOH(0.5mL)和THF(0.5mL)溶剂中,27℃反应1小时,将反应液减压浓缩得粗品,粗品用FA.H
2O/ACN体系经prep-HPLC分离,将制备液冻干后得到化合物2(11.4mg,99.8%纯度,白色粉末)。LC-MS:[M+H]
+=449.05。
1H NMR(400MHz,DMSO-d
6)10.59(s,1H),8.46(s,1H),8.26(d,J=2.0Hz,1H),7.79(dd,J=8.4,2.0Hz,1H),7.60(d,J=8.4Hz,1H),7.56(s,1H),7.44–7.38(m,2H),7.29(dd,J=5.6,3.2Hz,2H),7.11(dd,J=12.0,5.6Hz,2H),7.03–6.98(m,2H),5.38(s,2H),3.84(s,2H).
实施例3
化合物3:2-(2-氯苯基)-N-(4-(((5-氟吡啶-2-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺
合成路线
步骤(1)中间体3-2的制备
将中间体1-5(500mg,1.41mmol)溶于THF(4mL)中,加入中间体3-1(162mg,1.41mmol),t-BuOK(317.9mg,2.82mmol)室温条件下搅拌1h。停止反应,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE:EA=10:1~1:1)纯化得到中间体3-2(145mg,收率33.4%,浅黄色固体)。LC-MS:[M+H]
+=489。
步骤(2)中间体3-3的制备
将中间体3-2(87mg,0.193mmol),中间体1-9(苄硫醇)(71.6mg,0.578mmol),Pd
2(dba)
3(27.4mg,0.0386mmol),Xantphos(22mg,0.0386mmol),DIEA(74.5mg,0.578mol)溶于1,4-二氧六环(5mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体3-3(50mg,收率52.9%,黄色固体)。LC-MS:[M+H]
+=492。
步骤(3)化合物3的制备
将中间体3-3(50mg,0.102mmol),中间体1-11(DCDMH)(40mg,0.204mmol),溶于CH
3CN(2mL),AcOH(0.1mL)和H
2O(0.1mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(5mL),后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物3(12.4mg,纯度99.745%,白色固体)。LC-MS:[M+H]
+=450。
1H NMR(400MHz,DMSO-d
6)δ10.55(s,1H),8.24(d,J=2.1Hz,1H),8.14(d,J=3.1Hz,1H),7.79(dd,J=8.5,2.0Hz,1H),7.72(ddd,J=9.0,8.1,3.1Hz,1H),7.56(d,J=8.5Hz,1H),7.48(s,1H),7.45–7.38(m,2H),7.33–7.25(m,2H),7.01(dd,J=9.1,3.6Hz,1H),5.64(s,2H),3.84(s,2H).
实施例4
化合物4:N-(4-((4-氯苯氧基)甲基)-3-氨磺酰苯基)-2-(2-氯苯基)乙酰胺
合成路线:
步骤(1)中间体4-2的制备
将中间体1-6(500mg,1.34mmol)、中间体4-1(170mg,1.3mmol)、K
2CO
3(358mg,2.6mmol)溶于DMF(10mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后得粗品,粗品经硅胶柱纯化得到中间体4-2(280mg,收率46.3%,黄色固体)。LC-MS:[M+H]
+=465。
步骤(2)中间体4-3的制备
将中间体4-2(280mg,0.6mmol),中间体1-9(苄硫醇)(148.8mg,1.2mmol),Pd
2(dba)
3(85.3mg,0.12mmol),Xantphos(70mg,0.12mmol),DIEA(232.2mg,1.8mmol)溶于1,4-二氧六环(10mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体4-3(230mg,收率75.7%,黄色固体)。LC-MS:[M+H]
+=508。
步骤(3)化合物4的制备
将中间体4-3(230mg,0.45mmol),中间体1-11(DCDMH)(196mg,0.9mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.2mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物4(24.8mg,纯度95.2%,白色固体)。LC-MS:[M+H]
+=465。
1H NMR(600MHz,DMSO-d
6)δ10.56(s,1H),8.26(d,J=2.2Hz,1H),7.79(dd,J=8.4,2.2Hz,1H),7.64–7.51(m,3H),7.46–7.36(m,2H),7.36–7.18(m,4H),7.09–6.97(m,2H),5.40(s,2H),3.84(s,2H).
实施例5
化合物5:2-(2-氯苯基)-N-(4-((2,4-二氯苯氧基)甲基)-3-氨磺酰苯基)乙酰胺
合成路线
步骤(1)化合物5的制备
将中间体4-3(230mg,0.45mmol),中间体1-11(DCDMH)(196mg,0.9mmol),溶于CH
3CN(4 mL),AcOH(0.2mL)和H
2O(0.2mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物5(50mg,纯度99.7%,白色固体)。LC-MS:[M+H]
+=499。
1H NMR(600MHz,DMSO-d
6)δ10.59(s,1H),8.28(d,J=2.2Hz,1H),7.81(dd,J=8.4,2.2Hz,1H),7.65(d,J=8.6Hz,1H),7.62(d,J=2.6Hz,1H),7.58(s,2H),7.46–7.35(m,3H),7.33–7.25(m,2H),7.17(d,J=9.0Hz,1H),5.49(s,2H),3.85(s,2H).
实施例6
化合物6:2-(2-氯苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体6-2的制备
将中间体1-6(600mg,1.62mmol)、中间体6-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL)升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,减压浓缩EA相即得产品,反应成功,得中间体6-2。LC-MS:[M+H]
+=455/457。
步骤(2)中间体6-3的制备
将中间体6-2(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(10mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,减压浓缩后得粗品,粗品经硅胶柱层析(PE/EA=10:1-6:1)分离纯化,减压浓缩过柱液即得中间体6-3。LC-MS:[M+H]
+=499/501。
步骤(3)化合物6的制备
将中间体6-3(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。再将反应液滴加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩得粗品,粗品用H
2O/ACN体系经prep-HPLC纯化,冻干制备液即得化合物6。LC-MS:[M+H]
+=456/458。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.26(d,J=2.2Hz,1H),7.82–7.76(m,3H),7.59(d,J=6.7Hz,3H),7.44–7.38(m,2H),7.32–7.25(m,2H),7.19–7.14(m,2H),5.49(s,2H),3.84(s,2H).
实施例7
化合物7:2-(2-氯苯基)-N-(4-((2,4-二氟苯氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线:
步骤(1)中间体7-2的制备
将中间体1-6(600mg,1.62mmol)、中间体7-1(223mg,1.60mmol)、K
2CO
3(440mg,3.20mmol)溶于DMF(10mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=4/1)纯化得到中间体7-2。LC-MS:[M+H]
+=465。
步骤(3)中间体7-3的制备
将中间体7-2(520mg,1.1mmol),中间体1-9(苄硫醇)(276mg,2.2mmol),Pd
2(dba)
3(156.4mg,0.22mmol),Xantphos(115.6mg,0.22mmol),DIEA(424mg,3.3mmol)溶于1,4-二氧六环(10mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体7-3。LC-MS:[M+H]
+=510。
步骤(4)化合物7的制备
将中间体7-3(384mg,0.75mmol),中间体1-11(DCDMH)(297mg,1.5mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.2mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物7。LC-MS:[M+H]
+=467。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.27(d,J=1.8Hz,1H),7.81(d,J=8.4Hz,1H),7.61(d,J=8.4Hz,1H),7.55(s,2H),7.46–7.38(m,2H),7.37–7.26(m,3H),7.18(td,J=9.4,5.5Hz,1H),7.01(t,J=8.8Hz,1H),5.45(s,2H),3.85(s,2H).
实施例8
化合物8:2-(2-氯苯基)-N-(4-(((4,5-二氯-1-甲基-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线
步骤1:中间体8-2的制备
将称量好的中间体1-6(500mg,1.34mmol)溶于THF(20mL)中,加入中间体8-1(160mg,1.608mmol)、Ag
2CO
3(740mg,2.68mmol),加完70℃回流反应过夜。LCMS监控显示有产物生成,反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩得粗品,粗品通过硅胶柱层析(PE/EA=5/1~2/1)纯化得到中间体8-2。LC-MS:[M+H]
+=434。
步骤2:中间体8-3的制备
将称量好的中间体8-2(310mg,0.713mmol)溶于1,4-二氧六环(10mL)中,加入中间体1-9(苄硫醇)(178mg,1.423mmol),Pd
2(dba)
3(66mg,0.071mmol),Xantphos(42mg,0.071mmol),DIEA(277mg,2.139mmol),氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相饱和食盐水洗,硫酸钠干燥,反应液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=2/1)纯化,得中间体8-3。LC-MS:[M+Na]
+=500.15。
步骤3:化合物8的制备
将中间体8-3(60mg,0.125mmol),溶于CH
3CN(2mL),AcOH(0.25mL)和H
2O(0.25mL)中,加入中间体1-11(DCDMH)(50mg,0.251mmol),在室温条件下反应5min将反应液滴加到搅拌下的氨水中(0.5mL),将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液减压浓缩得粗品,粗品经过Prep-HPLC纯化得化合物8。LC-MS:[M+H]
+=503。
1H NMR(400MHz,DMSO-d
6)δ10.66(s,1H),8.31(d,J=2.1Hz,1H),7.88(dd,J=8.4,2.2Hz,1H),7.64–7.55(m,3H),7.44(ddd,J=9.5,5.1,2.3Hz,2H),7.35–7.29(m,2H),5.66(s,2H),3.88(s,2H),3.25(s,3H).
实施例9
化合物9:2-(2-氯苯基)-N-(4-((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线:
步骤(1)中间体9-2的制备
将中间体1-6(600mg,1.62mmol)、中间体9-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,减压浓缩EA相即得中间体9-2。LC-MS:[M+H]
+=449。
步骤(2)中间体9-3的制备
将中间体9-2(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(10mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=10:1-6:1)分离纯化,减压浓缩后得粗品,粗品经制备硅胶柱层析即得中间体9-3。LC-MS:[M+H]
+=493。
步骤(3)中间体9-4的制备
将中间体9-3(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液滴加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩得粗品,粗品用prep-HPLC纯化,冻干制备液即得化合物9。LC-MS:[M+H]
+=450。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.26(d,J=2.2Hz,1H),7.95(dd,J=3.0,1.8Hz,1H),7.82(dd,J=8.5,2.2Hz,1H),7.68–7.60(m,2H),7.58(s,2H),7.47–7.36(m,2H),7.35–7.25(m,2H),7.14(dd,J=8.9,3.4Hz,1H),5.45(s,2H),3.84(s,2H).
实施例10
化合物10:2-(2-氯苯基)-N-(4-((3-氰基-4-氟苯氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线
步骤(1)中间体10-2的制备
将中间体1-6(600mg,1.62mmol)、中间体10-1(220mg,1.6mmol)、K
2CO
3(440mg,3.2mmol)溶于DMF(10mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后得粗品,粗品经硅胶柱层析得到中间体10-2。LC-MS:[M+H]
+=473。
步骤(2)中间体10-3的制备
将中间体10-2(450mg,0.95mmol),中间体1-9(苄硫醇)(235mg,1.9mmol),Pd
2(dba)
3(90mg,0.1mmol),Xantphos(60mg,0.1mmol),DIEA(367mg,2.85mmol)溶于1,4-二氧六环(10mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体10-3。LC-MS:[M+H]
+=517。
步骤(4)化合物10的制备
将中间体10-3(200mg,0.38mmol),中间体1-11(DCDMH)(190mg,0.96mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.2mL),在室温条件下反应1小时将反应液滴加到搅拌下的氨水中(10mL),之后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物10。LC-MS:[M+H]
+=474。
1H NMR(400MHz,DMSO-d
6)δ10.58(s,1H),8.26(s,1H),7.83(d,J=8.4Hz,1H),7.67–7.52(m,4H),7.45(dt,J=14.2,8.4Hz,4H),7.33–7.25(m,2H),5.42(s,2H),3.85(s,2H).
实施例11
化合物11:N-(4-((3-氯-4-氟苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺的制备
合成路线:
步骤(1)中间体11-2的制备
将中间体1-6(600mg,1.62mmol)、中间体11-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相经减压浓缩即得中间体11-2。LC-MS:[M+H]
+=482。
步骤(2)中间体11-3的制备
将中间体11-2(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(10mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,减压浓缩得粗品,粗品经制备硅胶层析柱(PE/EA=10:1-6:1)分离纯化得过柱液,过柱液经减压浓缩即得中间体11-3(黄色固体产品290mg)。LC-MS:[M+H]
+=526。
步骤(3)化合物11的制备
将中间体11-3(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液滴加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩得粗品,粗品经制备型高效液相色谱纯化,冻干制备液即得化合物11。LC-MS:[M+H]
+=483。
1H NMR(400MHz,DMSO-d
6)δ10.56(s,1H),8.25(s,1H),7.81(d,J=8.5Hz,1H),7.61(d,J=8.5Hz,1H),7.58(s,2H),7.46–7.23(m,6H),7.05–6.97(m,1H),5.39(s,2H),3.84(s,2H).
实施例12
化合物12:2-(2-氯苯基)-N-(4-((3-(甲基磺酰基)苯氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线:
步骤(1)中间体12-2的制备
将中间体1-6(200mg,0.54mmol)、中间体12-1(100mg,0.58mmol)、K
2CO
3(152mg,1.1mmol)溶于DMF(4mL)中,室温下搅拌2h。反应液加水(20mL)后乙酸乙酯(10mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析纯化得到中间体12-2。LC-MS:[M+H]
+=508。
步骤(2)中间体12-3的制备
将中间体12-2(180mg,0.35mmol),中间体1-9(苄硫醇)(130mg,1.05mmol),Pd
2(dba)
3(32mg,0.035mmol),Xantphos(20mg,0.035mmol),DIEA(135mg,1.05mmol)溶于1,4-二氧六环(2mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱层析(PE/EA=5/1~3/1)纯化,得到中间体12-3。LC-MS:[M+H]
+=552。
步骤(3)化合物12的制备
将中间体12-3(150mg,0.27mmol),中间体1-11(DCDMH)(108mg,0.54mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.1mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(5mL),后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物12。LC-MS:[M+H]
+=509。
1H NMR(400MHz,DMSO-d
6)δ10.58(s,1H),8.27(d,J=2.2Hz,1H),7.83(dd,J=8.4,2.2Hz,1H),7.66(d,J=8.4Hz,1H),7.59(t,J=3.8Hz,2H),7.56–7.53(m,1H),7.53–7.49(m,1H),7.46–7.38(m,2H),7.35(ddd,J=8.2,2.4,1.0Hz,1H),7.30(ddd,J=5.2,4.2,3.0Hz,2H),5.49(s,2H),3.85(s,2H),3.21(s,3H).
实施例13
化合物13:2-(2-氯苯基)-N-(4-(((1,1-二氧代四氢噻吩-3-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=473.0
实施例14
化合物14:2-(2-氯苯基)-N-(3-氨磺酰-4-(((四氢呋喃-3-基)氧基)甲基)苯基)乙酰胺
合成路线:
步骤(1)中间体14-2的制备
将中间体1-6(400mg,1.07mmol)、中间体14-1(113.2mg,1.29mmol)、K
2CO
3(295.3mg,2.14mmol)溶于DMF(5mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析纯化得到中间体14-2。LC-MS:[M+H]
+=423。
步骤(2)中间体14-3的制备
将中间体14-2(70mg,0.115mmol),中间体1-9(苄硫醇)(61.4mg,0.495mmol),Pd
2(dba)
3(23.4mg,0.033mmol),Xantphos(19mg,0.033mmol),DIEA(63.8mg,0.495mmol)溶于1,4-二氧六环(5ml)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱层析(PE/EA=5/1~3/1)纯化,得到中间体14-3。LC-MS:[M+H]
+=468。
步骤(3)化合物14的制备
将中间体14-3(50mg,0.107mmol),中间体1-11(DCDMH)(42.1mg,0.214mmol),溶于CH
3CN(2mL),AcOH(0.1mL)和H
2O(0.1mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(5mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干制备液后得到化合物14。LC-MS:[M+H]
+=424。
1H NMR(400MHz,DMSO-d
6)δ10.64(s,2H),8.38(s,8H),8.24(s,2H),7.82(d,J=8.4Hz,2H),7.69–7.29(m,8H),7.28(s,1H),5.45(s,2H),5.19(s,2H),3.90(s,3H),3.85(s,5H),4.40–2.48(m,55H),2.48(s,10H),2.48(s,13H),2.15(dt,J=14.4,8.2Hz,2H),1.97(dd,J=12.6,6.2Hz,14H),,3.80–3.69(m,5H),2.20–2.11(m,2H).
实施例15
化合物15:N-(4-((3-乙酰基-4-氟苯氧基)甲基)-3-氨磺酰苯基)-2-(2-氯苯基)乙酰胺的制备
合成路线:
步骤(1)中间体15-2的制备
将中间体1-6(376mg,1.04mmol)、中间体15-1(160mg,1.04mmol)、K
2CO
3(287mg,2.08mmol)溶于DMF(5mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析纯化得到中间体15-2。LC-MS:[M+H]
+=490。
步骤(2)中间体15-3的制备
将中间体15-2(87mg,0.18mmol),中间体1-9(苄硫醇)(43.4mg,0.35mmol),Pd
2(dba)
3(24.9mg,0.035mmol),Xantphos(20.2mg,0.035mmol),DIEA(69.7mg,0.54mmol)溶于1,4-二氧六环(5mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体15-3。LC-MS:[M+H]
+=534。
步骤(3)中间体15的制备
将中间体15-3(80mg,0.15mmol),中间体1-11(59mg,0.3mmol),溶于CH
3CN(2mL),AcOH(0.1mL)和H
2O(0.1mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(10mL),后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干制备液后得到化合物15。LC-MS:[M+H]
+=491。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.25(d,J=2.1Hz,1H),7.81(dd,J=8.4,2.2Hz,1H),7.63(d,J=8.5Hz,3H),7.57(s,1H),7.47–7.39(m,1H),7.38–7.35(m,0H),7.33–7.24(m,2H),5.42(s,2H),3.84(s,2H),2.55(d,J=4.3Hz,3H).
实施例16
化合物16:2-(2-氯苯基)-N-(3-氨磺酰基-4-((对甲苯氧基)甲基)苯基)乙酰胺的制备
合成路线:
步骤(1)中间体16-2的制备
将中间体1-6(500mg,1.34mmol)、中间体16-1(140mg,1.34mmol)、K
2CO
3(358mg,2.59mmol)溶于DMF(10mL)中,60℃下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析纯化得到中间体16-2。LC-MS:[M+H]
+=444。
步骤(2)中间体16-3的制备
将中间体16-2(280mg,0.63mmol),中间体1-9(苄硫醇)(150mg,1.26mmol),Pd
2(dba)
3(120mg,0.18mmol),Xantphos(105mg,0.18mmol),DIEA(240mg,1.88mmol)溶于1,4-二氧六环(4mL)中,在110℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体16-3。LC-MS:[M+H]
+=488。
步骤(4)化合物16
将中间体16-3(180mg,0.37mmol),中间体1-11(145mg,0.74mmol),溶于CH
3CN(4mL),AcOH(0.2ml)和H
2O(0.2ml),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/CAN体系经prep-HPLC分离,冻干制备液后得到化合物16。LC-MS:[M+H]
+=445。
1H NMR(400MHz,DMSO-d
6)δ10.54(s,1H),8.25(s,1H),7.78(d,J=8.4Hz,1H),7.59(d,J=8.4Hz,1H),7.55(s,2H),7.45–7.38(m,2H),7.33–7.26(m,2H),7.07(d,J=8.4Hz,2H),6.88(d,J=8.4Hz,2H),5.38(s,2H),3.84(s,2H),2.21(s,3H).
实施例17
化合物17:2-(2-氯苯基)-N-(4-((4-氟-3-甲基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体17-2的制备
将中间体17-1(203mg,1.608mmol)、K
2CO
3(369mg,2.68mmol)溶于DMF(20mL)中,室温搅拌15min,加入中间体1-6(500mg,1.34mmol)、加完室温反应2h。反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=10/1)纯化得到中间体17-2。LC-MS:[M+H]
+=462。
步骤(2)中间体17-3的制备
将称量好的中间体17-2(180mg,0.389mmol)溶于1,4-二氧六环(5mL)中,加入中间体1-9(苄硫醇)(73mg,0.583mmol),Pd
2(dba)
3(36mg,0.039mmol),Xantphos(23mg,0.039mmol),DIEA(151mg,1.167mmol),氮气保护在90℃条件下反应过夜,将反应液加水,用EA萃取,有机相用饱和食盐水洗,用无水硫酸钠干燥,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=10/1~5/1)纯化,得到中间体17-3。LC-MS:[M+H]
+=506。
步骤(3)化合物17的制备
将中间体17-3(170mg,0.336mmol),溶于CH
3CN(4mL),AcOH(0.5mL)和H
2O(0.5mL)中,加入中间体1-11(DCDMH)(133mg,0.672mmol),在室温条件下反应0.5小时。将反应液滴加到搅拌下的氨水中(1mL)后室温搅拌10min,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,减压浓缩反应液得粗品,粗品通过Prep-HPLC纯化得到化合物17。LC-MS:[M+H]
+=463。
1H NMR(400MHz,DMSO-d
6)δ10.59(s,1H),8.29(s,1H),7.83(d,J=8.7Hz,1H),7.69(d,J=8.6Hz,1H),7.59(d,J=4.8Hz,2H),7.47–7.28(m,5H),7.22–6.98(m,2H),5.47(d,J=8.3Hz,2H),3.87(s,2H),2.31(d,J=16.0Hz,1H),2.21(s,2H).
实施例18
化合物18:2-(2-氯苯基)-N-(4-((4-氟-3-甲氧基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体18-2的制备
将中间体1-6(600mg,1.62mmol)、中间体18-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,即得中间体18-2。LC-MS:[M+H]
+=478。
步骤(2)中间体18-3的制备
将中间体18-2(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(10mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液经减压浓缩得到粗品,粗品经硅胶柱层析(PE/EA=10:1-6:1)纯化,减压浓缩过柱液即得中间体18-3产品。LC-MS:[M+H]
+=522。
步骤(3)化合物18的制备
将中间体18-3(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。然后将反应液滴加入搅拌的氨水(1mL)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经prep-HPLC纯化,冻干制备液即得化合物18。LC-MS:[M+H]
+=479.1。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.28(s,1H),7.80(d,J=8.5Hz,1H),7.62(d,J=7.0Hz,3H),7.48–7.38(m,3H),7.33–7.26(m,2H),6.95(d,J=7.9Hz,1H),5.51(s,2H),3.84(s,2H),3.77(s,3H).
实施例19
化合物19:2-(2-氯苯基)-N-(4-((4-氟-3-(2-氧代吡咯烷-1-基)苯氧基)甲基)-3-氨磺酰苯基)乙酰胺
参考实施例1制备得到。LC-MS:[M+H]
+=532.1。
实施例20
化合物20:2-(2-氯-6-氟苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线
步骤(1)中间体20-2的制备
将中间体1-2(500mg,2.18mmol)溶于DCM(5mL)中,加入中间体20-1(411.8mg,2.18mmol),T
3P(2.08g,327mmol),Et
3N(662mg,6.54mmol),室温下反应1h后反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后过柱(PE:EA=5:1~2:1)得到中间体20-2。LC-MS:[M+H]
+=400。
步骤(3)中间体20-3的制备
将中间体20-2(640mg,1.6mmol)溶于THF(6ml),加入LiAlH
4(182mg,4.8mmol),室温下搅拌1h。加入H
2O(1mL),NaOH溶液(1mL)后抽滤,减压浓缩即得到中间体20-3。不处理直接用于下一步。
步骤(4)中间体20-4的制备
将中间体20-3(610mg,1.64mmol)溶于DCM(5mL)中,滴加SOCl
2(391mg,3.29mmol)室温条件下搅拌1h。停止反应,反应液浓缩后经硅胶柱层析(PE:EA=10:1~5:1)纯化,得到中间体20-4。LC-MS:[M+H]
+=390。
步骤(5)中间体20-5的制备
将中间体20-4(352mg,0.9mmol)、中间体2-1(121mg,1.08mmol)、K
2CO
3(248.4mg,1.8mmol)溶于DMF(5mL)中,室温下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE:EA=10:1~5:1)纯化得到中间体20-5。LC-MS:[M+H]
+=466。
步骤(6)中间体20-6的制备
将中间体20-5(335mg,0.72mmol),中间体1-9(苄硫醇)(267mg,2.15mmol),Pd
2(dba)
3(102.4mg,0.144mmol),Xantphos(83.2mg,0.144mmol),DIEA(277.4mg,2.15mmol)溶于1,4-二氧六环 (5mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体20-6。LC-MS:[M+H]
+=510。
步骤(7)化合物20的制备
将中间体20-6(200mg,0.39mmol),中间体1-11(138.8mg,0.705mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.1mL),在室温条件下反应5min。将反应液滴加到搅拌下的氨水中(5mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物20。LC-MS:[M+H]
+=467。
1H NMR(400MHz,DMSO-d
6)δ10.64(s,1H),8.25(d,J=2.2Hz,1H),7.77(dd,J=8.5,2.2Hz,1H),7.64–7.51(m,3H),7.40–7.30(m,2H),7.23(s,1H),7.12(t,J=8.8Hz,2H),7.05–6.97(m,2H),5.39(s,2H),3.89(d,J=1.1Hz,2H).
实施例21
化合物21:2-(2-氯-4-氟苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体21-2的制备
将称量好的中间体1-2(2.0g,8.693mmol)溶于DCM(50mL)中,加入中间体21-1(2-氯-4-氟苯乙酸)(2.0g,10.432mmol),T
3P(11g,17.386mmol)和TEA(2.6g,26.079mmol),室温条件下反应1h,反应液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=4/1)纯化得到中间体21-2。LC-MS:[M+H]
+=400。
步骤(2)中间体21-3的制备
将称量好的中间体21-2(2.2g,5.491mmol)溶于THF(50mL)中,搅拌下缓慢加入四氢铝锂(627mg,16.474mmol),加完室温反应10min,TLC显示有少量原料没反应完,补加1.0eq四氢铝锂无效果,反应液加入1mL水和1mL 1.0M NaOH溶液,并加入200mL乙酸乙酯,过滤,滤液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=3/1)纯化得到中间体21-3。LC-MS:[M+H]
+=372。
步骤(3)中间体21-4的制备
将称量好的中间体21-3(1.0g,2.684mmol)溶于DCM(40mL)中,滴加SOCl
2(639mg,5.367mmol),室温条件下搅拌1h。停止反应,反应液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=10/1)纯化后得到中间体21-4。LC-MS:[M+H]
+=390。
步骤(4)中间体21-5的制备
将称量好的中间体21-4(800mg,2.046mmol)溶于DMF(20mL)中,加入中间体2-1(4-氟苯酚)(276mg,2.455mmol)、K
2CO
3(565mg,4.092mmol),加完室温反应2h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=8/1)纯化得到中间体21-5。LC-MS:[M+H]
+=466。
步骤(5)中间体21-6的制备
将称量好的中间体21-5(850mg,1.821mmol)溶于30mL 1,4-二氧六环中,加入中间体1-9(苄硫醇)(453mg,3.643mmol)、Pd
2(dba)
3(166mg,0.182mmol)、Xantphos(105mg,0.182mmol)和DIEA(709mg,5.463mmol),加完氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,反应液减压浓缩得粗品,粗品经过硅胶柱层析(PE/EA=5/1)纯化得到中间体21-6。LC-MS:[M+H]
+=510。
步骤(6)化合物21的制备
将称量好的中间体21-6(400mg,0.784mmol)溶于CH
3CN(10mL),加入中间体1-11(DCDMH)(232mg,1.176mmol),AcOH(1mL)和H
2O(1mL),在室温条件下反应5min,将反应液加入到氨水(2mL)中,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液减压浓缩得粗品,粗品经过Prep-HPLC纯化得到化合物21。LC-MS:[M+H]+=467。
1H NMR(400MHz,DMSO-d
6)δ10.56(s,1H),8.27(d,J=2.2Hz,1H),7.80(dd,J=8.5,2.2Hz,1H),7.63(d,J=8.5Hz,1H),7.57(s,2H),7.46(ddd,J=11.5,8.7,4.5Hz,2H),7.21(td,J=8.5,2.7Hz,1H),7.18–7.09(m,2H),7.06–6.99(m,2H),5.40(s,2H),3.85(s,2H).
实施例22
化合物22:2-(2-氯-5-氟苯基)-N-(4-((4-氟苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体22-2的制备
将的中间体1-2(9g,0.039mol)、中间体22-1(2-氯-5氟苯乙酸)(8g,0.0468mol)、TEA(12g,0.117mol)、T
3P(25g,0.078mol)溶于DCM(90mL)中,室温搅拌反应0.5h。向反应液中加水和DCM,充分搅拌后分出DCM相,水相用DCM萃取两遍,合并DCM相,过滤,滤液减压浓缩即得中间体22-2。LC-MS:[M+H]
+=400。
步骤(2)中间体22-3的制备
将中间体22-2(14g,0.037mol)溶于THF(100mL)中并降温至0℃,将LiAlH
4(4.22g,0.111mol)加入其中,室温搅拌反应10min。后处理,向反应液中加入1mL水和2M的NaOH水溶液3mL,再加大量的EA,过滤,滤液减压浓缩即得中间体22-3。LC-MS:[M+H]
+=372。
步骤(3)中间体22-4的制备
将中间体22-3(10g,0.028mol)溶于DCM(100mL)中并降温至0℃,将SOCl
2(6.61g,0.056mol)加入其中,升至室温搅拌反应1h。后处理,将反应液减压浓缩即得中间体22-4。LC-MS:[M+H]
+=390。
步骤(4)中间体22-5的制备
将中间体22-4(600mg,1.62mmol)、中间体2-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相减压浓缩即得中间体22-5。LC-MS:[M+H]
+=466。
步骤(5)中间体22-6制备
将中间体22-5(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(10mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,EA相减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=10:1-6:1)纯化,过柱液减压浓缩即得中间体20-6。LC-MS:[M+H]
+=510。
步骤(6)化合物22的制备
将中间体20-6(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液滴加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得化合物22。LC-MS:[M+H]
+=467。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.24(d,J=2.1Hz,1H),7.79(dd,J=8.4,2.0Hz,1H),7.61 (d,J=8.5Hz,1H),7.56(s,2H),7.48(dd,J=8.8,5.3Hz,1H),7.33(dd,J=9.5,3.1Hz,1H),7.20–7.07(m,3H),7.04–6.96(m,2H),5.39(s,2H),3.86(s,2H).
实施例23
化合物23:2-(2-氯苯基)-N-(4-((((1-甲基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体23-2的制备
将称量好的中间体1-6(500mg,1.34mmol)溶于DMF(10mL)中,加入中间体23-1(158mg,1.608mmol)、K
2CO
3(370mg,2.68mmol),加完室温反应2h。反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=3/1)纯化得到中间体23-2。LC-MS:[M+H]
+=434。
步骤(2)中间体23-3的制备
将称量好的中间体23-2(400mg,0.920mmol)溶于1,4-二氧六环(20mL)中,加入中间体1-9(苄硫醇)(229mg,1.840mmol),Pd
2(dba)
3(85mg,0.092mmol),Xantphos(54mg,0.092mmol),DIEA(357mg,2.76mmol),氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,反应液经减压浓缩后得粗品,粗品经硅胶柱层析(PE/EA=3/1~1/1)纯化,得到中间体23-3。LC-MS:[M+H]
+=478。
步骤(3)化合物23的制备
将中间体23-3(370mg,0.774mmol),溶于CH
3CN(16mL),AcOH(2mL)和H
2O(2mL)中,加入中间体1-11(DCDMH)(305mg,1.548mmol),在室温条件下反应10min再将反应液在搅拌下滴加到氨水中(4mL),室温搅拌10min,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,减压浓缩经过Prep-HPLC纯化得到化合物23。LC-MS:[M+H]
+=435.15。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.25(d,J=2.2Hz,1H),7.82(dd,J=8.5,2.2Hz,1H),7.61 (d,J=8.5Hz,1H),7.50(s,2H),7.47–7.38(m,3H),7.35–7.28(m,2H),7.22(s,1H),5.26(s,2H),3.86(s,2H),3.72(s,3H).
实施例24
化合物24:2-(2-氯苯基)-N-(4-(((3-氟-1-甲基-1H-吡唑-5-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=453.1。
实施例25
化合物25:2-(2-氯苯基)-N-(4-(((1-甲基-1H-咪唑-5-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=435.1。
实施例26
化合物26:2-(2-氯苯基)-N-(4-(((1-甲基-1H-咪唑-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=435.1。
实施例27
化合物27:2-(2-氯苯基)-N-(4-(((1-甲基-1H-咪唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=435.1。
实施例28
化合物28:2-(2-氯苯基)-N-(4-((环丙基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=409.1。
实施例29
化合物29:2-(2-氯苯基)-N-(4-((环丁基甲氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=423.1。
实施例30
化合物30:2-(2-氯苯基)-N-(4-((环戊基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体30-2的制备
将称量好的中间体1-6(700mg,1.876mmol)溶于20mL DMF中,加入碳酸钾(777mg,5.629mmol)和中间体30-1(376mg,3.753mmol),加完室温反应2h,反应液加水,用EA萃取,有机相用饱和食盐水洗涤,用无水硫酸钠干燥,反应液减压浓缩后经硅胶柱层析(PE/EA=10/1)纯化得到中间体30-2。LC-MS:[M+H]
+=436。
步骤(2)中间体30-3的制备
将称量好的中间体30-2(170mg,0.389mmol)溶于1,4-二氧六环(10mL)中,加入中间体1-9(苄硫醇)(73mg,0.584mmol),Pd
2(dba)
3(36mg,0.039mmol),Xantphos(23mg,0.039mmol),DIEA(152mg,1.17mmol),氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相用饱和食盐水洗涤,用无水硫酸钠干燥,反应液减压浓缩后经过Prep-TLC(PE/EA=5/1)纯化得到中间体30-3。LC-MS:[M+H]
+=480。
步骤(3)化合物30的制备
将中间体30-3(100mg,0.208mmol),溶于CH
3CN(2mL),AcOH(0.25mL)和H
2O(0.25mL)中,加入中间体1-11(DCDMH)(83mg,0.417mmol),在室温条件下反应1.0小时,再将反应液加入氨水(2mL)中,室温搅拌10min,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液减压浓缩后经过Prep-HPLC纯化得到化合物30。LC-MS:[M+H]
+=437。
1H NMR(400MHz,DMSO-d
6)δ10.60(s,1H),8.25(d,J=2.2Hz,1H),7.84(dd,J=8.4,2.1Hz,1H),7.54–7.39(m,5H),7.35–7.29(m,2H),5.45(s,2H),4.02(d,J=7.1Hz,2H),3.87(s,2H),2.18(d,J=7.5Hz,1H),1.70(d,J=8.0Hz,2H),1.53(ddd,J=15.7,13.1,7.7Hz,4H),1.27–1.22(m,2H).
实施例31
化合物31:2-(2-氯苯基)-N-(4-(环丁氧基甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=409.1。
实施例32
化合物32:2-(2-氯苯基)-N-(3-氨磺酰基-4-(((四氢-2H-吡喃-4-基)氧基)甲基)苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=439.1。
实施例33
化合物33:2-(2-氯苯基)-N-(4-((氧杂环丁烷-3-基甲氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=425.1。
实施例34
化合物34:2-(2-氯苯基)-N-(3-氨磺酰基-4-((((四氢呋喃-3-基)甲氧基)甲基)苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=439.1。
实施例35
化合物35:2-(2-氯苯基)-N-(4-((氧杂环丁烷-3-基氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=411.1。
实施例36
化合物36:N-(4-((氮杂环丁烷-3-基氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=410.1。
实施例37:
化合物37:2-(2-氯苯基)-N-(4-((吡咯烷-3-氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=508.1
实施例38
化合物38:2-(2-氯苯基)-N-(4-((哌啶-4-氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=438.1。
实施例39
化合物39:2-(2-氯苯基)-N-(4-((哌啶-3-氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=438.1。
实施例40
化合物40:2-(2-氯苯基)-N-(3-氨磺酰-4-(((四氢-2H-吡喃-3-基)氧基)甲基)苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=439.1。
实施例41
化合物41:N-(4-(((2-氮杂二环[2.2.1]庚烷-5-基)氧基)甲基)-3-氨磺酰苯基)-2-(2-氯苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=450.1。
实施例42
化合物42:N-(4-(((3-氮杂二环[3.1.1]庚烷-6-基)氧基)甲基)-3-氨磺酰苯基)-2-(2-氯苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=450.1。
实施例43
化合物43:N-(4-(((2-氮杂二环[2.2.2]辛烷-5-基)氧基)甲基)-3-氨磺酰苯基)-2-(2-氯苯基)乙酰胺的制备
参考实施例1制备得到。LC-MS:[M+H]
+=450.1。
实施例44
化合物44:2-(2-氯苯基)-N-(4-((3-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体44-2的制备
将中间体1-6(600mg,1.62mmol)、中间体44-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃,搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相减压浓缩即得中间体44-2。LC-MS:[M+H]
+=455。
步骤(2)中间体44-3的制备
将中间体44-2(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047 mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(10mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,过柱液经减压浓缩即得中间体44-3。LC-MS:[M+H]
+=499。
步骤(3)化合物44的制备
将中间体44-3(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液加入到搅拌下的氨水中(10mL)后,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得化合物44。LC-MS:[M+H]
+=456。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.26(d,J=2.2Hz,1H),7.82(dd,J=8.5,2.2Hz,1H),7.62(d,J=8.5Hz,1H),7.59(s,2H),7.50(dd,J=10.1,5.9Hz,2H),7.45–7.38(m,3H),7.36(dd,J=8.1,2.0Hz,1H),7.32–7.26(m,2H),5.45(s,2H),3.85(s,2H).
实施例45
化合物45:N-(4-((3-(氨基甲基)苯氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺的制备
合成路线
步骤(1)中间体45-2的制备
将中间体45-1(300mg,2.43mmol)溶于THF(15mL),向溶液中加入Boc
2O(639mg,2.95mmol),冰浴下反应,反应2h后反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后得到中间体45-2,不处理直接投入下一步。LC-MS:[M+H]
+=224.1。
步骤(2)中间体45-3的制备
将中间体1-6(525mg,1.41mmol)、中间体45-2(315mg,1.41mmol)、K
2CO
3(390mg,2.83mmol) 溶于DMF(5mL)中,室温下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)纯化得到中间体45-3。LC-MS:[M+H]
+=559。
步骤(3)中间体45-4的制备
将中间体45-3(325mg,0.58mmol),中间体1-9(苄硫醇)(216.3mg,1.74mmol),Pd
2(dba)
3(82.5mg,0.116mmol),Xantphos(67mg,0.116mmol),DIEA(225mg,1.74mmol)溶于1,4-二氧六环(5mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体45-4。LC-MS:[M+H]
+=603。
步骤(4)中间体45-5的制备
将中间体45-4(68mg,0.1134mmol),中间体1-11(DCDMH)(22.4mg,0.1134mmol),溶于CH
3CN(4mL),AcOH(0.2mL)和H
2O(0.1mL),在室温条件下反应1小时将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到中间体45-5。LC-MS:[M+H]
+=560。
步骤(6)化合物45的制备
将中间体45-5(50mg,0.088mmol)溶于DCM(2mL),加入HCl(1mL),反应2h,将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得粗品,粗品用H
2O/ACN体系经prep-HPLC分离,冻干制备液后得到化合物45。LC-MS:[M+1]=460。
1H NMR(400MHz,DMSO-d
6)δ10.60(s,1H),8.25(s,3H),7.81(d,J=7.8Hz,1H),7.60(d,J=8.3Hz,1H),7.41(t,J=8.7Hz,2H),7.29(dd,J=8.1,3.9Hz,4H),7.22(d,J=7.4Hz,2H),7.13(s,1H),6.99(d,J=7.6Hz,1H),6.94(d,J=7.8Hz,1H),5.42(s,2H),4.22(d,J=5.9Hz,2H),3.84(s,2H).
实施例46
化合物46:2-(2-氯-6-氟苯基)-N-(4-(((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线
步骤(1)中间体46-1的制备
将中间体20-4(2.15g,5.55mmol)、中间体9-1(627mg,5.55mmol)、K
2CO
3(1.53g,11.1mmol)溶于DMF(20mL)中,室温下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1) 得到中间体46-1。LC-MS:[M+1]=467。
步骤(2)中间体46-2的制备
将中间体46-1(1.33g,2.85mmol),中间体1-9(苄硫醇)(1.05g,8.5mmol),Pd
2(dba)
3(405mg,0.57mmol),Xantphos(329mg,0.57mmol),DIEA(1.1g,8.5mmol)溶于1,4-二氧六环(10mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱(PE/EA=5/1~3/1)纯化,得到中间体46-2。LC-MS:[M+1]=511。
步骤(3)化合物46的制备
将中间体46-2(345mg,0.67mmol),中间体1-11(DCDMH)(133mg,0.67mmol),溶于CH
3CN(5mL),AcOH(0.2mL)和H
2O(0.1mL),在室温条件下反应5min将反应液滴加到搅拌下的氨水中(5mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干制备液得到化合物46。LC-MS:[M+1]=468。
1H NMR(400MHz,DMSO-d
6)δ10.65(s,1H),8.25(d,J=2.2Hz,1H),7.95(dd,J=2.9,1.8Hz,1H),7.78(dd,J=8.5,2.2Hz,1H),7.68–7.60(m,2H),7.56(s,2H),7.40–7.30(m,2H),7.26–7.19(m,1H),7.13(dd,J=8.9,3.4Hz,1H),5.45(s,2H),3.89(d,J=1.3Hz,2H).
实施例47
化合物47:2-(2-氯-5-氟苯基)-N-(4-((((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体47-1的制备
将中间体22-4(600mg,1.62mmol)、中间体9-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL)升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相减压浓缩即得中间体47-1。LC-MS:[M+H]
+=469。
步骤(2)中间体47-2的制备
将中间体47-1(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,EA相减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,过柱液减压浓缩即得中间体47-2。LC-MS:[M+H]
+=511。
步骤(3)化合物47的制备
将中间体47-2(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得化合物47。LC-MS:[M+H]
+=468。
1H NMR(400MHz,DMSO-d
6)δ10.59(s,1H),8.24(d,J=2.2Hz,1H),7.95(dd,J=3.0,1.8Hz,1H),7.80(dd,J=8.5,2.2Hz,1H),7.67–7.60(m,2H),7.57(s,2H),7.47(dd,J=8.8,5.3Hz,1H),7.32(dd,J=9.5,3.1Hz,1H),7.20–7.09(m,2H),5.45(s,2H),3.85(s,2H).
实施例48
化合物48:2-(2-氯-4-氟苯基)-N-(4-((((6-氟吡啶-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体48-1的制备
将中间体21-4(600mg,1.62mmol)、中间体9-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL)升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相减压浓缩即得产品,反应成功,得中间体48-1。LC-MS:[M+H]
+=468。
步骤(2)中间体48-2的制备
将中间体48-1(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,过柱液减压浓缩即得中间体48-2。LC-MS:[M+H]
+=511。
步骤(3)化合物48的制备
将中间体48-2(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得化合物48。LC-MS:[M+H]
+=468。
1H NMR(400MHz,DMSO-d
6)δ10.56(s,1H),8.24(d,J=2.2Hz,1H),7.97–7.91(m,1H),7.80(dd,J=8.5,2.2Hz,1H),7.67–7.59(m,2H),7.57(s,2H),7.43(ddd,J=11.5,8.7,4.5Hz,2H),7.22–7.10(m,2H),5.44 (s,2H),3.83(s,2H).
实施例49
化合物49:2-(2-氯-6-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体49-2的制备
将中间体1-2(2.43g,10.6mmol)溶于DCM(20mL)中,加入中间体20-1(2g,10.6mmol),T
3P(10.1g,15.9mmol),Et
3N(4.8g,47.7mmol),室温下反应1h后反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE:EA=5:1~2:1)纯化后得到中间体49-2。LC-MS:[M+H]
+=400。
步骤(2)中间体49-3的制备
将中间体49-2(4g,10mmol)溶于THF(10mL),加入LiAlH
4(5.7g,15mmol),室温下搅拌1h。加入H
2O(1mL),NaOH溶液(2mL)后抽滤,滤液减压浓缩即得到中间体49-3粗品3.4g。不处理直接用于下一步。
步骤(3)中间体49-4的制备
将中间体49-3(3.4g,9.2mmol)溶于DCM(10mL)中,滴加SOCl
2(2.2g,18.2mmol)室温条件下搅拌1h。停止反应,反应液减压浓缩后经硅胶柱层析(PE:EA=10:1~5:1)纯化得到中间体49-4。LC-MS:[M+H]
+=400。
步骤(4)中间体49-5的制备
将中间体49-4(300mg,0.76mmol)、中间体6-1(91.3mg,0.76mmol)、K
2CO
3(211.7g,1.53mmol)溶于DMF(2mL)中,室温下搅拌1h。反应液加水(50mL)后乙酸乙酯(20mL)萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经过硅胶柱层析(PE/EA=5/1~3/1)得到中间体49-5。LC-MS:[M+H]
+=473。
步骤(5)中间体49-6的制备
将中间体49-5(255mg,0.54mmol),中间体1-9(苄硫醇)(200.5mg,1.62mmol),Pd
2(dba)
3(76.7mg,0.108mmol),Xantphos(62.4mg,0.108mmol),DIEA(209mg,1.62mmol)溶于1,4-二氧六环(5mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱层析(PE/EA=5/1~3/1)纯化,得到中间体49-6。LC-MS:[M+H]
+=517。
步骤(6)化合物49的制备
将中间体49-6(254mg,0.49mmol),中间体1-11(DCDMH)(97mg,0.49mmol),溶于CH
3CN(5mL),AcOH(0.2mL)和H
2O(0.1mL),在室温条件下反应5min。将反应液滴加到搅拌下的氨水中(5ml)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相, 用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干制备液后得到化合物49。LC-MS:[M+H]
+=474。
1H NMR(400MHz,DMSO-d
6)δ10.66(s,1H),8.26(d,J=2.2Hz,1H),7.78(d,J=8.9Hz,3H),7.58(s,3H),7.41–7.30(m,2H),7.27–7.20(m,1H),7.16(d,J=8.9Hz,2H),5.49(s,2H),3.89(s,2H).
实施例50
化合物50:2-(2-氯-5-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体50-1的制备
将中间体22-4(600mg,1.62mmol)、中间体6-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相减压浓缩即得中间体50-1。LC-MS:[M+H]
+=473。
步骤(2)中间体50-2的制备
将中间体50-1(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,EA相减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,过柱液减压浓缩即得中间体50-2。LC-MS:[M+H]
+=517。
步骤(3)化合物50的制备
将中间体50-2(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得产品,反应成功,得化合物50。LC-MS:[M+H]
+=474。
1H NMR(400MHz,DMSO-d
6)δ10.58(s,1H),8.25(d,J=2.2Hz,1H),7.82–7.73(m,3H),7.60(s,1H),7.58(d,J=2.5Hz,2H),7.47(dd,J=8.8,5.3Hz,1H),7.32(dd,J=9.5,3.1Hz,1H),7.17(td,J=9.0,2.8Hz,3H),5.48(s,2H),3.85(s,2H).
实施例51
化合物51:2-(2-氯-4-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体51-1的制备
将中间体21-4(600mg,1.62mmol)、中间体6-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,EA相减压浓缩即得中间体51-1。LC-MS:[M+H]
+=473。
步骤(2)中间体51-2的制备
将中间体51-1(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,浓缩层析柱分离纯化(PE/EA=10:1-6:1),过柱液减压浓缩即得中间体51-2。LC-MS:[M+H]
+=517。
步骤(3)化合物51的制备
将中间体51-2(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得化合物51。LC-MS:[M+H]
+=474。
1H NMR(400MHz,DMSO-d
6)δ10.59(s,1H),8.28(d,J=2.2Hz,1H),7.80(ddt,J=7.0,4.7,2.5Hz,3H),7.65–7.55(m,3H),7.46(ddd,J=11.5,8.7,4.5Hz,2H),7.25–7.15(m,3H),5.51(s,2H),3.85(s,2H).
实施例52
化合物52:2-(2-氯-3-氟苯基)-N-(4-((4-氰基苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体52-2的制备
将中间体1-2(9g,0.039mol)、中间体52-1(2-氯-3-氟苯乙酸)(8g,0.0468mol)、TEA(12g,0.117mol)、T
3P(25g,0.078mol)溶于DCM(90mL)中,室温搅拌反应0.5h。向反应液中加水和DCM,充分搅拌后分出DCM相,水相用DCM萃取两遍,合并DCM相,反应液减压浓缩得中间体52-2。LC-MS:[M+H]
+=400。
步骤(2)中间体52-3的制备
将中间体52-2(14g,0.037mol)溶于THF(100mL)中,并降温至0℃,将LiAlH
4(4.22g,0.111mol)将其中室温搅拌反应10min。后处理,向反应液中加入1mL水和2M的NaOH水溶液3mL,再加大量的EA,过滤,滤液减压浓缩即得中间体52-3。LC-MS:[M+H]
+=372。
步骤(3)中间体52-4的制备
将中间体52-3(10g,0.028mol)溶于DCM(100mL)中并降温至0℃,将SOCl
2(6.61g,0.056mol)加入其中,升至室温搅拌反应1h。后处理,将反应液减压浓缩即得中间体52-4。LC-MS:[M+H]
+=390。
步骤(4)中间体52-5的制备
将中间体52-4(600mg,1.62mmol)、中间体6-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,将EA相减压浓缩即得中间体52-5。LC-MS:[M+H]
+=473。
步骤(5)中间体52-6的制备
将中间体52-5(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,EA相减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,过柱液减压浓缩即得中间体52-6。LC-MS:[M+H]
+=517。
步骤(6)化合物52的制备
将中间体52-6(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液滴加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩后经Prep-HPLC纯化,冻干制备液即得化合物52。LC-MS:[M+H]
+=474。
1H NMR(400MHz,DMSO-d
6)δ10.61(s,1H),8.26(d,J=2.2Hz,1H),7.78(ddt,J=7.1,4.7,2.5Hz,3H),7.60(d,J=8.1Hz,3H),7.39–7.22(m,3H),7.21–7.12(m,2H),5.49(s,2H),3.90(s,2H).
实施例53
化合物53:2-(2-氯-6-氟苯基)-N-(4-((((5-氟吡啶-2-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体53-2的制备
将中间体20-4(500mg,1.278mmol)溶于THF(5mL)中,加入中间体53-1(162mg,1.41mmol),Ag
2CO
3(702.9mg,2.56mmol),70℃下搅拌8h。停止反应,将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品,粗品经硅胶柱层析纯化(PE:EA=10:1~1:1)得中间体53-2。LC-MS:[M+H]
+=467。
步骤(2)中间体53-3的制备
将中间体53-2(217mg,0.46mmol),中间体1-9(苄硫醇)(173.6mg,1.4mmol),Pd
2(dba)
3(65.4mg,0.092mmol),Xantphos(53.2mg,0.092mmol),DIEA(180.6mg,1.4mmol)溶于1,4-二氧六环(5mL)中,在115℃条件下反应16小时。将反应液减压浓缩得到粗品。粗品经硅胶柱层析(PE/EA=5/1~3/1)纯化,得到中间体53-3。LC-MS:[M+H]
+=511。
步骤(3)化合物53的制备
将中间体53-3(175mg,0.34mmol),中间体1-11(DCDMH)(67mg,0.34mmol),溶于CH
3CN(4mL),AcOH(0.1mL)和H
2O(0.1mL),在室温条件下反应1小时。将反应液滴加到搅拌下的氨水中(5mL)后室温搅拌0.5小时。将反应液用水(10mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液后得到化合物53。LC-MS:[M+H]
+=468。
1H NMR(400MHz,DMSO-d
6)δ10.63(s,1H),8.24(d,J=2.2Hz,1H),8.13(d,J=3.1Hz,1H),7.78–7.67(m,2H),7.56(d,J=8.5Hz,1H),7.48(s,2H),7.40–7.31(m,2H),7.26–7.17(m,1H),7.07–6.97(m,1H),5.64(s,2H),3.90(d,J=8.9Hz,2H).
实施例54
化合物54:2-(2-氯-5-氟苯基)-N-(4-(((5-氟吡啶-2-基氧基)甲基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体54-1的制备
将中间体22-4(600mg,1.62mmol)、中间体53-1(280mg,1.95mmol)、Ag
2CO
3(447mg,3.24mmol)溶于THF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,减压浓缩EA相即得中间体54-1。LC-MS:[M+H]
+=469。
步骤(2)中间体54-2的制备
将中间体54-1(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,减压浓缩过柱液即得中间体54-2。LC-MS:[M+H]
+=511。
步骤(3)化合物54的制备
将中间体54-2(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将DCDMH(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液滴加到搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液即得化合物54。LC-MS:[M+H]
+=468。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.23(d,J=2.2Hz,1H),8.13(d,J=3.1Hz,1H),7.80–7.69(m,2H),7.56(d,J=8.5Hz,1H),7.48(dd,J=8.7,5.3Hz,3H),7.33(dd,J=9.5,3.1Hz,1H),7.17(td,J=8.5,3.1Hz,1H),7.01(dd,J=9.1,3.6Hz,1H),5.64(s,2H),3.86(s,2H).
实施例55
化合物55:2-(2-氯-4-氟苯基)-N-(4-((((5-氟吡啶-2-基氧基)甲基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体55-1的制备
将中间体21-4(600mg,1.62mmol)、中间体53-1(280mg,1.95mmol)、Ag
2CO
3(447mg,3.24mmol)溶于THF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,减压浓缩EA相即得中间体55-1。LC-MS:[M+H]
+=469。
步骤(2)中间体55-2的制备
将中间体55-1(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,反应液减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)纯化,减压浓缩过柱液即得中间体55-2。LC-MS:[M+H]
+=511。
步骤(3)化合物55的制备
将中间体55-2(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。将反应液滴加入搅拌的氨水(20mg,1.20mmol)中,室温搅拌反应10min。后处理,将反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液即得化合物55。LC-MS:[M+H]
+=468。
1H NMR(400MHz,DMSO-d
6)δ10.46(s,1H),8.13(d,J=2.1Hz,1H),7.78(dd,J=8.4,2.1Hz,1H),7.63(d,J=8.4Hz,2H),7.44(ddd,J=11.6,8.8,4.5Hz,2H),7.32(s,2H),7.19(td,J=8.6,2.7Hz,2H),5.37(t,J=5.6Hz,1H),4.81(d,J=5.5Hz,2H),3.82(s,2H).
实施例56
化合物56:2-(2-氯苯基)-N-(4-(((1-甲基-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体56-1的制备
将中间体1-4(5g,0.013mol)溶入1,4-二氧六环(50mL)中加入中间体1-9(苄硫醇)(4.8g,0.039mol),DIEA(5g,0.039mol),Pd
2(dba)3(2.4g,0.0026mol),xantphos(1.35g,0.0026mol),N
2置换后110℃下过夜反应。加入EA,水萃取有机相,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,加入PE:EA(10:1)50mL,打浆过滤后得到中间体56-1的产物5g,收率90.9%。
步骤(2)中间体56-2的制备
将中间体56-1(5g,0.012mol)溶入ACN(50mL)中,加入AcOH(3.6g,0.06mol),H
2O(5mL),在冰浴条件下分批加入NCS(N-氯代丁二酰亚胺)(3.2g,0.024mol)后室温下搅拌1h。反应液加水乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩,得中间体56-2的产物4g。
步骤(3)中间体56-3的制备
将中间体56-2(4g,0.01mol)溶入乙腈(40mL)中,加入4-甲氧基苄胺(2.9g,0.02mmol)室温条件下反应1小时。将反应液减压浓缩得到中间体56-3产物3.8g。
步骤(4)中间体56-4的制备
将中间体56-3(3.5g,7mmol)溶于THF(35mL),在冰浴条件下分批加入LAH(氢化铝锂,518mg,14mmol),在冰浴下反应30min。加入1mL NaOH(3M)水溶液淬灭后过滤,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品经硅胶柱层析(PE/EA=5:1~1:1)纯化得到中间体56-4的产物2.6g。
步骤(5)中间体56-5的制备
将中间体56-4(1.34g,0.03mol)溶于DCM(5mL),在室温条件下加入SOCl
2(0.67g.0.06mmol),在室温下反应1h。直接减压浓缩即得到中间体56-5产品1.4g。
步骤(6)中间体56-6的制备
将中间体76-5(1.4g,2.8mmol)溶于THF(15mL),加入中间体8-1(1-甲基-1H-吡唑-3-醇)(329mg,3.6mmol),碳酸银(1.54g,5.6mmol),70℃下反应3h,过滤后加入EA(20*3mL)萃取三次,干燥后经硅胶柱层析(PE/EA=5:1~1:1)纯化,减压浓缩过柱液即得中间体56-6的产品490mg,收率31.6%。
步骤(7)化合物56的制备
将中间体56-6(375mg,0.67mmol)溶于DCM(4mL),加入TFA(2mL),室温下过夜反应,直接减压浓缩后得到黄色粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物56的产品32.6mg,纯度99.298%,收率11.2%。LC-MS:[M+H]
+=435。
1H NMR(400MHz,DMSO-d
6)δ10.54(s,1H),8.22(d,J=2.0Hz,1H),7.79(dd,J=8.5,2.0Hz,1H),7.58(d,J=8.5Hz,1H),7.47(s,1H),7.46(s,2H),7.44–7.39(m,2H),7.30(ddd,J=5.1,4.1,3.0Hz,2H),5.68(d,J=2.3Hz,1H),5.44(s,2H),3.84(s,2H),3.65(s,3H).
实施例57
化合物57:2-(2-氯苯基)-N-(4-(((1-环丙基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体57-2的制备
在25mL反应瓶中加入中间体57-1(900mg,4.8mmol),B
2pin
2(联硼酸频那醇酯,2.54g,9.8mmol),醋酸钾(1.41g,14.4mmol),Pd(dppf)Cl
2(731mg,1.0mmol),1,4-二氧六环(3mL),氮气保护,100摄氏度反应过夜。处理:加水(30mL),水相用乙酸乙酯(30mL)萃取两次,合并有机相,用饱和氯化钠(50mL)洗涤、无水硫酸钠干燥,减压浓缩后经硅胶柱层析纯化(PE/EA=3/1),得中间体57-2产品1.2g。
步骤(2)中间体57-3的制备
将步骤(1)所得中间体57-2产品1.2g加入甲醇(10mL),双氧水(3mL 30%),室温反应过夜。加入水(30mL),用亚硫酸钠淬灭反应,减压浓缩除去甲醇后再用EA 30mL*3萃取出产物。干燥,减压浓缩后得中间体57-3的产品900mg,直接投下一步。
步骤(3)中间体57-4的制备
在25mL反应瓶中加入中间体57-3(900mg,4.8mmol),中间体1-6(1.19g,3.2mmol),碳酸钾(1.33g,9.6mmol),DMF(10mL),氮气保护,室温反应过夜。加水(100mL),水相用乙酸乙酯(40mL) 萃取两次,合并有机相,用饱和氯化钠(100mL)洗涤两次,干燥,减压浓缩后经硅胶柱层析纯化(PE/EA=5/1~3/1),得中间体57-4的产品230mg。
步骤(4)中间体57-5的制备
在25mL反应瓶中加入中间体57-4(230mg,0.5mmol),中间体1-9(苄硫醇)(186mg,1.5mmol),Pd
2(dba)
3(100mg,0.1mmol),Xantphos(58mg,0.1mmol),DIEA(194mg,1.5mmol),1,4-二氧六环(6mL),氮气保护,110摄氏度反应过夜。反应液过滤后得粗品,粗品减压浓缩后经硅胶柱层析纯化(PE/EA=5/1~3/1),得中间体57-5的产品230mg。
步骤(5)化合物57的制备
在25mL反应瓶中加入中间体57-5(230mg,0.46mmol),醋酸30μL,乙腈3mL,水10μL,冰浴条件下分批加入中间体1-11(DCDMH)(184mg,0.92mmol),加完10min送样,LCMS显示有40%左右产物。在反应体系中加入氨水(5mL),水(20mL)搅拌10min,水相再用乙酸乙酯(30mL)萃取两次,合并有机相,用饱和氯化钠(50mL)洗涤后,用无水硫酸钠干燥,减压浓缩得粗品,粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液即得化合物57的产物40mg。LC-MS:[M+H]
+=461.05
1H NMR(400MHz,DMSO-d
6):δ10.54(s,1H),8.22(s,1H),7.80(d,J=8.3Hz,1H),7.59(d,J=8.5Hz,1H),7.53(s,1H),7.49(s,2H),7.46–7.37(m,2H),7.33–7.25(m,2H),7.20(s,1H),5.23(s,2H),3.84(s,2H),3.64–3.51(m,1H),0.97–0.90(m,2H),0.90–0.84(m,2H).
实施例58
化合物58:2-(2-氯苯基)-N-(4-((3-(甲基磺酰亚胺酰基)苯氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线:
步骤(1)中间体58-2的制备
将称量好的中间体1-6(1.0g,2.68mmol)溶于DMF(15mL)中,加入中间体58-1(414mg,2.949mmol)、K
2CO
3(741mg,5.36mmol),加完室温反应2h。反应液加水后乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩后经过硅胶柱层析(PE/EA=10/1~5/1)纯化得中间体58-2的产物900mg。
步骤(2)中间体58-3的制备
将称量好的中间体58-2(850mg,1.783mmol)溶于30mL甲醇中,加入碳酸铵(686mg,7.132mmol),搅拌中加入醋酸碘苯(1.7g,5.348mmol),加完室温反应1h,反应液加饱和亚硫酸钠溶液淬灭,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,反应液减压浓缩后经过硅胶柱层析化(PE/EA=2/1~1/2)纯化得中间 体58-3的产物800mg。LC-MS:[M+H]
+=509.
步骤(3)中间体58-4的制备
将称量好的中间体58-3(600mg,1.181mmol)溶于1,4-二氧六环(20mL)中,加入中间体1-9(苄硫醇)(294mg,2.363mmol),Pd
2(dba)
3(108mg,0.118mmol),Xantphos(69mg,0.118mmol)和DIEA(610mg,4.726mol),氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,反应液减压浓缩后经硅胶柱层析(DCM/MeOH=100/1)纯化,得到中间体58-4的产物600mg。LC-MS:[M+H]
+=551.
步骤(4)化合物58的制备
将称量好的中间体58-4(350mg,0.635mmol)溶于CH
3CN(8mL),加入中间体1-11(DCDMH)(150mg,0.762mmol),AcOH(1mL)和H
2O(1mL),在室温条件下反应5min,将反应液加入到氨水(2mL)中,将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化得到化合物58的产物78.1mg。LC-MS:[M+H]
+=508.1
1H NMR(400MHz,DMSO-d
6):δ10.61(s,1H),8.28(d,J=2.2Hz,1H),7.86(dd,J=8.5,2.2Hz,1H),7.69–7.59(m,6H),7.47–7.41(m,3H),7.32(ddd,J=5.1,4.1,3.0Hz,2H),5.52(s,2H),3.87(s,2H),3.52(s,3H).
实施例59
化合物59:2-(2-氯苯基)-N-(4-(1-((6-氟吡啶-3-基)氧基)乙基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体59-2的制备
将中间体59-1(3g,0.01mol)、三丁基(1-乙氧基乙烯)锡(5.6g,0.015mol)、Pd
2(dba)
3(915mg,0.001mol)、CsF(3g,0.02mol)、t-Bu
3P(0.2g,0.001mol)溶于1,4-二氧六环(30mL)中,置换氮气,升温至110℃搅拌反应过夜。后处理,向反应液中加入KF水溶液和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相后经减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=3:1-1:1)纯化,减压浓缩过柱液即得中间体59-2的产品600mg。LC-MS:[M+H]
+=328。
步骤(2)中间体59-3的制备
将中间体59-2(600mg,1.83mmol)溶于1M的HCl/1,4-二氧六环(12mL,9.17mmol)中,室温搅拌反应0.5h。后处理,将反应液减压浓缩即得中间体59-3的产品510mg。LC-MS:[M+H]
+=300。
步骤(3)中间体59-4的制备
将中间体59-3(530mg,1.77mmol)、Fe(495mg,8.85mmol)、NH
4Cl(938mg,17.7mmol)溶于EtOH/H
2O(6mL/1.5mL)中,升温至70℃搅拌反应2h。后处理,将反应液过滤,滤液减压浓缩即得中间体59-4的产品500mg。LC-MS:[M+H]
+=270。
步骤(4)中间体59-5的制备
将中间体59-4(500mg,1.86mmol)、中间体1-3(2-氯苯乙酸)(316mg,1.86mmol)、TEA(563mg,5.58mmol)、T
3P(887mg,2.79mmol)溶于DCM(8.0mL)中,室温搅拌反应2h。后处理,向反应液中加水和DCM,充分搅拌后分出DCM相,水相用DCM萃取两遍,合并DCM相,反应液减压浓缩后经硅胶柱层析(PE/EA=3:1-2:1)纯化即得中间体59-5产品440mg。LC-MS:[M+H]
+=422。
步骤(5)中间体59-6的制备
将中间体59-5(100mg,0.24mmol)溶于MeOH(2.0mL)中,冰浴下将NaBH
4(18mg,0.48mmol)加入反应中,在室温下搅拌反应0.5h。后处理,反应液经PREP-TLC纯化。刮板浸泡后,减压浓缩浸泡液即得中间体59-6产品42mg。LC-MS:[M+H]
+=406。
步骤(6)中间体59-7的制备
将中间体59-6(40mg,0.096mmol)、SOCl
2(24mg,0.192mmol)溶于DCM,温室搅拌反应2h。后处理,直接减压浓缩即得中间体59-7的产品30mg。LC-MS:[M+H]
+=442。
步骤(7)中间体59-8的制备
将中间体59-7(30mg,0.069mmol)、中间体9-1(2-氟-5-羟基吡啶)(12mg,0.083mmol)、K
2CO
3(20mg,0.138mmol)溶于DMF(1.0mL),并升温至40℃搅拌过夜反应。后处理,将反应液用水洗涤,EA萃取两遍,合并EA相,减压浓缩至2-3mL粗品,粗品经Prep-TLC纯化,刮板浸泡后得浸泡液,浸泡液减压浓缩后得中间体59-8的产品26mg。LC-MS:[M+H]
+=519/521。
步骤(8)化合物59的制备
将中间体59-8(30mg,0.058mmol)溶于甲醇(0.5mL)中,再将水合肼(15mg,0.29mmol)加入进去,室温搅拌反应0.5h。后处理,将反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液即得化合物59的产品7mg。LC-MS:[M+H]
+=464/466。
1H NMR(400MHz,DMSO-d
6):δ10.54(s,1H),8.41(s,1H),8.22(d,J=2.2Hz,1H),7.88–7.82(m,2H),7.73(dd,J=8.5,2.1Hz,2H),7.54(dt,J=7.4,2.9Hz,2H),7.40(ddd,J=9.3,4.8,2.5Hz,2H),7.31–7.25(m,2H),6.98(dd,J=8.9,3.4Hz,1H),6.11–6.06(m,1H),3.81(s,2H),1.59(d,J=6.2Hz,3H).
实施例60
化合物60:N-(4-(((4-氯-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯苯基)乙酰胺的制备
合成路线
步骤(1)中间体60-1的制备
将称量好的1,2-二氢-3H-吡唑-3-酮(1.0g,11.893mmol)溶于DCM(20mL)中,加入Boc酸酐(2.9g,13.083mmol)和TEA(三乙胺)(3.6g,35.679mmol),加完室温反应12h。反应液直接旋干,用EA稀释,用0.1N盐酸调节pH至5.6~6.0,分出有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩得到中间体60-1的产品2.0g,为黄色油状液体。
步骤(2)中间体60-2的制备
将称量好的中间体1-6(500mg,1.34mmol)溶于THF(20mL)中,加入中间体60-1(297mg,1.609mmol)、Ag
2CO
3(740mg,2.68mmol),70℃回流反应24h。LCMS监控显示有产物生成,反应液过滤、滤液减压浓缩得粗品,粗品经硅胶柱层析(PE/EA=10/1~5/1)纯化得到中间体60-2的产物420mg。
步骤(3)中间体60-3的制备
将称量好的中间体60-2(370mg,0.879mmol)溶于1,4-二氧六环(15mL)中,加入中间体1-9(苄硫醇)(219mg,1.759mmol),Pd
2(dba)
3(81mg,0.088mmol),Xantphos(51mg,0.088mmol),DIEA(341mg,2.639mmol),氮气保护在110℃条件下反应过夜,将反应液加水,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,反应液减压浓缩后经硅胶柱层析(PE/EA=5/1)纯化,得到中间体60-3产物270mg。
步骤(4)中间体60-4的制备
将中间体60-3(170mg,0.301mmol)溶于CH
3CN(2mL),AcOH(0.25mL)和H
2O(0.25mL)中,加入中间体1-11(DCDMH)(116mg,0.603mmol),在室温条件下反应10min,将反应液滴加到搅拌下的氨水中(0.5mL),将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩得到中间体60-4的产品200mg,直接用作下一步反应。
步骤(5)化合物60的制备
将称量好的中间体60-4(200mg,0.361mmol)溶于DME(2mL)中,加入碳酸钠(46mg,0.432mmol),加完100℃反应0.5h。将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液得到化合物60的产物41.1mg。LC-MS:[M+H]
+=455.05.
1H NMR(400MHz,DMSO-d
6):δ12.29(s,1H),10.58(s,1H),8.27(d,J=2.0Hz,1H),7.89–7.79(m,2H),7.61(d,J=8.5Hz,1H),7.54–7.38(m,4H),7.35–7.27(m,2H),5.58(s,2H),3.86(s,2H).
实施例61
化合物61:2-(2-氯苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体61-2的制备
将中间体1-6(400mg,1.08mmol)、中间体61-1(217mg,1.62mmol)、K
2CO
3(300mg,2.16mmol)溶于DMF(5mL)中,室温搅拌过夜反应。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA(15mL*2)萃取两遍,合并EA相,反应液减压浓缩后经硅胶柱层析(PE/EA=5:1-3:1)纯化,减压浓缩过柱液即得中间体61-2的产品300mg。LC-MS:[M+H]
+=470/472。
步骤(2)中间体61-3的制备
将中间体61-2(300mg,0.64mmol)、中间体1-9(苄硫醇)(120mg,0.96mmol)、Pd
2(dba)
3(58mg,0.064mmol)、DIEA(250mg,1.92mmol)、Xantphos(37mg,0.064mmol)溶于1,4-二氧六环(3mL),氮气保护,然后110℃搅拌反应过夜。原料反应完全。后处理,向反应液中加水(15mL)和EA(15mL),充分搅拌后分出EA相,水相用EA(10mL*2)萃取两遍,合并EA相,反应液减压浓缩后经硅胶柱层析柱(PE/EA=10:1-0:1)纯化,减压浓缩过柱液即得中间体61-3产品300mg。LC-MS:[M+H]
+=514/516。
步骤(3)化合物61的制备
将中间体61-3(200mg,0.40mmol)溶于乙腈/水(2mL/0.2mL),再将中间体1-11(DCDMH)(110mg,0.60mmol)、AcOH(120mg,2.0mmol)加入其中。室温搅拌反应15min。将反应液滴加到搅拌下的氨水(1mL)中,室温搅拌反应20min。后处理,将反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液即得白色固体20mg。LC-MS:[M+H]
+=471/473。
1H NMR(400MHz,DMSO-d
6):δ10.59(s,1H),8.28(d,J=2.2Hz,1H),7.99(s,1H),7.85(dd,J=8.4,1.9Hz,1H),7.70(d,J=5.9Hz,1H),7.64(d,J=8.5Hz,1H),7.55(d,J=5.1Hz,2H),7.49–7.41(m,2H),7.35–7.30(m,2H),5.34(s,2H),3.88(s,2H).
实施例62
化合物62:2-(2-氯-4-氟苯基)-N-(4-(((1-甲基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体62-2的制备
将中间体21-4(600mg,1.62mmol)、中间体23-1(280mg,1.95mmol)、K
2CO
3(447mg,3.24mmol)溶于DMF(10mL),升温至60℃搅拌反应3h。后处理,向反应液中加水和EA,充分搅拌后分出EA相,然后用EA萃取水相3次,合并EA相,减压浓缩EA相即得中间体62-2的产品460mg。LC-MS:[M+H]
+=452/454。
步骤(2)中间体62-3的制备
将中间体62-2(450mg,0.94mmol)、中间体1-9(苄硫醇)(233mg,1.88mmol)、Pd
2(dba)
3(45mg,0.047mmol)、DIEA(365mg,2.82mmol)、Xantphos(27mg,0.047mmol)溶于1,4-二氧六环(5mL),氮气保护,然后110℃搅拌反应过夜。后处理,向反应液中加水和EA,充分搅拌后分出EA相,水相用EA萃取两遍,合并EA相,减压浓缩后经硅胶柱层析(PE/EA=10:1-6:1)分离纯化,减压浓缩过柱液即得黄色固体产品290mg。LC-MS:[M+H]
+=496/498。
步骤(3)中间体62-4的制备
将中间体62-3(200mg,0.38mmol)溶于乙腈/水(4mL/0.4mL),再将中间体1-11(DCDMH)(150mg,0.76mmol)、AcOH(114mg,1.9mmol)加入其中。室温搅拌反应15min。后处理,将反应液直接减压浓缩后得中间体62-4产品150mg。LC-MS:[M+H]
+=472/474。
步骤(4)化合物62的制备
将中间体62-4(120mg,0.24mmol)加入氨水(1mL)中,室温搅拌反应10min。后处理,将反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化,冻干制备液即得化合物62的产品39mg。LC-MS:[M+H]
+=453/455。
1H NMR(400MHz,DMSO-d
6):δ10.53(s,1H),8.22(d,J=2.2Hz,1H),7.79(dd,J=8.5,2.2Hz,1H),7.59(d,J=8.4Hz,1H),7.48(s,2H),7.47–7.38(m,3H),7.19(td,J=8.4,2.7Hz,2H),5.24(s,2H),3.82(d,J=8.2Hz,2H),3.70(s,3H).
实施例63
化合物63:2-(2-氯苯基)-N-(4-(((1-(环丙基甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体63-2的制备
将中间体63-1(1g,5.2mmol)溶于DMF(10mL)中,加入环丙基甲基溴(696mg,5.2mmol),碳酸钾(1.42g,10.4mmol),室温下反应2h反应液加水,乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得中间体63-2的产品1.1g。LC-MS:[M+H]
+=249.20。
步骤(2)中间体63-3的制备
将中间体63-2(1g,4mmol)溶于MeOH(10mL)中加入双氧水(2.28g,20mmol),室温下反应5h加入亚硫酸钠溶液萃灭反应液,反应液加乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得到中间体63-3产品478mg。LC-MS:[M+H]
+=139。
步骤(3)中间体63-4的制备
将中间体1-6(500mg,1.35mmol)溶入DMF(5mL)中,加入中间体63-3(225mg,1.62mmol)、碳酸钾(375.3mg,2.7mmol)后室温下搅拌2h。反应液加水,乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1),得到中间体63-4产品650mg。LC-MS:[M+H]
+=474。
步骤(4)中间体63-5的制备
将多批次合成的中间体63-4(660mg,1.4mmol)溶入1,4-二氧六环(8mL)中,加入中间体1-9(苄硫醇)(518mg,4.2mmol),Pd
2(dba)
3(256mg,0.28mmol),Xantphos(145mg,0.28mmol),DIEA(520mg,1.2mol),在110℃条件下反应16小时。将反应液减压浓缩经硅胶柱层析(PE/EA=5/1~3/1)得到中间体63-5产物460mg。LC-MS:[M+H]
+=517。
步骤(5)化合物63的制备
将中间体63-5(200mg,0.38mmol),中间体1-11(DCDMH)(151mg,0.774mmol),溶于CH
3CN(1mL),AcOH(116mg)和H
2O(0.1mL),在室温条件下反应5min。将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(20mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H2O/ACN体系经prep-HPLC分离,冻干后得到化合物63的产品24.2mg。LC-MS:[M+H]
+=476。
1H NMR(400MHz,DMSO-d
6):δ10.54(s,1H),8.23(d,J=2.2Hz,1H),7.80(dd,J=8.4,2.2Hz,1H),7.61(d,J=8.4Hz,1H),7.52(s,1H),7.42(ddd,J=8.9,5.2,2.3Hz,3H),7.33–7.26(m,2H),7.21(d,J=0.6Hz,1H),5.24(s,2H),3.89–3.77(m,4H),1.19–1.08(m,1H),0.52–0.43(m,2H),0.32–0.26(m,2H).
实施例64
化合物64:2-(2-氯-5-氟苯基)-N-(4-(((1-甲基-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
1.合成路线
步骤(1)中间体64-1的制备
将中间体22-4(400mg,1.03mmol)溶入DMF(3mL)中,加入中间体23-1(100mg,1.03mmol)、碳酸钾(284mg,2.06mmol)后室温下搅拌2h。反应液加水乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得中间体64-1的产品400mg,收率86.3%。LC-MS:[M+H]
+=452。
步骤(2)中间体64-2的制备
将中间体64-1(400mg,0.88mmol)溶入1,4-二氧六环(4mL)中,加入中间体1-9(苄硫醇)(329mg,2.65mmol),Pd
2(dba)
3(161mg,0.176mmol),Xantphos(101.7mg,0.1mmol),DIEA(330mg,2.65mmol),在110℃条件下反应16小时。将反应液减压浓缩经硅胶柱层析(PE/EA=5/1~3/1)得中间体64-2的产物400mg,收率90.1%。LC-MS:[M+H]
+=496。
步骤(3)化合物64的制备
将中间体64-2(65mg,0.13mmol),中间体1-11(DCDMH)(38.7mg,0.197mmol)溶于CH
3CN(1mL),AcOH(39mg)和H
2O(0.1mL),在室温条件下反应5min。
将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(20mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H2O/ACN体系经prep-HPLC分离,冻干后得到产品,为化合物64的产物10mg,收率16.9%。LC-MS:[M+H]
+=454。
1H NMR(400MHz,DMSO-d
6):δ10.55(s,1H),8.21(d,J=2.0Hz,1H),7.78(dd,J=8.6,1.9Hz,1H),7.59(d,J=8.4Hz,1H),7.52–7.40(m,4H),7.32(dd,J=9.5,3.0Hz,1H),7.19(d,J=3.7Hz,1H),7.16(dd,J=8.5,3.1Hz,1H),5.24(s,2H),3.85(s,2H),3.70(s,3H).
实施例65
化合物65:2-(2-氯-5-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体65-1的制备
将中间体61-1(207mg,1.5mmol)溶入DMF(3mL)中,加入中间体22-4(400mg,1.0mmol)、碳酸钾(282mg,2.04mmol)后室温下搅拌2h。反应液加水乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得中间体65-1的产品250mg,收率50%。LC-MS:[M+H]
+=488。
步骤(2)中间体65-2的制备
将中间体65-1(250mg,0.5mmol)溶入1,4-二氧六环(5mL)中,加入中间体1-9(苄硫醇)(190mg,1.5mmol),Pd
2(dba)
3(93.9mg,0.1mmol),Xantphos(59mg,0.1mmol),DIEA(191mg,1.5mmol),在110℃条件下反应16小时。将反应液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得到中间体65-2产品218mg,收率81.9%。LC-MS:[M+H]
+=532。
步骤(3)化合物65的制备
将中间体65-2(204mg,0.39mmol),中间体1-11(DCDMH)(150.6mg,0.76mmol),溶于CH
3CN(2mL),AcOH(115mg)和H
2O(0.1mL),在室温条件下反应5min(得到中间体65-3)。将上述反应液滴加到搅拌下的氨水中(10ml)后室温搅拌0.5小时。将反应液用水(20mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得化合物65的产品26.2mg,收率13.7%。LC-MS:[M+H]
+=489。
1H NMR(400MHz,DMSO-d
6):δ10.58(s,1H),8.23(s,1H),7.96(s,1H),7.81(d,J=6.3Hz,1H),7.67(d,J=5.9Hz,1H),7.61(d,J=8.4Hz,1H),7.57–7.42(m,3H),7.33(dd,J=9.3,2.6Hz,1H),7.22–7.12(m,1H),5.31(s,2H),3.86(s,2H).
实施例66
化合物66:2-(2-氯苯基)-N-(4-(((1-(1,1-二氟丙基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体66-2的制备
将中间体63-1(500mg,2.57mmol)溶于DMF(5mL)中,加入中间体66-1(溴二氟丙烯)(605mg,3.85mmol)、K
2CO
3(709mg,5.14mmol)后,N
2保护室温下反应过夜。停止反应,反应液加水,EA萃取后合并EA相,反应液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)纯化,得到中间体66-2产品410mg,收率59.2%。LC-MS:[M+H]
+=271。
步骤(2)中间体66-3的制备
将中间体66-2(410mg,1.51mmol)溶入甲醇(10mL)中,加入钯碳(100mg)后,氢气保护室温下搅拌5h。反应液过滤,滤液减压浓缩得到中间体66-3产品410mg。LC-MS:[M+H]
+=273。
步骤(3)中间体66-4的制备
将中间体66-3(410mg,1.51mmol)溶入甲醇(5mL)中,加入双氧水(5mL,30%)后室温下搅拌2h。反应液0℃下用饱和亚硫酸钠淬灭后乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得到产物,得到中间体66-4产品180mg,收率72.8%。LC-MS:[M+H]
+=163。
步骤(4)中间体66-5的制备
将中间体66-4(180mg,1.1mmol)溶入DMF(4mL)中,加入中间体1-6(410mg,1.1mmol)、碳酸钾(455mg,3.3mmol)后室温下搅拌2h。反应液加水乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得到中间体66-5的产品360mg,收率65.6%。LC-MS:[M+H]
+=499。
步骤(5)中间体66-6的制备
将中间体66-5(360mg,0.72mmol)溶入1,4-二氧六环(5mL)中,加入中间体1-9(苄硫醇)(267mg,2.16mmol),Pd
2(dba)
3(64mg,0.07mmol),Xantphos(40mg,0.07mmol),DIEA(280mg,2.16mmol),在110℃条件下反应16小时。将反应液减压浓缩经硅胶柱层析(PE/EA=5/1~3/1)得到产物,得中间体66-6产品300mg,收率76.9%。LC-MS:[M+H]
+=542。
步骤(6)化合物66的制备
将中间体66-6(300mg,0.55mmol),中间体1-11(DCDMH)(216mg,1.1mmol),溶于CH
3CN(3mL),AcOH(165mg,2.75mmol)和H
2O(0.1mL),在室温条件下反应5min。将反应液滴加到搅拌下的氨水中(10mL)后室温搅拌0.5小时。将反应液用水(20mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离,冻干后得到化合物66产品83.4mg,收率30.3%。LC-MS:[M+H]
+=499。
1H NMR(400MHz,DMSO-d
6):δ10.54(s,1H),8.23(d,J=2.2Hz,1H),7.81(dd,J=8.4,2.2Hz,1H),7.60(d,J=8.4Hz,1H),7.55(s,1H),7.49(s,2H),7.42(ddd,J=8.4,5.4,2.2Hz,2H),7.34–7.24(m,3H),6.20(t,J=4.4Hz,1H),6.06(t,J=4.4Hz,1H),5.92(t,J=4.4Hz,1H),5.25(s,2H),4.13(t,J=7.2Hz,2H),3.84(s,2H),2.41–2.22(m,2H).
实施例67
化合物67:2-(2-氯-4-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-4-基)氧基)甲基)-3-氨磺酰苯基)乙酰胺的制备
合成路线
步骤(1)中间体67-1的制备
将中间体61-1(200mg,1.5mmol)溶入DMF(3mL)中,加入中间体21-4(400mg,1.0mmol)、碳酸钾(410mg,3.0mmol)后室温下搅拌2h。反应液加水乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩后经硅胶柱层析(PE/EA=5/1~3/1)得到中间体67-1产品240mg,收率50%。LC-MS:[M+H]
+=488。
步骤(2)中间体67-2的制备
将中间体67-1(240mg,0.5mmol)溶入1,4-二氧六环(5mL)中,加入中间体1-9(苄硫醇)(124mg,1.0mmol),Pd
2(dba)
3(46mg,0.05mmol),Xantphos(30mg,0.05mmol),DIEA(200mg,1.5mmol),在110℃条件下反应16小时。将反应液减压浓缩经硅胶柱层析(PE/EA=5/1~3/1)得到中间体67-2产品210mg,收率78.9%。LC-MS:[M+H]
+=532。
步骤(3)化合物67的制备
将中间体67-2(210mg,0.39mmol),中间体1-11(DCDMH)(156mg,0.78mmol),溶于CH
3CN(2mL),AcOH(120mg)和H
2O(0.1mL),在室温条件下反应5min。将反应液滴加到搅拌下的氨水中(10ml)后室温搅拌0.5小时。将反应液用水(20mL)稀释后,再加DCM(10mL)萃取三次。合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,过滤,滤液减压浓缩得到粗品。粗品用H2O/ACN体系经prep-HPLC分离,冻干后得到化合物67产品13.1mg,收率6.9%。LC-MS:[M+H]+=489。
1H NMR(400MHz,DMSO-d
6):δ10.56(s,1H),8.24(d,J=2.2Hz,1H),7.96(s,1H),7.84–7.78(m,1H),7.67(d,J=5.4Hz,1H),7.61(d,J=8.4Hz,1H),7.52(d,J=6.0Hz,2H),7.44(ddd,J=11.4,8.8,4.4Hz,2H),7.19(td,J=8.6,2.8Hz,1H),5.31(s,2H),3.83(s,2H).
实施例68
化合物68:N-(4-(((4-氯-1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯-4-氟苯基)乙酰胺的制备
化合物69:N-(4-(((4-氯-1-(二氟甲基)-1H-吡唑-5-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯-4-氟苯基)乙酰胺的制备
合成路线
步骤(1)中间体68-1的制备
将称量好的中间体21-4(500mg,1.286mmol)溶于THF(20mL)中,加入中间体60-1(355mg,1.928mmol)、Ag
2CO
3(709mg,2.571mmol),70℃回流反应过夜。LCMS监控显示有产物生成,反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,反应液减压浓缩后经硅胶柱层析(PE/EA=10/1)纯化得到中间体68-1的产物560mg。
步骤(2)中间体68-2的制备
将称量好的中间体68-1(560mg,1.039mmol)溶于DME/H
2O(7.5mL/7.5mL)中,加入Na
2CO
3(133mg,1.247mmol),100℃反应1h。反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,通过硅胶柱层析(PE/EA=2/1)纯化得到中间体68-2的产品320mg。
步骤(3)中间体68-3及中间体69-1的制备
将称量好的中间体68-2(320mg,0.729mmol)溶于乙腈(10mL)中,加入溴氟甲基磷酸二乙酯(585mg,2.188mmol)和KF(170mg,2.916mmol),70℃反应过夜反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,通过Prep-TLC(PE/EA=2/1)纯化得到中间体68-3的产品90mg,及其异构体中间体69-1产品90mg。
步骤(4)中间体68-4及中间体69-2的制备
将称量好的中间体68-3(90mg,0.184mmol)和中间体69-1(90mg,0.184mmol)分两锅分别溶于1,4-二氧六环(2mL)中,分别加入中间体1-9(苄硫醇)(46mg,0.368mmol),Pd
2(dba)
3(17mg,0.018mmol), Xantphos(11mg,0.018mmol),DIEA(72mg,0.555mmol),加完氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,通过Prep-TLC纯化(PE/EA=2/1),得到产物,得中间体68-4的产品80mg,得其异构体中间体69-2的产品80mg。
步骤(5)化合物68和化合物69的制备
将中间体68-4(80mg,0.150mmol)和中间体69-2(80mg,0.150mmol)分两锅分别溶于CH
3CN(2ml),AcOH(0.25mL)和H
2O(0.25mL)中,分别加入中间体1-11(DCDMH)(45mg,0.226mmol),在室温条件下反应5min将反应液滴加到搅拌下的氨水中(0.5mL),将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离得到产物化合物68(10.2mg)和化合物69(13.6mg),为白色固体。
化合物68:LC-MS:M碎片=355.05.
1H NMR(400MHz,DMSO-d
6):δ10.62(s,1H),8.47(d,J=10.7Hz,1H),8.29(d,J=2.2Hz,1H),7.84(dd,J=8.4,2.2Hz,1H),7.76(s,1H),7.65–7.60(m,2H),7.57–7.40(m,4H),7.22(td,J=8.5,2.7Hz,1H),5.61(s,2H),3.86(s,2H).
化合物69:LC-MS:M碎片=355.05.
1H NMR(400MHz,DMSO-d
6):δ10.65(s,1H),8.30(d,J=2.2Hz,1H),7.92–7.79(m,2H),7.72(s,1H),7.62(dd,J=19.7,10.3Hz,4H),7.47(ddd,J=11.5,8.7,4.4Hz,2H),7.22(td,J=8.5,2.7Hz,1H),5.74(s,2H),3.87(s,2H).
实施例69
化合物70:N-(4-(((4-氯-1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)-2-(2-氯-5-氟苯基)乙酰胺的制备
合成路线
步骤(1)中间体70-1的制备
将称量好的中间体22-4(1.0g,2.571mmol)溶于THF(20mL)中,加入中间体60-1(710mg,3.857mmol)、Ag
2CO
3(1.4g,5.142mmol),70℃回流反应过夜。反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,通过硅胶柱层析(PE/EA=8/1)纯化得到中间体70-1的产物1.2g。
步骤(2)中间体70-2的制备
将称量好的中间体70-1(1.2g,2.227mmol)溶于DME/H
2O(7.5mL/7.5mL)中,加入Na
2CO
3(284mg,2.673mmol),100℃反应2h。反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,通过硅胶柱层析(PE/EA=2/1)纯化得到中间体70-2的产物900mg。
步骤(3)中间体70-3和中间体71-1的制备
将称量好的中间体70-2(900mg,2.052mmol)溶于乙腈(25mL)中,加入溴氟甲基磷酸二乙酯(1.6g,6.155mmol)和KF(477mg,8.206mmol),70℃反应过夜。反应液加水用乙酸乙酯萃取两遍,合并有机相,依次用饱和食盐水洗涤,无水硫酸钠干燥,通过硅胶柱层析纯化(PE/EA=8/1~4/1)得到产物,得中间体70-3的产品400mg,及其异构体中间体71-1产品200mg。
步骤(4)中间体70-4和中间体71-2的制备
将称量好的中间体70-3(400mg,0.818mmol)和中间体71-1(200mg,0.409mmol)分两锅分别溶于1,4-二氧六环(2mL/1mL)中,分别加入中间体1-9(苄硫醇)(204mg/102mg,1.637mmol/0.818mmol),Pd
2(dba)
3(76mg/38mg,0.082mmol/0.041mmol),Xantphos(48mg/24mg,0.082mmol/0.041mmol),DIEA(318mg/159mg,2.456mmol/1.228mmol),加完氮气保护在100℃条件下反应过夜,将反应液加水,用EA萃取,有机相饱和食盐水洗,硫酸钠干燥,通过硅胶柱层析纯化(PE/EA=6/1~3/1),得到产物,得到中间体70-4产品400mg,及其异构体中间体71-2产品200mg。
步骤(5)化合物70和化合物71的制备
将中间体70-4(400mg,0.752mmol)和中间体71-2(200mg,0.376mmol)分两锅分别溶于CH
3CN(4mL),AcOH(0.5mL)和H
2O(0.5mL)中,分别加入中间体1-11(DCDMH)(224mg/112mg,1.128mmol/0.564mmol),在室温条件下反应5min将反应液滴加到搅拌下的氨水中(0.5mL),将反应液加水,用EA萃取,合并有机相,用饱和食盐水洗涤,无水硫酸钠干燥后,反应液减压浓缩得到粗品。粗品用H2O/ACN体系经prep-HPLC分离纯化得到产物,得到化合物70的产品155.8mg和得到化合物71的产品14.7mg。
化合物70:LC-MS:[M+H]
+=522.95.
1H NMR(400MHz,DMSO-d
6):δ10.63(s,1H),8.45(s,1H),8.29(d,J=2.1Hz,1H),7.84(dd,J=8.5,2.1 Hz,1H),7.76(s,1H),7.67–7.60(m,2H),7.59–7.41(m,3H),7.35(dd,J=9.5,3.1Hz,1H),7.19(td,J=8.5,3.1Hz,1H),5.62(s,2H),3.89(s,2H).
化合物71:LC-MS:Ms碎片=355.00.
1H NMR(400MHz,DMSO-d
6):δ10.50(s,1H),8.15(d,J=2.1Hz,1H),7.80(dd,J=8.4,2.0Hz,1H),7.65(d,J=8.4Hz,1H),7.50(dd,J=8.8,5.3Hz,1H),7.34(dd,J=8.6,3.9Hz,3H),7.19(td,J=8.5,3.1Hz,1H),5.38(t,J=3.7Hz,1H),4.84(d,J=5.6Hz,2H),3.87(s,2H).
实施例70
化合物72:2-(2-氯苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
化合物73:2-(2-氯苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-5-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体72-1的制备
将称量好的中间体60-3(1.5g,2.659mmol)溶于DME(10mL)和水(10mL)中,加入碳酸钠(339mg,3.191mmol),100℃反应2h。有新点生成,反应液加水,用EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,通过硅胶柱层析纯化(PE/EA=5/1~2/1)得到中间体72-1的产品880mg。
步骤(2)中间体72-2和73-1的制备
将称量好的中间体72-1(880mg,1.897mmol)溶于乙腈(25mL)中,加入溴氟甲基磷酸二乙酯(1.5g,5.690mmol)、KF(441mg,7.587mmol),加完70℃反应过夜。反应液加水,用EA萃取,有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得到中间体72-2的产物及其异构体中间体73-1的混合物1.1g,未经纯化直接用作下一步反应。
步骤(3)化合物72和化合物73的制备
将上一步所获的中间体72-2及其异构体中间体73-1的混合物(1.1g,2.141mmol)溶于冰醋酸(30mL)和水(10mL)中,分批加入NCS(858mg,6.421mmol),加完室温反应3h,反应液加水,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,减压浓缩得到粗品1.1g。将粗品溶于20mL THF中,滴加到搅拌的20mL氨水中,室温反应10min,LCMS监控显示有产物生成,反应液加水,用EA萃取,有机相饱和食盐水洗,无水硫酸钠干燥,反应液减压浓缩得到粗品。粗品用H
2O/ACN体系经prep-HPLC分离纯化得到 化合物72产品240mg以及其异构体化合物73的产品103.3mg。
化合物72:LC-MS:[M+H]
+=471.05.
1H NMR(400MHz,DMSO-d
6):δ10.59(s,1H),8.26(d,J=2.1Hz,1H),8.07(d,J=2.8Hz,1H),7.84(dd,J=8.5,2.1Hz,1H),7.75(s,1H),7.63(s,1H),7.61(d,J=4.0Hz,1H),7.51(s,2H),7.47–7.40(m,2H),7.32(dd,J=9.3,4.9Hz,2H),6.12(d,J=2.8Hz,1H),5.55(s,2H),3.87(s,2H).
化合物73:LC-MS:[M+H]
+=471.05.
1H NMR(400MHz,DMSO-d
6):δ10.62(s,1H),8.29(d,J=2.2Hz,1H),7.84(dd,J=8.5,2.2Hz,1H),7.68(d,J=2.7Hz,1H),7.65(s,1H),7.63(s,2H),7.57(d,J=1.7Hz,1H),7.54(s,1H),7.44(ddd,J=6.6,5.8,3.7Hz,2H),7.34–7.29(m,2H),5.87(d,J=1.8Hz,1H),5.55(s,2H),3.87(s,2H).
实施例71
化合物74:2-(2-氯-5-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
步骤(1)中间体74-1的制备
在250mL反应瓶中加入中间体22-2(4.807g,12mmol),中间体1-9(苄硫醇)(4.471g,36mmol),Pd
2(dba)
3(2.197g,2.4mmol),DIEA(4.652g,36mmol),Xantphos(1.388g,2.4mmol),1,4-二氧六环(95mL),氮气保护。110摄氏度反应过夜。处理:反应液减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=5:1),得中间体74-1的产物4.2g。
步骤(2)中间体74-2的制备
在250mL反应瓶中加入中间体74-1(4.2g,9.46mmol),NCS(3.59g,28.38mmol),AcOH(1.556g,2.84mmol),ACN/H
2O(84mL/0.84mL)。室温反应30分钟后加入PMBNH
2(1.946g,14.192mmol),室温继续反应30分钟。处理:反应液减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=6:1),得中间体74-2的产物3.8g。
步骤(3)中间体74-3的制备
在100mL反应瓶中加入中间体74-2(3.8g,7.294mmol),THF 76mL,分批加入氢化铝锂(553mg,14.588mmol),室温反应2小时。处理:反应液用3.8ml水淬灭,调成弱酸性,用乙酸乙酯萃取两次,合并有机相,干燥、减压浓缩,得中间体74-3的产物2.3g。
步骤(4)中间体74-4的制备
在100mL反应瓶中加入中间体74-3(2.135g,4.331mmol),DCM 20mL,滴加SOCl
2(1.031g,8.662mmol),室温反应过夜。处理:反应液减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=6:1),得中间体74-4的产物2.4g。
步骤(5)中间体74-5的制备
在50mL反应瓶中加入中间体74-4(2.328g,4.55mmol),THF 23mL,中间体60-1(1.006g,5.463mmol),Ag
2CO
3(2.51g,9.105mmol),70摄氏度反应过夜。处理:反应液用乙酸乙酯萃取两次,合并有机相,减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=8:1),得中间体74-5产物2.3g。
步骤(6)中间体74-6的制备
在50mL反应瓶中加入中间体74-5(2.3g,3.49mmol),DME/H
2O(15mL/15mL),Na
2CO
3(517mg,4.885mmol),100摄氏度反应6小时。处理:反应液用乙酸乙酯萃取两次,合并有机相,干燥、浓缩,得中间体74-6的产物2.0g。
步骤(7)中间体74-7的制备
在50mL反应瓶中加入中间体74-6(1.0g,1.7mmol),MeCN 20mL,溴氟甲基磷酸二乙酯(1.4g,5.1mmol)KF(415mg,7.1mmol),70摄氏度反应过夜。处理:反应液用乙酸乙酯萃取两次,合并有机相,减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=5:1),得中间体74-7的产物567mg。
步骤(8)化合物74的制备
在25mL反应瓶中加入中间体74-7(188mg,0.31mmol),MeCN/H
2O(0.8mL/0.8mL),CAN(509mg,0.9mmol),室温反应过夜。处理:反应液用乙酸乙酯萃取两次,合并有机相,干燥、浓缩,得化合物74的产物27mg。LC-MS:[M+H]
+=355.
1H NMR(400MHz,DMSO-d
6)δ10.64(s,1H),8.29(d,J=1.9Hz,1H),7.84(dd,J=8.2,2.0Hz,1H),7.73–7.61(m,4H),7.58(d,J=1.1Hz,1H),7.54(s,1H),7.50(dd,J=8.8,5.3Hz,1H),7.35(dd,J=9.4,3.0Hz,1H),7.20(td,J=8.5,3.0Hz,1H),5.87(d,J=1.5Hz,1H),5.56(s,2H),3.89(s,2H).
实施例72
化合物75:2-(2-氯-4-氟苯基)-N-(4-(((1-(二氟甲基)-1H-吡唑-3-基)氧基)甲基)-3-氨磺酰基苯基)乙酰胺的制备
合成路线
实验过程
步骤(1)中间体75-1的制备
在250mL反应瓶中加入中间体21-2(4.01g,10mmol),中间体1-9(苄硫醇)(3.72g,30mmol),Pd
2(dba)
3(1.831g,2mmol),DIEA(3.87g,30mmol),Xantphos(1.15g,2mmol),1,4-二氧六环(10mL),氮气保护。110摄氏度反应过夜。处理:反应液减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=5:1),得中间体75-1的产物4.3g。
步骤(2)中间体75-2的制备
在250mL反应瓶中加入中间体75-1(2.3g,5.181mmol),NCS(1.97g,15.543mmol),AcOH(1.556g,25.905mmol),ACN/H
2O(46mL/0.46mL)。室温反应30分钟后加入PMBNH
2(1.066g,7.772mmol),室温继续反应30分钟。处理:反应液减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=6:1),得中间体75-2的产物1.65g。
步骤(3)中间体75-3的制备
在100mL反应瓶中加入中间体75-2(1.45g,2.78mmol),THF(29mL),分批加入氢化铝锂(159mg,4.17mmol),室温反应2小时。处理:反应液用1.45ml水淬灭,调成弱酸性,用乙酸乙酯萃取两次,合并有机相,干燥、浓缩,得中间体75-3的产物1.25g。
步骤(4)中间体75-4的制备
在100mL反应瓶中加入中间体75-3(1.15g,2.33mmol),DCM(12mL),滴加SOCl
2(556mg,4.66mmol),室温反应过夜。处理:反应液减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=6:1),得中间体75-4的产物1.17g。
步骤(5)中间体75-5的制备
在50mL反应瓶中加入中间体75-4(1.17g,2.29mmol),THF(12mL),中间体60-1(506mg,2.75mmol),Ag
2CO
3(1.26g,4.57mmol),70摄氏度反应过夜。处理:反应液用乙酸乙酯萃取两次,合并有机相,减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=8:1),得中间体75-5的产物800mg。
步骤(6)中间体75-6的制备
在50mL反应瓶中加入中间体75-5(395mg,0.6mmol),DME/H
2O(4mL/4mL),Na
2CO
3(77mg,0.72mmol),100摄氏度反应6小时。处理:反应液用乙酸乙酯萃取两次,合并有机相,干燥、浓缩,得中间体75-6的产物315mg。
步骤(7)中间体75-7的制备
在50mL反应瓶中加入中间体75-6(336mg,0.6mmol),MeCN 5mL,溴氟甲基磷酸二乙酯(480mg,1.8mmol)、KF(139mg,2.4mmol),70摄氏度反应过夜。处理:反应液用乙酸乙酯萃取两次,合并有机相,减压浓缩后经硅胶柱层析纯化,洗脱剂(PE/EA=5:1),得中间体75-7的产物130mg。
步骤(8)化合物75的制备
在25mL反应瓶中加入中间体75-7(250mg,0.41mmol),MeCN/H
2O(1.3mL/1.3mL),CAN(硝酸铈铵,675mg,1.23mmol),室温反应过夜。处理:反应液用乙酸乙酯萃取两次,合并有机相,干燥、浓缩,粗品用H
2O/ACN体系经prep-HPLC分离。得化合物75的产物38mg。LC-MS:[M+H]
+=355.
1H NMR(400MHz,DMSO-d
6)δ10.62(s,1H),8.29(d,J=2.1Hz,1H),7.84(dd,J=8.3,2.2Hz,1H),7.66(dd,J=14.2,5.6Hz,4H),7.58(d,J=1.7Hz,1H),7.54(s,1H),7.47(ddd,J=11.5,8.7,4.5Hz,2H),7.22(td,J=8.5,2.7Hz,1H),5.87(d,J=1.8Hz,1H),5.56(s,2H),3.86(s,2H).
生物试验
实施例A:体外生物活性评价
利用FLIPR(荧光成像读板仪)法对本发明中化合物的拮抗特性进行测定,所述化合物是由HEK293细胞(人肾上皮细胞系,ATCC)中所表达的hP2X4(人嘌呤能P2X受体亚型4,登录号NM_001256796.2)激活所诱导的细胞内钙升高的抑制剂。
将稳定表达hP2X4的HEK293细胞置于37℃,湿度5%的细胞培养箱中,以含有10%FBS(胎牛血清,Biosera,FB-1058/500),1%青霉素-链霉素(Gibco,15140-122),和1mg/mL G418(CABIOCHE,345810)的DMEM高糖培养基进行培养。在FLIPR实验前18-24小时,将细胞以400000细胞/毫升的密度接种到384孔中(10000细胞/孔),在细胞培养箱中温育过夜。实验当天,弃去培养基,将细胞在FLIPR缓冲液(每30mL缓冲液中含有0.3mL丙磺舒(Thermo,P36400),0.6mL 1M HEPES(Invitrogen,15630080)和29.1mL HBSS(Invitrogen,14065056)中进行洗涤。每孔加入20μL 0.5×Calcium 6荧光染料(Molecular Devices,R8190),在37℃下染料荷载温育1.5小时。随后将10μL供试化合物(以10mM的浓度溶解于DMSO中并用缓冲液进行系列稀释)或溶媒加入各孔,并使其在37℃下预孵育30min。然后将细胞板放入FLIPR中,进行基线荧光测量(激发波长为485nm,发射波长为525-535nm)。随后以10μL/孔加入激动剂(终浓度5μM的BZ-ATP(Sigma,B6396))或溶媒(超纯水),以1秒的时间间隔测量荧光值2分钟,最后对输出的荧光计数进行分析。
使用上述方法获得的IC
50示于表1中。
表1.对于实施例中的化合物对P2X4受体所获得的IC
50
化合物编号 | IC 50/nM | 化合物编号 | IC 50/nM | 化合物编号 | IC 50/nM |
1 | 24.3 | 27 | B | 56 | 67.6 |
2 | 27.10 | 30 | C | 57 | 51.2 |
3 | 25.1 | 33 | C | 59 | B |
4 | 124 | 34 | C | 60 | 12.8 |
6 | 9.8 | 35 | C | 61 | 17.7 |
7 | 88.4 | 39 | C | 62 | 13.7 |
9 | 7.6 | 40 | C | 63 | B |
10 | 18.3 | 42 | C | 64 | 17.3 |
12 | 13.0 | 43 | C | 65 | 3 |
16 | 70.5 | 46 | 5.9 | 66 | B |
18 | C | 47 | 3.8 | 67 | 5.8 |
19 | C | 48 | 4.6 | 68 | 71.9 |
20 | 31.8 | 49 | 32.8 | 69 | 27.0 |
21 | 54.2 | 50 | 59.9 | 70 | 112.9 |
22 | 32.4 | 51 | 189.9 | 72 | 30.5 |
23 | 16.5 | 52 | 166.5 | 73 | 35.9 |
24 | B | 53 | 12.2 | 74 | 17.9 |
25 | B | 54 | 18.6 | 75 | 13.5 |
26 | C | 55 | B |
其中,A:IC
50≤10nM,B:10<IC
50≤50nM,C:50<IC
50≤200nM。
由表1数据可见,本发明的化合物具有良好的P2X4抑制活性,我们特别优选IC
50≤200nM的化合物,更优选IC
50≤50nM的化合物。
实施例B:体外细胞毒性测试
对本发明中化合物的体外细胞毒性测试在HepG2细胞中利用CCK-8法进行测定。收集对数期的HepG2细胞(北纳生物),调整细胞悬液浓度,以50000细胞/孔在96孔细胞培养板中铺板,将细胞置于5%,37℃的细胞培养箱中孵育过夜,待板中细胞融合度达到80-90%后,换液加入各浓度梯度的供试化合物或溶媒(DMSO),在5%,37℃的细胞培养箱中孵育48小时。处理结束后,弃去板内培养基,用PBS洗涤2遍,每孔加入100μL CCK-8工作液(碧云天生物技术),37℃避光孵育1.5小时,酶标仪上检测OD
450nm处各孔的吸光值,分析计算各化合物的CC
50。
使用上述方法获得的CC
50示于表2中。
表2.对于部分化合物所获得的CC
50
化合物 | HepG2CC 50(μM) | 化合物 | HepG2CC 50(μM) |
1 | >100 | 54 | >100 |
2 | >100 | 55 | 54.3 |
3 | 53.6 | 57 | >100 |
6 | >100 | 60 | >100 |
9 | 94.92 | 61 | >100 |
10 | >100 | 62 | >100 |
20 | 41.62 | 63 | 51.72 |
21 | >100 | 64 | >100 |
22 | >100 | 65 | >100 |
23 | >100 | 66 | >100 |
44 | >100 | 67 | >100 |
46 | 54.8 | 72 | >100 |
47 | 55.5 | 73 | 51.23 |
48 | 67.9 | 74 | 99.78 |
49 | >100 | 75 | 54.42 |
由表2数据可见,本发明的大部分化合物都具有较好的安全性,CC
50范围均>40μM,满足一般化合物体外对细胞毒性的要求,我们优选CC
50>40μM的化合物,更优选CC
50>100μM的化合物。
实施例C:体外代谢稳定性试验
对本发明中化合物的体外代谢稳定性利用各种属肝微粒体体外温孵法进行测定。在肝微粒体反应体系中(1mg/mL肝微粒体蛋白,25U/mL 6-磷酸葡萄糖脱氢酶,1mM NADP,6mM D-6-磷酸葡萄糖,5mM MgCl
2)加入适量供试化合物,放入37℃水浴锅中温孵启动反应,于各时间点取100μL反应液加入至含400μL 0℃预冷的内标工作液(含200ng/mL地塞米松、双氯酚酸、甲苯磺丁脲、拉贝洛尔的乙腈溶液)离心管中,终止反应,4℃离心机10000rpm离心10min,取上清液进LC-MS进行分析检测,获得供试化合物在各种属肝微粒体中的体外代谢半衰期。
使用上述方法获得的T
1/2示于表3中。
表3.对于部分化合物所获得的T
1/2
注:NA表示基本不代谢;“/”表示未测。
由表3数据可见,本发明的化合物在人、大鼠、豚鼠中都具有较好的代谢稳定性。
实施例D:大鼠的药代动力学(PK)分析
本发明优选上述实施例中的若干化合物及其对照化合物D1、D2进行大鼠药物代谢动力学实验,相关实验情况如下:
大鼠:SD大鼠,SPF级,6只,雄性,体重范围180-200g(来源&合格证号:由海谱生物提供);
给药方式:PO/IV
给药剂量:PO/IV:1mg/kg
制剂:PO组DMSO溶解,加入4%Tween80,超声10min溶解;
IV组乙醇和PEG400,超声5min,加入所需体积的纯水,超声5min溶解。
混悬液取上、中、下层各2份,澄清溶液取中层2份,每份准确吸取100μL至1.5mLEP管,在给药前取样,取样后置于-80℃冰箱保存,随血浆样品一起送样生物分析检测。
取样点:PO组取血时间点为0.167、0.5、1、2、3、4、6、8、10和24h;
IV组取血时间点为0.033、0.167、0.5、1、2、4、6、8、10和24h。
PO组动物给药前通宵禁食不禁水,给药后4h返还食物,IV组全程不禁食不禁水;
样品处理:
1、两组大鼠给药后,根据采样时间点,从大鼠颈静脉收集血液,每个时间点采集约0.2-0.3mL血液于抗凝EP管中(内含4μL EDTA-K2,375mg/mL),缓慢上下倒置3次,置于冰盒内保存(不超过30分钟),
2、在4℃下使用3500×g离心10分钟,移取上清液至标记的EP管中,样本需储存在-80℃。
3、使用Tolbutamide为内标化合物(IS),对样品进行蛋白沉淀提取。样品提取物用LC-MS/MS系统进行分析,该系统运用Sciex Exion LC AD高效液相色谱系统以及XBridge BEH C18(2.1×50mm,2.5μm)色谱柱进行梯度洗脱,AB Sciex Qtrap 4500质谱进行分析。质谱使用电喷雾离子源(ESI)正离子模式监测Tolbutamide,其母离子→子离子质荷比(m/z)分别为433→263.2和271.1→155。
数据分析:
数据将使用WinNonlin(version 5.2.1 Pharsight,Mountain View,CA)通过非房室模型进行分析,得到PK参数(根据不同给药途径选择C
max,T
max,AUC
last,T
1/2,F等参数)。结果示于表4中。
表4部分化合物在动物体内的药代动力学参数表
注:C
max表示达峰浓度,T
max表示达峰时间,T
1/2表示消除半衰期,AUC
last表示从0时间到最后一个可定量时间点的血浆浓度-时间曲线下面积,F表示生物利用度,“/”表示未测。
结论:由上表可知,本发明化合物的药代动力学性质较好,其中,大部分化合物的生物利用度较高,部分化合物在C
max、T
1/2方面的表现也较好。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (15)
- 一种如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物;R 2-1选自无取代或任选被一个、两个或更多个Ra取代的下列基团:C 1~C 20烷基、C 3~C 20环烷基、3-20元杂环基、C 6~C 20芳基、5-20元杂芳基;每个Ra相同或不同,彼此独立地选自卤素、OH、CN、NO 2、氧代(=O)、COOH、 无取代或任选被一个、两个或更多个Ra1取代的下列基团:C 1~C 20烷基、C 3~C 20环烷基、C 1~C 20烷氧基、C 1~C 20烷硫基、-C(=O)-C 1~C 20烷基、-C(=O)-OC 1~C 20烷基、-O-C(=O)-C 1~C 20烷基、-SO 2-C 1~C 20烷基、-S(=O)-C 1~C 20烷基、3-20元杂环基、C 6~C 20芳基、5-20元杂芳基、NH 2;每个Ra1相同或不同,彼此独立地选自卤素、OH、COOH、CN、NO 2、氧代(=O),无取代或任选被一个、两个或更多个Ra2取代的下列基团:C 1~C 20烷基、C 3~C 20环烷基、C 1~C 20烷氧基、NH 2;每个Ra2相同或不同,彼此独立地选自卤素、OH、CN、NO 2、氧代(=O)、C 1~C 20烷基、C 1~C 20烷氧基;R 2-2选自氢、卤素、OH、CN、NO 2,无取代或任选被一个、两个或更多个Rb取代的下列基团:C 1~C 20烷基、C 1~C 20烷氧基;每个Rb相同或不同,彼此独立地选自卤素、OH、CN、NO 2;R 3-1选自卤素、OH、CN、NO 2,无取代或任选被一个、两个或更多个Rc取代的下列基团:C 1~C 20烷基、C 1~C 20烷氧基或C 3~C 20环烷基;每个Rc相同或不同,彼此独立地选自卤素、OH、CN、NO 2;n选自0、1、2、3或4;优选地,R 2为 或为 其中,R 2-1如上述所定义,R 2-3选自卤素、OH、CN、NO 2,无取代或任选被一个、两个或更多个Rb取代的下列基团:C 1~C 20烷基、C 1~C 20烷氧基;每个Rb相同或不同,彼此独立地选自卤素、OH、CN、NO 2;优选地,R 2-1为C 1~C 10烷基、被一个或多个R 2-1a取代的C 1~C 10烷基、C 3~C 10环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、被一个或多个R 2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、C 6~C 10芳基、被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~10元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~10元杂芳基”;R 2-3为卤素、OH、C 1~C 10烷基、C 1~C 10烷氧基;R 2-1a独立地为C 3~C 6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-1c、R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个或多个R 2-1c-1取代的C 1~C 6烷基、C 1~C 6 烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3、 C 3~C 10环烷基,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基;R 2-1c-1、R 2-1c-2和R 2-1c-3独立地为卤素、OH、COOH、CN、NO 2、氧代(=O),无取代或任选被一个、两个或更多个Ra2取代的下列基团:C 1~C 6烷基、C 1~C 6烷氧基、NH 2;每个Ra2相同或不同,彼此独立地选自卤素、OH、CN、NO 2、氧代(=O)、C 1~C 6烷基、C 1~C 6烷氧基、C 3~C 6环烷基;n为0、1、2或3;R 3-1独立地为卤素、羟基、氰基、C 1~C 6烷基、卤素取代的C 1~C 6烷基、C 1~C 6烷氧基或C 3~C 10环烷基。
- 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,R 2-1为H、C 1~C 10烷基、被一个或多个R 2-1a取代的C 1~C 10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、被一个或多个R 2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、C 6~C 10芳基、被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 2-2选自氢、卤素、OH、C 1~C 6烷基、C 1~C 6烷氧基;R 2-1a独立地为C 3~C 6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-1c、R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个或多个R 2-1c-1取代的C 1~C 6烷基、C 1~C 6烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3、 C 3~C 6环烷基,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~6元杂环烷基;R 2-1c-1独立地为卤素、NH 2、C 3~C 6环烷基;R 2-1c-2和R 2-1c-3独立地为NH 2或C 1~C 6烷基;n为0、1、2或3;R 3-1独立地为卤素、羟基、氰基、C 1~C 6烷基、卤素取代的C 1~C 6烷基、C 1~C 6烷氧基或C 3~C 6环烷基;优选地,R 2-1为C 1~C 10烷基、被一个或多个R 2-1a取代的C 1~C 10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、C 6~C 10芳基、被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;和/或,R 2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;和/或,R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个或多个R 2-1c-1取代的C 1~C 6烷基、C 1~C 6烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3或 优选R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、C 1~C 6烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3或 更优选R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、-C(=O)R 2-1c-2或-S(=O) 2R 2-1c-3;和/或,R 2-1c-2和R 2-1c-3独立地为C 1~C 6烷基;和/或,R 3-1独立地为卤素。
- 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,所述的如式I所示的化合物为以下任一方案:方案1:R 2-1为C 1~C 10烷基、被一个或多个R 2-1a取代的C 1~C 10烷基、C 3~C 10环烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、C 6~C 10芳基、被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 2-2为氢、C 1~C 6烷基、C 1~C 6烷氧基;R 2-1a独立地为C 3~C 6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个或多个R 2-1c-1取代的C 1~C 6烷基、C 1~C 6烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3、 C 3~C 6环烷基;R 2-1c-1独立地为卤素、NH 2、C 3~C 6环烷基;R 2-1c-2和R 2-1c-3独立地为NH 2或C 1~C 6烷基;n为0、1、2或3;R 3-1独立地为卤素;或者,方案2:R 2-1为C 1~C 10烷基、被一个或多个R 2-1a取代的C 1~C 10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、C 6~C 10芳基、被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 2-2为氢、C 1~C 6烷基;R 2-1a独立地为C 3~C 6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个或多个R 2-1c-1取代的C 1~C 6烷基、C 1~C 6烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3或 C 3~C 6环烷基;R 2-1c-1独立地为卤素、NH 2、环丙基;R 2-1c-2和R 2-1c-3独立地为NH 2或C 1~C 6烷基;n为0、1、2或3;R 3-1独立地为卤素;或者,方案3:R 2-1为C 1~C 10烷基、被一个或多个R 2-1a取代的C 1~C 10烷基、“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、C 6~C 10芳基、被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、 或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 2-2为氢、C 1~C 6烷基;R 2-1a独立地为C 3~C 6环烷基或“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、C 1~C 6烷氧基、被一个、两个或多个R 2-1c-1取代的C 1~C 6烷基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3、 C 3~C 6环烷基;R 2-1c-2和R 2-1c-3独立地为NH 2或C 1~C 6烷基;R 2-1c-1独立地为卤素、NH 2、环丙基;n为0、1、2或3;R 3-1独立地为卤素;或者,方案4:R 2-1为被一个或多个R 2-1a取代的C 1~C 10烷基、被一个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 2-2为氢、C 1~C 3烷基;R 2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个、两个或多个R 2-1c-1取代的C 1~C 6烷基、C 1~C 6烷氧基、-C(=O)R 2-1c-2、-S(=O) 2R 2-1c-3、 环丙烷;R 2-1c-1独立地为卤素、NH 2、环丙基;R 2-1c-2和R 2-1c-3独立地为C 1~C 6烷基;n为0、1、2或3;R 3-1独立地为卤素;或者,方案5:R 2-1为被一个或多个R 2-1d取代的C 6~C 10芳基、“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;R 2-2为氢、甲基;R 2-1d和R 2-1e独立地为氰基、卤素、C 1~C 6烷基、被一个、两个或多个R 2-1c-1取代的C 1~C 6烷基、-C(=O)R 2-1c-2或-S(=O) 2R 2-1c-3;R 2-1c-1独立地为卤素、NH 2、环丙基;R 2-1c-2和R 2-1c- 3独立地为C 1~C 6烷基;n为0、1、2或3;R 3-1独立地为卤素。
- 如权利要求1所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,当R 2-1为C 1~C 10烷基、或被一个或多个R 2-1a取代的C 1~C 10烷基时,所述的C 1~C 10烷基为C 1~C 6烷基;和/或,当R 2-1为“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、或被一个或多个R 2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O、 S和S(=O) 2中的一种或多种的3~10元杂环烷基”为“杂原子数为1个或2个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~8元杂环烷基”;和/或,当R 2-1为C 6~C 10芳基、或被一个或多个R 2-1d取代的C 6~C 10芳基时,所述的C 6~C 10芳基为苯基;和/或,当R 2-1为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”;和/或,当R 2-2为C 1~C 6烷基时,所述的C 1~C 6烷基可为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,当R 2-1a独立地为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙基、环丁基、环戊基或环己基;和/或,当R 2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”为“杂原子数为1个或2个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”;和/或,当R 2-1c、R 2-1d和R 2-1e独立地为卤素时,所述的卤素为氟、氯、溴或碘;和/或,当R 2-1c、R 2-1d和R 2-1e独立地为C 1~C 6烷基、或被一个或多个R 2-1c-1取代的C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,当R 2-1c、R 2-1d和R 2-1e独立地为C 1~C 6烷氧基时,所述的C 1~C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基;和/或,当R 2-1c-2和R 2-1c-3独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,当R 3-1独立地为卤素、或被卤素取代的C 1~C 6烷基时,所述的卤素为氟、氯、溴或碘;和/或,当R 3-1独立地为C 1~C 6烷基、或被卤素取代的C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,当R 3-1独立地为C 1~C 6烷氧基时,所述的C 1~C 6烷氧基为甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基;和/或,当R 3-1独立地为C 3~C 6环烷基时,所述的C 3~C 6环烷基为环丙基、环丁基、环戊基或环己基。
- 如权利要求4所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物,其特征在于,当R 2-1为C 1~C 10烷基、或被一个或多个R 2-1a取代的C 1~C 10烷基时,所述的C 1~C 10烷基为甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;和/或,当R 2-1为“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”、或被一个或多个R 2-1c取代的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O、S和S(=O) 2中的一种或多种的3~10元杂环烷基”为氧杂环丁烷、四氢呋喃基、四氢吡喃基、吡咯烷基、哌啶基、2-氮杂双环[2.2.1]庚烷、3-氮杂双环[3.1.1]庚烷基、3-氮杂双环[2.2.2]辛烷基或四氢噻吩-1,1-二氧化物,例如和/或,当R 2-1为C 6~C 10芳基、或被一个或多个R 2-1d取代的C 6~C 10芳基时,所述的C 6~C 10芳基可为苯基;和/或,当R 2-1为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”、或被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”为“杂原子数为1个或2个,杂原子为N的5~6元杂芳基”,例如吡唑基、咪唑基或吡啶基, 又例如和/或,当R 2-1a独立地为C 3~C 6环烷基时,所述的C 3~C 6的环烷基为环丙基、环丁基或环戊基;和/或,当R 2-1a独立地为“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”时,所述的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的3~6元杂环烷基”为“杂原子数为1个或2个,杂原子为O的3~6元杂环烷基”,例如氧杂环丁烷基或四氢呋喃基,又例如和/或,当R 2-1c、R 2-1d和R 2-1e独立地为卤素时,所述的卤素为氟或氯;和/或,当R 2-1c、R 2-1d和R 2-1e独立地为C 1~C 6烷基、或被一个或多个R 2-1c-1取代的C 1~C 6烷基时,所述的C 1~C 6烷基为甲基、乙基、丙基;和/或,当R 2-1c、R 2-1d和R 2-1e独立地为C 3~C 10环烷基时,所述的C 3~C 10环烷基为环丙基、环丁基、环戊基。和/或,当R 2-1c、R 2-1d和R 2-1e独立地为C 1~C 6烷氧基时,所述的C 1~C 6烷氧基为甲氧基;和/或,当R 2-1c-1为C 3~C 6烷基时,所述的C 3~C 10环烷基为环丙基;和/或,当R 2-1c-2和R 2-1c-3独立地为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基;和/或,当R 2-2为C 1~C 6烷基时,所述的C 1~C 6烷基为甲基;和/或,当R 3-1独立地为卤素、或被卤素取代的C 1~C 6烷基时,所述的卤素为氟或氯。
- 如权利要求5所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体或其同位素化合物,其特征在于,和/或,当R 2-1为被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”时,所述的被一个或多个R 2-1e取代的“杂原子数为1个、2个或3个,杂原子选自N、O和S中的一种或多种的5~6元杂芳基”为
- 一种药物组合物,其包含物质A和至少一种药用辅料;所述的物质A为如权利要求1-8中任一项所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
- 一种物质A在制备P2X4受体拮抗剂或药物中的应用;所述的物质A为如权利要求1-8中任一项所述的如式I所示的化合物、其药学上可接受的盐、其立体异构体、其互变异构体、其同位素化合物、其晶型、其氮氧化物、其溶剂合物或其药学上可接受的盐的溶剂合物。
- 如权利要求12所述的应用,其特征在于,所述的药物用于治疗或预防动物的泌尿道疾病、呼吸系统疾病、疼痛相关的疾病、自身免疫病、炎症、睡眠障碍、精神疾病、关节炎、神经退行性疾病、外伤性脑损伤、血栓症、消化道疾病、性功能障碍、心血管系统疾病、子宫内膜异位、肌肉骨骼和结缔组织发育障碍、癌症或眼科疾病。
- 如权利要求12所述的应用,其特征在于,所述的药物用于预防或治疗动物的至少部分由P2X4介导的疾病;所述的至少部分由P2X4介导的疾病可为泌尿道疾病、呼吸系统疾病、疼痛相关的疾病、自身免疫病、炎症、睡眠障碍、精神疾病、关节炎、神经退行性疾病、外伤性脑损伤、血栓症、消化道疾病、性功能障碍、心血管系统疾病、子宫内膜异位、肌肉骨骼和结缔组织发育障碍、癌症或眼科疾病。
- 如权利要求13或14所述的的应用,其特征在于,所述的泌尿道疾病为尿失禁、膀胱过度活动症、排尿困难或膀胱炎;和/或,所述的呼吸系统疾病为呼吸障碍,例如呼吸衰竭、特发性肺纤维化、慢性阻塞性肺病、哮喘、支气管痉挛、咳嗽(如慢性咳嗽);和/或,所述的疼痛相关的疾病为炎性疼痛、手术疼痛、内脏疼痛、牙痛、经前期疼痛、中枢性疼痛、由灼伤所致疼痛、偏头痛、簇性头痛、慢性疼痛或瘙痒;和/或,所述的神经退行性疾病为老年痴呆症、帕金森、癫痫或脑卒中;和/或,所述的心血管系统疾病为心肌梗死、动脉粥样硬化、心衰、高血压或血液病;和/或,所述的消化道疾病为结肠综合症、炎性肠病或胃肠功能紊乱;和/或,所述的自身免疫病为关节炎,例如类风湿性关节炎。和/或,所述的眼科疾病为干眼综合症、干眼症、眼神经疼痛、眼外伤和术后眼部疼痛。
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CN107848974A (zh) * | 2015-06-10 | 2018-03-27 | 拜耳制药股份公司 | 芳族磺酰胺衍生物 |
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WO2018104305A1 (en) * | 2016-12-09 | 2018-06-14 | Bayer Pharma Aktiengesellschaft | Field of application of the invention |
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