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CN114539256B - Tricyclic compounds and medical uses thereof - Google Patents

Tricyclic compounds and medical uses thereof Download PDF

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CN114539256B
CN114539256B CN202111375827.7A CN202111375827A CN114539256B CN 114539256 B CN114539256 B CN 114539256B CN 202111375827 A CN202111375827 A CN 202111375827A CN 114539256 B CN114539256 B CN 114539256B
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CN114539256A (en
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余健
李文明
祝伟
邹昊
张超
李云飞
李正涛
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Shanghai Tuojie Biomedical Technology Co ltd
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract

The present disclosure relates to tricyclic compounds and their medical uses. Specifically, the present disclosure provides compounds represented by formula I or pharmaceutically acceptable salts thereof, which have NLRP3 inflammatory inhibitory activity and are useful for treating or preventing NLRP 3-related diseases.

Description

Tricyclic compounds and medical uses thereof
Technical Field
The present disclosure relates to the field of medicine, and in particular to tricyclic compounds and their medical uses.
Background
NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP 3) is a protein-encoding gene that belongs to the family of nucleotide binding and oligomerization domain-like receptors (NLRs), also known as "pus-containing domain protein 3" (Inoue et al, immunology,2013, 139, 1-18). The gene encodes a protein comprising a pyridine domain, a nucleotide binding site domain (NBD) and a Leucine Rich Repeat (LRR) motif. NLRP3 interacts with adapter proteins, apoptosis-related spotting proteins (ASCs), and zymogen-1 in response to sterile inflammatory risk signals to form NLRP3 inflammasomes. Activation of the NLRP3 inflammasome then leads to the release of the inflammatory cytokines IL-1b and IL-18, which, when the activation of the NLRP3 inflammasome is deregulated, drives the onset of many diseases.
Studies have shown that activation of NLRP3 inflammasome is associated with a variety of diseases, including: inflammatory-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and auto-inflammatory diseases. Thus, there is a need to provide new NLRP3 inflammatory body pathway inhibitors to provide new alternatives to the treatment of the above-mentioned diseases.
Disclosure of Invention
In a first aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from aromatic or heteroaromatic rings, ring B is selected from 4-8 membered carbocycle or heterocycle, and ring C is selected from 3-8 membered carbocycle or heterocycle; and ring B and ring a are connected by 2 common atoms, and ring C and ring B are connected by 2,3 or 4 common atoms;
ring D is selected from
X is selected from CR 5 Or N, Y is selected from O or NR 6 ；
R 1 、R 2 、R 3 And R is 4 : i) Independently selected from hydrogen, deuterium, halogen, -OR 7a 、-SR 7a 、-C(＝O)R 7a 、-OC(＝O)R 7a 、-C(＝O)OR 7a 、-C(＝O)NR 7a R 7b 、-NR 7a R 7b 、-NR 7a C(＝O)R 7b 、-NR 7a S(＝O) 2 R 7b 、-S(＝O) 2 R 7a 、-S(＝O) 2 NR 7a R 7b -CN, -NO2, or the following optionally substituted with one or more substituents: c (C) 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heteroaryl, heterocyclyl, said substituents being selected from the group consisting of: deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen;
alternatively, ii) R 1 And R is 2 Composed ofGroup R 3 And R is 4 A group consisting of carbocycles, heterocycles, aryl or heteroaryl groups, respectively, with the carbon atoms to which they are attached, said carbocycles, heterocycles, aryl or heteroaryl groups being optionally substituted with: deuterium, halogen, -OR 9a 、-SR 9a 、-C(＝O)R 9a 、-OC(＝O)R 9a 、-C(＝O)OR 9a 、-C(＝O)NR 9a R 9b 、-NR 9a R 9b 、-NR 9a C(＝O)R 9b 、-NR 9a S(＝O) 2 R 9b 、-S(＝O) 2 R 9a 、-S(＝O) 2 NR 9a R 9b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen;
alternatively, iii) R 1 And R is 2 Independently selected from the groups described in i), R 3 And R is 4 The group consisting of forms, with the carbon atom to which they are attached, a carbocycle, heterocycle, aryl or heteroaryl group, said carbocycle, heterocycle, aryl or heteroaryl group being optionally substituted with a group as set forth in ii);
R 5 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl methylene, said C 1-4 Alkyl, C 3-6 Cycloalkyl and C 3-6 Cycloalkyl methylene groups are optionally substituted with one or more of the following substituents: deuterium, halogen, -OR 5a or-NR 5a R 5b ；
R 6 Selected from hydrogen, deuterium, -CN, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl methylene, said C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl methylene groups are optionally substituted with one or more deuterium or halogen;
R 5a 、R 5b independently selected from hydrogen, deuterium, or C optionally substituted with one or more of deuterium or halogen 1-4 An alkyl group;
R 7a 、R 7b independently selected from hydrogen, deuterium, or optionally taken by one or moreThe substituents substituted with the following groups: c (C) 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl methylene, aryl, heteroaryl or heterocyclyl, said substituents being selected from: deuterium, halogen, -NH 2 、-OH、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl methylene, said substituents optionally further substituted with one or more deuterium or halogen;
R 8a 、R 8b 、R 9a 、R 9b independently selected from hydrogen, deuterium, or the following groups optionally substituted with one or more substituents: c (C) 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl methylene, said substituents being selected from: deuterium, halogen, -NH 2 、-OH、-CN、C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl methylene, said substituents optionally further substituted with one or more deuterium or halogen;
in some embodiments, ring a, ring B, and ring C consist of:
wherein R is 10a Independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl methylene, optionally substituted with one or more deuterium or halogen;
R 10b selected from hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl methylene, optionally substituted with one or more deuterium or halogen; m is an integer selected from 1-3.
In some embodiments, ring a, ring B, and ring C consist of:
wherein R is 10a As defined above; r is R 11a Is a substituent of ring B, R 11a Independently selected from hydrogen, deuterium, halogen or C optionally substituted with one or more halogens 1-4 An alkyl group; n is an integer selected from 0-8.
In other embodiments, ring a, ring B, and ring C consist of:
R 12a 、R 12b 、R 12c 、R 12d independently selected from hydrogen, deuterium or halogen.
In some embodiments of the disclosure, Y is selected from O.
In yet other embodiments, Y is selected from NR 6 ，R 6 Selected from hydrogen, deuterium, CN or C optionally substituted by one or more of deuterium or halogen 1-6 An alkyl group; preferably hydrogen or-CN.
In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is selected from:
wherein ring D is as defined for the compounds of formula I.
In some embodiments, in the compound of formula I or formula II-a to formula II-t or a pharmaceutically acceptable salt thereof, X is selected from CR 5 ，R 5 Selected from hydrogen, deuterium, halogen or C 1-4 Alkyl, said C 1-4 The alkyl group is optionally substituted with one or more of the following substituents: deuterium, halogen, -OR 5a or-NR 5a R 5b 。
In other embodiments, X is selected from N.
In some embodiments, in a compound of formula I or formula II-a to formula II-t, or a pharmaceutically acceptable salt thereof, R 1 、R 2 、R 3 And R is 4 Independently selected from hydrogen, deuterium, halogen, -OR 7a 、-SR 7a 、-CN、-NO 2 Or the following optionally substituted with one or more substituents: c (C) 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heteroaryl, heterocyclyl, said substituents being selected from the group consisting of: deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen; the R is 7a 、R 8a And R is 8b As defined for the compounds of formula I.
In some embodiments, R 1 And R is 3 Independently selected from hydrogen or deuterium, R2 and R4 are independently selected from the following group C optionally substituted with one or more substituents 1-6 An alkyl, aryl or heteroaryl group, said substituents being selected from the group consisting of: deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R 1 And R is 3 Independently selected from hydrogen or deuterium, R2 and R4 are independently selected from C optionally substituted with one or more substituents 1-6 Alkyl, said substituents being selected from: deuterium, halogen, -OR 8a 、-SR 8a 、-NR 8a R 8b -CN or-NO 2 。
In other embodiments, ring D is selected from:
in other embodiments, in a compound of formula I or formula II-a through formula II-t, or a pharmaceutically acceptable salt thereof, R 1 And R is 2 Independently selected from hydrogen, deuterium, halogen, -OR 7a 、-SR 7a 、-CN、-NO 2 Or the following optionally substituted with one or more substituents: c (C) 1-6 Alkyl, C 3-10 Cycloalkyl, aryl, heteroaryl, heterocyclyl, said substituents being selected from the group consisting of: deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen; the R is 8a And R is 8b As defined for compounds of formula I;
R 3 and R is 4 The group consisting of and to which they are connectedForms a carbocycle, heterocycle, aryl or heteroaryl, said carbocycle, heterocycle, aryl or heteroaryl being optionally substituted with: deuterium, halogen, C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R 3 And R is 4 The group consisting of forms, with the carbon atom to which they are attached, a 3-to 7-membered carbocyclic or heterocyclic ring, which is optionally substituted with: deuterium, halogen or C 1-4 Alkyl, said C 1-4 The alkyl group is optionally further substituted with one or more deuterium or halogen.
In some embodiments, R 1 Selected from hydrogen or deuterium, R 2 Selected from the following groups optionally substituted with one or more substituents: c (C) 1-6 An alkyl, aryl, heteroaryl or heterocyclyl group, said substituents being selected from the group consisting of: deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R 1 Selected from hydrogen or deuterium, R 2 Selected from aryl or heteroaryl optionally substituted with one or more substituents selected from: deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R 2 Selected from:
wherein R is 2a 、R 2b Independently selected from hydrogen, deuterium, halogen, -OR 8a 、-SR 8a 、-C(＝O)R 8a 、-OC(＝O)R 8a 、-C(＝O)OR 8a 、-C(＝O)NR 8a R 8b 、-NR 8a R 8b 、-NR 8a C(＝O)R 8b 、-NR 8a S(＝O) 2 R 8b 、-S(＝O) 2 R 8a 、-S(＝O) 2 NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen; r is R 2c Selected from hydrogen or C optionally substituted by one or more deuterium or halogen 1-4 An alkyl group;
p is an integer selected from 1-5, q is an integer selected from 1-4.
In some embodiments, R 2a 、R 2b Independently selected from hydrogen, deuterium, halogen, -OR 8a 、-SR 8a 、-NR 8a R 8b 、-CN、-NO 2 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, ring D is selected from:
in other embodiments, R 1 And R is 2 Group of, and R 3 And R is 4 A group consisting of carbocycles or heterocycles, respectively, with the carbon atoms to which they are attached, said carbocycles and heterocycles being optionally substituted with: deuterium, halogen, -OR 9a 、-SR 9a 、C 1-4 Alkyl or C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen; the R is 9a 、R 9b As defined for the compounds of formula I.
In some embodiments, R 1 And R is 2 Group of, and R 3 And R is 4 The group consisting of, respectively, carbon atoms to which they are attached form a carbocycle, which carbocycle is optionally substituted with: deuterium, halogen or C 1-4 Alkyl, said C 1-4 The alkyl group is optionally further substituted with one or more deuterium or halogen.
In some embodiments, ring D is selected from:
in a second aspect, the present disclosure also provides a series of compounds, or pharmaceutically acceptable salts thereof, selected from the group consisting of:
in a third aspect, the present disclosure also provides a series of compounds, or pharmaceutically acceptable salts thereof, selected from:
in a fourth aspect, the present disclosure also provides a pharmaceutical composition comprising a compound according to the first or second or third aspect, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.
In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of the foregoing compound, or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the foregoing compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of the compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1% to 99% of the compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2% to 98% of the compound or pharmaceutically acceptable salt thereof.
In a fifth aspect, the present disclosure also provides the use of a compound according to the first or second or third aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the fourth aspect, in the manufacture of a medicament for treating a disease associated with NLRP3 activity.
The present disclosure also provides a method of treating a patient suffering from a disease associated with NLRP3 activity by administering to the patient a therapeutically effective amount of a compound according to the first or second or third aspects of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the fourth aspect.
Diseases associated with NLRP3 activity include inflammatory-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or auto-inflammatory diseases.
The present disclosure also provides the use of a compound according to the first or second or third or fourth aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the fifth aspect, in the manufacture of a medicament for the treatment of an inflammatory-related disease, an immune disease, an inflammatory disease, an autoimmune disease and/or an autoinflammatory disease.
The present disclosure also provides a method of treating a patient suffering from an inflammatory-related disease, an immune disease, an inflammatory disease, an autoimmune disease and/or an auto-inflammatory disease by administering to the patient a therapeutically effective amount of a compound of the first or second or third aspects of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the fourth aspect. The inflammatory-related disease, immune disease, inflammatory disease, autoimmune disease and/or auto-inflammatory disease may be specifically selected from: autoinflammatory fever syndrome (e.g., cold-related periodic syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis-related diseases (e.g., gout, chondrocalcification, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (e.g., hyperoxalic acid urine disease, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, type I or type II diabetes and complications thereof (e.g., nephrosis, retinopathy)), neuroinflammation-related diseases (e.g., brain infection, acute injury, multiple sclerosis, alzheimer's disease, and neurodegenerative disease), cardiovascular and metabolic-related disorders or diseases (e.g., reduced risk of cardiovascular disease (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral Arterial Disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g., acne, adenosis), sarcoidosis, hyperplasia, cancer, myelodysplasia (e.g., myelosis), myelosis, cancer (e.g., myelosis).
Pharmaceutically acceptable salts of the compounds of the present disclosure are selected from inorganic salts or organic salts, and the compounds of the present disclosure can be reacted with acidic or basic substances to the corresponding salts.
In another aspect, the compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure.
In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of tautomers are between a and B as shown below.
All compounds in the present disclosure may be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.
The compounds of the present disclosure may be asymmetric, e.g., have one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. The present disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "optionally halogen-or cyano-substituted C1-6 alkyl" means that halogen or cyano may be, but need not be, present, and that the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.
In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations. Although all of the above structural formulae are depicted as certain isomeric forms for simplicity, the present disclosure may includeAll isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
Term interpretation:
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
"pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary agent, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl group,C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
"carbocycle" refers to a saturated or partially unsaturated, monocyclic or polycyclic, cyclic hydrocarbon group containing from 3 to 20 carbon atoms, preferably containing from 3 to 8 carbon atoms. The carbocycle may be further fused to an aromatic ring, a heteroaromatic ring, a heterocyclic ring, a cyclic hydrocarbon, and when fused to a heteroaromatic ring or a heterocyclic ring, the fused bonds do not contain heteroatoms at either end.
"heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:
etc.
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from, for example, halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The heterocyclyl ring may be fused to an aromatic, heteroaromatic or cyclic hydrocarbon wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
etc.
"aryl" or "aromatic ring" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroAryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The aryl ring may be fused to a heteroaryl ring, a heterocycle, or a cyclic hydrocarbon, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
"heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples of which include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine,etc.
Examples of heteroaryl groups containing nitrogen atoms include, but are not limited to, pyrrolyl, piperazinyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazinyl, tetrazolyl, triazolyl, pyridinyl, pyrazolyl, oxazolyl, thiazolyl, and the like.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy, C 2-6 Alkynyloxy, C 3-6 Cycloalkyl, 3-to 6-membered heterocycloalkyl, C 5-8 Cycloalkenyl, C 3-6 Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C 5-8 Cycloalkenyloxy, C 6-10 Aryl or 5-to 6-membered heteroaryl optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The heteroaryl ring may be fused to an aromatic ring, a heterocyclic ring, or a cyclic hydrocarbon, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
"halogen" means fluorine, chlorine, bromine or iodine.
Detailed Description
The present disclosure is further described below in connection with examples, which are not intended to limit the scope of the disclosure.
Experimental methods for which specific conditions are not noted in the examples in this disclosure are generally in accordance with conventional conditions, or in accordance with conditions recommended by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS). The optical isomer (isomer) spatial configuration of the compound can be further confirmed by measuring parameters of the single crystal.
HPLC was performed using Waters ACQUITY ultra high performance LC, shimadzu LC-20A systems, shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatography (ACQUITY UPLC BEH C18.1.7UM 2.1X50MM column, ultimate XB-C183.0.150 mm column or Xtime C18.2.1.30 mm column).
The MS was measured by using a Waters SQD2 mass spectrometer, scanning in positive/negative ion mode, and the mass scanning range was 100-1200.
Chiral HPLC analysis was performed using a chiral HPLC analysis of 3um, chiral pak AD-3X 4.6mm I.D.,3um, chiral pak AS-3 150X 4.6mm I.D.,3um, chiral pak AS-3X 4.6mm I.D.,3um, chiral pak OD-3X 4.6mm I.D.,3um, chiral Cel OJ-H150X 4.6mm I.D.,5um, chiral Cel OJ-3X 4.6mm I.D.,3um column;
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Flash column purification systems used Combiflash Rf150 (teldyne ISCO) or isolaraone (Biotage).
The forward column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh of yellow sea silica gel as a carrier, or uses Santai prefill of Changzhou to prefill ultra-pure phase silica gel column (40-63 μm,60, 12g, 25g,40g,80g or other specifications).
Reverse phase column chromatography typically uses a three-teng prep-packed ultrapure C18 silica gel column (20-45 μm,40g,80g,120g,220g or other specifications).
The high pressure Column purification system uses Waters AutoP, in combination with Waters XBridge BEH C OBD Prep Column,5 μm,19mm X150 mm or Atlantis T3OBD Prep Column, +.>5μm，19mm X 150mm。
Chiral preparative columns used DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 um) or Phenomnex-Amylose-1 (250 mm. Times.30 mm,5 um).
Known starting materials in the present disclosure may be synthesized using or following methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shao far chemistry (Accela ChemBio Inc), dary chemicals, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The microwave reaction used was a CEM Discover-S908860 type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The reaction progress in the examples was monitored by Thin Layer Chromatography (TLC).
Example 1
Step 1: synthesis of cyclopropane-1, 2-diyl dimethanol (Compound 2 b)
A solution of compound 2a (5 g,44.61 mmol) in tetrahydrofuran (150 mL) was cooled to 0deg.C, lithium aluminum hydride (3.39 g,89.22 mmol) was slowly added and the mixture stirred at 0deg.C for 1 hour and then stirred at 70deg.C for complete reaction. After the mixture was cooled to room temperature, it was quenched by pouring into ice water (50 mL), extracted with dichloromethane (60 ml×3), and the combined organic phases were washed with brine (30 ml×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to give the crude product. Purification by flash column chromatography (eluent: 40-80% ethyl acetate in petroleum ether) afforded compound 2b (2.92 g, 64% yield).
1H NMR:(400MHz,CDCl3)δppm 4.24-3.97(m,2H),3.26(br t,J＝10.4Hz,2H),2.85(br s,2H),1.44-1.26(m,2H),0.82(dt,J＝5.2,8.0Hz,1H),0.22(q,J＝5.2Hz,1H)
Step 2: synthesis of cyclopropane-1, 2-diylbis (methylene) dimesylate (Compound 2 c)
A solution of compound 2b (2.9 g,28.40 mmol) and triethylamine (15.79 mL,113.6 mmol) in dichloromethane (40 mL) was cooled to 0deg.C, then methanesulfonyl chloride (5.06 mL,65.3 mmol) was added dropwise and the mixture was stirred at room temperature to react well. The mixture was poured into ice water (100 mL), extracted with dichloromethane (60 ml×3), the combined organic phases were washed with brine (30 ml×3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to give compound 2c (7.0 g, yield 95%).
1H NMR:(400MHz,CDCl3)δppm 4.61-4.38(m,2H),4.20-4.04(m,2H),3.06(s,6H),1.66-1.48(m,2H),1.15-1.07(m,1H),0.56(q,J＝5.6Hz,1H).
Step 3: synthesis of 5a, 6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxaazepine (Compound/racemate 2 d)
Compound 1a (2.28 g,27.10 mmol), potassium carbonate (9.36 g,67.74 mmol) and compound 2c (7.0 g,27.10 mmol) were mixed in DMF (160 mL) and the mixture was allowed to react thoroughly under stirring at 100deg.C under nitrogen. After cooling to room temperature, brine (300 mL) was added, extracted with ethyl acetate (200 ml×3), and the combined organic phases were washed with brine (150 ml×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude product. Purification by flash column chromatography (eluent: 0-30% ethyl acetate in petroleum ether) afforded compound 2d (1.5 g, 37% yield).
1H NMR:(500MHz,CDCl3)δppm 7.22(d,J＝2.0Hz,1H),5.52(d,J＝2.0Hz,1H),4.78(dd,J＝7.5,15.0Hz,1H),4.63(dd,J＝5.5,13.0Hz,1H),4.13-3.99(m,2H),1.84-1.72(m,1H),1.64-1.55(m,1H),1.08-0.97(m,1H),0.65(q,J＝5.0Hz,1H)
Step 4: synthesis of 3-bromo-5 a, 6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine (Compound/racemate 2 e)
A solution of compound 2d (700 mg,4.66 mmol) in acetonitrile (15 mL) was cooled to 0deg.C and NBS (871.1 mg,4.89 mmol) was added in portions and the mixture was stirred at room temperature to react well. Ethyl acetate (40 mL) was added to dilute, washed with brine (15 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give crude product, which was purified by flash column chromatography (eluent: 10-35% ethyl acetate in petroleum ether) to give compound (racemate) 2e (1.0 g, yield 94%).
1H NMR:(400MHz,CDCl3)δppm 7.22(s,1H),4.80-4.70(m,2H),4.16-4.06(m,2H),1.84-1.73(m,1H),1.72-1.64(m,1H),1.09-1.02(m,1H),0.72-0.66(m,1H)
LCMS:tR＝0.648min in 5-95AB_1min_220&254_Shimadzu chromatography(Agilent Pursult 5C18 20*2.0mm),MS(ESI)m/z＝229.0/231.0[M+H]+
Step 5: synthesis of 5a, 6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine-3-sulfonamide (Compound/racemate 2 f)
Sulfur dioxide is introduced into tetrahydrofuran (50 mL) at-78deg.C for 15 minutes for further use. Compound 2e (500 mg,2.18 mmol) in tetrahydrofuran (3 mL) was cooled to-78deg.C and n-butyllithium solution (2.5M in n-hexane, 2.62 mL) was slowly added dropwise. Then stirred at-78℃for 30 seconds. Then, a tetrahydrofuran solution (2 mL) containing the sulfur dioxide was added thereto, and the mixture was stirred at-78℃to react well. Quench with water (5 mL), separate the organic layers, extract with water (5 mL. Times.2), collect and combine the aqueous phases. Trisodium citrate dihydrate (1284 mg,4.36 mmol) was added. After cooling the mixture to 10deg.C, a solution of hydroxylamine sulfonic acid (370.25 mg,3.274 mmol) in water (5 mL) was added. The mixture was stirred at room temperature to react well. Extraction with ethyl acetate (20 mL. Times.3), washing the combined organic phases with brine (20 mL), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate in vacuo afforded the crude product, which was purified by flash column chromatography (eluent: 90-100% ethyl acetate in petroleum ether) to give compound (racemate) 2f (40.8 g, yield 8.2%).
LCMS:tR＝0.0.275/0.299min in 5-95AB_1min_220&254_Agilent chromatography(Agilent Pursult 5C18 20*2.0mm),MS(ESI)m/z＝230.1[M+H]+
Step 6: synthesis of N- ((1, 2,3,5,6, 7-hexahydro-s-indacen-4-yl) carbamoyl) -5a, 6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine-3-sulfonamide (Compound/racemate 2)
A solution of compound 2f (20.0 mg,0.087 mmol) in tetrahydrofuran (1.5 mL) was cooled to 0deg.C and sodium hydride (60% mineral oil) (5.24 mg,0.131 mmol) was added under nitrogen. The resulting mixture was stirred at 0deg.C for 5 minutes, then a solution of compound 2g (17.4 mg,0.087 mmol) in tetrahydrofuran (1 mL) was added, and the final mixture was stirred at 0deg.C for complete reaction. Quench with water (3 mL) and adjust ph=2-3 with 30% citric acid solution. Extraction with ethyl acetate (20 mL. Times.2), washing of the combined organic phases with brine (20 mL. Times.2), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate in vacuo afforded the crude product, purification by flash column chromatography [ C-18 column, methanol/water 10-60%) ] followed by lyophilization afforded compound (racemate) 2 (5.8 mg, yield 15.5%).
LCMS:TJN200838-287-1B tR＝1.115min in10-80AB_2min_220&254_Shimadzu chromatography(Xtimate C18,2.1*30mm3um,SN:3U4),MS(ESI)m/z＝429.0[M+H]+
1H NMR(400MHz,D2O)δppm 7.53(s,1H),7.04(s,1H),4.66-4.63(m,2H),4.40-4.18(m,2H),2.83(t,J＝6.8Hz,4H),2.66(t,J＝6.8Hz,4H),2.05-1.92(m,4H),1.86-1.71(m,1H),1.66-1.52(m,1H),1.05-0.95(m,1H),0.80-0.71(m,1H)
Resolution of compound 2 obtained from multiple preparations by chiral Column [ Column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um), condition:40% (0.1% NH) 3 -H 2 O,EtOH),flow rate:80mL/min]Compound 2-1 (rt=2.051 min,7.0 mg) and compound 2-2 (rt=2.234 min,8.2 mg) were obtained.
Compounds 2-1 and 2-2 are each selected from one of the following compounds:
example 2
Step 1: synthesis of 5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine (Compound 1 k)
Compound 1i (150 mg,0.71 mmol) was dissolved in dioxane (2.5 mL), potassium carbonate (288 mg,2.12 mmol), 1j (130 mg,0.85 mmol) and water (0.5 mL) were added, and catalyst Pd (dppf) Cl2 (87.7 mg,0.106 mmol) was added under nitrogen. The mixture was stirred at 80℃for complete reaction. After cooling to room temperature, water (10 mL) was added for dilution, extraction with ethyl acetate (15 mL x 2), and the combined organic phases were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give crude product, which was purified by flash column chromatography (eluent: 5-30% ethyl acetate in petroleum) to give compound 1k (101 mg, yield 58.9%).
1H NMR:(400MHz,CDCl3)δppm 8.22(d,J＝5.2Hz,1H),7.09-6.93(m,2H),6.86(s,1H),6.77(d,J＝7.6Hz,1H),4.00-3.97(m,3H),2.97(t,J＝7.6Hz,2H),2.77(t,J＝7.2Hz,2H),2.17(t,J＝7.2Hz,2H).
ES-LCMS m/z 241.2[M+H]+.
Step 2: synthesis of 4- (4-isocyanato-2, 3-dihydro-1H-inden-5-yl) -2-methoxypyridine (Compound 1 l)
A solution of compound 1k (35 mg,0.146 mmol) and triethylamine (17.69 mg,0.175 mmol) in tetrahydrofuran (2 mL) was cooled to 0deg.C and triphosgene (25.07 mg,0.084 mmol) was added and the mixture was stirred under nitrogen at 70deg.C to react well. After cooling to room temperature, filtration was carried out, and the cake was washed with tetrahydrofuran (5 mL), and the combined filtrates were concentrated under vacuum to give compound 1l (38 mg, yield 98%).
ES-LCMS m/z 299.1[M+MeOH+H]+.
Step 3: synthesis of N- ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5a, 6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine-3-sulfonamide (Compound/racemate) 4
A solution of compound 2f (23.2 mg,0.10 mmol) in tetrahydrofuran was cooled to 0℃and sodium hydride (60% mineral oil) was added under nitrogen. The mixture was stirred at 0deg.C for 15 min, then 1l (30 mg,0.11 mmol) of compound in tetrahydrofuran was added. The resulting mixture was stirred at room temperature under nitrogen to react well. Water was added for dilution, adjusted to ph=3 with citric acid (30%) and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude compound 4 (3.6 mg, yield 5.8%) by purification.
LCMS:tR＝1.720min in 10-80AB_4min_220&254_Shimadzu chromatography(Xtimate C18,2.1*30mm3um,SN:3U41),MS(ESI)m/z＝496.1[M+H]+
1H NMR:(400MHz,DMSO_d6)δppm 8.13(d,J＝5.2Hz,1H),7.83(s,1H),7.42(s,1H),7.21(d,J＝7.2Hz,1H),7.11(d,J＝7.6Hz,1H),6.86(dd,J＝1.2,5.2Hz,1H),6.71(s,1H),4.71(dd,J＝5.6,12.8Hz,1H),4.60(dd,J＝7.2,14.8Hz,1H),4.52-4.37(m,2H),3.87(s,3H),2.91(t,J＝7.2Hz,2H),2.71-2.58(m,2H),2.03-1.94(m,2H),1.82-1.72(m,1H),1.62-1.53(m,1H),0.99-0.92(m,1H),0.83(q,J＝4.8Hz,1H)
Resolution of compound 4 obtained in multiple preparations by chiral Column, [ Column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um), condition:45% (0.1% NH) 3 -H 2 O,EtOH),flow rate:80mL/min]Compound 4-1 (rt=2.309 minutes,13.2 mg) and compound 4b-2 (rt=2.488 minutes,9.7 mg) were obtained.
Compounds 4-1 and 4-2 are each selected from one of the following compounds:
biological evaluation
The following further description explains the present disclosure in connection with test examples, which are not meant to limit the scope of the present disclosure.
Experimental example 1 determination of NLRP3 inflammasome inhibitory Activity in human monocytes
1. Laboratory instrument and reagent
1.1 laboratory apparatus
Plate washer:BioTek 405Select 405TSUS Microplate Washer 96and 384Well w/Ultrasonic(6025)(BioTek,cat#405TSUS)
Plate reader:PerkinElmer 2104EnVision Multilabel Plate Readers
1.2 Experimental reagents
2. Experimental protocol
Day 1: PBMCs were isolated from human blood by density gradient centrifugation and washed twice with PBS containing 2% fbs (300 g centrifugation for 8 min). Monocytes were then isolated from PBMCs using the human pan-monocyte isolation kit and LS column. Cells were stained with CD14-FITC for 30 min at 4℃and FACS was run on BD FACSVerse to analyze the purity of pan-monocytes. Count and adjust cell density to 2.5x10 5 Cells/ml. Seeding cells into 96-well plates, 2.5x10 4 Monocytes/100 mL suspension/well. At 5% CO 2 Incubate overnight at 37 ℃.
Day 2: the test compound was pre-titrated so that all drop points, including DMSO control wells, contained 0.1% DMSO. Media was removed, monocytes were pretreated (by adding 150mL of compound (diluted in serum-free 1640 medium) or DMSO to the respective wells at 5% CO 2 Incubation was performed for 0.5 hours at 37 ℃). The cells were then treated (by adding 25mL of 1640 (serum free) solution containing 700ng/mL LPS (final concentration 100 ng/mL), 5% CO at 37 ℃C 2 Incubation for 3.5 hours). At the end of the 3.5 hour incubation, the cells were stimulated (25 mL of 40mM ATP (final concentration would be 5 mM) was added) and treated for 45 minutes. 80mL of the supernatant was transferred to a new plate and stored at-80 ℃.
Day 3: the supernatant solution was diluted 20-fold for human monocyte IL-1bELISA according to the manufacturer's instructions.
Day 3-4: ELISA experiments
1) Day 3: 100 mL/well capture antibody (diluted with coating buffer) was added to the plate. Seal plates and incubate overnight at 4 ℃.
2) Day 4: the wells were blotted and washed 3 times with 300 uL/. Gtoreq.wash buffer each. After the last wash, the plate was inverted and blotted on absorbent paper to remove any residual buffer.
3) Test dilutions were added to the plates, 200 uL/well. Incubate for 1 hour at room temperature.
4) Blotted/washed as in step 2.
5) Standard and sample dilutions were prepared with test dilutions.
6) Each standard, sample and control was added to the corresponding well, 100 mL/well. Seal plate and incubate at room temperature for 2 hours.
7) Blotting/washing is as in step 2, but 5 washes are performed.
8) The detection antibody was diluted with the assay diluent and added to the wells at 100 mL/well.
9) Seal plate and incubate at room temperature for 1 hour.
10 Blotting/washing as in step 2, but 5 washes.
11 The enzyme reagent was diluted with the test diluent and added to the well at 100 mL/well. Seal plate and incubate at room temperature for 30 minutes.
12 Blotting/washing, using a 30 second-1 minute soak step, for a total of 7 washes.
13 100mL of substrate solution was added to each well. Plates (no plate sealant) were incubated in the dark at room temperature for 30 minutes.
14 Add 50mL of stop solution to each well.
15 Absorbance at 450nm was read by instrument Envision within 30 minutes after stopping the reaction. If wavelength correction is available, the absorbance at 570nm is subtracted from the absorbance at 450 nm.
3. Experimental results

Claims (9)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein, ring a, ring B and ring C consist of:
R 12a 、R 12b independently selected from hydrogen, deuterium, or halogen;
ring D is selected from:
y is selected from O.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from:
wherein ring D is as defined in claim 1.
3. A compound or pharmaceutically acceptable salt thereof selected from:
4. a pharmaceutical composition comprising a compound of claims 1-3, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
5. Use of a compound of claims 1-3, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 4, in the manufacture of a medicament for the treatment of a disease associated with NLRP3 activity.
6. Use of a compound according to claims 1-3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of an inflammatory-related disease.
7. Use of a compound according to claims 1-3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for the treatment of an immune disorder, an inflammatory disorder.
8. Use of a compound according to claims 1-3 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the manufacture of a medicament for autoimmune and/or auto-inflammatory diseases.
9. A compound:
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110366549A (en) * 2017-01-23 2019-10-22 基因泰克公司 Compound as interleukin-1 activity inhibitor
WO2020018975A1 (en) * 2018-07-20 2020-01-23 Genentech, Inc. Sulfonimidamide compounds as inhibitors of interleukin-1 activity
WO2020086732A1 (en) * 2018-10-24 2020-04-30 Novartis Inflammasome Research, Inc. Compounds and compositions for treating conditions associated with nlrp activity
WO2020102576A1 (en) * 2018-11-16 2020-05-22 Novartis Inflammasome Research, Inc. Compounds and compositions for treating conditions associated with nlrp activity

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110366549A (en) * 2017-01-23 2019-10-22 基因泰克公司 Compound as interleukin-1 activity inhibitor
WO2020018975A1 (en) * 2018-07-20 2020-01-23 Genentech, Inc. Sulfonimidamide compounds as inhibitors of interleukin-1 activity
WO2020086732A1 (en) * 2018-10-24 2020-04-30 Novartis Inflammasome Research, Inc. Compounds and compositions for treating conditions associated with nlrp activity
WO2020102576A1 (en) * 2018-11-16 2020-05-22 Novartis Inflammasome Research, Inc. Compounds and compositions for treating conditions associated with nlrp activity

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