CN114539256A - Tricyclic compound and medical use thereof - Google Patents

Tricyclic compound and medical use thereof Download PDF

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CN114539256A
CN114539256A CN202111375827.7A CN202111375827A CN114539256A CN 114539256 A CN114539256 A CN 114539256A CN 202111375827 A CN202111375827 A CN 202111375827A CN 114539256 A CN114539256 A CN 114539256A
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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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Abstract

The present disclosure relates to tricyclic compounds and their medical uses. Specifically, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, which has NLRP3 inflammatory body inhibitory activity and can be used for treating or preventing NLRP 3-related diseases.

Description

Tricyclic compound and medical use thereof
Technical Field
The disclosure relates to the field of medicine, in particular to tricyclic compounds and medical application thereof.
Background
NOD-like receptor protein 3 (NLRP 3) is a gene encoding a protein belonging 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, 11-18). The gene encodes a protein comprising a pyridine domain, a nucleotide binding site domain (NBD) and a Leucine Rich Repeat (LRR) motif. In response to sterile inflammatory risk signals, NLRP3 interacts with adaptor proteins, apoptosis-related speckled-like proteins (ASCs), and zymogen-1 to form NLRP3 inflammasome. Later, the activation of NLRP3 inflammasome leads to the release of inflammatory cytokines IL-1b and IL-18, and when the activation of NLRP3 inflammasome is deregulated, many diseases are driven to occur.
Studies have shown that activation of the NLRP3 inflammasome is associated with multiple classes of disease, including: inflammatory-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and autoinflammatory diseases. Therefore, there is a need to provide new NLRP3 inflammasome pathway inhibitors to provide new alternatives for 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,
Figure BDA0003363728530000011
wherein ring A is selected from an aromatic or heteroaromatic ring, ring B is selected from a 4-8 membered carbocyclic or heterocyclic ring, and ring C is selected from a 3-8 membered carbocyclic or heterocyclic ring; and ring B is connected to ring a through 2 common atoms and ring C is connected to ring B through 2,3 or 4 common atoms;
ring D is selected from
Figure BDA0003363728530000012
X is selected from CR5Or N, Y is selected from O or NR6；
R1、R2、R3And R4: i) independently selected from hydrogen, deuterium, halogen, -OR7a、-SR7a、-C(＝O)R7a、-OC(＝O)R7a、-C(＝O)OR7a、-C(＝O)NR7aR7b、-NR7aR7b、-NR7aC(＝O)R7b、-NR7aS(＝O)2R7b、-S(＝O)2R7a、-S(＝O)2NR7aR7b-CN, -NO2, or the following optionally substituted with one or more substituents: c1-6Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, heterocyclyl, said substituents being selected from: deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl is optionally further substituted with one or more of deuterium or halogen;
or, ii) R1And R2Group of and R3And R4A group of compounds which form, respectively with the carbon atom to which they are attached, a carbocycle, heterocycle, aryl or heteroaryl, said carbocycle, heterocycle, aryl or heteroaryl being optionally substituted with: deuterium, halogen, -OR9a、-SR9a、-C(＝O)R9a、-OC(＝O)R9a、-C(＝O)OR9a、-C(＝O)NR9aR9b、-NR9aR9b、-NR9aC(＝O)R9b、-NR9aS(＝O)2R9b、-S(＝O)2R9a、-S(＝O)2NR9aR9b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl is optionally further substituted with one or more of deuterium or halogen;
or, iii) R1And R2Independently selected from the group of i), R3And R4Form a carbocyclic ring, heterocyclic ring, aryl or heteroaryl group with the carbon atoms to which they are attached, said carbocyclic ring, heterocyclic ring, aryl or heteroaryl group being optionally substituted with groups as described in ii);
R5selected from hydrogen, deuterium, halogen, C1-4Alkyl radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene radical, said C1-4Alkyl radical, C3-6Cycloalkyl and C3-6The cycloalkylmethylene group is optionally substituted with one or more substituents as follows: deuterium, halogen, -OR5aor-NR5aR5b；
R6Selected from hydrogen, deuterium, -CN, C1-6Alkyl radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene radical, said C1-6Alkyl radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene optionally substituted with one or more of deuterium or halogen;
R5a、R5bindependently selected from hydrogen, deuterium or C optionally substituted by one or more deuterium or halogen1-4An alkyl group;
R7a、R7bindependently selected from hydrogen, deuterium, or the following groups optionally substituted with one or more substituents: c1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkylmethylene, aryl, heteroaryl or heterocyclyl, the substituents being selected from: deuterium, halogen, -NH2、-OH、-CN、C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene, the above substituents optionally further substituted with one or more of deuterium or halogen;
R8a、R8b、R9a、R9bindependently selected from hydrogen, deuterium or the following groups optionally substituted with one or more substituents: c1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6A cycloalkylmethylene group, the substituents selected from: deuterium, halogen, -NH2、-OH、-CN、C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene, the above substituents optionally further substituted with one or more of deuterium or halogen;
in some embodiments, ring a, ring B, and ring C constitute:
Figure BDA0003363728530000031
wherein R is10aIndependently selected from hydrogen, deuterium, halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene, the above groups optionally substituted with one or more of deuterium or halogen;
R10bselected from hydrogen, C1-4Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkylmethylene, the above groups optionally substituted with one or more of deuterium or halogen; m is an integer selected from 1 to 3.
In some embodiments, ring a, ring B, and ring C constitute:
Figure BDA0003363728530000032
Figure BDA0003363728530000041
wherein R is10aAs defined above; r11aIs a substituent of ring B, R11aIndependently selected from hydrogen, deuterium, halogen or C optionally substituted by one or more halogens1-4An alkyl group; n is an integer selected from 0 to 8.
In other embodiments, ring a, ring B, and ring C consist of:
Figure BDA0003363728530000042
Figure BDA0003363728530000051
R12a、R12b、R12c、R12dindependently selected from hydrogen, deuterium or halogen.
In some embodiments of the present disclosure, Y is selected from O.
In yet other embodiments, Y is selected from NR6，R6Selected from hydrogen, deuterium, CN or C optionally substituted with one or more deuterium or halogen1-6An alkyl group; preferably hydrogen or-CN.
In some embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is selected from:
Figure BDA0003363728530000052
Figure BDA0003363728530000061
Figure BDA0003363728530000062
wherein ring D is as defined for compounds of formula I.
In some embodiments, in the compound of formula I or formula II-a through formula II-t or a pharmaceutically acceptable salt thereof, X is selected from CR5，R5Selected from hydrogen, deuterium, halogen or C1-4Alkyl radical, said C1-4Alkyl is optionally substituted with one or more substituents as follows: deuterium, halogen, -OR5aor-NR5aR5b。
In other embodiments, X is selected from N.
In some embodiments, in the compound of formula I or formula II-a through formula II-t, or a pharmaceutically acceptable salt thereof, R1、R2、R3And R4Independently selected from hydrogen, deuterium, halogen, -OR7a、-SR7a、-CN、-NO2Or the following optionally substituted with one or more substituents: c1-6Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, heterocyclyl, said substituents being selected from: deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl is optionally further substituted with one or more of deuterium or halogen; the R is7a、R8aAnd R8bAs defined for compounds of formula I.
In some embodiments, R1And R3Independently selected from hydrogen or deuterium, R2 and R4 are independently selected from the following group C optionally substituted with one or more substituents1-6Alkyl, aryl or heteroaryl, said substituents being selected from: deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R1And R3Independently selected from hydrogen or deuterium, R2 and R4 are independently selected from C optionally substituted with one or more substituents1-6An alkyl group, the substituent being selected from: deuterium, halogen, -OR8a、-SR8a、-NR8aR8b-CN or-NO2。
In other embodiments, ring D is selected from:
Figure BDA0003363728530000071
in other embodiments, in the compound of formula I or formula II-a through formula II-t, or a pharmaceutically acceptable salt thereof, R1And R2Independently selected from hydrogen, deuterium, halogen, -OR7a、-SR7a、-CN、-NO2Or the following optionally substituted with one or more substituents: c1-6Alkyl radical, C3-10Cycloalkyl, aryl, heteroaryl, heterocyclyl, said substituents being selected from: deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl is optionally further substituted with one or more of deuterium or halogen; the R is8aAnd R8bAs defined for compounds of formula I;
R3and R4Form a carbocyclic ring, heterocyclic ring, aryl or heteroaryl group with the carbon atoms to which they are attached, the carbocyclic ring, heterocyclic ring, aryl or heteroaryl group being optionally substituted with: deuterium, halogen, C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R3And R4Form a 3-7 membered carbocyclic or heterocyclic ring with the carbon atoms to which they are attached, the carbocyclic or heterocyclic ring being optionally substituted with: deuterium, halogen or C1-4Alkyl radical, said C1-4Alkyl is optionally further substituted with one or more deuterium or halogen.
In some embodiments, R1Selected from hydrogen or deuterium, R2Selected from the following groups optionally substituted with one or more substituents: c1-6An alkyl, aryl, heteroaryl or heterocyclyl group, the substituents being selected from: deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R1Selected from hydrogen or deuterium, R2Selected from aryl or heteroaryl optionally substituted with one or more substituents selected from: deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, R2Selected from:
Figure BDA0003363728530000081
wherein R is2a、R2bIndependently selected from hydrogen, deuterium, halogen, -OR8a、-SR8a、-C(＝O)R8a、-OC(＝O)R8a、-C(＝O)OR8a、-C(＝O)NR8aR8b、-NR8aR8b、-NR8aC(＝O)R8b、-NR8aS(＝O)2R8b、-S(＝O)2R8a、-S(＝O)2NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl is optionally further substituted with one or more of deuterium or halogen; r2cSelected from hydrogen or C optionally substituted by one or more deuterium or halogen1-4An alkyl group;
p is an integer selected from 1 to 5 and q is an integer selected from 1 to 4.
In some embodiments, R2a、R2bIndependently selected from hydrogen, deuterium, halogen, -OR8a、-SR8a、-NR8aR8b、-CN、-NO2、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl groups are optionally further substituted with one or more deuterium or halogen.
In some embodiments, ring D is selected from:
Figure BDA0003363728530000091
in other embodiments, R1And R2Group of and R3And R4A group of compounds which form, respectively with the carbon atom to which they are attached, a carbocycle or heterocycle, said carbocycle and heterocycle being optionally substituted with: deuterium, halogen, -OR9a、-SR9a、C1-4Alkyl or C3-6Cycloalkyl radical, said C1-4Alkyl or C3-6Cycloalkyl is optionally further substituted with one or more of deuterium or halogen; the R is9a、R9bAs defined for compounds of formula I.
In some embodiments, R1And R2Group of and R3And R4(ii) each forms a carbocyclic ring with the carbon atom to which they are attached, the carbocyclic rings being optionally substituted with: deuterium, halogen or C1-4Alkyl radical, said C1-4Alkyl is optionally further substituted with one or more deuterium or halogen.
In some embodiments, ring D is selected from:
Figure BDA0003363728530000092
Figure BDA0003363728530000101
in a second aspect, the present disclosure also provides a series of compounds, or pharmaceutically acceptable salts thereof, selected from:
Figure BDA0003363728530000102
Figure BDA0003363728530000111
in a third aspect, the present disclosure also provides a series of compounds, or pharmaceutically acceptable salts thereof, selected from:
Figure BDA0003363728530000112
Figure BDA0003363728530000121
in a fourth aspect, the present disclosure also provides a pharmaceutical composition comprising a compound of the first or second aspect or the third aspect, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.
In some embodiments, the unit dose of the pharmaceutical composition is from 0.001mg to 1000 mg.
In certain embodiments, the pharmaceutical composition comprises from 0.01 to 99.99% of the aforementioned 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 aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of the compound or a pharmaceutically acceptable salt thereof.
In a fifth aspect, the present disclosure also provides the use of a compound of the first or second aspect or the third aspect, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the fourth aspect, in the manufacture of a medicament for the treatment of a disease associated with NLRP3 activity.
The present disclosure also provides a method of treating a patient for a disease associated with NLRP3 activity by administering to the patient a therapeutically effective amount of a compound of the first or second aspect or the third aspect of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the fourth aspect.
Diseases associated with NLRP3 activity include inflammatory-related diseases, immune diseases, inflammatory diseases, autoimmune diseases, and/or autoinflammatory diseases.
The present disclosure also provides the use of a compound of the first or second aspect or the third or fourth aspect or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of 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 with an inflammatory-related disease, an immune disease, an inflammatory disease, an autoimmune disease, and/or an autoinflammatory disease by administering to the patient a therapeutically effective amount of a compound of the first or second aspect or the third aspect of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the fourth aspect. The inflammatory body-related disease, immune disease, inflammatory disease, autoimmune disease and/or autoinflammatory disease may be specifically selected from: autoinflammatory fever syndrome (e.g., cryopyrin-associated periodic syndrome), sickle cell anemia, systemic lupus erythematosus, liver-related diseases (e.g., chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis, alcoholic liver disease), inflammatory arthritis-related diseases (e.g., gout, chondrocytosis, osteoarthritis, rheumatoid arthritis, acute or chronic arthritis), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-related inflammation, type I or type II diabetes and complications thereof (e.g., nephropathy, retinopathy)), neuroinflammation-related diseases (e.g., brain infections, acute injury, multiple sclerosis, Alzheimer's disease, and neurodegenerative disease), cardiovascular and metabolic-related disorders or diseases (e.g., reduction of cardiovascular risk (CvRR)), Atherosclerosis, type I and type II diabetes and related complications, Peripheral Artery Disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g., acne, hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, diseases/disorders associated with cancer (e.g., myeloproliferative tumors, leukemia, myelodysplastic syndrome (MDS), myelofibrosis, lung cancer, colon cancer).
The pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic or organic salts, and the compounds described in this disclosure can react with acidic or basic substances to form the corresponding salts.
In another aspect, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which fall within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as 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 present 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 referred to as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactam isomerizations. Examples of tautomers are between a and B as shown below.
Figure BDA0003363728530000131
All compounds in this disclosure can 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 disclosed compounds may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is 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), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The disclosure also includes some isotopically-labeled compounds of the present disclosure that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Can be incorporated into the present disclosureExamples of isotopes of open compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I and36cl, and the like.
Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compound of examples can have a natural abundance of deuterium greater than that of deuterium of at least 1000 times the abundance of deuterium, deuterium of at least 2000 times the abundance of deuterium, deuterium of at least 3000 times the abundance of deuterium, deuterium of at least 4000 times the abundance of deuterium, deuterium of at least 5000 times the abundance of deuterium, deuterium of at least 6000 times the abundance of deuterium, or deuterium of greater abundance. The 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 by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of the formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like.
"optionally" or "optionally" means 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, "C1-6 alkyl optionally substituted with halogen or cyano" means that halogen or cyano may, 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 described in this disclosure, a bond
Figure BDA0003363728530000141
To representUnspecified configuration, i.e. if chiral isomers are present in the chemical structure, the bond
Figure BDA0003363728530000142
Can be that
Figure BDA0003363728530000143
Or
Figure BDA0003363728530000144
Or at the same time contain
Figure BDA0003363728530000145
And
Figure BDA0003363728530000146
two configurations. While all of the above structural formulae are drawn to certain isomeric forms for the sake of simplicity, the present disclosure may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
Interpretation of terms:
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifier that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, methyl, ethyl, isopropyl, ethyl, propyl, isopropyl, and the like,N-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more groups independently selected from halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
"cycloalkyl" means 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.
"carbocyclic" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Carbocycles may be further fused to aromatic rings, heteroaromatic rings, heterocyclic rings, cyclic hydrocarbons, and when fused to heteroaromatic or heterocyclic rings, the fused chemical bond does not contain heteroatoms at both ends.
"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group containing 3 to 20 ring atoms wherein one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) but excludes the cyclic moiety of-O-O-, -O-S-or-S-S-,the remaining ring atoms are carbon. Preferably 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 include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocycloalkyl includes spirocyclic, fused and bridged heterocycloalkyl groups. Non-limiting examples of "heterocycloalkyl" include:
Figure BDA0003363728530000161
Figure BDA0003363728530000162
and so on.
The heterocycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from, for example, halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The heterocyclyl ring may be fused to an aromatic, heteroaromatic or cyclic hydrocarbon wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure BDA0003363728530000163
and the like.
"aryl" or "aromatic ring" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share 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, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The aryl ring may be fused to a heteroaromatic, heterocyclic or cyclic hydrocarbon wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure BDA0003363728530000171
"heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-or 6-membered. For example. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridylPyrimidine, thiadiazole, pyrazine,
Figure BDA0003363728530000172
and so on.
Examples of nitrogen atom-containing heteroaryl groups include, but are not limited to, pyrrolyl, piperazinyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazinyl, tetrazolyl, triazolyl, pyridyl, pyrazolyl, oxazolyl, thiazolyl, or 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, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl, said C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyloxy radical, C2-6Alkynyloxy, C3-6Cycloalkyl, 3-to 6-membered heterocycloalkyl, C5-8Cycloalkenyl radical, C3-6Cycloalkoxy, 3-to 6-membered heterocycloalkoxy, C5-8Cycloalkenyloxy, C6-10Aryl or 5-to 6-membered heteroaryl is optionally substituted with one or more groups selected from halogen, deuterium, hydroxy, oxo, nitro, cyano.
The heteroaryl ring may be fused to an aromatic, heterocyclic or cyclic hydrocarbon, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure BDA0003363728530000173
"halogen" means fluorine, chlorine, bromine or iodine.
Detailed Description
The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.
Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS). The spatial configuration of the optical isomers (isomers) of the compounds can be further confirmed by measuring parameters of the single crystal.
HPLC measurements were 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 C181.7UM 2.1.1X 50MM column, Ultimate XB-C183.0. 150mm column or xtmate C182.1. 30mm column).
MS is measured by a Waters SQD2 mass spectrometer, scanning is carried out in a positive/negative ion mode, and the mass scanning range is 100-1200.
Chiral HPLC analysis and determination using Chiralpak IC-3100 × 4.6mm I.D., 3um, Chiralpak AD-3150 × 4.6mm I.D., 3um, Chiralpak AD-350 × 4.6mm I.D., 3um, Chiralpak AS-3150 × 4.6mm I.D., 3um, Chiralpak AS-4.6 mm I.D., 3 μm, Chiralcel OD-3150 × 4.6mm I.D., 3um, Chiralcel OD- × 4.6mm I.D., 3 μm, Chiralcel OJ-H150 × 4.6mm I.D., 5um, Chiralcel OJ-3150 × 4.6mm I.D., 3um chromatographic column;
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by 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.
The flash column purification system used either Combiflash Rf150(TELEDYNE ISCO) or Isolara one (Biotage).
The forward column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel of the Titan yellow sea silica gel as a carrier, or uses a hyperpure normal phase silica gel column (40-63 μm, 60, 12g, 25g, 40g, 80g or other specifications) pre-filled by Santai in Changzhou.
Reverse phase column chromatography typically uses a column of ultrapure C18 silica gel (20-45 μm,
Figure BDA0003363728530000191
40g, 80g, 120g, 220g or other specifications).
The high pressure Column purification system used Waters AutoP in combination with Waters Xbridge BEH C18 OBD Prep Column,
Figure BDA0003363728530000192
5 μm, 19mm X150 mm or Atlantis T3OBD Prep Column,
Figure BDA0003363728530000193
5μm，19mm X 150mm。
the chiral preparative column used DAICEL CHIRALPAK IC (250 mm. times.30 mm,10um) or Phenomenex-Amylose-1(250 mm. times.30 mm,5 um).
Known starting materials in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan science, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoshi Chemicals (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
A CEM Discover-S908860 type microwave reactor was used for the microwave reaction.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC).
Example 1
Figure BDA0003363728530000194
Figure BDA0003363728530000201
Step 1: synthesis of cyclopropane-1, 2-diyldimethanol (Compound 2b)
Figure BDA0003363728530000202
A solution of compound 2a (5g,44.61mmol) in tetrahydrofuran (150mL) was cooled to 0 deg.C and lithium aluminium hydride (3.39g,89.22mmol) was added slowly and the mixture stirred at 0 deg.C for 1h and then at 70 deg.C to react well. After the mixture was cooled to room temperature, it was quenched into ice water (50mL), extracted with dichloromethane (60 mL. times.3), and the combined organic phases were washed with brine (30 mL. times.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 (2.92g, 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) dimethanesulfonate (Compound 2c)
Figure BDA0003363728530000203
A solution of compound 2b (2.9g,28.40mmol) and triethylamine (15.79mL,113.6mmol) in dichloromethane (40mL) was cooled to 0 deg.C, methanesulfonyl chloride (5.06mL,65.3mmol) was added dropwise, and the mixture was stirred at room temperature for complete reaction. The mixture was poured into ice water (100mL), extracted with dichloromethane (60mL × 3), the combined organic phases were washed with brine (30mL × 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to give compound 2c (7.0g, 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).
And step 3: synthesis of 5a,6,6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine (Compound/racemate 2d)
Figure BDA0003363728530000211
Compound 1a (2.28g,27.10mmol), potassium carbonate (9.36g,67.74mmol) and compound 2c (7.0g,27.10mmol) were mixed in DMF (160mL) and the mixture was stirred well under nitrogen at 100 ℃. After cooling to room temperature, brine (300mL) was added, extracted with ethyl acetate (200 mL. times.3), and the combined organic phases were washed with brine (150 mL. times.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: 0-30% ethyl acetate in petroleum ether) afforded compound 2d (1.5g, 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)
And 4, step 4: synthesis of 3-bromo-5 a,6,6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine (Compound/racemate 2e)
Figure BDA0003363728530000212
A solution of compound 2d (700mg,4.66mmol) in acetonitrile (15mL) was cooled to 0 deg.C and NBS (871.1mg,4.89mmol) was added in portions and the mixture was stirred at room temperature for complete reaction. Ethyl acetate (40mL) was added for dilution, washed with brine (15 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude product which was purified by flash column chromatography (eluent: 10-35% ethyl acetate in petroleum ether) to give compound (racemate) 2e (1.0g, 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]+
And 5: synthesis of 5a,6,6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine-3-sulfonamide (Compound/racemate 2f)
Figure BDA0003363728530000221
Sulfur dioxide was bubbled through tetrahydrofuran (50mL) at-78 ℃ for 15 minutes for use. Compound 2e (500mg,2.18mmol) in tetrahydrofuran (3mL) was cooled to-78 deg.C and a solution of n-butyllithium (2.5M in n-hexane, 2.62mL) was slowly added dropwise. Then stirred at-78 ℃ for 30 seconds. Then, a solution of the above sulfur dioxide in tetrahydrofuran (2mL) was added and the mixture was stirred at-78 ℃ to react well. Quenched by the addition of water (5mL), separated, the organic layer extracted with water (5 mL. times.2), collected and the aqueous phases combined. Trisodium citrate dihydrate (1284mg,4.36mmol) was added. After cooling the mixture to 10 ℃ a solution of hydroxylamine sulfonic acid (370.25mg,3.274mmol) in water (5mL) was added. The mixture was stirred at room temperature for complete reaction. Extraction with ethyl acetate (20 mL. times.3) and combined organic phases washed with brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated in vacuo to give the crude product which is purified by flash column chromatography (eluent: 90-100% ethyl acetate in petroleum ether) to afford compound (racemate) 2f (40.8g, 8.2% yield).
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,6,6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine-3-sulfonamide (Compound/racemate 2)
Figure BDA0003363728530000222
A solution of compound 2f (20.0mg,0.087mmol) in tetrahydrofuran (1.5mL) was cooled to 0 deg.C and sodium (60% mineral oil) (5.24mg,0.131mmol) was added under nitrogen. The resulting mixture was stirred at 0 ℃ for 5 minutes, then a solution of compound 2g (17.4mg,0.087mmol) in tetrahydrofuran (1mL) was added and the final mixture was stirred at 0 ℃ for complete reaction. Quench with water (3mL) and adjust pH 2-3 with 30% citric acid solution. Extraction with ethyl acetate (20mL × 2), combined organic phases washed with brine (20mL × 2), dried over anhydrous sodium sulfate and filtered, and the filtrate concentrated in vacuo to give a crude product which is purified by flash column chromatography [ C-18 column, methanol/water 10-60%) ] followed by lyophilization afforded compound (racemate) 2(5.8mg, 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)
Compound 2 from multiple preparations was resolved on a chiral Column [ Column: DAICEL CHIRALPAK AD (250 mm. about.30 mm,10um), Condition: 40% (0.1% NH)3-H2O,EtOH),flow rate:80mL/min]Compound 2-1(Rt ═ 2.051min,7.0mg) and compound 2-2(Rt ═ 2.234min,8.2mg) were obtained.
Compounds 2-1 and 2-2 are each selected from one of the following compounds:
Figure BDA0003363728530000231
example 2
Figure BDA0003363728530000232
Step 1: synthesis of 5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-amine (Compound 1k)
Figure BDA0003363728530000233
Compound 1i (150mg,0.71mmol) was dissolved in dioxane (2.5mL), potassium carbonate (288mg,2.12mmol), 1j (130mg,0.85mmol) and water (0.5mL) were added, and the catalyst Pd (dppf) Cl2(87.7mg,0.106mmol) was added under nitrogen. The mixture was stirred at 80 ℃ to react well. After cooling to room temperature, water (10mL) was added for dilution, extracted with ethyl acetate (15mLx2), the combined organic phases were washed with brine (15mLx2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the crude product which was purified by flash column chromatography (eluent: 5-30% ethyl acetate in petroleum ether) to give compound 1k (101mg, 58.9% yield).
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 1l)
Figure BDA0003363728530000241
A solution of compound 1k (35mg,0.146mmol) and triethylamine (17.69mg,0.175mmol) in tetrahydrofuran (2mL) was cooled to 0 deg.C and triphosgene (25.07mg,0.084mmol) was added and the mixture was stirred well under nitrogen at 70 deg.C. After cooling to room temperature, it was filtered, the filter cake was washed with tetrahydrofuran (5mL), and the combined filtrates were concentrated in vacuo to give compound 1l (38mg, 98% yield).
ES-LCMS m/z 299.1[M+MeOH+H]+.
And step 3: synthesis of N- ((5- (2-methoxypyridin-4-yl) -2, 3-dihydro-1H-inden-4-yl) carbamoyl) -5a,6,6a, 7-tetrahydro-5H-cyclopropeno [ e ] pyrazolo [5,1-b ] [1,3] oxazepine-3-sulfonamide (Compound/racemate) 4
Figure BDA0003363728530000242
A solution of compound 2f (23.2mg,0.10mmol) in tetrahydrofuran was cooled to 0 ℃ and sodium hydride (60% mineral oil) was added under nitrogen. The mixture was stirred at 0 ℃ for 15 minutes, then a solution of compound 1l (30mg,0.11mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature under nitrogen for complete reaction. Water was added to dilute the solution, 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 the crude product, which was purified to give compound 4(3.6mg, yield 5.8%).
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)
Compound 4 obtained in multiple preparations was resolved on a chiral Column, [ Column: DAICEL CHIRALPAK AD (250 mm. about.30 mm,10um), Condition: 45% (0.1% NH)3-H2O,EtOH),flow rate:80mL/min]Compound 4-1(Rt ═ 2.309minutes,13.2mg) and compound 4b-2(Rt ═ 2.48) were obtained8minutes,9.7mg)。
Compounds 4-1 and 4-2 are each selected from one of the following compounds:
Figure BDA0003363728530000251
biological evaluation
The present disclosure is further described and explained below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.
Experimental example 1 NLRP3 inflammatory body inhibitory Activity assay in human monocytes
1. Laboratory instruments and reagents
1.1 Experimental instruments
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
Figure BDA0003363728530000252
Figure BDA0003363728530000261
2. Experimental protocol
Day 1: PBMCs were separated from human blood by density gradient centrifugation and washed twice with PBS containing 2% FBS (300g for 8 min). Monocytes were then isolated from PBMCs using a 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 FACSVersese to analyze the purity of the pan-monocytes. Count and adjust cell density to 2.5x105Cells/ml. Cells were seeded into 96-well plates, 2.5 × 104Monocytes/100 mL suspension/well. At 5% CO2Incubate overnight at 37 ℃.
Day 2: test compounds were pre-titrated so that all titration points, including DMSO control wells, contained 0.1% DMSO. Media was removed, monocytes pretreated (by adding 150mL of compound (diluted in serum-free 1640 media) or DMSO to the respective wells, at 5% CO2Incubation at 37 ℃ for 0.5 hour). The cells were then treated (25 mL by addition of 1640 (serum free) solution containing 700ng/mL LPS (final concentration 100ng/mL) at 37 ℃ with 5% CO2Medium incubation for 3.5 hours). At the end of the 3.5 hour incubation, the cells were stimulated (25 mL of 40mM ATP was added (final concentration would be 5mM) 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.
Days 3-4: ELISA experiments
1) Day 3: 100 mL/well of capture antibody (diluted with coating buffer) was added to the plate. Plates were sealed and incubated overnight at 4 ℃.
2) Day 4: the wells were aspirated off and washed 3 times with 300 uL/. gtoreq.wash buffer each time. After the last wash, the plate was inverted and blotted dry on absorbent paper to remove any residual buffer.
3) The plate was filled with test dilutions up to 200 uL/well. Incubate at room temperature for 1 hour.
4) Suck dry/wash 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. Plates were sealed and incubated for 2 hours at room temperature.
7) Suck dry/wash as step 2, but wash 5 times.
8) The detection antibody was diluted with test diluent and added to the wells at 100 mL/well.
9) Plates were sealed and incubated for 1 hour at room temperature.
10) Suck dry/wash as step 2, but wash 5 times.
11) The enzyme reagent was diluted with the assay diluent and added to the wells at 100 mL/well. Plates were sealed and incubated for 30 minutes at room temperature.
12) Suck dry/wash with 30 sec-1 min soak step for a total of 7 washes.
13) 100mL of substrate solution was added to each well. Plates (without plate sealant) were incubated for 30 minutes at room temperature in the dark.
14) To each well was added 50mL of stop solution.
15) The absorbance at 450nm was read by the instrument Envision within 30 minutes after the reaction had stopped. If wavelength correction is available, the absorbance at 570nm is subtracted from the absorbance at 450 nm.
3. Results of the experiment
Figure BDA0003363728530000271

Claims (10)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
Figure FDA0003363728520000011
wherein ring a, ring B and ring C consist of:
Figure FDA0003363728520000012
ring C is selected from a 3-8 membered carbocyclic or heterocyclic ring, ring C and ring B are connected by 2,3 or 4 atoms in common;
R10aindependently selected from hydrogen, deuterium, halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C3-6Cycloalkyl or C3-6Cycloalkylmethylene, the above groups optionally substituted with one or more of deuterium or halogen;
R11ais a substituent of the ring B, R11aIndependently selected from hydrogen, deuterium, halogen or C optionally substituted by one or more halogens1-4An alkyl group; n is an integer selected from 0 to 8;
ring D is selected from
Figure FDA0003363728520000013
Figure FDA0003363728520000021
Y is selected from O or NR6；R6Selected from hydrogen or-CN.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a, ring B and ring C constitute:
Figure FDA0003363728520000022
R12a、R12bindependently selected from hydrogen, deuterium or halogen.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from:
Figure FDA0003363728520000023
wherein ring D is as defined in claim 1.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, ring D is selected from:
Figure FDA0003363728520000031
5. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, a compound of formula I selected from:
Figure FDA0003363728520000032
Figure FDA0003363728520000041
6. a compound, or pharmaceutically acceptable salt thereof, selected from:
Figure FDA0003363728520000051
7. a pharmaceutical composition comprising a compound of claims 1-6, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient.
8. Use of a compound according to claims 1-6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for the treatment of a disease associated with NLRP3 activity.
9. Use of a compound according to claims 1-6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, for 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.
10. A compound:
Figure FDA0003363728520000052
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Citations (4)

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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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