CN116375728A - Thiophene pyrrolotriazinone compound and application thereof - Google Patents

Thiophene pyrrolotriazinone compound and application thereof Download PDF

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CN116375728A
CN116375728A CN202211683628.7A CN202211683628A CN116375728A CN 116375728 A CN116375728 A CN 116375728A CN 202211683628 A CN202211683628 A CN 202211683628A CN 116375728 A CN116375728 A CN 116375728A
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孙梁琨
贾涛
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Chengdu Zeiling Biomedical Technology Co ltd
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Abstract

The invention belongs to the field of chemical medicines, and provides a compound shown in a formula I or pharmaceutically acceptable salt thereof. The invention provides a compound with a thiophene pyrrolotriazinone skeleton, which can be used for preparing NLRP3 inflammatory corpuscle inhibitors, and provides a new choice for preparing medicines for treating related diseases caused by abnormal activation of NLRP3 inflammatory corpuscles.

Description

Thiophene pyrrolotriazinone compound and application thereof
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a thiophene pyrrolotriazinone compound, a preparation method thereof and application thereof in medicines.
Background
The inflammation corpuscles are protein complexes capable of recognizing pathogen-associated molecular patterns (pathogen associated molecular patterns, PAMPs) or damage-associated molecular patterns (damage associated molecular patterns, DAMPs) and the like in cells, and the assembly of the inflammation corpuscles triggers proteolysis, so that dormant procaspase-1 is cleaved into active caspase-1, cytokine precursors pro-IL-1 beta and pro-IL-18 are respectively converted into mature IL-1 beta and IL-18 with biological activity, and various biological effects are generated in a mode of regulating and controlling the expression of inflammation-associated genes and the like. As receptors for innate immunity of the body, inflammatory body activation can resist pathogen infection and stress injury, but uncontrolled activation can also cause amplification of inflammatory effects and organ damage. The current research on the nucleotide binding oligomerization domain (NOD) -like receptor family of protein 3 (NOD-like receptor family, pyrin domain-containing protein 3, NLRP 3) with pyrin domain is the most popular.
NLRP3 inflammatory corpuscles consist of a sensor (NLRP 3), an adapter (ASC, also known as PYCARD) and an effector (caspase 1). Classical NLRP3 inflammatory small body activation is stimulated and activated by the co-stimulation of two signals, wherein the first signal activates a TLR4 (Toll like receptor) signal path, promotes NF- κB to enter the nucleus, induces the generation of precursors such as IL-1 beta, IL-18 and the like, and induces posttranslational modification of NLRP 3. The second signal promotes the formation of the NLRP3/ASC/pro-caspase-1 complex, i.e., when activated, polymerizes with Apoptosis-related speckle-like proteins (ASC, apoptisis-Associated Specklike Protein containing a CARD) containing caspase activation and recruitment domains, ASC interacts with cysteine protease caspase-1 to form a complex called an inflammatory body, the precursor form of caspase (pro-caspase-1) self-cleaves to an activated form, and the 2-activated caspase-1 (caspase-1) cleaves the precursor forms of pro-inflammatory cytokines IL-1 beta and IL-18 to convert them to the active forms IL-1 beta and IL-18 and release them out of the cell, recruiting inflammatory cell aggregation, and expanding the inflammatory response. ASC spot-like proteins can also recruit and activate caspase-8 (caspase-8), cleaving precursor forms of IL-I beta and IL-18 to convert to mature forms and initiate apoptosis. Non-classical NLRP3 inflammatory body activation does not depend on TLR4 signaling pathway activation, it is that caspase-11 directly recognizes intracellular LPS, initiates NLRP3 inflammatory body activation, and promotes activation and release of Gasderm D to mediate cell death.
Aberrant activation of NLRP3 is associated with a number of diseases, including mainly cancer, autoimmune diseases, chronic metabolic diseases, and neurological-related diseases. Such as colon cancer, melanoma, diabetes, gout, low temperature protein related periodic syndrome (CAPS), inflammatory Bowel Disease (IBD), NASH, gout, alzheimer's disease, and parkinson's disease. NLRP3 is upstream of cytokines and can block inflammation from sources, so that the development of new NLRP3 inflammatory corpuscle inhibitors has higher research value.
Disclosure of Invention
The invention aims at a thiophene pyrrolotriazinone compound, or a stereoisomer, a solvate, a metabolite, a deuterate, a prodrug, a pharmaceutically acceptable salt or a eutectic crystal thereof, and a pharmaceutical composition containing the thiophene pyrrolotriazinone compound, which is used for treating related diseases caused by abnormal activation of NLRP3 inflammatory bodies.
The invention firstly provides a compound shown in a formula I or pharmaceutically acceptable salt thereof, which is characterized by comprising the following structure:
Figure BDA0004019918490000021
x is selected from NH, O and S;
R 1 selected from H, halogen, 3-8 membered cycloalkyl, C1-C8 alkyl, N-C1-C8 alkylamino;
R 3 selected from H, C-C8 alkyl;
r is selected from
Figure BDA0004019918490000022
N-heterocycles>
Figure BDA0004019918490000023
Y is NH or none;
R 2 Selected from the group consisting of substituted or unsubstituted C1-C10 alkyl groups, substituted or unsubstituted C1-C10 ester groups, substituted or unsubstituted 3-to 8-membered cycloalkyl groups, substituted or unsubstituted 4-to 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 11-membered spirocycloalkyl groups, substituted or unsubstituted 6-to 10-membered aryl groups, substituted or unsubstituted 5-to 10-membered heteroaryl groups, substituted or unsubstituted,
Figure BDA0004019918490000024
n1 is an integer from 1 to 3;
R 2 wherein the substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 4-10 membered bridged cycloalkyl, substituted or unsubstituted 5-11 membered spirocycloalkyl contains 0-3 heteroatoms, heteroAn atom is N, O, S;
R 2 wherein the substituted or unsubstituted 5-to 10-membered heteroaryl contains 1 to 3 heteroatoms, and the heteroatoms are N;
R 2 wherein the substituent of the substituted C1-C10 alkyl group, the substituted C1-C10 ester group is selected from halogen, hydroxy, nitrile, amino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 hetero atoms selected from at least one of N, O, S, and,
Figure BDA0004019918490000025
At least one of 6-10 membered aryl groups, R 4 Selected from unsubstituted or hydroxy-substituted C1-C4 alkyl groups, n2, n3 are independently selected from integers from 1 to 3;
R 2 wherein the substituents of the substituted 3-to 8-membered cycloalkyl, substituted 4-to 10-membered bridged cycloalkyl, substituted 5-to 11-membered spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, C1-C8 alkoxycarbonyl, C1-C8 ester, substituted or unsubstituted C1-C8 alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, C1-C8 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C8 alkyl group in the substituent is selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, R 5 Selected from C1-C4 alkyl and 3-6 membered cycloalkyl;
R 2 wherein the substituent of the substituted 6-10 membered aryl group and the substituted 5-10 membered heteroaryl group is at least one selected from halogen, hydroxy, nitrile, C1-C8 alkoxycarbonyl, C1-C8 ester, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl and C1-C8 alkoxy, and the substituent of the substituted C1-C8 alkyl in the substituent is selected from halogen, hydroxy and amino;
the N heterocycle is selected from a substituted or unsubstituted 3-8 membered N heteroalkane ring, a substituted or unsubstituted 4-8 membered N heterobridged alkane ring, a substituted or unsubstituted 5-11 membered N heterospiroalkane ring, which contains 0-2O or S heteroatoms besides N;
in the N heterocycle, the substituted 3-8 membered N-heteroalkyl ring and the substituted 4-8 membered N-heteroalkyl ringThe substituent groups of the bridged alkane ring and the substituted 5-11 membered N-hetero-spiro alkane ring are selected from C1-C6 alkyl halogen, hydroxy, nitrile,
Figure BDA0004019918490000031
At least one of them.
Wherein, in the compound of the formula I, R 1 Selected from H, halogen, 3-6 membered cycloalkyl, C1-C6 alkyl, N-C1-C6 alkylamino.
Preferably, in the above compound of formula I, R 1 Selected from H, halogen, 3-6 membered cycloalkyl, C1-C4 alkyl, N-C1-C4 alkylamino.
Most preferably, in the above compound of formula I, R 1 Selected from H, cl, br, cyclopropyl, ethyl, methyl, N-ethylamino.
Wherein, in the compound of the formula I, R 2 Selected from the group consisting of substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C1-C8 ester groups, substituted or unsubstituted 3-to 6-membered cycloalkyl groups, substituted or unsubstituted 4-to 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 9-membered spirocycloalkyl groups, substituted or unsubstituted 6-to 10-membered aryl groups, substituted or unsubstituted 5-to 10-membered heteroaryl groups, substituted or unsubstituted,
Figure BDA0004019918490000032
Preferably, in the above compound of formula I, R 2 Selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 ester groups, substituted or unsubstituted 3-to 6-membered cycloalkyl groups, substituted or unsubstituted 4-to 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 7-membered spirocycloalkyl groups, substituted or unsubstituted 6-to 10-membered aryl groups, substituted or unsubstituted 5-to 10-membered heteroaryl groups, substituted or unsubstituted,
Figure BDA0004019918490000033
More preferably, in the above compound of formula I, R 2 Selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C1-C4 ester groups, substituted or unsubstituted 3-to 6-membered cycloalkyl groups, substituted or unsubstituted 10-membered bridged cycloalkyl groups, and substituted or unsubstituted 5-to 7-membered spiro groups Cycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5, 6 or 9 membered heteroaryl,
Figure BDA0004019918490000034
Wherein, in the compound of the formula I, R 2 Wherein the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted spirocycloalkyl contains 0 to 2 heteroatoms, and the heteroatoms are N, O, S; r is R 2 Wherein the substituted or unsubstituted heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are N.
Preferably, in the above compound of formula I, R 2 Wherein the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted spirocycloalkyl contains 0 to 2 heteroatoms, and the heteroatoms are N, O, S; r is R 2 Wherein the substituted or unsubstituted heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are N.
Wherein, in the compound of the formula I, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of halogen, hydroxy, nitrile, amino, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 2 hetero atoms selected from at least one of N, O, S, and,
Figure BDA0004019918490000041
At least one of 6-10 membered aryl groups, R 4 Selected from unsubstituted or hydroxy-substituted C1-C4 alkyl; n2 and n3 are independently selected from integers of 1 to 2.
Wherein, in the compound of the formula I, R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, C1-C6 alkoxycarbonyl, C1-C6 ester, substituted or unsubstituted C1-C6 alkyl, 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, C1-C6 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C6 alkyl group in the substituent is selected from the group consisting of halogen, hydroxy, amino, 3-to 6-membered cycloalkaneRadical R 5 Selected from C1-C4 alkyl and 3-6 membered cycloalkyl.
Wherein, in the compound of the formula I, R 2 Wherein the substituent of the substituted aryl and the substituted heteroaryl is at least one selected from halogen, hydroxyl, nitrile, C1-C6 alkoxycarbonyl, C1-C6 ester, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C6 alkyl and C1-C6 alkoxy, and the substituent of the substituted C1-C6 alkyl in the substituent is selected from halogen, hydroxyl and amino.
Preferably, in the above compound of formula I, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of halogen, hydroxy, nitrile, amino, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 2 hetero atoms selected from at least one of N, O, S, and,
Figure BDA0004019918490000042
At least one of 6-10 membered aryl groups, R 4 Selected from unsubstituted or hydroxy-substituted C1-C4 alkyl groups, n2, n3 are independently selected from 1.
Preferably, in the above compound of formula I, R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, C1-C4 alkoxycarbonyl, C1-C4 ester, substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, C1-C4 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C4 alkyl group in the substituent is selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, R 5 Selected from C1-C4 alkyl and 3-6 membered cycloalkyl.
Preferably, in the above compound of formula I, R 2 Wherein the substituent of the substituted aryl or the substituted heteroaryl is at least one selected from halogen, hydroxy, nitrile, C1-C4 alkoxycarbonyl, C1-C4 ester, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl and C1-C4 alkoxy, and the substituent of the substituted C1-C4 alkyl in the substituent is selected from halogen and hydroxyAmino group.
More preferably, in the above compound of formula I, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of a hydroxyl group, an amino group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group containing 1 hetero atom selected from N, O, S,
Figure BDA0004019918490000043
At least one of phenyl groups.
More preferably, in the above compound of formula I, R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, t-butoxycarbonyl, C1-C4 ester, substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, C1-C4 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C4 alkyl group in the substituent is selected from halogen, hydroxy, cyclopropyl, R 5 Selected from methyl, cyclopropyl.
More preferably, in the above compound of formula I, R 2 Wherein the substituent of the substituted aryl or the substituted heteroaryl is at least one selected from halogen, hydroxy, nitrile, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl and C1-C4 alkoxy, and the substituent of the substituted C1-C4 alkyl in the substituent is selected from halogen.
Most preferably, in the above compound of formula I, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of hydroxy, amino, cyclopropyl,
Figure BDA0004019918490000051
At least one of phenyl groups.
Most preferably, in the above compound of formula I, R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from F, hydroxy, cyano, amino, -Boc, methoxycarbonyl, methyl, trifluoromethyl, hydroxymethyl,
Figure BDA0004019918490000052
Cyclopropyl, cyclobutyl,>
Figure BDA0004019918490000053
methoxy group,/->
Figure BDA0004019918490000054
At least one of them.
Most preferably, in the above compound of formula I, R 2 Wherein the substituent of the substituted aryl or the substituted heteroaryl is at least one selected from F, cl, hydroxyl, cyano, methyl, ethyl, propyl, trifluoromethyl and methoxy.
Wherein R is selected from the group consisting of the compounds of formula I
Figure BDA0004019918490000056
Figure BDA0004019918490000057
Figure BDA0004019918490000061
Wherein, in the compound of the formula I, the N heterocycle is selected from a substituted or unsubstituted 3-6 membered N heteroalkane ring, a substituted or unsubstituted 4-8 membered N heterobridged alkane ring, a substituted or unsubstituted 5-9 membered N heterospiroalkane ring, which contains 0-1O heteroatom besides N; in the N heterocycle, the substituent groups of the substituted 3-6 membered N-heteroalkyl ring, the substituted 4-8 membered N-heterobridged alkyl ring and the substituted 5-9 membered N-heterospirane ring are selected from C1-C4 alkyl, halogen, hydroxyl, nitrile group,
Figure BDA0004019918490000062
At least one of them.
Preferably, in the compounds of formula I, the N-heterocyclic ring is selected from a substituted or unsubstituted 4-6 membered N-heteroalkane ring, an unsubstituted 4-8 membered N-heterobridged alkane ring, an unsubstituted 5-7 membered spiroalkane ring, which contains 0-1O heteroatom in addition to N; n-heterocyclesWherein the substituent of the substituted 4-6 membered N-heteroalkyl ring is selected from methyl, hydroxy,
Figure BDA0004019918490000063
At least one of them.
Most preferably, in the above compound of formula I, the N-heterocyclic ring is selected from
Figure BDA0004019918490000064
Figure BDA0004019918490000065
Wherein, in the compound of the formula I, R 3 Selected from H, C-C6 alkyl.
Preferably, in the above compound of formula I, R 3 Selected from H, C-C4 alkyl.
Most preferably, in the above compound of formula I, R 3 Selected from H and methyl.
The invention also provides specific compounds in the formula I, and the structural formula is as follows:
Figure BDA0004019918490000071
Figure BDA0004019918490000081
Figure BDA0004019918490000091
Figure BDA0004019918490000101
the invention also provides a pharmaceutical composition which is prepared from the compound or pharmaceutically acceptable salt thereof serving as an active ingredient and pharmaceutically acceptable auxiliary ingredients.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof and the pharmaceutical composition in preparation of NLRP3 inhibitors.
Definition of terms:
unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps. Those skilled in the art will appreciate that such terms as "comprising" encompass the meaning of "consisting of …".
In the present invention, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
When lower and upper limits of a range of values are disclosed, any number and any range encompassed within the range are specifically disclosed. In particular, each range of values (in the form "about a to b", or equivalently, "about a-b") of values disclosed herein is understood to mean each value and range encompassed within the broader range.
For example, the expression "C 1-6 "is understood to cover any subrange therein as well as every point value, e.g. C 2-5 、C 3-4 、C 1-2、C 1-3 、C 1-4 、C 1-5 Etc. and C 1 、C 2 、C 3 、C 4 、C 5 、C 6 Etc. For example, the expression "C 3-10 "also should be understood in a similar manner, for example, any subrange and point value contained therein, e.g., C 3-9 、C 6-9 、C 6-8 、C 6-7 、C 7-10 、C 7-9 、C7-8、C 8-9 Etc. and C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 Etc. Also for example, the expression "3-10 membered" should be understood to encompass any subrange therein as well as every point value therein, e.g., 3-4 membered, 3-5 membered, 3-6 membered, 3-7 membered, 3-8 membered, 3-9 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 5-7 membered, 5-8 membered, 6-7 membered, etc., as well as 3, 4, 5, 6, 7, 8, 9, 10 membered, etc. Also for example, the expression "5-10 membered" should be understood in a similar manner, e.g. any subrange and point value contained therein, e.g. 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-7 membered, 6-8 membered, 6-9 membered, 6-10 membered, 7-8 membered etc. and 5, 6, 7, 8, 9, 10 membered etc.
In the present invention, unless otherwise indicated, halogen means fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise indicated, "alkyl" includes straight or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Similarly, "C 1-4 C in alkyl' 1-4 Refers to groups comprising 1, 2, 3 or 4 carbon atoms arranged in a linear or branched form.
In the present invention, unless otherwise indicated, "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-polycyclic (e.g., bicyclic) aromatic group or ring having a conjugated pi-electron system. As used herein, the term "C6-10 aryl" refers to an aromatic group containing 6 to 10 carbon atoms. Examples include, but are not limited to, phenyl, naphthyl, and the like. The aryl groups or aromatic rings in the present invention are optionally substituted with one or more substituents described herein.
In the present invention, unless otherwise indicated, "heteroaryl" or "heteroaromatic ring" refers to an aromatic ring having a conjugated pi electron system in which one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P and S, with the remaining ring atoms being C. Heteroaryl or heteroaromatic rings may be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl group may contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 9, 10 ring atoms. Examples of heteroaryl groups are, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like; the term also encompasses the case where a heteroaryl or heteroaromatic ring may optionally be further fused to an aryl, or heteroaryl ring to form a fused ring. Heteroaryl or heteroaromatic rings in the present invention are optionally substituted with one or more substituents described herein.
In the present invention, unless otherwise indicated, "substituted" means that one or more hydrogen atoms in the group are each replaced by the same or different substituents.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium @ 2 H) The tritium is 3 H) A) is provided; isotopes of carbon (e.g 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g., 37 Cl); isotopes of iodine (e.g 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 17 O and O 18 O); isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 34 S)。
In the present invention, "polymorph" refers to the distinct solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof. In general, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including single, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may form true solvates, but in some cases may also retain only adventitious water or a mixture of water plus a portion of the adventitious solvent. The compounds of the invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention. The present invention also encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
In the present invention, "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers. It is to be understood that the scope of the present invention encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
In the present invention, pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For reviews of suitable salts see, e.g., "Remington's Pharmaceutical Sciences", mack Publishing Company, easton, pa., (2005); and "manual of pharmaceutically acceptable salts: properties, selection and application "(Handbook of Pharmaceutical Salts: properties, selection, and Use), stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art. By "pharmaceutically acceptable acid addition salt" is meant a salt with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, and the like. These salts can be prepared by methods known in the art. By "pharmaceutically acceptable base addition salt" is meant a salt formed with an inorganic or organic base that is capable of maintaining the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline hexylcaffeine. These salts can be prepared by methods known in the art.
In the present invention, unless otherwise indicated, "esters" refer to esters derived from the compounds described herein, which include physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves be esters.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming nitrogen oxides because nitrogen requires available lone pair electrons to oxidize to oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming nitrogen oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming nitroxides. Synthetic methods for preparing nitrogen oxides of heterocyclic and tertiary amines are well known to those skilled in the art and include oxidizing heterocyclic and tertiary amines with peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxanes) such as dimethyl dioxirane. These methods for preparing nitrogen oxides have been widely described and reviewed in the literature, see for example: t.l.gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750 (a.r.katritzky and a.j.boulton, eds., academic Press); and G.W.H.Cheeseman and E.S.G.Werstiuk, advances in Heterocyclic Chemistry, vol.22, pp 390-392 (A.R.Katritzky and A.J.Boulton, eds., academic Press).
In the present invention, "metabolite" refers to a substance that forms in vivo upon administration of the compounds of the present invention. Metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by assay methods. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
In the present invention, "prodrug" means that certain derivatives of the compounds of the present invention can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered into or onto the body. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
In this application, "pharmaceutical composition" refers to a formulation of a compound of the invention with a medium commonly accepted in the art for delivery of biologically active compounds to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of organisms, facilitate the absorption of active ingredients and further exert biological activity.
In this application, "pharmaceutically acceptable carrier" 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, stabilizer, isotonizing agent, solvent, or emulsifying agent that is approved by the relevant government regulatory agency or is acceptable for use in humans or livestock.
The above preferred conditions can be arbitrarily combined to obtain the preferred examples of the present invention without departing from the common sense in the art.
The invention has the beneficial effects that:
the invention provides a compound with a thiophene pyrrolotriazinone skeleton, which can be used for preparing NLRP3 inflammatory corpuscle inhibitors, and provides a new way for treating related diseases caused by abnormal activation of NLRP3 inflammatory corpuscles.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Table 1 abbreviations for part of the reagents used in the examples
Reagent(s) Abbreviations (abbreviations)
Petroleum ether PE
Acetic acid ethyl ester EtOAc
Dichloromethane (dichloromethane) DCM
Methanol MeOH
Ethanol EtOH
N, N-dimethylformamide DMF
Tetrahydrofuran (THF) THF
Preparation of intermediate 1g
Figure BDA0004019918490000141
a step: 4H-thiazole [3,2-B ]]Pyrrole-5-carboxylic acid methyl ester 1a (1 equiv) and hydrazine hydrate (5 equiv) were added to ethanol solution and reacted at 85℃under reflux, and TLC monitored the progress of the reaction. After the reaction, a white precipitate formed, which was filtered, washed with water and dried to give crude product 1b without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ11.69(s,1H),9.47(s,1H),7.35(d,J＝5.2Hz,1H),7.04(s,1H),6.95(d,J＝5.2Hz,1H),4.38(s,2H).
b, step b: the crude product 1b (1 equiv) and trimethyl orthoisobutyrate (1.2 equiv) were dissolved in DMF solution, stirred in an oil bath at 130 ℃ for 30min, then cooled to room temperature, potassium tert-butoxide (1.2 equiv) was added to the reaction system, the reaction solution was stirred in an oil bath at 90 ℃, and TLC monitored the progress of the reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water and acidified to pH 5 with 2M HCl. The precipitate formed, was filtered and washed thoroughly with water and DCM to give the compound as an off-white solid 1c without further purification. 1 H NMR(400MHz,CDCl 3 )δ10.13(s,1H),7.53(s,1H),7.50(d,J＝5.4Hz,1H),7.28(d,J＝5.4Hz,1H),3.52(spt,J＝6.7Hz,1H),1.44(d,J＝6.7Hz,6H).
c, step c: compound 1c (1 equiv) and ethyl 2-chloroacetate (1.2 equiv) were dissolved in DMF and Cs was added 2 CO 3 (3 equiv) the reaction mixture was stirred at room temperature and TLC monitored the progress of the reaction. After the reaction, the reaction mixture was diluted with water, acidified with 2M HCl, and extracted 3 times with ethyl acetate. The organic extracts were combined with 10% NaHCO 3 The organic layer was washed with anhydrous Na 2 SO 4 Drying, filtration and evaporation gave crude product 1d without further purification. 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝5.6Hz,2H),7.26(d,J＝4.2Hz,1H),4.80(s,2H),4.24(q,J＝7.1Hz,2H),3.49(spt,J＝6.7Hz,1H),1.42(d,J＝6.7Hz,6H),1.29(t,J＝6.6Hz,3H).
d, step d: compound 1d (1 equiv) and solid NCS (1.2 equiv) were placed in THF solution and the reaction system was heated to react at 55 ℃. TLC monitored the progress of the reaction. After completion of the reaction, 10% Na was used 2 CO 3 The solution is quenched and extracted 2-3 times with ethyl acetate. Washing the mixed organic extract with brine and anhydrousNa 2 SO 4 Drying, filtering and evaporating. Silica gel column chromatography purification was performed using petroleum ether and ethyl acetate system (0% -25%), and the compound obtained was white solid 1e. 1 H NMR(400MHz,CDCl 3 )δ7.39(s,1H),7.19(s,1H),4.79(s,2H),4.24(d,J＝7.1Hz,2H),3.37(spt,J＝6.7Hz,1H),1.41(d,J＝6.7Hz,6H),1.30(d,J＝7.1Hz,3H).
And e, step e: compound 1e (1 equiv) and hydrazine hydrate (5 equiv) were added to an ethanol solution and reacted by heating at 85 ℃ and TLC monitored the progress of the reaction. A white solid formed which was filtered, washed with water and dried to give crude product 1f without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ9.18(s,1H),7.80(s,1H),7.46(s,1H),4.52(s,2H),4.27(s,2H),3.58(spt,J＝6.6Hz,1H),1.29(d,J＝6.6Hz,6H).
f, step f: compound 1f (1 equiv) and CDI (1.2 equiv) were dissolved in 1, 4-dioxane solution, and the reaction system was stirred with heating in an oil bath at 100 ℃ and monitored by TLC for reaction progress. After the reaction, the excess solvent was removed by a heated rotary evaporator, the residue was diluted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution, and then with anhydrous Na 2 SO 4 The organic layer was dried. Purifying by a dichloromethane ethyl acetate system (1% -5%) silica gel column chromatography to obtain 1g of intermediate. 1 H NMR(400MHz,DMSO-d 6 )δ12.35(s,1H),7.81(s,1H),7.53(s,1H),5.09(s,2H),3.62–3.58(m,1H),1.27(d,J＝6.6Hz,6H).
EXAMPLE 1 (Ex.1)
2-chloro-5-isopropyl-7- ((5- ((tetrahydro-2H-pyran-4-yl) amino) -1,3, 4-oxadiazol-2-yl) methyl) thieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000151
In a 25mL round bottom flask, 1g (100 mg,1 equiv) of intermediate, 4-aminotetrahydropyran (2 equiv), BOP (1.1 equiv) in DMF solvent was added dropwise followed by DIEA (2 equiv). The reaction mixture was reacted at room temperature and TLC monitored the progress of the reaction. After the reaction is finished, water is added for dilution, and ethyl acetateExtraction is carried out three times, the organic layer is washed by saturated sodium chloride solution, and anhydrous Na is adopted 2 SO 4 The organic layer was dried. Purification by column chromatography on silica gel using methylene chloride methanol (1% -5%) afforded example 1 (ex.1). 1 H NMR(400MHz,CDCl 3 )δ7.38(s,1H),7.16(s,1H),5.32(d,J＝8.0Hz,1H),5.29(s,2H),3.94(dd,J＝8.6,3.1Hz,2H),3.79–3.72(m,1H),3.46(td,J＝11.5,1.8Hz,3H),3.32(spt,J＝6.7Hz,1H),2.06–2.00(m,2H),1.59–1.51(m,2H),1.37(d,J＝6.7Hz,6H).
EXAMPLE 2 (Ex.2)
2-chloro-5-isopropyl-7- ((5-morpholin-1, 3, 4-oxadiazol-2-yl) methyl) thieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000161
In a 25mL round bottom flask, 1g (100 mg,1 equiv) of intermediate, morpholine (2 equiv), BOP (1.1 equiv) in DMF solvent was added dropwise followed by DIEA (2 equiv). The reaction mixture was reacted at room temperature and TLC monitored the progress of the reaction. After the reaction, water is added for dilution, ethyl acetate is used for extraction for three times, saturated sodium chloride solution is used for washing the organic layer, and anhydrous Na is used for 2 SO 4 The organic layer was dried. Purification by column chromatography on silica gel using methylene chloride methanol (1% -5%) afforded example 2 (ex.2). 1 H NMR(400MHz,CDCl 3 )δ7.41(s,1H),7.18(s,1H),5.33(d,J＝6.5Hz,2H),3.79–3.74(m,4H),3.48(dd,J＝5.8,3.8Hz,4H),3.35(spt,J＝6.7Hz,1H),1.39(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ164.79,156.52,153.87,142.45,134.11,131.59,127.13,126.46,113.33,104.90,66.02(2C),46.22,43.37(2C),30.31,20.00(2C).
EXAMPLE 3 (Ex.3)
2-chloro-5-isopropyl-7- ((5- (4-methylpiperazin-1-yl) -1,3, 4-oxadiazol-2-yl) methyl) thieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000162
In a 25mL round bottom flask, 1g (100 mg,1 equiv) of intermediate, N-methylpiperazine (2 equiv), BOP (1.1 equiv) in DMF solvent was added dropwise followed by DIEA (2 equiv). The reaction mixture was reacted at room temperature and TLC monitored the progress of the reaction. After the reaction, water is added for dilution, ethyl acetate is used for extraction for three times, saturated sodium chloride solution is used for washing the organic layer, and anhydrous Na is used for 2 SO 4 The organic layer was dried. Purification by column chromatography on silica gel using methylene chloride methanol (1% -5%) afforded example 3 (ex.3). 1 H NMR(400MHz,CDCl 3 )δ7.40(s,1H),7.17(s,1H),5.30(s,2H),3.54–3.49(m,4H),3.33(dt,J＝13.4,6.7Hz,1H),2.50–2.46(m,4H),2.32(s,3H),1.37(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ164.84,156.28,153.85,142.38,134.02,131.55,127.10,126.50,113.31,104.83,53.96(2C),46.28(2C),45.98,43.33,30.30,19.99(2C).
The synthesis method of examples 4 to 49 was the same as that of example 1, except that the amino group species was changed. The amino group species, the structural formula of the obtained compound, and the nuclear magnetic data of the obtained compound are shown in table 2.
TABLE 2 Structure and Nuclear magnetic data for examples 4-49
Figure BDA0004019918490000163
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Figure BDA0004019918490000171
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Figure BDA0004019918490000181
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Figure BDA0004019918490000191
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Figure BDA0004019918490000201
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Figure BDA0004019918490000211
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Figure BDA0004019918490000221
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Figure BDA0004019918490000231
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Figure BDA0004019918490000241
EXAMPLE 50 (Ex.50)
2-chloro-5-isopropyl-7- ((5- (4-tetrahydrofuran-3-yl) -1,3, 4-oxadiazol-2-yl) methyl) thieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000242
In a 25mL round bottom flask, intermediate 1f (1 equiv,200 mg), 3-tetrahydrofuranic acid (1 equiv) was dissolved in 1, 4-dioxane solvent. Phosphorus oxychloride (200 μl) was added dropwise while stirring at room temperature, and the reaction system was placed in an oil bath at 90deg.C for reaction, and TLC monitored the progress of the reaction. After the reaction, ethyl acetate is diluted and saturated NaHCO is added 3 Quenching the solution, separating an organic layer, extracting with ethyl acetate for three times, spin-drying and concentrating the organic layer, and purifying by using a petroleum ether ethyl acetate system (10% -25%) silica gel column chromatography to obtain the target compound Ex.50. 1 H NMR(400MHz,CDCl 3 )δ7.42(s,1H),7.18(s,1H),5.44(s,2H),4.11(dd,J＝8.7,7.8Hz,1H),4.01–3.87(m,3H),3.68–3.61(m,1H),3.35(dt,J＝13.4,6.7Hz,1H),2.38–2.32(m,2H),1.37(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ168.26,162.62,153.87,142.63,134.22,131.66,127.17,126.36,113.30,105.06,71.02,68.22,43.45,36.07,30.65,30.28,19.98(2C).
The synthesis methods of examples 51 to 82 were the same as those of example 50, except that the carboxylic acid species, the structural formula of the obtained compound and the nuclear magnetic data of the obtained compound were changed as shown in Table 3.
TABLE 3 Structure and Nuclear magnetic data for examples 51-82
Figure BDA0004019918490000251
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Figure BDA0004019918490000261
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Figure BDA0004019918490000271
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Figure BDA0004019918490000281
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Figure BDA0004019918490000291
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Figure BDA0004019918490000301
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Figure BDA0004019918490000311
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Figure BDA0004019918490000321
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Figure BDA0004019918490000331
EXAMPLE 83 (Ex.83)
2-bromo-7- ((5- (2-chloro-6- (trifluoromethyl) pyridin-3-yl) -1,3, 4-oxadiazol-2-yl) methyl) -5-isopropylthieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000332
a step: compound 1d (1 equiv) and solid NBS (1.2 equiv) were placed in THF solution and the reaction system was heated to react at 55 ℃. TLC monitored the progress of the reaction. After completion of the reaction, 10% Na was used 2 CO 3 The solution is quenched and extracted 2-3 times with ethyl acetate. The mixed organic extracts were washed with brine, anhydrous Na 2 SO 4 Drying, filtering and evaporating. Silica gel column chromatography purification was performed using petroleum ether and ethyl acetate system (0% -25%), and the compound obtained was white solid 2e. 1 H NMR(400MHz,CDCl 3 )δ7.38(s,1H),7.30(s,1H),4.78(s,2H),4.24(q,J＝7.2Hz,2H),3.37(spt,J＝6.7Hz,1H),1.40(d,J＝6.7Hz,6H),1.29(t,J＝7.1Hz,3H).
b, step b: compound 2e (1 equiv) and hydrazine hydrate (5 equiv) were added to an ethanol solution and reacted by heating at 85 ℃ and TLC monitored the progress of the reaction. A white solid formed which was filtered, washed with water and dried to give crude product 2f without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ9.19(s,1H),7.86(s,1H),7.45(s,1H),4.52(s,2H),4.26(d,J＝3.9Hz,2H),3.59(spt,J＝6.6Hz,1H),1.28(d,J＝6.6Hz,6H).
Figure BDA0004019918490000341
In a 25mL round bottom flask, intermediate 2f (1 equiv,200 mg), 2-chloro-6-trifluoromethyl nicotinic acid (1 equiv) was dissolved in 1, 4-dioxane solvent. Phosphorus oxychloride (200 μl) was added dropwise while stirring at room temperature, and the reaction system was placed in an oil bath at 90deg.C for reaction, and TLC monitored the progress of the reaction. After the reaction, ethyl acetate is diluted and saturated NaHCO is added 3 Quenching the solution, separating the organic layer, extracting with ethyl acetate three times, and concentrating the organic layer by spin dryingPurifying by using petroleum ether ethyl acetate system (10% -25%) silica gel column chromatography to obtain the target compound Ex.83. 1 H NMR(400MHz,CDCl 3 )δ7.41(s,1H),7.18(s,1H),5.43(s,2H),3.33(spt,J＝6.6Hz,1H),3.31–3.23(m,1H),2.11–2.03(m,2H),1.92–1.85(m,2H),1.80–1.75(m,2H),1.70–1.64(m,2H),1.36(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ171.17,162.07,153.86,142.48,134.08,131.59,127.12,126.44,113.30,104.94,77.48,77.16,76.84,43.37,36.05,31.17(2C),30.27,25.54(2C),19.97(2C).
EXAMPLE 84 (Ex.84)
2-bromo-5-isopropyl-7- (1- (5- (6-methylpyridin-3-yl) -1,3, 4-oxadiazol-2-yl) ethyl) thieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000342
a step: compound 1c (1 equiv) and ethyl 2-chloropropionate (1.2 equiv) are dissolved in DMF and Cs is added 2 CO 3 (3 equiv) the reaction mixture was stirred at room temperature and TLC monitored the progress of the reaction. After the reaction, the reaction mixture was diluted with water, acidified with 2M HCl, and extracted 3 times with ethyl acetate. The organic extracts were combined with 10% NaHCO 3 The organic layer was washed with anhydrous Na 2 SO 4 Drying, filtering and evaporating to dryness, and purifying by silica gel column chromatography to obtain the intermediate 3d. 1 H NMR(400MHz,CDCl 3 )δ7.26(dd,J＝5.3,2.2Hz,1H),7.08(d,J＝1.8Hz,1H),6.93(dd,J＝5.3,1.8Hz,1H),6.58(qd,J＝7.1,1.7Hz,1H),4.17(qd,J＝7.1,1.9Hz,2H),3.30–3.18(m,1H),1.81(dd,J＝7.2,2.0Hz,3H),1.44(dd,J＝7.0,2.1Hz,6H),1.16(td,J＝7.1,2.1Hz,3H).
b, step b: compound 3d (1 equiv) and solid NCS (1.2 equiv) were placed in THF solution and the reaction system was heated to react at 55 ℃. TLC monitored the progress of the reaction. After completion of the reaction, 10% Na was used 2 CO 3 The solution is quenched and extracted 2-3 times with ethyl acetate. The mixed organic extracts were washed with brine, anhydrous Na 2 SO 4 Drying, filtering and evaporating. By petroleum ether andethyl acetate (0% -25%) was purified by column chromatography on silica gel to give the compound as a white solid 3e. 1 H NMR(400MHz,CDCl 3 )δ6.98(s,1H),6.87(s,1H),6.56(q,J＝7.0Hz,1H),4.18(qd,J＝6.9,1.0Hz,2H),3.26–3.18(m,1H),1.77(dd,J＝7.3,1.0Hz,3H),1.42(dd,J＝7.0,1.0Hz,6H),1.19(td,J＝7.1,1.1Hz,3H).
c, step c: compound 3e (1 equiv) and hydrazine hydrate (5 equiv) were added to an ethanol solution and reacted by heating at 85 ℃ and TLC monitored the progress of the reaction. A white solid formed which was filtered, washed with water and dried to give crude product 3f without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ9.34(s,1H),7.29(s,1H),7.13(s,1H),6.06(q,J＝7.1Hz,1H),4.31(s,2H),3.27(spt,J＝7.0Hz,1H),1.65(d,J＝7.0Hz,3H),1.36(d,J＝7.0Hz,6H).
d, step d: in a 25mL round bottom flask, intermediate 3f (1 equiv,200 mg), 6-methylnicotinic acid (1 equiv) was dissolved in 1, 4-dioxane solvent. Phosphorus oxychloride (200 μl) was added dropwise while stirring at room temperature, and the reaction system was placed in an oil bath at 90deg.C for reaction, and TLC monitored the progress of the reaction. After the reaction, ethyl acetate is diluted and saturated NaHCO is added 3 Quenching the solution, separating an organic layer, extracting with ethyl acetate for three times, spin-drying and concentrating the organic layer, and purifying by using a petroleum ether ethyl acetate system (10% -25%) silica gel column chromatography to obtain the target compound Ex.84. 1 H NMR(400MHz,CDCl 3 )δ9.10(s,1H),8.35(d,J＝7.8Hz,1H),7.45(s,1H),7.39(d,J＝7.8Hz,1H),7.18(s,1H),6.49(q,J＝7.0Hz,1H),3.34(dt,J＝13.6,6.8Hz,1H),2.72(s,3H),1.97(d,J＝6.9Hz,3H),1.38(d,J＝6.7Hz,3H),1.27(d,J＝6.7Hz,3H).
Example 85 (Ex.85)
2-chloro-5-isopropyl-7- ((5- (pyridin-3-yl) -4H-1,2, 4-triazol-3-yl) methyl) thieno [2',3':4,5] pyrrolo [1,2-d ] [1,2,4] triazin-8 (7H) -one
Figure BDA0004019918490000351
In a 25ml round bottom flask, raw material 1f (100 mg,1 equiv) was dissolved in methanol solvent, and then addedSodium methoxide (0.5 equiv) was added thereto and stirred at room temperature until dissolved, followed by adding 3-cyanopyridine (1 equiv) to the reaction system and refluxing. TLC monitored the progress of the reaction. After the reaction is finished, a dichloromethane methanol system (1% -5%) is subjected to silica gel column chromatography purification to obtain the target compound Ex.85. 1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),9.01(s,1H),8.61(d,J＝3.4Hz,1H),8.18(d,J＝8.1Hz,1H),7.81(s,1H),7.48(s,1H),7.44(dd,J＝8.1,4.6Hz,1H),5.04(s,2H),3.61(spt,J＝6.6Hz,2H),1.30(d,J＝6.6Hz,6H).
The beneficial effects of the present invention are demonstrated by specific test examples below.
Biological test example: pharmacological test of the Compounds of the invention
The invention also provides pharmacological activity screening experiments of the partial compounds, namely in vitro IL-I beta inhibition experiments. THP-1 is a human myeloid leukemia monocyte originally derived from acute mononuclear leukemia patients. THP-1 is an acute monocytic leukemia cell line commonly used in various laboratories and is an ideal cell for studying immunity and inflammation.
Materials: LPS, nigericin, PMA.
Preparation of the compound: 1) Compound was made up with 100% DMSO to 10mmol/L stock solution; 2) LPS was formulated as a 1mg/mL stock solution with Opti-MEM; 3) Nigericin was prepared as a 10mM stock solution with absolute ethanol; 4) PMA was formulated with 100% DMSO as a master solution at 100. Mu.g/mL.
The method comprises the following steps: THP-1 cells (3X 10) 3 ) Inoculated in 48-well plates and cultured with PMA (100 ng/mL) for 24 hours, then the medium was changed to Opti-MEM, and treated with LPS (1 mg/mL concentration) for 3 hours, then treated with 2. Mu.M compound for 40min, finally treated with Nigericin (10 mM concentration) for 40min, and the supernatant was collected. IL-I beta in the supernatant was detected by ELISA kit.
And reading and recording the original data of each hole, and correspondingly converting the original data. The production rate of interleukin IL-1 beta by the compound is calculated as follows:
inhibition (%) = 1- (drug well OD value-blank well OD value)/(negative control well OD value-blank well OD value), with no drug and induction factor added cell wells as blank control, with no drug added cell wells with LPS and ATP added as negative control. The results are shown in Table 4.
Inhibitory Effect of the compounds of Table 4 on THP-1 cells
Figure BDA0004019918490000361
/>
Figure BDA0004019918490000371
/>

Claims (11)

1. A compound of formula i or a pharmaceutically acceptable salt thereof, characterized by the structure:
Figure FDA0004019918480000011
x is selected from NH, O and S;
R 1 selected from H, halogen, 3-8 membered cycloalkyl, C1-C8 alkyl, N-C1-C8 alkylamino;
R 3 selected from H, C-C8 alkyl;
r is selected from
Figure FDA0004019918480000012
N-heterocycles>
Figure FDA0004019918480000013
Y is NH or none;
R 2 selected from the group consisting of substituted or unsubstituted C1-C10 alkyl groups, substituted or unsubstituted C1-C10 ester groups, substituted or unsubstituted 3-to 8-membered cycloalkyl groups, substituted or unsubstituted 4-to 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 11-membered spirocycloalkyl groups, substituted or unsubstituted 6-to 10-membered aryl groups, substituted or unsubstituted 5-to 10-membered heteroaryl groups, substituted or unsubstituted,
Figure FDA0004019918480000014
n1 is an integer from 1 to 3;
R 2 wherein the substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 4-10 membered bridged cycloalkyl, substituted or unsubstituted 5-11 membered spirocycloalkyl contains 0-3 heteroatoms, and the heteroatoms are N, O, S;
R 2 wherein the substituted or unsubstituted 5-to 10-membered heteroaryl contains 1 to 3 heteroatoms, and the heteroatoms are N;
R 2 wherein the substituent of the substituted C1-C10 alkyl group, the substituted C1-C10 ester group is selected from halogen, hydroxy, nitrile, amino, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl containing 1-2 hetero atoms selected from at least one of N, O, S, and,
Figure FDA0004019918480000015
At least one of 6-10 membered aryl groups, R 4 Selected from unsubstituted or hydroxy-substituted C1-C4 alkyl groups, n2, n3 are independently selected from integers from 1 to 3;
R 2 wherein the substituents of the substituted 3-to 8-membered cycloalkyl, substituted 4-to 10-membered bridged cycloalkyl, substituted 5-to 11-membered spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, C1-C8 alkoxycarbonyl, C1-C8 ester, substituted or unsubstituted C1-C8 alkyl, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, C1-C8 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C8 alkyl group in the substituent is selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, R 5 Selected from C1-C4 alkyl and 3-6 membered cycloalkyl;
R 2 wherein the substituent of the substituted 6-10 membered aryl group and the substituted 5-10 membered heteroaryl group is at least one selected from halogen, hydroxy, nitrile, C1-C8 alkoxycarbonyl, C1-C8 ester, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C8 alkyl and C1-C8 alkoxy, and the substituent of the substituted C1-C8 alkyl in the substituent is selected from halogen, hydroxy and amino;
the N heterocycle is selected from a substituted or unsubstituted 3-8 membered N heteroalkane ring, a substituted or unsubstituted 4-8 membered N heterobridged alkane ring, a substituted or unsubstituted 5-11 membered N heterospiroalkane ring, which contains 0-2O or S heteroatoms besides N;
in the N heterocycle, the substituent groups of the substituted 3-8 membered N-heteroalkyl ring, the substituted 4-8 membered N-heterobridged alkyl ring and the substituted 5-11 membered N-heterospirane ring are selected from C1-C6 alkyl, halogen, hydroxyl, nitrile group,
Figure FDA0004019918480000021
At least one of them.
2. A compound according to claim 1, wherein,
R 1 selected from H, halogen, 3-6 membered cycloalkyl, C1-C6 alkyl, N-C1-C6 alkylamino;
preferably, R 1 Selected from H, halogen, 3-6 membered cycloalkyl, C1-C4 alkyl, N-C1-C4 alkylamino;
most preferably, R 1 Selected from H, cl, br, cyclopropyl, ethyl, methyl, N-ethylamino.
3. A compound according to claim 1 or 2, characterized in that,
R 2 selected from the group consisting of substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C1-C8 ester groups, substituted or unsubstituted 3-to 6-membered cycloalkyl groups, substituted or unsubstituted 4-to 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 9-membered spirocycloalkyl groups, substituted or unsubstituted 6-to 10-membered aryl groups, substituted or unsubstituted 5-to 10-membered heteroaryl groups, substituted or unsubstituted,
Figure FDA0004019918480000022
Preferably, R 2 Selected from the group consisting of substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 ester groups, substituted or unsubstituted 3-to 6-membered cycloalkyl groups, substituted or unsubstituted 4-to 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 7-membered spirocycloalkyl groups, substituted or unsubstituted 6-to 10-membered aryl groups, and substituted or unsubstituted 5-to 10-membered heteroaryl groups、
Figure FDA0004019918480000023
More preferably, R 2 Selected from the group consisting of substituted or unsubstituted C1-C4 alkyl groups, substituted or unsubstituted C1-C4 ester groups, substituted or unsubstituted 3-to 6-membered cycloalkyl groups, substituted or unsubstituted 10-membered bridged cycloalkyl groups, substituted or unsubstituted 5-to 7-membered spirocycloalkyl groups, substituted or unsubstituted 6-membered aryl groups, substituted or unsubstituted 5-, 6-or 9-membered heteroaryl groups, substituted or unsubstituted,
Figure FDA0004019918480000024
4. A compound according to any one of claims 1 to 3,
R 2 wherein the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted spirocycloalkyl contains 0 to 2 heteroatoms, and the heteroatoms are N, O, S; r is R 2 Wherein the substituted or unsubstituted heteroaryl contains 1 to 3 heteroatoms, and the heteroatoms are N;
preferably, R 2 Wherein the substituted or unsubstituted cycloalkyl, substituted or unsubstituted bridged cycloalkyl, substituted or unsubstituted spirocycloalkyl contains 0 to 2 heteroatoms, and the heteroatoms are N, O, S; r is R 2 Wherein the substituted or unsubstituted heteroaryl group contains 1 to 3 heteroatoms, and the heteroatoms are N.
5. A compound according to any one of claims 1 to 4,
R 2 wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of halogen, hydroxy, nitrile, amino, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 2 hetero atoms selected from at least one of N, O, S, and,
Figure FDA0004019918480000031
At least one of 6-10 membered aryl groups, R 4 Selected from unsubstituted orHydroxy-substituted C1-C4 alkyl; n2 and n3 are independently selected from integers of 1 to 2; r is R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, C1-C6 alkoxycarbonyl, C1-C6 ester, substituted or unsubstituted C1-C6 alkyl, 3-6 cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, C1-C6 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C6 alkyl group in the substituent is selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, R 5 Selected from C1-C4 alkyl and 3-6 membered cycloalkyl; r is R 2 Wherein the substituent of the substituted aryl and the substituted heteroaryl is at least one selected from halogen, hydroxyl, nitrile, C1-C6 alkoxycarbonyl, C1-C6 ester, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C6 alkyl and C1-C6 alkoxy, and the substituent of the substituted C1-C6 alkyl in the substituent is selected from halogen, hydroxyl and amino;
preferably, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of halogen, hydroxy, nitrile, amino, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocycloalkyl containing 1 to 2 hetero atoms selected from at least one of N, O, S, and,
Figure FDA0004019918480000032
Figure FDA0004019918480000033
At least one of 6-10 membered aryl groups, R 4 Selected from unsubstituted or hydroxy-substituted C1-C4 alkyl groups, n2, n3 are independently selected from 1; r is R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, C1-C4 alkoxycarbonyl, C1-C4 ester, substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1-2 heteroatoms selected from at least one of N, O, S, C1-C4 alkoxy, -SO 2 -R 5 At least one of (1), wherein theThe substituent of the substituted C1-C4 alkyl in the substituent is selected from halogen, hydroxy, amino, 3-6 membered cycloalkyl, R 5 Selected from C1-C4 alkyl and 3-6 membered cycloalkyl; r is R 2 Wherein the substituent of the substituted aryl and the substituted heteroaryl is at least one selected from halogen, hydroxyl, nitrile, C1-C4 alkoxycarbonyl, C1-C4 ester, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl and C1-C4 alkoxy, and the substituent of the substituted C1-C4 alkyl in the substituent is selected from halogen, hydroxyl and amino;
more preferably, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of a hydroxyl group, an amino group, a 3-to 6-membered cycloalkyl group, a 3-to 6-membered heterocycloalkyl group containing 1 hetero atom selected from N, O, S,
Figure FDA0004019918480000034
At least one of phenyl groups; r is R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from the group consisting of halogen, hydroxy, nitrile, amino, t-butoxycarbonyl, C1-C4 ester, substituted or unsubstituted C1-C4 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, C1-C4 alkoxy, -SO 2 -R 5 Wherein the substituent of the substituted C1-C4 alkyl group in the substituent is selected from halogen, hydroxy, cyclopropyl, R 5 Selected from methyl, cyclopropyl; r is R 2 Wherein the substituent of the substituted aryl and the substituted heteroaryl is at least one selected from halogen, hydroxy, nitrile, 3-6 membered cycloalkyl, substituted or unsubstituted C1-C4 alkyl and C1-C4 alkoxy, and the substituent of the substituted C1-C4 alkyl in the substituent is selected from halogen;
most preferably, R 2 Wherein the substituent of the substituted alkyl group or the substituted ester group is selected from the group consisting of hydroxy, amino, cyclopropyl,
Figure FDA0004019918480000041
Figure FDA0004019918480000042
At least one of phenyl groups; r is R 2 Wherein the substituents of the substituted cycloalkyl, substituted bridged cycloalkyl, substituted spirocycloalkyl are selected from F, hydroxy, cyano, amino, -Boc, methoxycarbonyl, methyl, trifluoromethyl, hydroxymethyl, (-) ->
Figure FDA0004019918480000043
Cyclopropyl, cyclobutyl,>
Figure FDA0004019918480000044
methoxy group,/->
Figure FDA0004019918480000045
At least one of (a) and (b); r is R 2 Wherein the substituent of the substituted aryl or the substituted heteroaryl is at least one selected from F, cl, hydroxyl, cyano, methyl, ethyl, propyl, trifluoromethyl and methoxy.
6. A compound according to any one of claims 1 to 5,
R is selected from
Figure FDA0004019918480000046
Figure FDA0004019918480000047
Figure FDA0004019918480000051
7. A compound according to claim 1 or 2, characterized in that,
the N heterocycle is selected from a substituted or unsubstituted 3-6 membered N heteroalkane ring, a substituted or unsubstituted 4-8 membered N heterobridged alkane ring, a substituted or unsubstituted 5-9 membered N heterospiroalkane ring, which contains 0-1O heteroatom in addition to N; in the N heterocycle, the substituted 3-6 membered N-heteroalkyl ringThe substituent of the substituted 4-8 membered N-heterobridged alkane ring and the substituted 5-9 membered N-heterospiro alkane ring is selected from C1-C4 alkyl, halogen, hydroxy, nitrile group,
Figure FDA0004019918480000052
At least one of (a) and (b);
preferably, the N-heterocycle is selected from the group consisting of a substituted or unsubstituted 4-6 membered N-heteroalkyl ring, an unsubstituted 4-8 membered N-heterobridged alkyl ring, an unsubstituted 5-7 membered spiroalkyl ring containing 0-1O heteroatom in addition to N; in the N heterocycle, the substituent of the substituted 4-6 membered N-heteroalkyl ring is selected from methyl, hydroxyl,
Figure FDA0004019918480000053
At least one of (a) and (b);
most preferably, the N-heterocycle is selected from
Figure FDA0004019918480000054
8. A compound according to claim 1, wherein,
R 3 selected from H, C-C6 alkyl;
preferably, R 3 Selected from H, C-C4 alkyl;
most preferably, R 3 Selected from H and methyl.
9. A compound according to any one of claims 1 to 8, having the formula:
Figure FDA0004019918480000055
Figure FDA0004019918480000061
Figure FDA0004019918480000071
Figure FDA0004019918480000081
10. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable auxiliary ingredient.
11. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 10, for the preparation of an NLRP3 inhibitor.
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