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CN-121986090-A - NLRP3 inflammation corpuscle inhibitor and application thereof

CN121986090ACN 121986090 ACN121986090 ACN 121986090ACN-121986090-A

Abstract

The invention belongs to the technical field of medicines, and relates to an NLRP3 inflammation small body inhibitor and application thereof. Specifically, the definition of each group of the compound represented by the general formula (I) or deuterated compound thereof or stereoisomer thereof or pharmaceutically acceptable salt thereof is defined in the specification. The research shows that the compound shown in the general formula (I), or the deuterated compound, or the stereoisomer, or the pharmaceutically acceptable salt thereof has higher biological activity on NLRP3 inflammatory corpuscles, and has important clinical development value Y-W-R 3 (I) for treating NLRP3 related diseases.

Inventors

  • LI LIN

Assignees

  • 纽罗克里生物科学有限公司

Dates

Publication Date
20260505
Application Date
20240809
Priority Date
20230811

Claims (11)

  1. A compound represented by the general formula (I) or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Y-W-R 3 (I) Wherein W is selected from Or alternatively Selected from single bond or double bond; r 1 is independently selected from hydrogen, oxo, thioxo, hydroxy, amino, carboxy, cyano, nitro, halo, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N (C 1-6 alkyl) 2 , or absent; R 2 is independently selected from hydrogen, oxo, thioxo, hydroxy, amino, carboxy, cyano, nitro, halo, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N (C 1-6 alkyl) 2 , or absent; The R 1 、R 2 is independently optionally substituted with 1-3 substituents selected from hydroxy, C 0-6 alkylamino, carboxy, cyano, nitro, halo, C 0-6 alkylcarbonyl, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 alkylsulfonyl; Or (b) R 1 、R 2 forms a 5-12 membered ring A with the C or N atom to which they are attached; The 5-12 membered ring A is optionally substituted with 1-4 substituents selected from hydroxy, amino, carboxy, cyano, nitro, halogen, carbonyl, oxo, C 1-6 alkyl, -NH-C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C 1-6 alkylsulfonyl, -N (C 1-6 alkyl) 2 ; R 3 is selected from -(CH 2 ) n -NR 4 -Z-(CH 2 ) m -R 5 、-(CH 2 ) n -NR 4 -Z-CR c R d -R 5 ; N is an integer of 0 to 6; m is an integer of 0 to 3; R 4 is selected from hydrogen or C 1-6 alkyl; Z is selected from c= O, C = S, S (O) or S (O) 2 ; R 5 is selected from 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, NR a R b 、OR b 、C 1-6 alkyl; r a is selected from hydrogen or C 1-6 alkyl; R c is selected from hydrogen or C 1-6 alkyl; R b is selected from the group consisting of hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N (C 1-6 alkyl) 2 ; Said R b is optionally substituted with 1-2 substituents selected from hydroxy, halogen, 3-7 membered cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy; R d is selected from the group consisting of hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N (C 1-6 alkyl) 2 ; Said R d is optionally substituted with 1-2 substituents selected from hydroxy, halogen, 3-7 membered cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, aryl, cyano, carboxy; Or (b) R c 、R d forms a 3-7 membered cycloalkyl group with the C atom to which they are attached; Or (b) When R 5 is selected from NR a R b , R a is linked to R 4 such that R 3 forms a 4-7 membered heterocyclyl; The R 5 is optionally substituted with 1-4 substituents selected from oxo, thio, hydroxy, amino, carboxy, cyano, nitro, halo, carbonyl, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, ureido, hydrazino; The substituents on R 5 may be further optionally substituted with 1-3 substituents selected from hydroxy, C 0-6 alkylamino, carboxy, cyano, nitro, halo, C 0-6 alkylcarbonyl, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered heterocyclyl, 3-6 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 alkylsulfonyl, ureyl, hydrazino; y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl; The Y is optionally substituted with 1-4 substituents selected from oxo, thio, hydroxy, amino, carboxy, cyano, nitro, halogen, carbonyl, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl; The substituents on Y may be further optionally substituted with 1-3 substituents selected from hydroxy, C 0-6 alkylamino, carboxy, cyano, nitro, halo, C 0-6 alkylcarbonyl, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halo C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-6 membered heterocyclyl, 3-7 membered cycloalkyl, 5-6 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, C 0-6 alkylsulfonyl.
  2. The compound of claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein W is selected from
  3. The compound according to claim 1 or2, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein, the R 1 、R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, 3-7 membered cycloalkyl, -N (C 1-6 alkyl) 2 , or absent; Preferably, R 1 、R 2 is independently selected from hydrogen, cyano, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, cyclopropyl, cyclobutyl, or absent.
  4. The compound of claim 1, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein R 3 is selected from -(CH 2 ) n -NR 4 -Z-(CH 2 ) m -R 5 、-(CH 2 ) n -NR 4 -Z-CR c R d -R 5 ; N is an integer of 0 to 2; m is an integer of 0 to 2; R 4 is selected from hydrogen or C 1-6 alkyl; Z is selected from c=o; R 5 is selected from 3-7 membered heterocyclyl, NR a R b 、OR b 、C 1-6 alkyl; r a is selected from hydrogen or C 1-6 alkyl; R c is selected from hydrogen or C 1-6 alkyl; R b is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; Said R b is optionally substituted with 1-2 substituents selected from hydroxy, halogen, 3-7 membered cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy; r d is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; The R d is optionally substituted with 1-2 substituents selected from hydroxy, halogen, 3-7 membered cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, aryl, cyano, carboxy.
  5. The compound of claim 4, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, N is 0; m is 0; R 5 is selected from 3-7 membered heterocyclyl; Said R 5 is optionally substituted with 1-4 substituents selected from hydroxy, amino, carboxy, cyano, halo, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, aryl; The substituents on R 5 may be further optionally substituted with 1-3 substituents selected from hydroxy, halogen, C 1-6 alkyl; preferably, R 5 is a 4-6 membered heterocyclyl containing 1N heteroatom.
  6. The compound of claim 4, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, N is 0; m is 0; R 5 is selected from NR a R b ;R a is selected from hydrogen or C 1-6 alkyl; R c is selected from hydrogen or C 1-6 alkyl; r b is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, cyclopropyl, cyclobutyl; Said R b is optionally substituted with 1-2 substituents selected from hydroxy, halogen, cyclopropyl, cyclobutyl, C 1-6 alkoxy; r d is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, cyclopropyl, cyclobutyl; The R d is optionally substituted with 1-2 substituents selected from hydroxy, halogen, cyclopropyl, cyclobutyl, halo C 1-6 alkyl, C 1-6 alkoxy, phenyl.
  7. The compound according to claim 1 or2, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Wherein Y is selected from phenyl, 5-14 membered heteroaryl; The Y is optionally substituted with 1-4 substituents selected from hydroxy, amino, cyano, halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, 3-7 membered cycloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; When the substituent on Y is selected from C 1-6 alkyl, 3-7 membered cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, said substituent is further optionally substituted with 1-3 substituents selected from hydroxy, halogen, C 1-6 alkyl, halo C 1-6 alkyl, 3-7 membered cycloalkyl; Preferably, said Y is substituted with hydroxy, Y may be further optionally substituted with 1 to 3 substituents selected from amino, cyano, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, cyclopropyl, and said substituents on Y may be further optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkyl, cyclopropyl, trifluoromethyl, difluoromethyl.
  8. A compound as described below, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  9. A pharmaceutical composition comprising a compound of any one of claims 1-8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers.
  10. Use of the compound according to any one of claims 1-8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with NLRP3 inflammatory bodies.
  11. Use of a compound as claimed in any one of claims 1 to 8, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 9, for the manufacture of a medicament for the prevention and/or treatment of an inflammatory-body related disease, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease.

Description

NLRP3 inflammation corpuscle inhibitor and application thereof Citation of related application The present invention claims priority to the patent application filed in china at 11/08/2023 entitled "NLRP3 inhibitor of inflammatory corpuscles and its use", application number 202311008972.0, the entire contents of which are incorporated herein by reference. Technical Field The invention belongs to the technical field of medicines, and particularly relates to an NLRP3 inflammation small body inhibitor and application thereof. Background Nucleotide binding oligomerization domain-like receptor protein 3 (NOD-like receptor protein, nlrp 3) belongs to the family of nucleotide binding oligomerization domain-like receptors (NLRs), also known as "heat-containing protein (pyrin) domain protein 3". NLRP3 comprises three modules of a thermo protein domain (PYD), a nucleotide binding site domain (NBD) and a Leucine Rich Repeat (LRR). When stimulated with a sterile inflammation risk signal, NLRP3 interacts with the adapter protein apoptosis-related speckle-like protein (ASC) and pro-caspase-1 (pro-caspase 1) to form NLRP3 inflammatory corpuscles. Activation of the NLRP3 inflammatory body results in the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18). Activation of NLRP3 inflammatory bodies typically requires two steps. The first step involves signaling in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMP), which in turn signal into cells, mediate activation of NF- κb signaling pathways, and up-regulate transcription levels of NLRP3 inflammatory small components including inactive NLRP3 and pro-IL-1 β. The second step is to activate signals, after P2X7 receptors and the like receive signal stimulus of ATP, nigericin and the like, NLRP3 monomers are oligomerized to form NLRP3 oligomers, and then ASC and pro-caspase 1 are recruited to assemble into NLRP3 inflammatory small complex. This triggers the conversion of pro-caspase 1 to caspase 1, as well as the production and secretion of mature IL-1β and IL-18. Activation of NLRP3 inflammatory bodies is associated with a variety of diseases. For example, autoinflammatory fever syndromes such as cold-related periodic syndromes (CAPS), sickle cell disease, systemic Lupus Erythematosus (SLE), chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, pseudogout (chondrocalcareous pigmentation disease), type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammation-related disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, alzheimer's disease), atherosclerosis and cardiovascular risks (e.g., hypertension), suppurative sweat gland, wound healing and scarring, and cancers (e.g., large intestine cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). Most treatments include symptomatic treatment, slowing the progression of the disease/disorder, and surgery as the last treatment. The developed NLRP3 inflammation small inhibitor has few varieties, and the NLRP3 inflammation small inhibitor with higher activity and better pharmacy is developed and becomes clinical requirement. Disclosure of Invention The invention researches the following compounds, or deuterated compounds, or stereoisomers, or pharmaceutically acceptable salts thereof, and discovers that the compounds, or deuterated compounds, or stereoisomers, or pharmaceutically acceptable salts thereof have higher biological activity on NLRP3 inflammatory corpuscles, and have important clinical development value for treating NLRP3 related diseases. In order to achieve the above object, the present invention provides the following solutions: a compound represented by the general formula (I) or a deuterated compound thereof or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: Y-W-R3 (I) Wherein W is selected from Or alternatively Selected from single bond or double bond; r 1 is independently selected from hydrogen, oxo, thioxo, hydroxy, amino, carboxy, cyano, nitro, halo, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N (C 1-6 alkyl) 2, or absent; R 2 is independently selected from hydrogen, oxo, thioxo, hydroxy, amino, carboxy, cyano, nitro, halo, carbonyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, halogenated C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, 5-7 membered cycloalkenyl, aryl, 5-7 membered heteroaryl, sulfonyl, -N (C 1-6 alkyl) 2, or absent; The R 1、R2 is independently optionally substituted with 1-3 substituents selected from hydroxy, C 0-6 alkylamino, carboxy, cyano, nitro, halo, C 0-6 alky