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CN-122003417-A - NEK7 inhibitor, pharmaceutical composition and application thereof

CN122003417ACN 122003417 ACN122003417 ACN 122003417ACN-122003417-A

Abstract

The present disclosure relates to NEK7 inhibitors, pharmaceutical compositions and uses thereof, the compounds having the structural formula (I). The compounds of the present disclosure have good NEK7 inhibitory activity and can be used for treating or preventing inflammatory several pathological diseases (Alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, crohn's disease, cancer, osteoarthritis, gout, etc.) regulated by NLRP3 inflammasome.

Inventors

  • DAI LIGUANG
  • ZHU LI
  • ZHU BING
  • ZHANG HUI
  • YANG YANQING
  • HU WEI
  • DU YUNLONG

Assignees

  • 北京普祺医药科技股份有限公司

Dates

Publication Date
20260508
Application Date
20240927
Priority Date
20230928

Claims (20)

  1. A compound shown in formula I Or a pharmaceutically acceptable salt, hydrate, solvate, active metabolite, polymorph, isotopic label, isomer or prodrug thereof, Wherein, the Ring a is C 6-10 aryl substituted with 0-4R A , C 3-10 cycloalkyl substituted with 0-4R A , 3-10 membered heterocyclyl substituted with 0-4R A , or 5-6 membered heteroaryl substituted with 0-4R A ; r is one of the following structural formulas Or alternatively R 4 is a group Wherein, the L is a direct bond, O or CR 21 R 22 ; R L is C 6-10 aryl substituted with 0-4R C , C 3-10 cycloalkyl substituted with 0-4R C , 3-10 membered heterocyclyl substituted with 0-4R C , or 5-6 membered heteroaryl substituted with 0-4R C ; x 1 is CR 31 or N; X 2 is C or N; X 3 is CR 32 or N; x 4 is C or N; z 1 is CH or N; Z 2 is O or S; z 3 is C or N; Z 4 is C or N; in ring 1 Indicating the presence of conjugated double bonds in ring 1; R 1 is selected from C 6-10 aryl substituted with 0-4R 0 , C 3-10 cycloalkyl substituted with 0-4R 0 , 3-10 membered heterocyclyl substituted with 0-4R 0 , 5-6 membered heteroaryl substituted with 0-4R 0 , C 1-6 alkyl substituted with 0-4R 0 , C 1-6 alkoxy substituted with 0-4R 0 , C 2-6 alkenyl substituted with 0-4R 0 , C 2-6 alkynyl substituted with 0-4R 0 , or NR 11 R 12 ; R 2 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 alkoxy; Each R A is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; R B is each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 6-10 aryl substituted with 0-4R B1 , C 3-10 cycloalkyl substituted with 0-4R B1 , 3-10 membered heterocyclyl substituted with 0-4R B1 , or 5-6 membered heteroaryl substituted with 0-4R B1 ; Each R B1 is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; Each R C is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; R 31 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; r 32 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; r 51 and R 52 are each independently hydrogen, halogen, deuterium, tritium, or C 1-6 alkyl, or R 51 、R 52 together with the carbon to which they are attached form a C 3-6 cycloalkyl; R 61 and R 62 are each independently hydrogen, halogen, deuterium, tritium, or C 1-6 alkyl, or R 61 、R 62 together with the carbon to which they are attached form a C 3-6 cycloalkyl; R 7 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 6-10 aryl substituted with 0-4R 70 , C 3-10 cycloalkyl substituted with 0-4R 70 , 3-10 membered heterocyclyl substituted with 0-4R 70 , or 5-6 membered heteroaryl substituted with 0-4R 70 ; R 70 is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered heterocyclyl, or NR 11 R 12 ; R 0 is each independently selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-8 membered heterocyclyl, or NR 11 R 12 ; R 11 and R 12 are each independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl or C 1-6 haloalkyl; R 21 and R 22 are each independently selected from hydrogen, halogen, deuterium, tritium, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, or R 21 and R 22 together with the attached carbon form a C 3-6 cycloalkyl; n is 1 or 2.
  2. The compound of claim 1, wherein ring a is C 6-10 aryl substituted with 0-4R A , C 3-10 cycloalkyl substituted with 0-4R A , 3-10 membered heterocyclyl substituted with 0-4R A , or 5-6 membered monocyclic heteroaryl substituted with 0-4R A .
  3. The compound of claim 2, wherein ring a is a benzene ring substituted with 0 or 1R A .
  4. The compound of claim 2, wherein ring a is a pyridine ring substituted with 0 or 1R A .
  5. The compound of claim 2, wherein ring a is a pyrimidine ring substituted with 0 or 1R A .
  6. The compound of any one of claims 1-5, wherein R A is halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, or C 1-6 haloalkoxy.
  7. The compound of any one of claims 1-5, wherein ring a has one of the following structures:
  8. The compound of any one of claims 1-7, wherein R 2 is hydrogen.
  9. The compound of any one of claims 1-7, wherein R 1 is C 3-10 cycloalkyl substituted with 0-4R 0 , 3-10 membered heterocyclyl substituted with 0-4R 0 , or C 1-6 alkyl substituted with 0-4R 0 ; Each R 0 is independently selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, or C 1-6 haloalkyl.
  10. A compound according to any one of claims 1 to 7 wherein R 1 is a C 3-10 cyclic hydrocarbon group such as cyclopropyl.
  11. The compound of any one of claims 1-7, wherein R 1 is 3-10 membered heterocyclyl substituted with 0-1R 0 , C 2-6 alkenyl substituted with 0-1R 0 , or C 1-6 alkyl substituted with 0-1R 0 ; R 0 is each independently selected from halogen, hydroxy, cyano or C 1-3 alkoxy.
  12. The compound of claim 11, wherein R 1 is one of the following groups:
  13. The compound of any one of claims 1-12, wherein R is isoxazolyl substituted with 1R 7 , oxazolyl substituted with 1R 7 , oxadiazolyl substituted with 1R 7 , triazolyl substituted with 1R 7 , thiazolyl substituted with 1R 7 , isothiazolyl substituted with 1R 7 , or thiadiazolyl substituted with 1R 7 ; Wherein R 7 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 6-10 aryl substituted with 0-1R 70 , C 3-10 cycloalkyl substituted with 0-1R 70 , 3-10 membered heterocyclyl substituted with 0-1R 70 , or 5-6 membered heteroaryl substituted with 0-1R 70 ; R 70 is each independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl.
  14. The compound of any one of claims 1-12, wherein R has the structure In the above structure Indicating the presence of conjugated double bonds within the ring structure; Wherein R 7 is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl substituted with 0-1R 70 ; R 70 is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, or 3-8 membered heterocyclyl; Z 2 is O or S; z 3 is C or N; Z 4 is C or N.
  15. The compound according to claim 14, wherein, Z 2 is O, Z 3 is CH, Z 4 is N, or Z 2 is N, Z 3 is CH, Z 4 is O, or Z 2 is S, Z 3 is CH, Z 4 is N, or Z 2 is S, Z 3 is N, and Z 4 is N.
  16. The compound of claim 14, wherein R has one of the following structural formulas Or alternatively Wherein R Ba is C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl substituted with 1R B1a , Wherein R B1a is C 1-6 alkyl or C 1-6 haloalkyl.
  17. The compound of any one of claims 1-10, wherein R has the structure Wherein R B is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, hydroxy, C 1-6 hydroxyalkyl, or C 1-6 haloalkyl; R 4 has the following structure L is O, CH 2 、CF 2 、CD 2 or R L is C 6-10 aryl substituted with 0-1R C , C 3-10 cycloalkyl substituted with 0-1R C , 3-10 membered heterocyclyl substituted with 0-1R C , or 5-6 membered heteroaryl substituted with 0-1R C ; R C is halogen or C 1-6 alkyl.
  18. A compound according to claim 17, wherein R B is hydrogen or C 1-6 haloalkyl, such as trifluoromethyl; L is O, CH 2 、CF 2 、CD 2 or R L is a 3-10 membered heterocyclyl substituted with 1R C ; r C is halogen or C 1-3 alkyl.
  19. The compound of any one of claims 1-18, wherein R L has one of the following structures Or alternatively Wherein R Bb is C 1-6 alkyl.
  20. The compound of claim 17, wherein R has one of the following structural formulas Wherein L is O or CH 2 ;R Bb is C 1-3 alkyl, R Bc is hydrogen or C 1-3 haloalkyl such as trifluoromethyl.

Description

NEK7 inhibitor, pharmaceutical composition and application thereof Technical Field The invention belongs to the field of biological medicine, and in particular relates to NEK7 kinase inhibitor compounds represented by a general formula (I), pharmaceutically acceptable salts, esters, stereoisomers, tautomers, pharmaceutical compositions containing the NEK7 kinase inhibitor compounds, pharmaceutical preparations and application of NEK7 kinase inhibitor compounds. The compound can selectively inhibit the NEK7 family of tyrosine kinases, and can be used for treating diseases mediated by abnormal expression of NEK7 kinase. Background Inflammation is a protective immune response stimulated by the host's innate immune system in response to allergens, immunogenic organisms, and the like. The innate immune response is tightly regulated by the host. It is noted that inflammation can lead to persistent infections, while excessive inflammation can lead to autoimmune diseases. Inflammatory bodies (inflammasomes) are cytoplasmic supramolecular protein complexes that activate cysteine-containing aspartic proteinase 1 (caspase 1) -mediated cytokines such as IL-1 beta and IL-18 and cause inflammation and cell apoptosis, central to innate immunity and inflammation. Up to now, 4 classes of inflammatory bodies have been found, NLRP1, NLRP3, NLRC4 and AIM2. Among them, NLRP3 is an important downstream effector of signals triggering inflammatory responses and is involved in driving the onset and progression of many chronic inflammatory diseases, neurodegenerative diseases, cardiovascular diseases. Activation of NLRP3 triggers the release of the pro-inflammatory cytokines IL-1 beta and IL-18 and induces a lytic cell death process called pyrophosphorylation. Blocking inflammatory responses mediated by inflammatory bodies is useful in the treatment of a number of diseases such as Alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, crohn's disease, cancer, osteoarthritis, gout and the like. NEK7 (NIMA-RELATED KINASE 7) protein kinase, which is the smallest of the NEKs families of 11 (NEK 1-NEK 11) mammals, is expressed in many tissues and its importance in mitotic regulation and NLRP3 inflammatory body activation has been established. Inhibition of NLRP3 signaling by NEK7 prevents the formation of NLRP3 inflammatory corpuscles, thereby inhibiting the production of IL-1 beta and IL-18 and cleavage of pore-forming GASDERMIN D. Apoptosis is associated with a number of inflammatory diseases, and therefore inhibitors of NLRP3 inflammatory body activation that block NLRP3-NEK7 interactions may have therapeutic or prophylactic activity in chronic inflammation, neurodegenerative diseases, cardiovascular diseases, and the like. A number of inhibitors have been widely used to interfere with effector signaling pathways involving IL 1 β or IL 18 without abrogating the inflammatory response. Inhibitors of NLRP3 inflammatory body activation that block NLRP3 NEK7 interactions may have therapeutic or prophylactic activity in several human diseases (e.g., type 2 diabetes, atherosclerosis, gout, and neurodegenerative diseases). Therefore, there is a need to develop inhibitors that selectively target NEK7 for the treatment or prevention of several pathological diseases (alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, crohn's disease, cancer, osteoarthritis, gout, etc.) that are mediated by NLRP3 inflammasome. Disclosure of Invention The present disclosure provides a compound of formula I The compounds of the present disclosure have good NEK7 inhibitory activity and can be used for treating or preventing inflammatory several pathological diseases (Alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, ulcerative colitis, crohn's disease, cancer, osteoarthritis, gout, etc.) regulated by NLRP3 inflammasome. The present disclosure also relates to pharmaceutical compositions comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, diluent or excipient. The present disclosure also relates to a method of treating or preventing a disorder mediated by NEK7-NLRP3 phase solution comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. The disclosure also relates to the use of a compound of the disclosure in the manufacture of a medicament for treating or preventing a NEK7-NLRP3 phase solution-mediated disorder. Detailed Description The present application will be described in further detail by way of examples. The features and advantages of the present application will become more apparent from the description. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration. Any