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EP-4737448-A1 - SARM1 ENZYME ACTIVITY INHIBITOR AND USE THEREOF

EP4737448A1EP 4737448 A1EP4737448 A1EP 4737448A1EP-4737448-A1

Abstract

Provided in the present invention is the use of an SARMI enzyme activity inhibitor in treatment of neurodegenerative diseases or neurological diseases or disorders. Particularly provided in the present invention are compounds of formula (I) serving as SARMI enzyme activity inhibitors and a pharmaceutical composition thereof

Inventors

  • NIU, DEQIANG
  • ZHU, ZHENDONG
  • FAN, MING
  • ZHENG, Zihua

Assignees

  • Artivila (ShenZhen) Innovation Center, Ltd.

Dates

Publication Date
20260506
Application Date
20240624

Claims (9)

  1. A compound represented by formula (I), or a racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof: wherein, X 1 , X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of CH and N; Z represents -CH 2 -, -CH 2 (CH 3 )- or-O-; represents a single bond or a double bond; Y represents a carbon atom or a nitrogen atom; R 1 is independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl, cyano, trifluoromethyl, amino, hydroxy, methoxy and -C(O)NH 2 , preferably selected from the group consisting of H, F, Cl, methyl, cyano, and -C(O)NH 2 ; R 2 is independently selected from the group consisting of H, halogen, C 1 -C 3 alkyl, cyano, trifluoromethyl, amino, hydroxy, methoxy, C 1 -C 3 alkyl-OC(O)- and C 1 -C 3 alkyl-NHC(O)-, preferably selected from the group consisting of H, cyano, Cl, methyl and methoxy; M represents O or S; L is selected from the group consisting of -CH 2 -CH 2 -, -CH 2 -, -O-, -S-, -NH- and -CO-, wherein either -CH 2 - moiety in -CH 2 -CH 2 - is optionally substituted by -O-, -S-, -CO- or -NH-; preferably, L is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH-O-, -O- and -CO-; and E is selected from the group consisting of and wherein, X 6 , X 7 and X 8 are each independently selected from the group consisting of CH and N, R 3 is independently selected from the group consisting of H, halogen, methyl, cyano, trifluoromethyl and nitro, preferably selected from the group consisting of H, F, Cl, Br, cyano, trifluoromethyl and nitro, and R 4 is independently selected from the group consisting of H, halogen, methyl, cyano, trifluoromethyl and nitro, preferably selected from the group consisting of H, F, Cl, Br, cyano, trifluoromethyl and nitro.
  2. The compound or the racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to claim 1, wherein E is selected from the group consisting of wherein X 6 , X 7 , X 8 , R 3 and R 4 are as defined in claim 1.
  3. The compound or the racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound represented by formula (I) has a structure represented by formula (II): wherein X 1 , X 2 , X 3 , X 4 , X 5 , L, Y, R 1 , R 3 and R 4 are as defined in claim 1.
  4. A compound or a racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
  5. Use of the compound or the racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the manufacture of a medicament for treating or preventing a neurodegenerative disease or neurological disease or condition.
  6. Use of the compound or the racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the manufacture of a SARM1 enzymatic activity inhibitor.
  7. Use of the compound or the racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in the manufacture of a medicament for treating or preventing an axonal degeneration-related disease or condition.
  8. The use according to any one of claims 5 to 7, wherein the neurodegenerative disease, neurological disease or condition or axonal degeneration-related disease or condition is selected from the group consisting of Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and peripheral neuropathy.
  9. A pharmaceutical composition comprising the compound or the racemate, enantiomer, diastereoisomer, deuterated compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, and a pharmaceutically acceptable carrier.

Description

FIELD The present disclosure relates to a compound for inhibiting SARM1 enzymatic activity, and/or use of the compound in treating and/or preventing a neurodegenerative or neurological disease or condition associated with SARM1 enzymatic activity. BACKGROUND Neurodegenerative diseases are a type of disorder that can seriously harm human health. They may result in a progressive disease, which can cause devastating damage, such as death of nerve cells. Central nervous system diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and Huntington's disease, and peripheral neurological diseases such as diabetic peripheral neuropathy (DPN) are already known to be the major neurodegenerative diseases. Most of these are related to aging. Actually, the onset risk of these diseases increases with age. However, they also affect middle-aged people or even younger people. With deepening researchinto the brain's structure and function, the roles of neurotransmitters and neurotrophic factors have been gradually elucidated, but many local causes of neurodegeneration remain unclear. Only for Parkinson's disease, the relationship between the disease and dopamine (a special neurotransmitter) has been clarified, and L-dopa(a precursor of dopamine) has been used as a drug to alleviate neurological symptoms and restore neurological functions. However, L-dopa cannot prevent the progression of neurodegeneration, and gradually loses effectiveness as the disease advances, leading to the degeneration and defects of dopamine-based nerve cells. Similarly, Alzheimer's disease is also caused by the degeneration and defects of various nerve cells, including acetylcholine-based nerve cells and monoamine-based nerve cells. As drugs to treat this disease, cholinesterase inhibitors have been put on the market or are in the process of being developed. However, L-dopa for treating Parkinson's disease is still limited to symptomatic treatment to temporarily improve neurological symptoms. Therefore, there is currently a lack of effective therapeutic drugs for neurodegenerative diseases. It has been found from studies that nerve axon damage occurs in a variety of neurological diseases such as neurodegenerative diseases and accidental injuries. Axonal degeneration can cause structural necrosis and dysfunction of the peripheral nervous system, ultimately leading to acquired or inherited degenerative diseases of the central nervous system. Although there is currently no highly effective pharmacological method that can accurately assess the weight ofthe incidence rate of the disease by axonal degeneration, it has been found in histopathological studies that significant axonal damage and degradation are observed in the early stages of various neuropathies such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis and peripheral neuropathy, indicating that axonal degeneration plays an important role in the development of neuropathy (Fischer et al., Neuro-degenerative Diseases, 2007, 4:431-442). Therefore, maintaining the integrity of neuronal structure and function by attenuating or even blocking axonal degeneration may be a therapeutic method that can benefit a variety of neurological diseases. In the absence of effective therapeutic drugs for neurodegenerative diseases in the prior art, the research and development of new compounds is urgently required, especially small chemical molecules, including compounds that have effect on neural axon degeneration. SUMMARY After long-term research, the inventors unexpectedly found a compound with significant inhibitory effect on SARM1 enzymatic activity, and found that the compound can improve axonal degeneration and be used to treat or prevent neurodegenerative diseases and related conditions. SARM1 (Sterile alpha and TIR motif containing 1) consists of three domains, namely ARM (Armadillo/HEAT repeat) domain at the N-terminal, two tandem SAM (Sterile alpha motif) domains, and TIR (Toll/Interleukin receptor) domain at the C-terminal. In addition, there is also a mitochondrial targeting signal peptide at the N-terminal. It is known that in wild-type neurons, axonal injury induces NAD+ depletion and axonal degeneration. Knocking out SARM1 in neurons can inhibit axonal degeneration, and maintain NAD+ at normal levels, indicating that SARM1 promotes NAD+ consumption and aggravates axonal degeneration. Milbrandt's research group at Washington University School of Medicine, USA, has synthesized TIR domain of SARM1 (SARM1-TIR) and found that it has NAD+ hydrolase activity. High-purity SARM1-TIR was further obtained through strict protein expression and purification in E. coli and a cell-free protein expression system. It has been finally demonstrated that SARM1-TIR can catalyze NAD+ to produce adenosine 5'-diphosphate ribose (ADPR) and cyclic adenosine 5'-diphosphate ribose (cADPR). SARM1 is a multifunctional signaling enzyme that can cata