Treatment of neuroinflammation

Abstract

Compositions and methods for treating neuroinflammatory diseases and conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (AES), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), vascular dementia (VAD), anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), transverse myelitis (TM), autoimmune encephalitis (AE), acute disseminated encephalomyelitis (ADEM), chronic meningitis (CM), central nervous system (CNS) vasculitis, Hashimoto's encephalitis (HE), neurosarcoidosis (NS), multiple system atrophy (MSA), migraine, chemotherapy-induced pain, or dementia-related pain, are provided herein.

Description

[Technical Field]

[0001] cross reference

[0001] This application claims the interests of U.S. Provisional Patent Application No. 63 / 454,011, filed on 22 March 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002]

[0002] In the medical field, there is a need for compounds and methods for the treatment of neuroinflammatory diseases and conditions. Solutions to this and other problems in the art are disclosed herein. [Overview of the project] [Means for solving the problem]

[0003]

[0003] Compositions and methods for treating neuroinflammatory diseases and conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), vascular dementia (VAD), anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), transverse myelitis (TM), autoimmune encephalitis (AE), acute disseminated encephalomyelitis (ADEM), chronic meningitis (CM), central nervous system (CNS) vasculitis, Hashimoto's encephalitis (HE), neurosarcoidosis (NS), multiple system atrophy (MSA), migraine, chemotherapy-induced pain, or dementia-related pain, are provided herein. The composition useful for treating neuroinflammatory diseases comprises a VAP-1 inhibitor.

[0004]

[0004] One embodiment is a method for treating a neuroinflammatory disease in a patient who requires treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (I)

[0005] [ka]

[0006] And, In formula (I),

[0007] [ka]

[0008] The substructure represented by

[0009] [ka]

[0010] And, The symbol --- represents a connection point. X 1 ga = N-, -NR 8 -, -O-, or -S- X 2 is -N- or -CH-, X 3 is -O-, -S-, -NH-, -CH2-, or -C(O)-, Y is bonded, -O-, -S-, -NR 7 -, -OCX2-, -(CH2) z2 It is W-, -C(O)O-, or -C(O)NH-, W is bonded, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, n7, n8, and n12 are independent integers between 0 and 4. m1, m2, m5, m6, m7, m8, m12, v1, v2, v5, v6, v7, v8, and v12 are independently 1 or 2. L 1 -O-, -S-, -NR 1L- a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R 1L is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 1 is independently hydrogen, halogen, -CX 1.1 3, -CHX 1.1 2, -CH2X 1.1 , -CN, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R 1C , -NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR 1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B OR 1D , -OCX 1.1 , -OCHX 1.1 , 2, R 12 substituted or unsubstituted alkyl, R 12 substituted or unsubstituted heteroalkyl, R 12 substituted or unsubstituted cycloalkyl, R 12A substituted or unsubstituted heterocycloalkyl, R 12 A substituted or unsubstituted aryl, or R 12 A substituted or unsubstituted heteroaryl, or at least one amino acid, and R 2 is hydrogen, halogen, -CX 2.1 3, -CHX 2.1 2, -CH2X 2.1 , -CN, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D , -C(O)NR 2B R 2C , -OR 2A , -OCX 2.1 3, -OCHX 2.1 2, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and R 3 and R 4 are independently hydrogen or -F, and R 5 is hydrogen, halogen, -CX 5.1 3, -CHX 5.1 2, -CH2X 5.1 , -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C , -ONR 5B R 5C , -NHC(O)NHNR 5B R 5C , -NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR5D 、 -C(O)NR 5B R 5C 、 -OR 5A 、 -NR 5B SO2R 5A 、 -NR 5B C(O)R 5D [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 7 Hydrogen, halogen, -CX 7.1 3, -CHX 7.1 2, -CH2X 7.1 -CN, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D -C(O)NR 7B R 7C , -OR 7A ,-OCX 7.1 3, -OCHX 7.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 8 Hydrogen, halogen, -CX 8.1 3, -CHX 8.1 2, -CH2X 8.1 -CN, -SO n8 R 8A , -SO v8 NR 8B R 8C , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D -C(O)NR 8B R 8C , -OR 8A ,-OCX 8.1 3, -OCHX 8.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 12 Hydrogen, halogen, -CX 12.1 3, -CHX 12.1 2, -CH2X 12.1 -CN, -SO n12 R 12A , -SO v12 NR 12B R 12C , -NR 12B R 12C , -C(O)R 12D , -C(O)OR 12D -C(O)NR 12B R 12C , -OR 12A ,-OCX 12.1 3, -OCHX 12.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 1A Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12A Substituted or unsubstituted alkyl, R 12A Substituted or unsubstituted heteroalkyl, R 12A Substituted or unsubstituted cycloalkyl, R 12A Substituted or unsubstituted heterocycloalkyl, R 12A Substitutable or unsubstituted aryl, or R 12A It is a substituted or unsubstituted heteroaryl, R 1B Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12B Substituted or unsubstituted alkyl, R 12B Substituted or unsubstituted heteroalkyl, R 12B Substituted or unsubstituted cycloalkyl, R 12B Substituted or unsubstituted heterocycloalkyl, R 12B Substitutable or unsubstituted aryl, or R 12B It is a substituted or unsubstituted heteroaryl, R 1CHydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12C Substituted or unsubstituted alkyl, R 12C Substituted or unsubstituted heteroalkyl, R 12C Substituted or unsubstituted cycloalkyl, R 12C Substituted or unsubstituted heterocycloalkyl, R 12C Substitutable or unsubstituted aryl, or R 12C R is either substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom. 1B substituents and R 1C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. R 1D Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12D Substituted or unsubstituted alkyl, R 12D Substituted or unsubstituted heteroalkyl, R 12D Substituted or unsubstituted cycloalkyl, R 12D Substituted or unsubstituted heterocycloalkyl, R 12D Substitutable or unsubstituted aryl, or R 12D It is a substituted or unsubstituted heteroaryl, R 2A , R 2B , R 2C , R 2D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 8A , R 8B , R 8C , R 8D , R 12A , R 12B , R 12C , and R 12DR is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom 2B substituents and R 2C substituents and R 5B substituents and R 5C substituents and R 6B substituents and R 6C substituents and R 7B substituents and R 7C substituents and R 8B substituents and R 8C With substituents, or R 12B substituents and R 12C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. X, X 1.1 , X 2.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , and X 12.1 These are independently -Cl, -Br, -I, or -F, The structure of equation (II)

[0011] [ka]

[0012] And, In formula (II), X 1 and X 4 Independently, =N- or =CH-, X 5 is =N- or -CR 5 -and, X 6 is =N- or -CR 6 -and, Y is bonded, -O-, -S-, -NR 7-, -OCX2-, -(CH2) z2 It is W-, -C(O)O-, or -C(O)NH-, W is bonded, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, and n7 are independent integers between 0 and 4. m1, m2, m5, m6, m7, v1, v2, v5, v6, and v7 are independently 1 or 2. L 1 -O-, -S-, -NR 1L -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R 1L is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 1 Hydrogen, halogen, -CX 1.1 3, -CHX 1.1 2, -CH2X 1.1 -CN, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C ,-ONR 1B R 1C , -NHC(O)NHNR 1B R 1C ,-NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D -C(O)NR 1B R 1C , -OR 1A , -NR1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B Ure 1D ,-OCX 1.1 3, -OCHX 1.1 2, R 12 Substituted or unsubstituted alkyl, R 12 Substituted or unsubstituted heteroalkyl, R 12 Substituted or unsubstituted cycloalkyl, R 12 Substituted or unsubstituted heterocycloalkyl, R 12 Substitutable or unsubstituted aryl, or R 12 A substituted or unsubstituted heteroaryl, or at least one amino acid, R 2 Hydrogen, halogen, -CX 2.1 3, -CHX 2.1 2, -CH2X 2.1 -CN, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D -C(O)NR 2B R 2C , -OR 2A ,-OCX 2.1 3, -OCHX 2.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 3 and R 4 These are independently hydrogen or -F, R 5 Hydrogen, halogen, -CX 5.1 3, -CHX 5.1 2, -CH2X 5.1 -CN, -N3, -SO n5 R5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C ,-ONR 5B R 5C , -NHC(O)NHNR 5B R 5C ,-NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D -C(O)NR 5B R 5C , -OR 5A , -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B Ure 5D ,-OCX 5.1 3, -OCHX 5.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 6 Hydrogen, halogen, -CX 6.1 3, -CHX 6.1 2, -CH2X 6.1 -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C ,-ONR 6B R 6C , -NHC(O)NHNR 6B R 6C ,-NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R6D , -C(O)OR 6D -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B Ure 6D ,-OCX 6.1 3, -OCHX 6.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 7 Hydrogen, halogen, -CX 7.1 3, -CHX 7.1 2, -CH2X 7.1 -CN, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D -C(O)NR 7B R 7C , -OR 7A ,-OCX 7.1 3, -OCHX 7.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 12 Hydrogen, halogen, -CX 12.1 3, -CHX 12.1 2, -CH2X 12.1 -CN, -SO n12 R 12A , -SO v12 NR 12B R 12C , -NR 12B R12C , -C(O)R 12D , -C(O)OR 12D -C(O)NR 12B R 12C , -OR 12A ,-OCX 12.1 3, -OCHX 12.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 1A Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12A Substituted or unsubstituted alkyl, R 12A Substituted or unsubstituted heteroalkyl, R 12A Substituted or unsubstituted cycloalkyl, R 12A Substituted or unsubstituted heterocycloalkyl, R 12A Substitutable or unsubstituted aryl, or R 12A It is a substituted or unsubstituted heteroaryl, R 1B Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12B Substituted or unsubstituted alkyl, R 12B Substituted or unsubstituted heteroalkyl, R 12B Substituted or unsubstituted cycloalkyl, R 12B Substituted or unsubstituted heterocycloalkyl, R 12B Substitutable or unsubstituted aryl, or R 12B It is a substituted or unsubstituted heteroaryl, R 1C Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12C Substituted or unsubstituted alkyl, R 12C Substituted or unsubstituted heteroalkyl, R 12C Substituted or unsubstituted cycloalkyl, R 12C Substituted or unsubstituted heterocycloalkyl, R 12C Substitutable or unsubstituted aryl, or R12C R is either substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom. 1B substituents and R 1C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. R 1D Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12D Substituted or unsubstituted alkyl, R 12D Substituted or unsubstituted heteroalkyl, R 12D Substituted or unsubstituted cycloalkyl, R 12D Substituted or unsubstituted heterocycloalkyl, R 12D Substitutable or unsubstituted aryl, or R 12D It is a substituted or unsubstituted heteroaryl, R 2A , R 2B , R 2C , R 2D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 12A , R 12B , R 12C , and R 12D R is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom 2B substituents and R 2C substituents and R 5B substituents and R 5C substituents and R 6B substituents and R 6C substituents and R7B substituents and R 7C substituents and R 8B substituents and R 8C With substituents, or R 12B substituents and R 12C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. X, X 1.1 , X 2.1 , X 5.1 , X 6.1 , X 7.1 , and X 12.1 These are independently -Cl, -Br, -I, or -F. Provide a method.

[0013]

[0005] Features of the present invention are described in detail in the appended claims. Features of the present invention will be better understood by referring to the following embodiments for carrying out the invention and the following appended drawings, which illustrate exemplary embodiments in which the principles of the present invention are utilized. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1A shows the daily body weight of the mouse. Figure 1B shows the percentage change in the mouse's body weight from baseline. [Figure 2] This figure shows the TNF-α levels in mouse serum. [Figure 3] Figure 3A shows the Iba1 IHC in the hippocampus of a mouse. Figure 3B shows the Iba1 IHC in the frontal cortex of a mouse. [Figure 4] Figure 4A shows the CD68 IHC in the hippocampus of a mouse. Figure 4B shows the CD68 IHC in the frontal cortex of a mouse. [Figure 5] Figure 5A shows the Aβ1-42 IHC in the hippocampus of a mouse. Figure 5B shows the Aβ1-42 IHC in the frontal cortex of a mouse. [Figure 6] This figure shows Aβ1-42 IF in the frontal cortex of a mouse. [Figure 7]This figure shows the ELISA results for brain TNF-α. [Figure 8] This figure shows the ELISA results for brain TREM2. [Figure 9] This figure shows the results of Western blot analysis of brain TREM2 Syk activity. [Figure 10] This figure shows the results of Western blot analysis for brain TREM2 p-Zap-70 activity. [Figure 11] This figure shows the results of Western blot analysis for brain TREM2 DAP12 activity. [Modes for carrying out the invention]

[0015] Built-in by reference

[0006] All publications, patents, and patent applications referenced herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application were specifically and individually incorporated by reference.

[0016]

[0007] Where used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural concepts unless the context makes it particularly clear. Thus, for example, a reference to “drug” includes multiple such drugs, and a reference to “cell” includes one or more cells (or more cells) and their equivalents known to those skilled in the art, etc. Where a range is used herein for physical properties such as molecular weight or chemical properties such as chemical formula, it is intended to include all combinations and subcombinations of the range and particular embodiments herein. Where the term “about” refers to a number or numerical range, the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range varies, in some examples, between 1% and 15% of the indicated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude, in other particular embodiments, one embodiment of which, for example, a composition, composition, method, or process of any substance described herein, consists of or essentially consists of the described features.

[0017] definition

[0008] Abbreviations used herein have their customary meanings in the fields of chemistry and biology. Chemical structures and chemical formulas shown herein are constructed according to standard rules of chemical valence known in the field of chemistry.

[0018]

[0009] When substituents are specified by their conventional chemical formula written from left to right, they equally encompass chemically identical substituents that would result from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0019]

[0010] The term “alkyl” means, unless otherwise specified, a straight (i.e., unbranched) or branched carbon chain (or carbon) or combination thereof, either by itself or as part of another substituent, which may be fully saturated, monounsaturated, or polyunsaturated, and which have the indicated number of carbon atoms (i.e., C1-C 10 Alkyl groups can include monovalent, divalent, and polyvalent groups (where ≠ 1 to 10 carbon atoms). Alkyl groups are non-cyclized chains. Examples of saturated hydrocarbon groups, but not limited to, include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, and their congeners and isomers, such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and their congeners and isomers. Unsaturated alkyl groups are groups having one or more double or triple bonds. Examples of unsaturated alkyl groups, but not limited to, include vinyl, 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and their higher congeners and isomers. Alkoxy are alkyl groups that are attached to the residual position of a molecule via an oxygen linker (-O-).

[0020]

[0011] The term “alkylene” means a divalent group derived from an alkyl group, as exemplified by -CH2CH2CH2CH2-, either by itself or as part of another substituent, unless otherwise specified. Typically, an alkyl (or alkylene) group has 1 to 24 carbon atoms, and preferably 10 or fewer carbon atoms as specified herein. A “low-order alkyl” or “low-order alkylene” is a short-chain alkyl or alkylene group that generally has 8 or fewer carbon atoms. The term “alkenylene” means a divalent group derived from an alkene, either by itself or as part of another substituent, unless otherwise specified.

[0021]

[0012] The term “heteroalkyl” means, by itself or in combination with other terms, a stable linear or branched chain or combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), unless otherwise specified, wherein the nitrogen and sulfur atoms may be oxidized as necessary, and the nitrogen heteroatom may be quaternized as necessary. The heteroatom (e.g., N, S, Si, or P) may be located at any internal position of the heteroalkyl group or at a position where the alkyl group is bonded to the remainder of the molecule. A heteroalkyl group is a non-cyclized chain. Examples, though not limited to them, include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl portion may contain one heteroatom (for example, O, N, S, Si, or P). The heteroalkyl portion may optionally contain two different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl portion may optionally contain three different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl portion may optionally contain four different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl portion may optionally contain five different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl portion may optionally contain up to eight different heteroatoms (e.g., O, N, S, Si, or P).

[0022]

[0013] Similarly, the term “heteroalkylene” means, without limitation, a divalent group derived from a heteroalkyl, either by itself or as part of another substituent, as exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-, unless otherwise specified. In the case of a heteroalkylene group, the heteroatom may occupy one or both of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not indicated by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, include groups that bond to the remaining position of a molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SO2R'. When “heteroalkyl” is mentioned, followed by a specific heteroalkyl group such as -NR'R'', it should be understood that the term heteroalkyl and -NR'R'' are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl group is mentioned for further clarification. Therefore, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups such as -NR'R''.

[0023]

[0014] The terms “cycloalkyl” and “heterocycloalkyl” mean, by themselves or in combination with other terms, the cyclic versions of “alkyl” and “heteroalkyl,” respectively, unless otherwise specified. Cycloalkyl and heterocycloalkyl are not aromatic. In addition, in the case of heterocycloalkyl, the heteroatom can occupy a position where the heterocycle bonds to the remaining position of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, and 2-piperazinyl. "Cycloalkylene" and "heterocycloalkylene" refer to divalent groups derived from cycloalkyl and heterocycloalkyl, respectively, either alone or as part of another substituent. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as bicyclo[2.2.1]heptane and bicyclo[2.2.2]octane.

[0024]

[0015] The terms “halo” or “halogen” mean a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent, unless otherwise specified. In addition, terms such as “haloalkyl” are intended to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

[0025]

[0016] Unless otherwise specified, the term "acyl" means -C(O)R, where R is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0026]

[0017] Unless otherwise specified, the term “aryl” means a polyunsaturated aromatic hydrocarbon substituent which may be a monocyclic or compound ring (preferably 1 to 3 rings), and the compound rings are fused to each other (i.e., fused aryl rings) or covalently bonded. A fused aryl ring refers to a compound ring which is fused to each other, with at least one of the fused rings being an aryl ring. The term “heteroaryl” refers to an aryl group (or ring) which contains at least one heteroatom such as N, O, or S, whose nitrogen and sulfur atoms may be oxidized as necessary, and whose nitrogen atom may be quaternized as necessary. Thus, the term “heteroaryl” includes a fused heteroaryl group (i.e., a compound ring which is fused to each other, with at least one of the fused rings being a heteroaromatic ring). A 5,6-fused heteroarylene refers to two fused rings which are one ring having 5 members and the other ring having 6 members, with at least one of the rings being a heteroaryl ring. Similarly, a 6,6-fused heteroarylene refers to two fused rings, one having 6 members and the other having 6 members, with at least one ring being a heteroaryl ring. A 6,5-fused heteroarylene refers to two fused rings, one having 6 members and the other having 5 members, with at least one ring being a heteroaryl ring. Heteroaryl groups can be bonded to the molecular remainder via carbon or heteroatoms.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridadinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, prinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl, benzimidazolyl, benzofuran, isobenzofuranil, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrzolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-i Examples include sooxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above-mentioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents listed below. "Arylene" and "heteroarylene" refer to divalent groups derived from aryl and heteroaryl, respectively, either alone or as part of another substituent. Heteroaryl group substituents may be -O-bonded to the ring heteroatom nitrogen.

[0027]

[0018] A spirocyclic ring is two or more rings that are bonded to each other by one atom. The individual rings in a spirocyclic ring may be identical or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings in a series of spirocyclic rings. Possible substituents for an individual ring in a spirocyclic ring are possible substituents for that ring when it is not part of a spirocyclic ring (e.g., substituents for a cycloalkyl or heterocycloalkyl ring). A spirocyclic ring may be a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylene, a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heterocycloalkylene, and the individual rings in the spirocyclic ring group may be any of the preceding list, which includes having all of one type of ring (e.g., all rings are substituted heterocycloalkylenes, in which case each ring may be the same or a different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic and each ring may be different. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted and each substituent may be different as required.

[0028]

[0019] Symbol

[0029] [ka]

[0030] The symbol indicates the bond point of the chemical part to the molecular or chemical formula remnant.

[0020] The term "oxo," as used herein, means oxygen that is double-bonded to a carbon atom.

[0031]

[0021] The term "alkylarylene" refers to an arylene moiety that is covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In some embodiments, the alkylarylene group has the following formula.

[0032] [ka]

[0033]

[0022] The alkylarylene moiety may be substituted on the alkylene moiety or arylene linker (e.g., at the 2, 3, 4, or 6 carbon) (e.g., by substituent) with halogens, oxo, -N3, -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyls, or substituted or unsubstituted 2-5 member heteroalkyls. In some embodiments, the alkylarylene is unsubstituted.

[0034]

[0023] Each of the above terms (for example, "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the group shown. Certain substituents for various groups are shown below.

[0035]

[0024] Substituents for alkyl and heteroalkyl groups (including groups commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) are not limited to any number in the range of 0 to (2m'+1) when m' is the total number of carbon atoms in the group, such as -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O It can be one or more of various bases selected from )NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR''. R, R', R'', R''', and R'''' each preferably independently refers to hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group (e.g., an aryl group substituted with 1 to 3 halogens), a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkyl group, an alkoxy or thioalkoxy group, or an arylalkyl group. If the compounds described herein contain more than one R group, for example, each R group is independently selected such that they become R', R'', R''', and R'''' groups, provided that there is more than one of these groups. When R' and R'' are bonded to the same nitrogen atom, they can be combined with that nitrogen atom to form a 4, 5, 6, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" includes groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyls (e.g., -CF3 and -CH2CF3) and acyls (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0036]

[0025] Similar to the substituents described for alkyl groups, substituents for aryl and heteroaryl groups are diverse, for example, numbers ranging from 0 to the total number of empty valencies on the aromatic ring system, such as -OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO The R groups are selected from 2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4) alkoxy, and fluoro(C1-C4) alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', and -NR'OR'', where R', R'', R''', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. If the compounds described herein contain more than one R group, for example, each of the R groups is independently selected such that they are R', R'', R''', and R'''' groups, respectively, provided that there is more than one of these groups.

[0037]

[0026] Substituents on a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be shown as ring substituents (commonly referred to as floating substituents) rather than on specific atoms of the ring. In such cases, the substituent may be bonded to any ring atom (according to the rules of chemical valency), and in the case of a fused ring or a spirocyclic ring, a substituent shown in association with one member of the fused ring or spirocyclic ring (a floating substituent on one ring) may be a substituent on any ring of the fused ring or spirocyclic ring (a floating substituent on a composite ring). If the substituent is bonded to a ring but not to a specific atom (a floating substituent), and the subscript of the substituent is an integer greater than 1, multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may be different as necessary. If the bond site to the remaining part of the molecule of the ring is not limited to one atom (a floating substituent), the bond site may be any atom of the ring, and in the case of a fused ring or a spirocyclic ring, it may be any atom of any ring of the fused ring or spirocyclic ring, subject to the rules of chemical valence. If the ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms, and the ring, fused ring, or spirocyclic ring is shown with one or more floating substituents (including, but not limited to, a bond site to the remaining part of the molecule), the floating substituents may be bonded to the heteroatoms. If a ring heteroatom bonded to one or more hydrogens is shown in a structure or formula with floating substituents (for example, a ring nitrogen with two bonds to a ring atom and a third bond to a hydrogen), and the heteroatom is bonded to a floating substituent, it will be understood that the substituent replaces hydrogen, subject to the rules of chemical valence.

[0038]

[0027] Two or more substituents may be linked together as needed to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found to bond to a cyclic base structure. In one embodiment, the ring-forming substituents bond to adjacent members of the base structure. For example, two ring-forming substituents bonded to adjacent members of a cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents bond to one member of the base structure. For example, two ring-forming substituents bonded to one member of a cyclic base structure form a spirocyclic structure. In yet another embodiment, the ring-forming substituents bond to non-adjacent members of the base structure.

[0039]

[0028] Two substituents on each adjacent atom of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q A -U- ring may be formed, where T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on each adjacent atom of the aryl or heteroaryl ring may be of the formula -A-(CH2) as needed. r -B- substituents may be substituted, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or single bonds, and r is an integer from 1 to 4. One of the single bonds of the new ring thus formed may be replaced with a double bond as needed. Alternatively, two substituents on each adjacent atom of the aryl or heteroaryl ring may be replaced with a double bond as needed. s -X'-(C''R''R''') dSubstituents R, R', R'', and R'''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted heteroalkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups.

[0040]

[0029] As used herein, the terms “heteroatom” or “ring heteroatom” mean that the terms include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0041]

[0030] When used herein, “substituent” means the following part (A) Oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, (B) (i) Oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, (ii) (a) Oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, (b) Oxo, halogen, -CF3, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC=(O)NHNH2, -NHC=(O)NH2, -NHSO2H, -NHC=(O)H, -NHC(O)-OH, -NHOH, -OCF3, -OCHF2, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl and Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and Alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and It means a base selected from.

[0042]

[0031] When used herein, "size-limited substituent" or "size-limited substituent group" is a group selected from all of the above substituents relating to the "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 20It is an alkyl group, where each substituted or unsubstituted heteroalkyl group is a substituted or unsubstituted 2-20 member heteroalkyl group, each substituted or unsubstituted cycloalkyl group is a substituted or unsubstituted C3-C8 cycloalkyl group, each substituted or unsubstituted heterocycloalkyl group is a substituted or unsubstituted 3-8 member heterocycloalkyl group, and each substituted or unsubstituted aryl group is a substituted or unsubstituted C6-C 10 It is an aryl group, where each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl.

[0043]

[0032] When used herein, "lower substituent" or "lower substituent group" is a group selected from all of the above substituents relating to the "substituent," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 member heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 member heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 It is an aryl group, meaning that each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl.

[0044]

[0033] In some embodiments, each substituent described herein in the compounds is substituted with at least one substituent. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described herein in the compounds is substituted with at least one substituent. In other embodiments, at least one or all of these groups are substituted with at least one size-limiting substituent. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent.

[0045]

[0034] In other embodiments of the compounds described herein, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C 20 It may be alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-20 member heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-8 member heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 The compound is aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds described herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C 20 Each alkylene is a substituted or unsubstituted heteroalkylene, each substituted or unsubstituted 2-20 member heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3-8 member heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10It is an arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 10-membered heteroarylene.

[0046]

[0035] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2-8 member heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3-7 member heterocycloalkyl, and each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C 10 The heteroaryl is aryl and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 9-membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, and each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C 10 The compound is an arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is the chemical species shown in the Examples section, figures, or tables below.

[0047]

[0036] Certain compounds in this disclosure have an asymmetric carbon atom (optical or chiral center) or a double bond, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers which can be defined as (R)- or (S)- in terms of absolute stereochemistry, or (D)- or (L)- in the case of amino acids, and individual isomers are included within the scope of this disclosure. The compounds in this disclosure do not include any which are known in the art to be too unstable to be synthesized and / or isolated. This disclosure is intended to include racemates and optically pure forms of compounds. Optically active (R)- and (S)- or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be divided using conventional techniques. Where a compound described herein contains an olefin bond or other geometric asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0048]

[0037] As used herein, the term “isomer” refers to compounds that have the same number and the same types of atoms, and therefore the same molecular weight, but differ in terms of the structural arrangement or stereochemistry of their atoms.

[0049]

[0038] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another.

[0039] It will be apparent to those skilled in the art that certain compounds in this disclosure exist in the form of tautomers, and that all tautomer forms of such compounds may be within the scope of this disclosure.

[0050]

[0040] Unless otherwise specified, the structures shown herein are also intended to include all stereochemical forms of the structure, i.e., R and S configurations for each chiral center. Thus, a single stereochemical isomer of the compounds of the present invention, as well as mixtures of enantiomers and diastereomers, are within the scope of this disclosure.

[0051]

[0041] Unless otherwise specified, the structures shown herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacing hydrogen with deuterium or tritium or carbon 13 C- or 14 Compounds having the structure of the present invention, except for replacement with C-enriched carbon, are within the scope of this disclosure.

[0052]

[0042] The compounds of the present disclosure may also contain atomic isotopes in unnatural proportions of one or more of the atoms constituting such compounds. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), Iodine-125( 125 I), or carbon-14 ( 14 They may be radiolabeled with radioactive isotopes such as C). All isotopic variations of the compounds of this disclosure, whether radioactive or not, are included within the scope of this disclosure.

[0053]

[0043] The term “isotope variant” refers to a compound that contains isotopes in unnatural proportions of one or more of the atoms constituting such a compound. In certain embodiments, the “isotope variant” of a compound is, but is not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), Nitrogen-14( 14 N), Nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), Fluorine-18( 18 F), phosphorus-31( 31 P), phosphorus-32( 32P), Lin-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), Sulfur-34( 34 S), Sulfur-35( 35 S), sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), bromine-79( 79 Br), Bromine-81( 81 Br), Iodine-123( 123 I) Iodine-125 125 I) Iodine-127( 127 I) Iodine-129( 129 I), and iodine-131( 131 I) contains one or more isotopes in non-natural proportions. In certain embodiments, the “isotope variant” of the compound is in a stable form, i.e., non-radioactive. In certain embodiments, the “isotope variant” of the compound is, but is not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), Nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), Fluorine-17( 17 F), phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), Sulfur-34( 34 S), sulfur-36( 36 S), Chlorine-35( 35 Cl), Chlorine-37( 37 Cl), bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127I) contains one or more isotopes in non-natural proportions. In certain embodiments, the “isotope variant” of the compound is an unstable form, i.e., radioactive. In certain embodiments, the “isotope variant” of the compound is, but is not limited to, tritium ( 3 H), carbon-11 ( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), Fluorine-18( 18 F), phosphorus-32( 32 P), Lin-33( 33 P), sulfur-35( 35 S), Chlorine-36( 36 Cl), Iodine-123( 123 I) Iodine-125 125 I) Iodine-129( 129 I), and iodine-131( 131 The compounds provided herein contain one or more isotopes listed in I) in non-natural proportions. Where feasible according to the judgment of those skilled in the art, any hydrogen may be, for example 2 It can be H, or any carbon for example 13 It can be C, or any nitrogen for example 15 It can be N, or any oxygen for example 18 It will be understood that it can be O. In certain embodiments, the “isotope variants” of the compound contain deuterium (D) in unnatural proportions.

[0054]

[0044] Throughout this application, options are described in the Markush group and should be noted that this includes, for example, amino acids in which each amino acid position may be greater than 1. Each member of the Markush group should be considered separately and thereby include other embodiments, and it is particularly intended that the Markush group should not be interpreted as a single unit.

[0055]

[0045] The terms "analog" or "analogue" are used according to their plain and common meaning in chemistry and biology to refer to a compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, for example, by replacing one atom with an atom of a different element, or by the presence of a particular functional group, or by replacing one functional group with another, or by the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to a reference compound in function and appearance but does not have the same structure or origin.

[0056]

[0046] The terms "a" or "an" as used herein mean one or more. In addition, the phrase "substituted with a[n]" as used herein means that a particular group may be substituted with any or all one or more of the substituents specified. For example, groups such as alkyl or heteroaryl groups may be "unsubstituted C1-C 20 If "substituted with alkyl or unsubstituted 2-20 member heteroalkyl," then one or more unsubstituted C1-C 20 It may contain alkyl and / or one or more unsubstituted 2-20 member heteroalkyl groups.

[0057]

[0047] Furthermore, a group may be referred to as "R-substituted" if a portion is substituted with an R substituent. When a portion is R-substituted, it is substituted with at least one R substituent, each R substituent being different as required. Where a particular R group is present in the description of a chemical group (such as formula (I)), a Roman alphabet symbol may be used to distinguish each occurrence of that particular R group. For example, multiple R 13 If substituents are present, each R 13 The substituent is R 13A , R 13B , R 13C , R 13D They may be distinguished as such, R 13A , R 13B , R 13C , R13D Each of these is R 13 Within the scope of the definition, it may be defined differently as needed.

[0058]

[0048] The description of the compounds in this disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted by one or more substituents, such substituents are selected in accordance with the principles of chemical bonding and in order to give a compound known to those skilled in the art that is not inherently unstable and / or may be unstable under ambient conditions such as aqueous, neutral, and certain known physiological conditions. For example, heterocycloalkyl or heteroaryl groups are bonded to the remaining position of the molecule via ring heteroatoms in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding an inherently unstable compound.

[0059]

[0049] The term “pharmaceutically acceptable salt” includes salts of active compounds prepared using pharmaceutically acceptable acids or bases depending on the specific substituents found on the compounds described herein. If the compounds of the Disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base, either alone or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to, salts of sodium, potassium, calcium, ammonium, organic amino or magnesium, or similar salts. If the compounds of the Disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid, either alone or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. Examples include salts of amino acids such as arginine and salts of organic acids such as glucuronic acid or galactunoric acid (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds in this disclosure possess both basic and acidic functionalities, which allow the compound to be converted into a base or an acid addition salt.

[0060]

[0050] Accordingly, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobroms, phosphates, sulfates, methanesulfons, nitrates, maleates, acetates, citrates, fumarates, propions, tartrates (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts may be prepared by methods known to those skilled in the art.

[0061]

[0051] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional means. The parent form of the compound may differ from the various salt forms in terms of certain physical properties, such as solubility in polar solvents. In some embodiments, the compounds of the Disclosure contain both basic and acidic functionalities, which allow the compound to be converted into a base or acid addition salt. The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional means.

[0062]

[0052] In addition to salt forms, the present disclosure provides compounds in prodrug forms. Prodrugs of the compounds described herein are compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration.

[0063]

[0053] Certain compounds in this disclosure can exist in solvated forms, including hydrated forms, as well as in non-solvated forms.

[0054] "Pharmacopoeia-acceptable excipients" and "pharmacopoeia-acceptable carriers" refer to substances that can be included in the compositions of the Disclosure to administer a compound to a subject and to assist in the subject's absorption, and which do not cause significant toxicological adverse effects to the patient. Non-limiting examples of pharmacopoeia-acceptable excipients include water, NaCl, standard saline, Ringer's lactate solution, standard sucrose, standard glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, lactose, amylose, or carbohydrates such as starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, and pigments. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances that do not react adversely with the compounds of the Disclosure. Those skilled in the art will recognize that other pharmaceutical excipients may be useful in this disclosure.

[0064]

[0055] The term “preparation” is intended to include formulations of an active compound with an encapsulating material as a carrier providing a capsule, wherein the active ingredient, with or without other carriers, is surrounded by the carrier and thus bound to the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0065]

[0056] "VAP-1 inhibitor" refers to a compound that reduces the activity of VAP-1 compared to a control such as a compound that is known to be absent or inactive (for example, the compounds described herein).

[0066]

[0057] "Contact" is used in its plain, ordinary sense and refers to a process that allows at least two distinct species (e.g., compounds including biomolecules or cells) to react, interact, or come close enough to physically touch. However, it should be recognized that the resulting reaction products may be produced directly from the reaction between the additive reagents or from intermediates from one or more of the additive reagents that may be produced in the reaction mixture.

[0067]

[0058] The term “contact” may include enabling two species to react, interact, or physically touch, where the two species may be a compound and a protein or enzyme (e.g., VAP-1) as described herein.

[0068]

[0059] As defined herein, terms relating to proteins such as “activation,” “to activate,” and / or “to activate” refer to the conversion of a protein from its initial inactive or inactive state to a biologically active derivative. This term refers to the activation of the amount of protein that has been reduced in signaling or enzymatic activity or in disease, i.e., activating, sensitizing, or upregulating them.

[0069]

[0060] The terms “agonist,” “activator,” and “upregulator” refer to substances that can detectably increase the expression or activity of a given gene or protein. Agonists can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the agonist. In certain examples, the expression or activity is 1.5, 2, 3, 4, 5, or 10 times higher than the expression or activity in the absence of the agonist. In some embodiments, an agonist is a molecule that interacts with a target to cause or promote an increase in the activation of the target. In some embodiments, an activator is a molecule that increases, activates, supports, enhances, sensitizes, or upregulates, for example, a gene, protein, ligand, receptor, or cell.

[0070]

[0061] As defined herein, terms related to protein-inhibitor interactions such as “inhibition,” “to inhibit,” and “to inhibit” mean to negatively affect (e.g., reduce) the activity or function of a protein compared to the activity or function of a protein in the absence of the inhibitor. In some embodiments, inhibition means to negatively affect (e.g., reduce) the concentration or level of a protein compared to the concentration or level of a protein in the absence of the inhibitor. In some embodiments, inhibition refers to the reduction of a disease or the symptoms of a disease. In some embodiments, inhibition refers to the reduction of the activity of a particular protein target. Thus, inhibition includes, at least in part, partially, or whole, blocking a stimulus, reducing, preventing, or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of a protein. In some embodiments, inhibition refers to the reduction of the activity of a target protein resulting from a direct interaction (e.g., the inhibitor binds to the target protein). In some embodiments, inhibition refers to the reduction of the activity of a target protein due to an indirect interaction (e.g., the inhibitor prevents the activation of the target protein by binding to a protein that activates the target protein).

[0071]

[0062] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” are interchangeable and refer to substances that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more compared to a control in the absence of the antagonist. In certain cases, the expression or activity is 1.5, 2, 3, 4, 5, or 10 times lower than the expression or activity in the absence of the antagonist. Antagonists can prevent, reduce, inhibit, or neutralize the activity of an agonist, and antagonists can also prevent, inhibit, or reduce the constitutive activity of a target, such as a target receptor, even in the absence of the identified agonist. In some embodiments, inhibitors are molecules that reduce, block, prevent, delay, inactivate, desensitize, or downregulate genes, proteins, ligands, receptors, or cells. Inhibitors may also be defined as molecules that reduce, block, or inactivate constitutive activity. An "antagonist" is a molecule that counteracts the action of an agonist.

[0072]

[0063] The terms “disease” or “condition” refer to a state or health condition of a patient or subject that can be treated with the compounds or methods provided herein. A disease may be an autoimmune disease. A disease may be an inflammatory disease.

[0073]

[0064] As used herein, the term “inflammatory disease” refers to a disease or condition characterized by abnormal inflammation (e.g., an increased level of inflammation compared to a control, such as a healthy person without the disease). Examples of inflammatory diseases include autoimmune diseases and uveitis (e.g., anterior uveitis, intermediate uveitis or squamous uveitis, posterior uveitis or chorioretinitis, including iridocyclitis and iritis, as well as panuveitis). Such conditions are often closely related to other diseases, disorders, and conditions. An unspecified list of inflammation-related diseases, disorders, and conditions includes Behçet's disease, Crohn's disease, Fuchs heterochromia iridocyclitis, polyangiogranulomatosis, HLA-B27-associated uveitis, arthritis (e.g., juvenile idiopathic arthritis), sarcoidosis, spondyloarthritis, sympathetic ophthalmitis, tubulointerstitial nephritis, uveitis syndrome, ankylosing spondylitis, chronic granulomatous diseases, enthesitis, inflammatory bowel disease, Kawasaki disease, multiple sclerosis, polyarteritis nodosa, psoriatic arthritis, reactive arthritis, sarcoidosis, systemic lupus erythematosus, Vogt-Koyanagi-Harada disease, Whipple disease, white spot syndrome, and masked syndrome. Uveitis can also be associated with infectious diseases such as brucellosis, herpes simplex virus, varicella-zoster virus, leptospirosis, Lyme disease, presumptive ocular histoplasmic syndrome, syphilis, toxocariasis, toxoplasmic chorioretinitis, tuberculosis, and Zika fever.

[0074]

[0065] White spot syndromes include, but are not limited to, acute posterior multiple plaque epithelial disease, scatter chorioretinopathy, multifocal choroiditis and panuveitis, multiple disappearing white spot syndrome, punctate inner choroidopathy, creeping choroidopathy, and acute zonal occult outer retina.

[0075]

[0066] Masked syndromes are classified into non-neoplastic and neoplastic types. Non-exclusive examples of non-neoplastic masked syndromes include retinitis pigmentosa, foreign body in the eye, juvenile xanthogranuloma, and retinal detachment. Non-exclusive examples of neoplastic masked syndromes include retinoblastoma, lymphoma, malignant melanoma, leukemia, and reticulosarcoma.

[0076]

[0067] The term “to treat” or “treatment” refers to any incentive for the success or improvement of an injury, disease, disease, or condition, including any objective or subjective parameters such as reducing, alleviating, reducing symptoms, or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, reducing the debilitation at the end of degeneration, or improving the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term “to treat” and its conjugations may also include the prevention of injury, disease, condition, or disease. In some embodiments, treating is prevention. In some embodiments, treating does not include prevention.

[0077]

[0068] As used herein (and as is well understood in the art), “to treat” or “treatment” further broadly includes any approach to obtain beneficial or desired outcomes in the condition of interest, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, reduction or improvement of one or more symptoms or conditions, whether partial or whole, detectable or undetectable; attenuation of the severity of the disease; stabilization of the disease condition (i.e., no worsening); prevention of transmission or spread of the disease; delay or slowing of the progression of the disease; improvement or mitigation of the disease condition; attenuation of disease recurrence; and remission. In other words, as used herein, “treatment” includes any cure, improvement, or prevention of the disease. Treatment may include preventing the onset of the disease, controlling the spread of the disease, eliminating the symptoms of the disease (e.g., eye pain, halos around lights, red-eye, very high intraocular pressure), completely or partially eliminating the underlying cause of the disease, shortening the duration of the disease, or a combination of these.

[0078]

[0069] As used herein, “treating” and “treatment” include prophylactic treatment. A treatment method includes administering a therapeutically effective amount of the compound described herein to a subject. The administration step may consist of a single dose or include a series of doses. The duration of treatment depends on various factors such as the severity of the condition, the patient’s age, the concentration of the compound, the activity of the composition used in the treatment, or a combination thereof. It will also be recognized that the effective dosage of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention plan. Changes in dosage may be made and revealed by standard diagnostic assays known in the art. In some examples, chronic administration may be required. For example, the composition is administered to the subject in an amount and duration sufficient to treat the patient.

[0079]

[0070] The term “prevent” refers to a reduction in the occurrence of symptoms of a disease in a patient. As shown above, prevention may be complete (no detectable symptoms) or partial, such that the observed symptoms are less likely to occur than without treatment. In some embodiments, prevention refers to slowing the progression of a disease, disorder, or condition or inhibiting the progression of a disease, disorder, or condition to an adverse or undesirable state.

[0080]

[0071] “Patient” or “Subject in need” refers to a living organism that is susceptible to or suffers from a disease or condition that can be treated by administration of the pharmaceutical composition provided in the present invention. Non-limiting examples include humans, other mammals such as cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is human.

[0081]

[0072] An “effective dose” is the amount of a compound sufficient to accomplish the stated purpose in the absence of the compound (e.g., to achieve the effect of administering the compound, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, or to reduce one or more symptoms of a disease or condition). An example of an “effective dose” is an amount sufficient to contribute to the treatment, prevention, or reduction of symptoms of a disease, which may also be referred to as a “therapeutably effective dose.” “Reduction” of symptoms (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of symptoms or the elimination of symptoms. A “preventively effective dose” of a drug is the amount of a drug that, when administered to a subject, would have the intended preventive effect, e.g., to prevent or delay the onset (or recurrence) of an injury, disease, condition, or state, or to reduce the likelihood of the onset (or recurrence) of an injury, disease, condition, or state, or its symptoms. Complete preventive effect does not necessarily occur with a single dose and may only occur after a series of doses. Therefore, a prophylactically effective dose may be administered in one or more doses. As used herein, “activity reduction dose” refers to the amount of antagonist required to reduce the activity of an enzyme in the absence of the antagonist. As used herein, “function interference dose” refers to the amount of antagonist required to interfere with the function of an enzyme or protein in the absence of the antagonist. The exact amount will depend on the purpose of the treatment and will be verifiable by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins).The therapeutically effective dose can be determined by measuring the relevant physiological effects and can be adjusted in relation to the administration regimen, diagnostic analysis of the patient's condition, etc. For example, measuring serum levels of a VAP-1 inhibitor (or, for example, its metabolites) at a specific time point after administration may be an indicator of whether a therapeutically effective dose has been administered.

[0082]

[0073] In the case of any of the compounds described herein, the therapeutically effective amount can first be determined from a cell culture assay. The target concentration will be the concentration of the active compound that can achieve the method described herein, measured using the method described herein or a method known in the art.

[0083]

[0074] As is well known in the art, therapeutically effective doses for use in humans can also be determined from animal models. For example, doses for humans can be formulated to achieve concentrations that have been found to be effective in animals. Doses in humans can be adjusted, as described above, by monitoring the efficacy of the compound and adjusting the dosage upward or downward. Adjusting doses to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of those skilled in the art. Adjusting doses to achieve maximum therapeutic window efficacy or toxicity in humans based on the above and other methods is well within the capabilities of those skilled in the art.

[0084]

[0075] As used herein, the term “therapeutably effective amount” refers to an amount of therapeutic agent sufficient to improve the disorder as described above. For example, for a given parameter, a therapeutically effective amount would show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness can also be expressed as a “-times” increase or decrease. For example, a therapeutically effective amount may have an effect of at least 1.2 times, 1.5 times, 2 times, or 5 times or more than the control.

[0085]

[0076] The dosage may vary depending on the patient's requirements and the compound being employed. In the context of this disclosure, the dose administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the presence, nature, and degree of any adverse side effects. Determining the appropriate dosage for a particular situation is within the scope of those skilled in the art. Generally, treatment is initiated with a smaller dose, below the optimal dose of the compound. The dose is then increased in small increments until the optimal effect for the situation is obtained. The dosage and interval can be individually adjusted to bring about a level of the compound being administered that is effective in treating specific clinical symptoms. This will provide a treatment regimen that is appropriate to the severity of the individual's disease state.

[0086]

[0077] As used herein, the term “administer” means oral or topical administration. The compositions of this disclosure can be delivered by topical routes and can be formulated as solutions, suspensions, emulsions, gels, and ointments. Oral preparations include tablets, pills, and capsules suitable for ingestion by patients.

[0087]

[0078] In any of the compounds described herein, the therapeutically effective amount can first be determined from a cell culture assay. The target concentration will be the concentration of the active compound that can achieve the method described herein, measured using the method described herein or a method known in the art.

[0088]

[0079] The dosage and interval of administration can be individually adjusted to bring about levels of the compound being administered that are effective in treating specific clinical symptoms. This will provide a treatment regimen that is tailored to the severity of the individual's disease state.

[0089]

[0080] Using the teachings provided herein, effective prophylactic or therapeutic regimens can be planned that are not inherently toxic and are effective in treating clinical symptoms presented by specific patients. The plan should involve careful selection of active compounds by taking into account factors such as the potency of the compound, relative bioavailability, patient weight, presence and severity of adverse side effects, preferred mode of administration, and toxicity profile of the selected drug.

[0090]

[0081] As used herein, “cell” means a cell that performs metabolic or other functions sufficient to store or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, the ability to produce offspring, or, in the case of gametes, the ability to combine with a second gamete to produce viable offspring. Cells may include prokaryotic cells and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells of plant and animal origin, such as mammalian cells, insect cells (e.g., Spodoptera) and human cells. Cells that are naturally non-adherent or have been treated, for example by trypsin treatment, to prevent adhesion to a surface may be useful.

[0091]

[0082] The terms “control” or “control experiment” are used in their plain, ordinary sense and refer to an experiment in which the subject and reagents of the experiment are treated as they would be in a parallel experiment, except for the omission of experimental procedures, reagents, or variables. In some examples, the control is used as a standard of comparison when evaluating the effect of an experiment. In some embodiments, the control is the result of measuring protein activity in the absence of the compounds described herein (including embodiments and examples).

[0092]

[0083] In the context of a substance or substance activity or function associated with a disease (e.g., VAP-1-related disease (e.g., uveitis)), the terms “associated” or “associated with” mean that the disease (e.g., uveitis) is caused (whole or partially) by the substance or substance activity or function, or that the symptoms of the disease are caused (whole or partially) by the substance or substance activity or function. For example, uveitis associated with VAP-1 activity or function may be uveitis resulting (whole or partially) from abnormal VAP-1 function (e.g., enzyme activity, protein-protein interaction, signaling pathway), or it may be uveitis in which specific symptoms of the disease are caused (whole or partially) by abnormal VAP-1 activity or function. As used herein, anything described as associated with a disease may be a target for treatment of the disease if it is a causative factor. For example, uveitis or VAP-1-related diseases (e.g., uveitis) associated with VAP-1 activity or function may be treated with the compounds described herein (e.g., VAP-1 modulators or VAP-1 inhibitors) in cases where an increase in VAP-1 activity or function (e.g., signaling pathway activity) causes the disease (e.g., uveitis). For example, inflammatory diseases or VAP-1-related inflammatory diseases associated with VAP-1 activity or function may be treated with VAP-1 modulators or VAP-1 inhibitors in cases where an increase in VAP-1 activity or function (e.g., signaling pathway activity) causes the disease.

[0093]

[0084] As used herein, the term “abnormal” means different from normal. When used to describe enzyme activity or protein function, abnormal means activity or function that is greater or less than the average of a normal control or a normal control sample that has not developed the disease. Abnormal activity may also mean an amount of activity that causes a disease, where reducing the abnormal activity to a normal or disease-unrelated amount (for example, by administering the compound or using the method described herein) reduces the symptoms of the disease or one or more diseases.

[0094]

[0085] As used herein, the terms “VAP-1 inhibitor,” “VAP-1 antagonist,” “vascular adhesion protein-1 inhibitor,” “vascular adhesion protein-1 antagonist,” and all other terms accepted in the related art, many of which are set forth below, refer to compounds that can modulate the VAP-1 receptor directly or indirectly in in vitro assays, in vivo models, and / or other means demonstrating therapeutic efficacy. These terms also refer to compounds that demonstrate at least some therapeutic benefit in human subjects.

[0095]

[0086] The phrase “enough to produce a change” means that there is a detectable difference between the levels of the indicator measured before (e.g., baseline level) and after the administration of a particular treatment. The indicator may include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., subject's sense of well-being).

[0096]

[0087] The “activity” of a molecule may describe or refer to its binding to a ligand or receptor, catalytic activity, ability to stimulate gene expression or cell signaling, differentiation, or maturation, antigenic activity, or modulation of the activity of other molecules.

[0097]

[0088] "Substantially pure" indicates that the component constitutes more than about 50% of the total composition, typically more than about 60% of the total composition. More typically, "substantially pure" refers to a composition in which at least 75%, at least 85%, or at least 90% of the total composition is the component of interest. In some cases, polypeptides constitute more than about 90% or more than about 95% of the total composition (as a percentage on a mass-to-mass basis).

[0098] VAP-1 inhibitors

[0089] Vascular adhesion protein-1 (VAP-1) is a member of the copper-containing amine oxidase / semicarbazide-sensitive amine oxidase (AOC / SSAO) family found in humans as membrane-bound and soluble forms. Membrane-bound VAP-1 is mainly expressed in endothelial cells, smooth muscle cells, and adipocytes, while soluble VAP-1 is mainly released into the plasma from vascular endothelial cells. VAP-1 has a distal adhesion domain and an extramembrane enzymatic amine oxidase site. As an adhesion molecule, VAP-1 is involved in leukocyte rolling, adhesion, and migration, which are important for the extravasation of leukocytes to inflammatory sites. VAP-1 also acts as an amine oxidase. Amine oxidases possess topaquinone (TPQ) as a cofactor in their active site and catalyze the conversion of primary amines, such as methylamine and aminoacetone, to their corresponding aldehydes, such as formaldehyde and methylglyoxal, releasing ammonia and hydrogen peroxide in the process. RCH2NH2+O2+H2O→RCHO+H2O2+NH3

[0090] Vascular adhesion protein-1 (VAP-1) inhibitors are being studied as potential therapeutic agents for inflammatory conditions such as rheumatoid arthritis, asthma, and diabetic retinopathy. The mechanism of action of VAP-1 inhibitors involves blocking the enzymatic activity of VAP-1. VAP-1 has been shown to have amine oxidase activity, which is involved in the production of reactive oxygen species (ROS) and the adhesion and migration of leukocytes across the endothelium. By inhibiting the amine oxidase activity of VAP-1, VAP-1 inhibitors can reduce ROS production and inhibit leukocyte adhesion and migration, resulting in a reduction of inflammation and tissue damage. The VAP-1 inhibitors used herein have already been described in WO2020 / 069330 and WO2020 / 069335, each of which is incorporated by reference in whole.

[0099] Neuroinflammation

[0091] Neuroinflammation refers to inflammation of nerve tissue, which can be caused by a variety of factors including infection, injury, autoimmune disorders, and neurodegenerative diseases. Neuroinflammation involves the activation of glial cells such as microglia and astrocytes, which release inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. Neuroinflammation is involved in several neurological and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), vascular dementia (VAD), anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), transverse myelitis (TM), autoimmune encephalitis (AE), acute disseminated encephalomyelitis (ADEM), chronic meningitis (CM), central nervous system (CNS) vasculitis, Hashimoto's encephalitis (HE), neurosarcoidosis (NS), multiple system atrophy (MSA), migraine, chemotherapy-induced pain, or dementia-related pain. Inflammatory responses in these conditions can exacerbate nerve damage and contribute to disease progression. To reduce nerve damage and improve outcomes in patients with neurological and psychiatric disorders, research is underway to further understand the underlying mechanisms of neuroinflammation and to develop therapies that modulate inflammatory responses.

[0100] Alzheimer's disease (AD)

[0092] Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory and cognitive function. It is the most common cause of dementia in older adults, and its prevalence increases with age. The pathological features of Alzheimer's disease are the accumulation of beta-amyloid plaques and tau protein entanglement in the brain, which leads to brain cell death and atrophy of brain tissue. These changes disrupt the exchange of information between brain cells and affect memory, thinking, and behavior. The symptoms of Alzheimer's disease usually begin with mild memory impairment, but as it progresses, they include impairments in language, spatial orientation, and decision-making. As the disease progresses, individuals may experience personality changes, mood swings, and loss of motor function.

[0101] Parkinson's disease (PD)

[0093] Parkinson's disease is a chronic and progressive neurological disorder that affects the movement and coordination of the body. The disease results from the degeneration of dopamine-producing neurons in the brain. Dopamine is a neurotransmitter that helps control motor and emotional responses. The symptoms of Parkinson's disease typically develop gradually and include tremors (usually occurring in one hand or arm), rigidity, slowed movement (bradykinesia), balance disorders, and difficulty walking. Other symptoms may include depression, anxiety, sleep disturbances, and cognitive impairment. The cause of Parkinson's disease is not fully understood, but it is thought to be a combination of genetic and environmental factors. Age is also a major risk factor, and the disease primarily affects people over 60 years of age.

[0102] Amyotrophic lateral sclerosis (ALS)

[0094] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disease that affects nerve cells involved in the control of voluntary muscles. As the disease progresses, these nerve cells, called motor neurons, deteriorate, leading to weakness and eventual paralysis of the muscles they control. Symptoms of ALS include muscle weakness, rigidity, and difficulty with single contractions, speech, swallowing, and breathing, as well as eventually complete paralysis. There is currently no cure for ALS, and the disease often leads to death within two to three years of diagnosis. Treatment options aim to alleviate symptoms, improve quality of life, and slow the progression of the disease.

[0103] Multiple sclerosis (MS)

[0095] Multiple sclerosis is a chronic neurological disorder that often impairs daily life by affecting the central nervous system. In MS, the immune system mistakenly attacks the myelin sheath that surrounds and protects nerve fibers in the brain, spinal cord, and optic nerve. This damage disrupts the flow of electrical impulses between the brain and body, resulting in a range of symptoms. The symptoms of MS are diverse and can include fatigue, muscle weakness, spasticity, difficulty walking, numbness and tingling, visual disturbances, bladder and bowel dysfunction, and cognitive impairment. Symptoms may come and go (relapse) or worsen (progress) over time.

[0104] The cause of MS is not fully understood, but it is thought to be a combination of genetic and environmental factors. MS is more common in women than men and typically develops between the ages of 20 and 40.

[0105] Traumatic brain injury (TBI)

[0096] Traumatic brain injury is a type of brain injury caused by a sudden blow or shake to the head or body. This can result from a car accident, a fall, a sports injury, or any other situation in which the head or body is subjected to force. The severity of TBI varies from mild to severe, and the symptoms can also vary depending on the severity of the injury. Mild TBI, also known as concussion, may result in brief loss of consciousness, confusion, headache, dizziness, or nausea. Severe TBI may result in long-term or permanent brain injury, including cognitive impairment, physical disability, or behavioral changes.

[0106] Complex Regional Pain Syndrome (CRPS)

[0097] Complex regional pain syndrome (CRPS) is a chronic pain condition that typically affects the arms, legs, hands, or feet. The exact cause of CRPS is not fully understood, but it is thought to involve an abnormal response of the immune and nervous systems to injury or trauma. The symptoms of CRPS can vary, but typically include severe pain, swelling, and stiffness in the area of ​​infection, as well as changes in skin color and temperature. Other symptoms may include muscle weakness, muscle spasms, and decreased mobility. The pain associated with CRPS can be persistent and severe and may spread to other parts of the body.

[0107] Optic neuritis (ON)

[0098] Optic neuritis is inflammation of the optic nerve. This is further classified into papillitis and retrobulbar optic neuritis. Papillitis is characterized by inflammation of the optic nerve head, and retrobulbar optic neuritis is characterized by inflammation of the posterior side of the nerve. In some cases, multiple sclerosis is one of the most common etiologies of optic neuritis. Additional causes include infections (e.g., syphilis, Lyme disease, herpes zoster), autoimmune disorders (e.g., lupus, neurosarcoidosis, neuromyelitis optica), inflammatory bowel disease, drug-induced causes (e.g., chloramphenicol, ethambutol, isoniazid, streptomycin, quinine, penicillamine, aminosalicylic acid, phenothiazine, phenylbutazone), vasculitis, B12 deficiency, and diabetes. Symptoms of optic neuritis include sudden blurred or hazy vision, pain associated with eye movements, color vision impairment, and depth perception impairment. In some cases, treatment involves corticosteroids.

[0108] Neuromyelitis optica (NMO)

[0099] Neuromyelitis optica (also known as Devic's disease, Devic's syndrome, or NMO) is a B-cell mediated disease associated with the combined inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). In some cases, symptoms include blindness, pain and sensory disturbances in the eyes, weakness, numbness and / or paralysis of the arms and legs, and loss of bladder and bowel control. During the disease course, complement activation and inflammation occur as a result of peripheral B-cell-derived autoantibodies NMO-IgG targeting CNS astrocyte aquaporin 4 (AQP4). In some cases, the inflammatory lesions resemble those of multiple sclerosis (MS), but differ from MS in their perivascular distribution. There are two variants of neuromyelitis optica: AQP4+NMO, which results in an attack of astrocytes in the optic nerve and spinal cord by the human body's own immune system, and AQP4-NMO, whose etiology is unknown.

[0109]

[0100] In some embodiments, neuromyelitis optica belongs to a group of similar diseases known as neuromyelitis optica spectrum disorder (NMOSD). In some cases, additional diseases belonging to NMOSD include standard Devic's disease, localized Devic's disease, Asian neuromyelitis optica type MS, longitudinal myelitis or optic neuritis associated with systemic autoimmune disease, optic neuritis, or NMO-IgG negative NMO.

[0110] Chronic traumatic encephalopathy (CTE)

[0101] Chronic traumatic encephalopathy (CTE) is a progressive neurological disorder caused by repeated head injuries. CTE is commonly seen in athletes participating in contact sports such as football, boxing, and hockey, as well as soldiers and individuals with a history of head injury. A typical feature of CTE is the accumulation of an abnormal protein called tau in the brain, which leads to damage and death of brain cells. The symptoms of CTE can be diverse and may not appear until several years after the initial head injury. Symptoms can include mood disorders, cognitive impairment, memory loss, and problems with impulse control and aggression.

[0111] Ischemic stroke (IS)

[0102] Ischemic stroke is a type of stroke that occurs when blood flow to the affected area of ​​the brain is suppressed by the blockage of blood vessels in the brain. This can cause brain damage and a wide range of symptoms depending on the severity of the stroke and the area of ​​the brain affected. The most common cause of ischemic stroke is atherosclerosis, which is the accumulation of plaque in the arteries that can narrow or block blood flow. Other causes of ischemic stroke include blood clots, cardiac conditions such as atrial fibrillation, and certain medical conditions such as sickle cell disease. Symptoms of ischemic stroke may include the sudden onset of weakness or numbness on one side of the body, difficulty speaking or understanding speech, sudden changes in vision, dizziness or loss of coordination, and severe headache.

[0112] Vascular dementia (VAD)

[0103] Vascular dementia is a type of dementia that occurs when the blood supply to the brain is impaired, resulting in damage to brain cells. This can occur as a result of a stroke or a series of unnoticed latent strokes. The symptoms of vascular dementia can vary but may include memory loss, difficulty concentrating, confusion, disorientation, speech and communication difficulties, and difficulties in decision-making and problem-solving. Other symptoms may include depression, anxiety, and behavioral and personality changes.

[0113] Anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD)

[0104] Anti-myelin oligodendrocyte glycoprotein (MOG) antibody disease is an autoimmune disorder affecting the central nervous system (CNS). MOGs are proteins found on the surface of myelin, the protective coating around nerve fibers in the CNS. In this condition, the body's immune system mistakenly attacks MOGs, leading to inflammation and damage to myelin. The symptoms of anti-MOG antibody disease can be diverse but may include optic neuritis (inflammation of the optic nerve), transverse myelitis (inflammation of the spinal cord), encephalitis (inflammation of the brain), and acute disseminated encephalomyelitis (ADEM), a rare autoimmune disorder affecting the brain and spinal cord.

[0114] Transverse myelitis (TM)

[0105] Transverse myelitis is a rare neurological disorder involving inflammation of the spinal cord. The inflammation can damage or destroy myelin, the fatty substance that covers nerve fibers, and can cause scarring of the spinal cord. This can result in a wide range of symptoms, which can vary in severity and duration. Symptoms of transverse myelitis may include back pain, weakness or paralysis of the arms or legs, sensory disturbances such as numbness or tingling, bladder or bowel dysfunction, and difficulty with coordination and balance.

[0115] Autoimmune encephalitis (AE)

[0106] Autoimmune encephalitis is a rare neurological disorder that occurs when the immune system mistakenly attacks healthy cells in the brain, resulting in inflammation and damage. The symptoms of autoimmune encephalitis are diverse and can vary greatly from person to person, but may include (a) cognitive and behavioral changes such as memory loss, confusion, personality changes, and mood swings; (b) motor disorders such as tremors, ataxia (loss of coordination), and myoclonus (muscle spasms); (c) seizures; (d) psychiatric symptoms such as hallucinations, delusions, and paranoia; and (e) autonomic dysfunction such as changes in blood pressure, heart rate, and body temperature.

[0116] Acute disseminated encephalomyelitis (ADEM)

[0107] Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune neurological disorder that typically develops after infection or vaccination. This condition occurs when the immune system attacks the myelin sheath that covers nerve fibers in the brain and spinal cord, resulting in inflammation and damage. Symptoms of ADEM can include fever, headache, vomiting, seizures, and confusion. Patients may also experience weakness or paralysis of the limbs, visual disturbances, and difficulty speaking or swallowing. In severe cases, ADEM can lead to coma or even death.

[0117] Chronic meningitis (CM)

[0108] Chronic meningitis is a persistent inflammation of the membranes covering the brain and spinal cord. Unlike acute meningitis, which is a medical emergency, chronic meningitis develops slowly and can last for weeks or months. The most common cause of chronic meningitis is bacterial or fungal infection, but the condition can also be caused by non-infectious factors such as certain drug treatments, cancer, autoimmune disorders, and sarcoidosis. Symptoms of chronic meningitis can include headache, fever, neck stiffness, photophobia, and confusion. Patients may also experience fatigue, weakness, and cognitive impairment. In some cases, chronic meningitis can lead to seizures or strokes.

[0118] Central nervous system vasculitis (CNS vasculitis)

[0109] Central nervous system vasculitis is a rare autoimmune disorder that affects the blood vessels in the brain and spinal cord. This condition occurs when the immune system mistakenly attacks healthy blood vessels, causing inflammation and damage. The damage can result in a range of neurological symptoms, including headaches, confusion, seizures, and focal neurological symptoms such as weakness, numbness, or loss of coordination.

[0119] Hashimoto's encephalitis (HE)

[0110] Hashimoto's encephalitis (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare autoimmune disorder affecting the brain. It is caused by an autoimmune reaction against the thyroid gland, resulting in the production of antibodies that affect brain neurons. The symptoms of Hashimoto's encephalitis can vary greatly from person to person but may include memory loss, confusion, personality changes, seizures, psychosis, headaches, tremors, and ataxia (loss of coordination).

[0120] Neurosarcoidosis (NS)

[0111] Neurosarcoidosis is a rare form of sarcoidosis, an inflammatory disorder that can affect multiple organs throughout the body. It specifically targets the nervous system, including the brain, spinal cord, and nerves. The signs and symptoms of neurosarcoidosis can vary greatly from person to person depending on the extent of infection in the nervous system. Some common symptoms may include headaches, seizures, visual or hearing impairments, facial numbness or weakness, cognitive problems such as memory loss or confusion, balance problems, limb weakness or paralysis, and pain in the joints, muscles, or bones.

[0121]

[0112] Multiple system atrophy (MSA) Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterized by the abnormal accumulation of the protein α-synuclein (α-syn) in oligodendrocytes, specialized cells that produce myelin, an insulating material that surrounds and protects nerve fibers. This accumulation of α-syn leads to inflammation, demyelination, and subsequent synaptic and neuronal loss, resulting in the characteristic symptoms of MSA, such as autonomic dysfunction and motor impairment.

[0122]

[0113] Migraine Migraine is a neurological condition characterized by recurrent episodes of moderate to severe headache, usually accompanied by other symptoms such as hypersensitivity to light, sound, or smell, nausea, and vomiting. Migraines can last from several hours to several days, be extremely debilitating, and can interfere with daily activities and quality of life.

[0123]

[0114] Chemotherapy-induced pain Chemotherapy-induced pain is a common side effect of cancer treatment that can be caused by the chemotherapy drugs themselves or the cancer itself. This pain can be acute, meaning it comes on suddenly and lasts for a short period, or chronic, lasting for months or even years after the end of treatment. Chemotherapy-induced pain can manifest in various ways, including peripheral neuropathy, which is damage to the nerves that control sensation and movement in the arms, legs, hands, and feet, causing pain, tingling, or numbness. Other pain symptoms include mucositis, which is inflammation of the mucous membrane lining the inside of the digestive tract, causing pain and discomfort in the mouth, throat, and digestive system. Some patients may also experience headaches, bone pain, or joint pain, which can be severe and debilitating.

[0124]

[0115] Dementia-related pain Dementia-related pain is pain experienced by individuals with dementia, a progressive neurological condition that affects cognitive function, memory, and behavior. Individuals with dementia may have difficulty expressing pain, which makes it challenging for caregivers and healthcare professionals to effectively identify and manage it. Dementia-related pain can manifest in various ways, including physical pain such as headaches, muscle aches, or joint pain, and neuropathic pain. Pain may also be associated with medical conditions commonly associated with dementia, such as arthritis, infections, or injuries resulting from falls. In addition to physical pain, individuals with dementia may also experience psychological or emotional distress, such as anxiety or depression, which can exacerbate the symptoms of physical pain.

[0125] Pharmaceutical composition

[0116] In certain embodiments, the compounds described herein are administered as pure chemical substances. In other embodiments, the compounds described herein are combined with a pharmaceutically appropriate or acceptable carrier (also referred to herein as a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) selected based on a chosen route of administration and standard pharmaceutical practice, such as as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)).

[0126]

[0117] The present invention provides a pharmaceutical composition comprising at least one compound described herein, or a stereoisomer thereof, a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with one or more pharmaceutically acceptable carriers. The carrier (or excipient) is acceptable or suitable if the carrier is compatible with the other components of the composition and is not harmful to the recipient of the composition (i.e., subject or patient).

[0127]

[0118] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or a pharmaceutically acceptable salt or solvate thereof.

[0119] One embodiment provides a method for preparing a pharmaceutical composition comprising mixing a compound or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable carrier.

[0128]

[0120] In certain embodiments, the compound or its pharmaceutically acceptable salt or solvate is substantially pure in that it contains less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts formed in one or more steps of the synthesis method.

[0129]

[0121] In certain embodiments, the compound or its pharmaceutically acceptable salt or solvate is substantially pure in that it contains less than about 5%, less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts formed in one or more steps of the synthesis method.

[0130]

[0122] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules made of hard or soft gelatin, methylcellulose, or other suitable materials that readily dissolve in the gastrointestinal tract. In some embodiments, suitable non-toxic solid carriers are used, such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005))).

[0131]

[0123] In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof is formulated for administration by injection. In some examples, the injectable formulation is an aqueous formulation. In some examples, the injectable formulation is a non-aqueous formulation. In some examples, the injectable formulation is an oil-based formulation, such as sesame oil.

[0132]

[0124] The dose of a composition comprising at least one compound described herein varies depending on the condition of the subject or patient (e.g., human). In some embodiments, such factors include basic health status, age, and other factors.

[0133]

[0125] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (prevented). The appropriate dose and appropriate duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dose and treatment regimen will provide an amount of the composition sufficient to give therapeutic and / or prophylactic benefits (e.g., improved clinical outcomes such as increased frequency of complete or partial remission, extended disease-free and / or overall survival, or reduced symptom severity). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body type, weight, or blood volume. In some embodiments, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is administered 1 to 4 times per day in doses of about 1 mg to about 1000 mg.

[0134] Treatment method

[0126] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (I)

[0135] [ka]

[0136] And, In formula (I),

[0137] [ka]

[0138] The substructure represented by

[0139] [ka]

[0140] And, The symbol --- represents a connection point. X 1 ga = N-, -NR 8 -, -O-, or -S- X 2 is -N- or -CH-, X 3 is -O-, -S-, -NH-, -CH2-, or -C(O)-, Y is bonded, -O-, -S-, -NR 7 -, -OCX2-, -(CH2) z2 It is W-, -C(O)O-, or -C(O)NH-, W is bonded, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, n7, n8, and n12 are independent integers between 0 and 4. m1, m2, m5, m6, m7, m8, m12, v1, v2, v5, v6, v7, v8, and v12 are independently 1 or 2. L 1 -O-, -S-, -NR 1L -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R 1L is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 1 Hydrogen, halogen, -CX 1.1 3, -CHX 1.1 2, -CH2X 1.1 -CN, -SO n1 R 1A , -SO v1 NR 1B R 1C , -NHNR 1B R 1C,-ONR 1B R 1C , -NHC(O)NHNR 1B R 1C ,-NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D -C(O)NR 1B R 1C , -OR 1A , -NR 1B SO2R 1A , -NR 1B C(O)R 1D , -NR 1B C(O)OR 1D , -NR 1B Ure 1D ,-OCX 1.1 3, -OCHX 1.1 2, R 12 Substituted or unsubstituted alkyl, R 12 Substituted or unsubstituted heteroalkyl, R 12 Substituted or unsubstituted cycloalkyl, R 12 Substituted or unsubstituted heterocycloalkyl, R 12 Substitutable or unsubstituted aryl, or R 12 A substituted or unsubstituted heteroaryl, or at least one amino acid, R 2 Hydrogen, halogen, -CX 2.1 3, -CHX 2.1 2, -CH2X 2.1 -CN, -SO n2 R 2A , -SO v2 NR 2B R 2C , -NR 2B R 2C , -C(O)R 2D , -C(O)OR 2D -C(O)NR 2B R 2C , -OR 2A ,-OCX 2.1 3, -OCHX 2.12. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 3 and R 4 These are independently hydrogen or -F, R 5 Hydrogen, halogen, -CX 5.1 3, -CHX 5.1 2, -CH2X 5.1 -CN, -N3, -SO n5 R 5A , -SO v5 NR 5B R 5C , -NHNR 5B R 5C ,-ONR 5B R 5C , -NHC(O)NHNR 5B R 5C ,-NHC(O)NR 5B R 5C , -N(O) m5 , -NR 5B R 5C , -C(O)R 5D , -C(O)OR 5D -C(O)NR 5B R 5C , -OR 5A , -NR 5B SO2R 5A , -NR 5B C(O)R 5D , -NR 5B C(O)OR 5D , -NR 5B Ure 5D ,-OCX 5.1 3, -OCHX 5.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 6 Hydrogen, halogen, -CX 6.1 3, -CHX 6.1 2, -CH2X 6.1-CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C ,-ONR 6B R 6C , -NHC(O)NHNR 6B R 6C ,-NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B Ure 6D ,-OCX 6.1 3, -OCHX 6.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 7 Hydrogen, halogen, -CX 7.1 3, -CHX 7.1 2, -CH2X 7.1 -CN, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D -C(O)NR 7B R 7C , -OR 7A ,-OCX 7.1 3, -OCHX 7.12. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 8 Hydrogen, halogen, -CX 8.1 3, -CHX 8.1 2, -CH2X 8.1 -CN, -SO n8 R 8A , -SO v8 NR 8B R 8C , -NR 8B R 8C , -C(O)R 8D , -C(O)OR 8D -C(O)NR 8B R 8C , -OR 8A ,-OCX 8.1 3, -OCHX 8.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 12 Hydrogen, halogen, -CX 12.1 3, -CHX 12.1 2, -CH2X 12.1 -CN, -SO n12 R 12A , -SO v12 NR 12B R 12C , -NR 12B R 12C , -C(O)R 12D , -C(O)OR 12D -C(O)NR 12B R 12C , -OR 12A ,-OCX 12.1 3, -OCHX 12.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 1A Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12A Substituted or unsubstituted alkyl, R 12A Substituted or unsubstituted heteroalkyl, R 12A Substituted or unsubstituted cycloalkyl, R 12A Substituted or unsubstituted heterocycloalkyl, R 12A Substitutable or unsubstituted aryl, or R 12A It is a substituted or unsubstituted heteroaryl, R 1B Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12B Substituted or unsubstituted alkyl, R 12B Substituted or unsubstituted heteroalkyl, R 12B Substituted or unsubstituted cycloalkyl, R 12B Substituted or unsubstituted heterocycloalkyl, R 12B Substitutable or unsubstituted aryl, or R 12B It is a substituted or unsubstituted heteroaryl, R 1C Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12C Substituted or unsubstituted alkyl, R 12C Substituted or unsubstituted heteroalkyl, R 12C Substituted or unsubstituted cycloalkyl, R 12C Substituted or unsubstituted heterocycloalkyl, R 12C Substitutable or unsubstituted aryl, or R 12C R is either substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom. 1B substituents and R 1C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. R 1D Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12D Substituted or unsubstituted alkyl, R 12DSubstituted or unsubstituted heteroalkyl, R 12D Substituted or unsubstituted cycloalkyl, R 12D Substituted or unsubstituted heterocycloalkyl, R 12D Substitutable or unsubstituted aryl, or R 12D It is a substituted or unsubstituted heteroaryl, R 2A , R 2B , R 2C , R 2D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 8A , R 8B , R 8C , R 8D , R 12A , R 12B , R 12C , and R 12D R is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom 2B substituents and R 2C substituents and R 5B substituents and R 5C substituents and R 6B substituents and R 6C substituents and R 7B substituents and R 7C substituents and R 8B substituents and R 8C With substituents, or R 12B substituents and R 12C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. X, X 1.1, X 2.1 , X 5.1 , X 6.1 , X 7.1 , X 8.1 , and X 12.1 These are independently -Cl, -Br, -I, or -F, The structure of equation (II)

[0141] [ka]

[0142] And, In formula (II), X 1 and X 4 Independently, =N- or =CH-, X 5 is =N- or -CR 5 -and, X 6 is =N- or -CR 6 -and, Y is bonded, -O-, -S-, -NR 7 -, -OCX2-, -(CH2) z2 It is W-, -C(O)O-, or -C(O)NH-, W is bonded, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, and n7 are independent integers between 0 and 4. m1, m2, m5, m6, m7, v1, v2, v5, v6, and v7 are independently 1 or 2. L 1 -O-, -S-, -NR 1L -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R 1Lis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 1 is independently hydrogen, halogen, -CX 1.1 3, -CHX 1.1 2, -CH2X 1.1 , -CN, -SO n1 R 1A , -SO v1 , -SO 1B R 1C , -NHNR 1B R 1C , -ONR 1B R 1C , -NHC(O)NHNR 1B R 1C , -NHC(O)NR 1B R 1C , -N(O) m1 , -NR 1B R 1C , -C(O)R 1D , -C(O)OR 1D , -C(O)NR 1B R 1C , -OR 1A , -NR 1B , -NR 1A , -NR 1B , -NR 1D [[ID=6o]], -NR 1B , C(O)OR 1D , -NR 1B , -OR 1D , -OCX 1.1 , -OCHX 1.1 , R 12 , substituted or unsubstituted alkyl, R 12 , substituted or unsubstituted heteroalkyl, R 12 , substituted or unsubstituted cycloalkyl, R 12 , substituted or unsubstituted heterocycloalkyl, R 12 , substituted or unsubstituted aryl, or R 12 , substituted or unsubstituted heteroaryl, or at least one amino acid, R 2 is hydrogen, halogen, -CX 2.13. -CHX 2.1 2. -CH2X 2.1 . -CN, -SO n2 R 2A . -SO v2 NR 2B R 2C . -NR 2B R 2C . -C(O)R 2D . -C(O)OR 2D . -C(O)NR 2B R 2C . -OR 2A . -OCX 2.1 3. -OCHX 2.1 2. Substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R 3 and R 4 are independently hydrogen or -F, R 5 is hydrogen, halogen, -CX 5.1 3. -CHX 5.1 2. -CH2X 5.1 . -CN, -N3, -SO n5 R 5A . -SO v5 NR 5B R 5C . -NHNR 5B R 5C . -ONR 5B R 5C . -NHC(O)NHNR 5B R 5C . -NHC(O)NR 5B R 5C . -N(O) m5 . -NR 5B R 5C . -C(O)R 5D . -C(O)OR 5D . -C(O)NR 5B R<00​​​​​​​​​​​​​5D , -NR 5B Ure 5D ,-OCX 5.1 3, -OCHX 5.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 6 Hydrogen, halogen, -CX 6.1 3, -CHX 6.1 2, -CH2X 6.1 -CN, -N3, -SO n6 R 6A , -SO v6 NR 6B R 6C , -NHNR 6B R 6C ,-ONR 6B R 6C , -NHC(O)NHNR 6B R 6C ,-NHC(O)NR 6B R 6C , -N(O) m6 , -NR 6B R 6C , -C(O)R 6D , -C(O)OR 6D -C(O)NR 6B R 6C , -OR 6A , -NR 6B SO2R 6A , -NR 6B C(O)R 6D , -NR 6B C(O)OR 6D , -NR 6B Ure 6D ,-OCX 6.1 3, -OCHX 6.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 7 Hydrogen, halogen, -CX 7.1 3, -CHX 7.12, -CH2X 7.1 -CN, -SO n7 R 7A , -SO v7 NR 7B R 7C , -NR 7B R 7C , -C(O)R 7D , -C(O)OR 7D -C(O)NR 7B R 7C , -OR 7A ,-OCX 7.1 3, -OCHX 7.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 12 Hydrogen, halogen, -CX 12.1 3, -CHX 12.1 2, -CH2X 12.1 -CN, -SO n12 R 12A , -SO v12 NR 12B R 12C , -NR 12B R 12C , -C(O)R 12D , -C(O)OR 12D -C(O)NR 12B R 12C , -OR 12A ,-OCX 12.1 3, -OCHX 12.1 2. A substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R 1A Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12A Substituted or unsubstituted alkyl, R 12A Substituted or unsubstituted heteroalkyl, R 12A Substituted or unsubstituted cycloalkyl, R 12ASubstituted or unsubstituted heterocycloalkyl, R 12A Substitutable or unsubstituted aryl, or R 12A It is a substituted or unsubstituted heteroaryl, R 1B Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12B Substituted or unsubstituted alkyl, R 12B Substituted or unsubstituted heteroalkyl, R 12B Substituted or unsubstituted cycloalkyl, R 12B Substituted or unsubstituted heterocycloalkyl, R 12B Substitutable or unsubstituted aryl, or R 12B It is a substituted or unsubstituted heteroaryl, R 1C Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12C Substituted or unsubstituted alkyl, R 12C Substituted or unsubstituted heteroalkyl, R 12C Substituted or unsubstituted cycloalkyl, R 12C Substituted or unsubstituted heterocycloalkyl, R 12C Substitutable or unsubstituted aryl, or R 12C R is either substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom. 1B substituents and R 1C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. R 1D Hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, R 12D Substituted or unsubstituted alkyl, R 12D Substituted or unsubstituted heteroalkyl, R 12D Substituted or unsubstituted cycloalkyl, R 12D Substituted or unsubstituted heterocycloalkyl, R 12D Substitutable or unsubstituted aryl, or R 12D It is a substituted or unsubstituted heteroaryl, R2A , R 2B , R 2C , R 2D , R 5A , R 5B , R 5C , R 5D , R 6A , R 6B , R 6C , R 6D , R 7A , R 7B , R 7C , R 7D , R 12A , R 12B , R 12C , and R 12D R is independently hydrogen, halogen, -CF3, -CCl3, -CBr3, -CI3, -COOH, -CONH2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom 2B substituents and R 2C substituents and R 5B substituents and R 5C substituents and R 6B substituents and R 6C substituents and R 7B substituents and R 7C substituents and R 8B substituents and R 8C With substituents, or R 12B substituents and R 12C Substituents may be linked as needed to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. X, X 1.1 , X 2.1 , X 5.1 , X 6.1 , X 7.1 , and X 12.1 These are independently -Cl, -Br, -I, or -F. A method is provided.

[0143]

[0127] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (I)

[0144] [ka]

[0145] A method is provided that is.

[0128] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (IA)

[0146] [ka]

[0147] A method is provided that is.

[0129] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (IB) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (IB)

[0148] [ka]

[0149] A method is provided that is.

[0130] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (I-B1) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (I-B1)

[0150] [ka]

[0151] A method is provided that is.

[0131] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (I-B2) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (I-B2)

[0152] [ka]

[0153] A method is provided that is.

[0132] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (IC)

[0154] [ka]

[0155] A method is provided that is.

[0133] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (ID) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (ID)

[0156] [ka]

[0157] A method is provided that is.

[0134] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (IE) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (IE)

[0158] [ka]

[0159] A method is provided that is.

[0135] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (IF) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (IF)

[0160] [ka]

[0161] A method is provided that is.

[0136] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II)

[0162] [ka]

[0163] A method is provided that is.

[0137] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-A) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-A)

[0164] [ka]

[0165] A method is provided that is.

[0138] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-B) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-B)

[0166] [ka]

[0167] A method is provided that is.

[0139] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-C) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-C)

[0168] [ka]

[0169] A method is provided that is.

[0140] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-D) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-D)

[0170] [ka]

[0171] A method is provided that is.

[0141] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-E) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-E)

[0172] [ka]

[0173] A method is provided that is.

[0142] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-F) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-F)

[0174] [ka]

[0175] A method is provided that is.

[0143] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-G) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-G)

[0176] [ka]

[0177] A method is provided that is.

[0144] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (II-H) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (II-H)

[0178] [ka]

[0179] A method is provided that is.

[0145] In some embodiments, a method is provided for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising compounds provided in Table 1.

[0180]

[0146] The compounds in Tables 1, 2, or 3 were characterized as VAP-1 inhibitors in the following publications WO2020 / 069330 and WO2020 / 069335.

[0181] [Table 1-1]

[0182] [Table 1-2]

[0183] [Table 1-3]

[0184] [Table 1-4]

[0185] [Table 1-5]

[0186] [Table 1-6]

[0187] [Table 1-7]

[0188] [Table 1-8]

[0189] [Table 1-9]

[0190] [Table 1-10]

[0191] [Table 1-11]

[0192] [Table 1-12]

[0193] [Table 1-13]

[0194] [Table 1-14]

[0195] [Table 1-15]

[0196]

[0147] In some embodiments, a method is provided for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising compounds provided in Table 2.

[0197] [Table 2-1]

[0198] [Table 2-2]

[0199]

[0148] In some embodiments, a method is provided for treating a neuroinflammatory disease in a patient who needs treatment for the neuroinflammatory disease, the method comprising the step of administering to the patient a pharmaceutical composition comprising compounds provided in Table 3.

[0200] [Table 3]

[0201]

[0149] In some embodiments, a method for treating a neuroinflammatory disease in a patient who needs treatment for a neuroinflammatory disease, wherein the neuroinflammatory disease is Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke A method is provided that is selected from (IS), vascular dementia (VAD), anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), transverse myelitis (TM), autoimmune encephalitis (AE), acute disseminated encephalomyelitis (ADEM), chronic meningitis (CM), central nervous system (CNS) vasculitis, Hashimoto's encephalitis (HE), neurosarcoidosis (NS), multiple system atrophy (MSA), migraine, chemotherapy-induced pain, or dementia-related pain.

[0202]

[0150] In some embodiments, the neuroinflammatory disease is Alzheimer's disease. In some embodiments, the neuroinflammatory disease is Parkinson's disease. In some embodiments, the neuroinflammatory disease is amyotrophic lateral sclerosis. In some embodiments, the neuroinflammatory disease is multiple sclerosis. In some embodiments, the neuroinflammatory disease is traumatic brain injury. In some embodiments, the neuroinflammatory disease is complex regional pain syndrome. In some embodiments, the neuroinflammatory disease is optic neuritis. In some embodiments, the neuroinflammatory disease is neuromyelitis optica. In some embodiments, the neuroinflammatory disease is chronic traumatic encephalopathy. In some embodiments, the neuroinflammatory disease is ischemic stroke.

[0203]

[0151] In some embodiments, the neuroinflammatory disease is vascular dementia. In some embodiments, the neuroinflammatory disease is anti-myelin oligodendrocyte glycoprotein antibody disease. In some embodiments, the neuroinflammatory disease is transverse myelitis. In some embodiments, the neuroinflammatory disease is autoimmune encephalitis. In some embodiments, the neuroinflammatory disease is acute disseminated encephalomyelitis. In some embodiments, the neuroinflammatory disease is chronic meningitis. In some embodiments, the neuroinflammatory disease is central nervous system (CNS) vasculitis. In some embodiments, the neuroinflammatory disease is Hashimoto's encephalitis. In some embodiments, the neuroinflammatory disease is neurosarcoidosis. In some embodiments, the neuroinflammatory disease is multiple system atrophy. In some embodiments, the neuroinflammatory disease is migraine. In some embodiments, the neuroinflammatory disease is chemotherapy-induced pain. In some embodiments, the neuroinflammatory disease is dementia-related pain. [Examples]

[0204]

[0152] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes based on them will be conceivable to those skilled in the art and will be understood to be within the spirit and scope of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety for all purposes. The following abbreviations, when used herein and throughout this description of the invention, will be understood to have the following meanings unless otherwise indicated.

[0205] [Table 4]

[0206] I. Biological evaluation Lipopolysaccharide (LPS) is a bacterial surface molecular glycolipid that can induce inflammation and tissue damage. LPS-induced neuroinflammation has manifested in the hippocampus and prefrontal cortex as microglial activation (labeled by Iba-1 and CD-68) and Aβ1-42 expression. Aβ activates microglia, inducing the release of pro-inflammatory cytokines such as TNF-α.

[0207] 1. Test Objectives The purpose of this study is to evaluate the efficacy of compounds (A, B, and C) against lipopolysaccharide (LPS)-induced neuroinflammation in C57BL / 6J mice.

[0208] 2. Test materials reagent • Lipopolysaccharide (LPS): Sigma-Aldrich, Catalog Number: L2880 • Physiological saline: Shijiazhuang Siyao CO., LTD., Catalog number: 2107271904 DMSO: Sigma, Catalog Number: 472301-100ML • K2EDTA tubing: BD, catalog number: 365974 • Mouse TNF-α ELISA kit: Invitrogen, catalog number: 88-7324 • Iba1: Abcam, Catalog Number: ab178847 • CD68: Cell Signaling, Catalog Number: 97778 • Aβ1-42: Abcam, Catalog number: ab201061 • F(ab')2-Goat anti-rabbit HRP antibody: Abcam, Catalog number: Ab6013 • Rabbit 2-stage test kit: ZSGB-Bio, catalog number: PV-9001 • TSA570: Wi See Biotechnology, catalog number D11011 DAPI: Invitrogen, catalog number: D3571 • DAPI: Invitrogen, Catalog Number: D3571 • Fading mounting agent: Absin, Catalog number: abs9240 Device • Electronic balance: Sartorius, catalog number: SECURA225D-1CN ·Electronic scale: Shanghai Yueping Scientific instrument Co., Ltd., Cat:YP10001Ultrasonic • Ultrasonic cleaner: Kunshang, Catalog number: KQ3200E • Electronic oscillator: Scientific Industries, catalog number: SI-0256 • Centrifuge: Thermo Scientific, Catalog number: 75002440 • Paraffin dehydrator: Leica, catalog number: EG1150C • Paraffin microtome: Leica, catalog number: RM2235 • Paraffin embedding machine: Leica, catalog number: EG1150H • Forward fluorescence microscope: Olympus, catalog number: BX53 compound The compound should be prepared according to the reported procedure and stored at 4°C.

[0209] animal

[0210] [Table 5]

[0211] 3. Method Grouping and regimens Forty 10-week-old female C57BL / 6 mice obtained from Shanghai Jihui Laboratory Animal Care Co., Ltd. were used in this experiment. All animals were tagged with ear tags. After one week of acclimatization, all mice were randomly divided into five groups based on body weight, as shown in Table 3.

[0212] [Table 6]

[0213] Reagent preparation ·LPS (0.75mg / mL stock solution) preparation: Weigh 3.75 mg of LPS and place it in an 8 mL polyethylene tube. Add 5 mL of PBS and mix by stirring or shaking. Divide into 1 mL aliquots of the stock solution and store at -20°C for use.

[0214] ·LPS (0.075mg / mL) preparation: Add 9 mL of PBS to 1 mL of LPS stock solution (0.75 mg / mL) and shake to mix. Prepare immediately before administration.

[0215] Preparation of compound A (0.6 mg / mL) (in 2% DMSO and 98% physiological saline): Weigh 30.0 mg of compound A and place it in a brown bottle. Add 1 mL of DMSO and vortex to obtain a homogeneous solution (stock solution, concentration = 30 mg / mL). Divide the stock solution into 40 μL aliquots and store at -80°C away from light for use.

[0216] Immediately before the procedure, add 1.96 mL of physiological saline to 1 mL of compound A stock solution (30 mg / mL) and shake to mix until completely dissolved (0.6 mg / mL). Preparation of compound B (0.6 mg / mL) (in 2% DMSO and 98% physiological saline): Weigh 30.1 mg of compound B and place it in a brown bottle. Add 1 mL of DMSO and vortex to obtain a homogeneous solution (stock solution, concentration = 30 mg / mL). Divide the stock solution into 40 μL aliquots and store at -80°C away from light for use.

[0217] Immediately before the procedure, add 1.96 mL of physiological saline to 1 mL of compound B stock solution (30 mg / mL) and shake to mix until completely dissolved (0.6 mg / mL). Preparation of compound C (0.6 mg / mL) (in 2% DMSO and 98% physiological saline): Weigh 30.4 mg of compound C and place it in a brown bottle. Add 1.01 mL of DMSO and vortex to obtain a homogeneous solution (stock solution, concentration = 30 mg / mL). Divide the stock solution into 40 μL aliquots and store at -80°C away from light for use.

[0218] Immediately before the procedure, add 1.96 mL of physiological saline to 1 mL of compound C stock solution (30 mg / mL) and shake to mix until completely dissolved (0.6 mg / mL). Model configuration and administration Mice were intraperitoneally injected with either LPS (750 μg / kg, 10 mL / kg) or an equal volume of physiological saline one hour after drug treatment from day 0 to day 4 (Table 3). The day of the first LPS injection was recorded as day 0.

[0219] endpoint On day 4, one hour after LPS treatment, all animals were anesthetized, blood was placed in K2EDTA tubes, plasma samples were separated at 3500 rpm for 10 minutes, and stored at -80°C for TNF-α level analysis.

[0220] The mice were perfused through the left ventricle with 10 mL of ice-cold saline for 3 minutes. The entire brain was removed and immersed in formalin for immunohistochemical analysis (CD-68 (microphages), Iba-1 microglia, and Aβ1-42 in the hippocampus and prefrontal cortex).

[0221] parameter ·body weight During the experiment, daily body weight and clinical observations were recorded before administration.

[0222] • ELISA: TNF-α levels 1) Corning® Costar® 9018 ELISA plates were coated with 100 μL / well of capture antibody in coating buffer (diluted as described in Reagent Preparation Point 1). The plates were sealed and incubated overnight at 4°C.

[0223] 2) The wells were aspirated and washed three times with over 250 μL / well of washing buffer. Allowing an immersion time (approximately 1 minute) between each washing step enhanced the effectiveness of the washing. The plate was wiped with blotting paper to remove any residual buffer.

[0224] 3) The wells were blocked with 200 μL of ELISA / ELISPOT dilution (1x). Incubated at room temperature for 1 hour. 4) Standards were prepared. Mouse TNFα standards were reconstituted by adding distilled water. The reconstitution volume was indicated on the label of the standard vial. The standards were reconstituted for 10–30 minutes. Gentle swirling or mixing was performed to ensure complete and homogeneous solubilization (concentration of reconstituted standard = 1000 pg / mL).

[0225] 5) Aspirate and wash at least once with washing buffer. 6) A total of eight standard curves were created by performing 2-fold serial dilutions of the highest concentration standard. To do this, 100 μL of ELISA / ELISPOT diluent (1x) was added to the first well, which was left empty. 200 μL / well of the highest concentration standard was added to the first empty wells A1 / A2. 100 μL of the highest concentration standard was transferred from wells A1 / A2 to wells B1 / B2. The contents of wells B1 and B2 were mixed by repeated aspiration and draining, and 100 μL was transferred to wells C1 / C2. Care was taken not to scratch the surface of the microwells. This procedure was repeated five times.

[0226] 7) 100 μL / well of the sample was added to a suitable well. 8) 100 μL of ELISA / ELISPOT dilution (1x) was added to the blank wells.

[0227] 9) The plate was sealed and incubated at room temperature for 2 hours (or overnight at 4°C for maximum sensitivity). 10) The detection antibody was prepared (see Reagent Preparation).

[0228] 11) Aspirate and wash as in Step 2. Repeat this process for a total of 3-5 washes. Allowing an immersion time (approximately 1 minute) between each wash step enhances the effectiveness of the wash. Wipe the plate with blotting paper to remove any residual buffer.

[0229] 12) Diluted detection antibody was added to all wells at a concentration of 100 μL / well. 13) The plate was sealed and incubated at room temperature for 1 hour. 14) Streptavidin-HRP was prepared. The HRP concentrate (100-fold) was diluted 1:100 in ELISA / ELISPOT diluent (1-fold).

[0230] 15) Aspirate and wash as in Step 2. Repeat this process for a total of 3-5 washes. Allowing an immersion time (approximately 1 minute) between each wash step enhances the effectiveness of the wash. Wipe the plate with blotting paper to remove any residual buffer.

[0231] 16) Diluted streptavidin-HRP was added at a concentration of 100 μL / well. 17) The plate was sealed and incubated at room temperature for 30 minutes. 18) As in Step 2, suction and wash, ensuring a 1-2 minute immersion time before suction. Repeat this process for a total of 5-7 washes.

[0232] 19) 100 μL / well of 1x TMB solution was added. 20) Incubated at room temperature for 15 minutes. 21) 100 μL / well of stop solution was added.

[0233] 22) Read the plate at 450 nm. If wavelength subtraction is available, subtract the 570 nm value from the 450 nm value and analyze the data. ·Immunohistochemistry 1) The paraffin slides were dewaxed and hydrated by immersing them in xylene for 30 minutes (10 minutes x 3 times) and then in an ethanol gradient for 5 minutes (from high to low concentration, 100%-100%-95%-80%). The slides were then immersed in water (in a water bottle) for 10 minutes.

[0234] 2) The slides were washed three times with PBS for 3 minutes each time. 3) The slides were immersed in a citrate recovery buffer solution (pH 9.0) for 20 minutes once the temperature reached 95°C. The slide holder was removed and allowed to cool to room temperature.

[0235] 4) Wash the slides with PBS for 3 minutes, 3 minutes each time. 5) Remove the fluid from the slide using tissue paper, draw a circle around the tissue using an immunohistochemistry pen, and mark the edges with a pencil. Add an endogenous peroxidase blocker in moderation and incubate at room temperature for 10 minutes.

[0236] 6) Wash the slides with PBS for 3 minutes, 3 minutes each time. 7) Primary antibodies Iba1, CD68, and Aβ1-42 were diluted 1:6000, 1:150, and 1:500 in PBS (1.5% BSA + 0.5% Triton X-100) as needed, and 200 μL of each was added to the circles (one slide at a time to avoid drying the slides). The slides were then incubated overnight at 4°C.

[0237] 8) Remove the slide box and leave it at room temperature for 20 minutes. Wash the slides four times with PBS for 3 minutes each time. 9) The reaction enhancer was added and incubated at room temperature for 20 minutes.

[0238] 10) The slides were washed four times with PBS for 3 minutes each time. 11) Enzyme-labeled goat anti-rabbit IgG polymer was added and incubated at room temperature for 20 minutes.

[0239] 12) The slides were washed four times with PBS for 3 minutes each time. 13) Add 150 μL of DAB chromogenic reagent (mix 250 μL of concentrated DAB solvent + 5 mL of DAB substrate solution in the dark and keep fresh) to the slide until a brown color is visible to the naked eye, and allow the color to develop.

[0240] 14) Once a vivid brown color appears, quickly stop the reaction by immersing the slide in water, then rinse with water for 10 minutes. 15) After drying the slides by shaking them by hand, the slides were restained in hematoxylin dye solution for 30 seconds and rinsed with water for 5 minutes.

[0241] 16) After drying the slides by shaking them by hand, the slides were placed in hydrochloric acid alcohol and separated for 1 second. Then the slides were quickly removed and washed with water for 15 minutes. 17) After washing, the slides were placed in a gradient ethanol solution (from low to high concentrations of 80%-95%-95%-100%-100%-100% ether for 5 minutes each), and then dehydrated with xylene (5 minutes x 3 times).

[0242] 18) The slide was sealed in neutral balsam. • Immunofluorescence 1) The paraffin slides were dewaxed and hydrated by immersing them in xylene for 30 minutes (10 minutes x 3 times) and then in an ethanol gradient for 5 minutes (from high to low concentration, 100%-100%-95%-80%). The slides were then immersed in water (in a water bottle) for 10 minutes.

[0243] 2) The slides were washed three times with PBS for 3 minutes each time. 3) The slides were immersed in a citrate recovery buffer solution (pH 9.0) for 20 minutes once the temperature reached 95°C. The slide holder was removed and allowed to cool to room temperature.

[0244] 4) Wash the slides with PBS for 3 minutes, 3 minutes each time. 5) Remove the fluid from the slide using tissue paper, draw a circle around the tissue using an immunohistochemistry pen, and mark the edges with a pencil. Add an endogenous peroxidase blocker in moderation and incubate at room temperature for 10 minutes.

[0245] 6) Wash the slides with PBS for 3 minutes, 3 minutes each time. 7) If necessary, dilute the primary antibody Aβ1-42 to 1:500 with PBS (1.5% BSA + 0.5% Triton X-100), and add 200 μL of each to the circle (one slide at a time to avoid drying the slide). Then, incubate the slides overnight at 4°C.

[0246] 8) Remove the slide box and leave it at room temperature for 20 minutes. Wash the slides four times with PBS for 3 minutes each time. 9) The tissue was incubated with the secondary antibody F(ab')2-goat anti-rabbit HRP at a ratio of 1:1000 at room temperature for 1 hour.

[0247] 10) Wash the slides with PBS for 3 minutes each time. 11) The tissue was incubated with TSA570 at a 1:400 ratio, away from light, at room temperature for 1 hour.

[0248] 12) The slides were washed four times with PBS for 3 minutes each time. 13) The tissue was incubated with DAPI at a ratio of 1:5000 at room temperature for 10 minutes. 14) The slides were mounted using a colorfast mounting medium.

[0249] 4.Results Clinical observation During the experiment, the control group showed no abnormal clinical phenomena, while the model group exhibited signs of typical disease behaviors, including decreased exercise and weight, hunchbacked posture, and anorexia nervosa.

[0250] 1.1 Weight and Change Compared to the control group, the model group showed a significant decrease in body weight from day 1 to day 4 (***P<0.001). Compared to the model group, the treatment groups (A, B, C) did not show a clear improvement in body weight loss (Figure 1). Comparing with ###:G1, calculated with body weight on D-3 as 100%, unpaired t-test, p<0.001, n=8.

[0251] 1.2 Cytokine Analysis Compared to the control group, the model group showed a significant increase in plasma TNF-α levels (***p<0.001). Compared to the model group, the groups treated with compound B and compound C significantly inhibited plasma TNF-α levels in mice (*P<0.05), while the group treated with compound A showed a slight inhibitory trend, indicating that the treatments with compound B and compound C have better anti-inflammatory TNF-α inhibitory effects (Figure 2). ###: Compared with G1, unpaired t-test, p<0.001, n=8. *: Compared with G2, unpaired t-test, p<0.05, n=8.

[0252] 1.3 Immunohistochemical analysis Iba-1 is a commonly used microglia membrane marker. Increased Iba-1-positive areas in both the hippocampus and cortex of the model group compared to the control group indicated the development of neuroinflammation. Compared to the model group, compounds A and B showed a slight tendency to inhibit the increase of Iba-1 in the hippocampus, while compound C significantly inhibited the increase of Iba-1 in the hippocampus (Figure 3a). In the cortex, all three treatments showed a significant Iba-1 inhibitory effect compared to the model group (Figure 3b). These three compounds have a positive effect in improving neuroinflammation by inhibiting the increase of microglia, and compound C is shown to act in both the hippocampus and cortex.

[0253] CD68 is expressed at high levels on the membranes of activated microglia but at low levels on the membranes of remaining microglia. Increased CD68 expression in both the hippocampus and cortex of the model group indicated microglial activation in neuroinflammation, and all three treatments showed a significant inhibitory effect on microglial activation in the hippocampus (Figure 4a). Treatment with compound A also showed this effect in the cortex (Figure 4b).

[0254] Aβ1-42 is a marker used to measure microglial activation and neuronal loss in the mouse hippocampus and cortex. Increased Aβ1-42 expression in both the hippocampus and cortex of the model group compared to the control group indicated the development of neuroinflammation. Compared to the model group, compound A showed a slight inhibitory trend towards increasing Aβ1-42 in the hippocampus (Figure 5a). In the cortex, all three treatments showed a inhibitory trend towards increasing Aβ1-42 compared to the model group, while compound B significantly inhibited the increase in Aβ1-42 (Figure 5b). #: Compared to G1, unpaired t-test, p<0.05, n=8. ###: Compared to G1, unpaired t-test, p<0.001. *: Compared to G2, unpaired t-test, p<0.05. **: Compared to G2, unpaired t-test, p<0.01. N=8. Figure 6 shows the effects of compounds A, B, and C on Aβ1-42 in the frontal cortex as determined by immunofluorescence. Figure 7 shows the effects of compounds A, B, and C on TNF-α levels in the brain. Figure 8 shows the effects of compounds A, B, and C on TREM2 levels in the brain. Figure 9 shows the effects of compounds A, B, and C on SYK levels in the brain as determined by Western blotting. Figure 10 shows the effects of compounds A, B, and C on p-Zap-70 levels in the brain as determined by Western blotting. Figure 11 shows the effects of compounds A, B, and C on DAP12 levels in the brain as determined by Western blotting.

[0255]

[0153] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes that a person skilled in the art could conceive of should be included in the spirit and scope of this application and within the scope of the appended claims.

Claims

1. A method for treating a neuroinflammatory disease in a patient requiring treatment, the method comprising the step of administering to the patient a pharmaceutical composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein the structure of formula (I) is 【Chemistry 1】 And, In formula (I), 【Chemistry 2】 The substructure represented by 【Transformation 3】 And, The symbol --- represents a connection point. X １ ga = N-, -NR ８ -, -O-, or -S- X ２ is -N- or -CH-, X ３ is -O-, -S-, -NH-, -CH ２ - or -C(O)-, Y is a bond, -O-, -S-, -NR ７ -, -OCX ２ -, -(CH ２ ) ｚ２ W-, -C(O)O-, or -C(O)NH-, and W is a bond, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, n7, n8, and n12 are independent integers from 0 to 4. m1, m2, m5, m6, m7, m8, m12, v1, v2, v5, v6, v7, v8, and v12 are independently 1 or 2, L １ The bonds are -O-, -S-, -NR １Ｌ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R １Ｌ is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R １ Hydrogen, halogen, -CX １．１ ３ EN-CHX １．１ ２ ien-CH ２ X １．１ -CN, -SO ｎ１ R １Ａ , -SO ｖ１ NR １Ｂ R １Ｃ ,-NHNR １Ｂ R １Ｃ , -ONR １Ｂ R １Ｃ , -NHC(O)NHNR １Ｂ R １Ｃ , -NHC(O)NR １Ｂ R １Ｃ , -N(O) ｍ１ , -NR １Ｂ R １Ｃ , -C(O)R １Ｄ , -C(O)OR １Ｄ , -C(O)NR １Ｂ R １Ｃ , -OR １Ａ , -NR １Ｂ SO ２ R １Ａ , -NR １Ｂ C(O)R １Ｄ , -NR １Ｂ C(O)OR １Ｄ , -NR １Ｂ OR １Ｄ , -OCX １．１ ３ , -OCHX １．１ ２ , R １２ Substituted or unsubstituted alkyl, R １２ Substituted or unsubstituted heteroalkyl groups, R １２ Substituted or unsubstituted cycloalkyl, R １２ Substituted or unsubstituted heterocycloalkyl, R １２ Substitutable or unsubstituted aryl, or R １２ A substituted or unsubstituted heteroaryl, or at least one amino acid, R ２ Hydrogen, halogen, -CX ２．１ ３ EN-CHX ２．１ ２ ien-CH ２ X ２．１ -CN, -SO ｎ２ R ２Ａ , -SO ｖ２ NR ２Ｂ R ２Ｃ , -NR ２Ｂ R ２Ｃ , -C(O)R ２Ｄ , -C(O)OR ２Ｄ , -C(O)NR ２Ｂ R ２Ｃ , -OR ２Ａ , -OCX ２．１ ３ , -OCHX ２．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ３ and R ４ These are independently hydrogen or -F, R ５ is hydrogen, halogen, -CX ５．１ ３ , -CHX ５．１ ２ , -CH ２ X ５．１ , -CN, -N ３ , -SO ｎ５ R ５Ａ , -SO ｖ５ NR ５Ｂ R ５Ｃ , -NHNR ５Ｂ R ５Ｃ , -ONR ５Ｂ R ５Ｃ , -NH C(O)NHNR ５Ｂ R ５Ｃ , -NH C(O)NR ５Ｂ R ５Ｃ , -N(O) ｍ５ , -NR ５Ｂ R ５Ｃ , -C(O)R ５Ｄ , -C(O)OR ５Ｄ , -C(O)NR ５Ｂ R ５Ｃ , -OR ５Ａ , -NR ５Ｂ SO ２ R ５Ａ , -NR ５Ｂ C(O)R ５Ｄ , -NR ５Ｂ C(O)OR ５Ｄ , -NR ５Ｂ OR ５Ｄ , -OCX ５．１ ３ , -OCHX ５．１ ２ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ６ Hydrogen, halogen, -CX ６．１ ３ EN-CHX ６．１ ２ ien-CH ２ X ６．１ -CN, -N ３ , -SO ｎ６ R ６Ａ , -SO ｖ６ NR ６Ｂ R ６Ｃ ,-NHNR ６Ｂ R ６Ｃ , -ONR ６Ｂ R ６Ｃ , -NHC(O)NHNR ６Ｂ R ６Ｃ , -NHC(O)NR ６Ｂ R ６Ｃ , -N(O) ｍ６ , -NR ６Ｂ R ６Ｃ , -C(O)R ６Ｄ , -C(O)OR ６Ｄ , -C(O)NR ６Ｂ R ６Ｃ , -OR ６Ａ , -NR ６Ｂ SO ２ R ６Ａ , -NR ６Ｂ C(O)R ６Ｄ , -NR ６Ｂ C(O)OR ６Ｄ , -NR ６Ｂ OR ６Ｄ , -OCX ６．１ ３ , -OCHX ６．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ７ Hydrogen, halogen, -CX ７．１ ３ EN-CHX ７．１ ２ ien-CH ２ X ７．１ -CN, -SO ｎ７ R ７Ａ , -SO ｖ７ NR ７Ｂ R ７Ｃ , -NR ７Ｂ R ７Ｃ , -C(O)R ７Ｄ , -C(O)OR ７Ｄ , -C(O)NR ７Ｂ R ７Ｃ , -OR ７Ａ , -OCX ７．１ ３ , -OCHX ７．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ８ Hydrogen, halogen, -CX ８．１ ３ EN-CHX ８．１ ２ ien-CH ２ X ８．１ -CN, -SO ｎ８ R ８Ａ , -SO ｖ８ NR ８Ｂ R ８Ｃ , -NR ８Ｂ R ８Ｃ , -C(O)R ８Ｄ , -C(O)OR ８Ｄ , -C(O)NR ８Ｂ R ８Ｃ , -OR ８Ａ , -OCX ８．１ ３ , -OCHX ８．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R １２ Hydrogen, halogen, -CX １２．１ ３ EN-CHX １２．１ ２ ien-CH ２ X １２．１ -CN, -SO ｎ１２ R １２Ａ , -SO ｖ１２ NR １２Ｂ R １２Ｃ , -NR １２Ｂ R １２Ｃ , -C(O)R １２Ｄ , -C(O)OR １２Ｄ , -C(O)NR １２Ｂ R １２Ｃ , -OR １２Ａ , -OCX １２．１ ３ , -OCHX １２．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R １Ａ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ａ Substituted or unsubstituted alkyl, R １２Ａ Substituted or unsubstituted heteroalkyl groups, R １２Ａ Substituted or unsubstituted cycloalkyl, R １２Ａ Substituted or unsubstituted heterocycloalkyl, R １２Ａ Substitutable or unsubstituted aryl, or R １２Ａ It is a substituted or unsubstituted heteroaryl, R １Ｂ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｂ Substituted or unsubstituted alkyl, R １２Ｂ Substituted or unsubstituted heteroalkyl groups, R １２Ｂ Substituted or unsubstituted cycloalkyl, R １２Ｂ Substituted or unsubstituted heterocycloalkyl, R １２Ｂ Substitutable or unsubstituted aryl, or R １２Ｂ It is a substituted or unsubstituted heteroaryl, R １Ｃ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｃ Substituted or unsubstituted alkyl, R １２Ｃ Substituted or unsubstituted heteroalkyl groups, R １２Ｃ Substituted or unsubstituted cycloalkyl, R １２Ｃ Substituted or unsubstituted heterocycloalkyl, R １２Ｃ Substitutable or unsubstituted aryl, or R １２Ｃ R is either substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom. １Ｂ substituents and R １Ｃ The substituents may link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds. R １Ｄ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｄ Substituted or unsubstituted alkyl, R １２Ｄ Substituted or unsubstituted heteroalkyl groups, R １２Ｄ Substituted or unsubstituted cycloalkyl, R １２Ｄ Substituted or unsubstituted heterocycloalkyl, R １２Ｄ Substitutable or unsubstituted aryl, or R １２Ｄ It is a substituted or unsubstituted heteroaryl, R ２Ａ , R ２Ｂ , R ２Ｃ , R ２Ｄ , R ５Ａ , R ５Ｂ , R ５Ｃ , R ５Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , R ６Ｄ , R ７Ａ , R ７Ｂ , R ７Ｃ , R ７Ｄ , R ８Ａ , R ８Ｂ , R ８Ｃ , R ８Ｄ , R １２Ａ , R １２Ｂ , R １２Ｃ , and R １２Ｄ These independently produce hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom ２Ｂ substituents and R ２Ｃ substituents and R ５Ｂ substituents and R ５Ｃ substituents and R ６Ｂ substituents and R ６Ｃ substituents and R ７Ｂ substituents and R ７Ｃ substituents and R ８Ｂ substituents and R ８Ｃ With substituents, or R １２Ｂ substituents and R １２Ｃ The substituents may link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds. X, X １．１ , X ２．１ , X ５．１ , X ６．１ , X ７．１ , X ８．１ , and X １２．１ These are independently -Cl, -Br, -I, or -F, The structure of equation (II) 【Chemistry 4】 And, In formula (II), X １ and X ４ Independently, =N- or =CH-, X ５ ga = N- or -CR ５ - and X ６ ga = N- or -CR ６ - and Y is bonded, -O-, -S-, -NR ７ -, -OCX ２ -, - (CH ２ ) ｚ２ It is W-, -C(O)O-, or -C(O)NH-, W is a bond, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, and n7 are independent integers from 0 to 4. m1, m2, m5, m6, m7, v1, v2, v5, v6, and v7 are independently 1 or 2, L １ The bonds are -O-, -S-, -NR １Ｌ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R １Ｌ is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R １ Hydrogen, halogen, -CX １．１ ３ EN-CHX １．１ ２ ien-CH ２ X １．１ -CN, -SO ｎ１ R １Ａ , -SO ｖ１ NR １Ｂ R １Ｃ ,-NHNR １Ｂ R １Ｃ , -ONR １Ｂ R １Ｃ , -NHC(O)NHNR １Ｂ R １Ｃ , -NHC(O)NR １Ｂ R １Ｃ , -N(O) ｍ１ , -NR １Ｂ R １Ｃ , -C(O)R １Ｄ , -C(O)OR １Ｄ , -C(O)NR １Ｂ R １Ｃ , -OR １Ａ , -NR １Ｂ SO ２ R １Ａ , -NR １Ｂ C(O)R １Ｄ , -NR １Ｂ C(O)OR １Ｄ , -NR １Ｂ OR １Ｄ , -OCX １．１ ３ , -OCHX １．１ ２ , R １２ Substituted or unsubstituted alkyl, R １２ Substituted or unsubstituted heteroalkyl groups, R １２ Substituted or unsubstituted cycloalkyl, R １２ Substituted or unsubstituted heterocycloalkyl, R １２ Substitutable or unsubstituted aryl, or R １２ A substituted or unsubstituted heteroaryl, or at least one amino acid, R ２ Hydrogen, halogen, -CX ２．１ ３ EN-CHX ２．１ ２ ien-CH ２ X ２．１ -CN, -SO ｎ２ R ２Ａ , -SO ｖ２ NR ２Ｂ R ２Ｃ , -NR ２Ｂ R ２Ｃ , -C(O)R ２Ｄ , -C(O)OR ２Ｄ , -C(O)NR ２Ｂ R ２Ｃ , -OR ２Ａ , -OCX ２．１ ３ , -OCHX ２．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ３ and R ４ These are independently hydrogen or -F, R ５ Hydrogen, halogen, -CX ５．１ ３ EN-CHX ５．１ ２ ien-CH ２ X ５．１ -CN, -N ３ , -SO ｎ５ R ５Ａ , -SO ｖ５ NR ５Ｂ R ５Ｃ ,-NHNR ５Ｂ R ５Ｃ , -ONR ５Ｂ R ５Ｃ , -NHC(O)NHNR ５Ｂ R ５Ｃ , -NHC(O)NR ５Ｂ R ５Ｃ , -N(O) ｍ５ , -NR ５Ｂ R ５Ｃ , -C(O)R ５Ｄ , -C(O)OR ５Ｄ , -C(O)NR ５Ｂ R ５Ｃ , -OR ５Ａ , -NR ５Ｂ SO ２ R ５Ａ , -NR ５Ｂ C(O)R ５Ｄ , -NR ５Ｂ C(O)OR ５Ｄ , -NR ５Ｂ OR ５Ｄ , -OCX ５．１ ３ , -OCHX ５．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ６ Hydrogen, halogen, -CX ６．１ ３ EN-CHX ６．１ ２ ien-CH ２ X ６．１ -CN, -N ３ , -SO ｎ６ R ６Ａ , -SO ｖ６ NR ６Ｂ R ６Ｃ ,-NHNR ６Ｂ R ６Ｃ , -ONR ６Ｂ R ６Ｃ , -NHC(O)NHNR ６Ｂ R ６Ｃ , -NHC(O)NR ６Ｂ R ６Ｃ , -N(O) ｍ６ , -NR ６Ｂ R ６Ｃ , -C(O)R ６Ｄ , -C(O)OR ６Ｄ , -C(O)NR ６Ｂ R ６Ｃ , -OR ６Ａ , -NR ６Ｂ SO ２ R ６Ａ , -NR ６Ｂ C(O)R ６Ｄ , -NR ６Ｂ C(O)OR ６Ｄ , -NR ６Ｂ OR ６Ｄ , -OCX ６．１ ３ , -OCHX ６．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ７ Hydrogen, halogen, -CX ７．１ ３ EN-CHX ７．１ ２ ien-CH ２ X ７．１ -CN, -SO ｎ７ R ７Ａ , -SO ｖ７ NR ７Ｂ R ７Ｃ , -NR ７Ｂ R ７Ｃ , -C(O)R ７Ｄ , -C(O)OR ７Ｄ , -C(O)NR ７Ｂ R ７Ｃ , -OR ７Ａ , -OCX ７．１ ３ , -OCHX ７．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R １２ Hydrogen, halogen, -CX １２．１ ３ EN-CHX １２．１ ２ ien-CH ２ X １２．１ -CN, -SO ｎ１２ R １２Ａ , -SO ｖ１２ NR １２Ｂ R １２Ｃ , -NR １２Ｂ R １２Ｃ , -C(O)R １２Ｄ , -C(O)OR １２Ｄ , -C(O)NR １２Ｂ R １２Ｃ , -OR １２Ａ , -OCX １２．１ ３ , -OCHX １２．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R １Ａ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ａ Substituted or unsubstituted alkyl, R １２Ａ Substituted or unsubstituted heteroalkyl groups, R １２Ａ Substituted or unsubstituted cycloalkyl, R １２Ａ Substituted or unsubstituted heterocycloalkyl, R １２Ａ Substitutable or unsubstituted aryl, or R １２Ａ It is a substituted or unsubstituted heteroaryl, R １Ｂ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｂ Substituted or unsubstituted alkyl, R １２Ｂ Substituted or unsubstituted heteroalkyl groups, R １２Ｂ Substituted or unsubstituted cycloalkyl, R １２Ｂ Substituted or unsubstituted heterocycloalkyl, R １２Ｂ Substitutable or unsubstituted aryl, or R １２Ｂ It is a substituted or unsubstituted heteroaryl, R １Ｃ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｃ Substituted or unsubstituted alkyl, R １２Ｃ Substituted or unsubstituted heteroalkyl groups, R １２Ｃ Substituted or unsubstituted cycloalkyl, R １２Ｃ Substituted or unsubstituted heterocycloalkyl, R １２Ｃ Substitutable or unsubstituted aryl, or R １２Ｃ R is either substituted or unsubstituted heteroaryl, or bonded to the same nitrogen atom. １Ｂ substituents and R １Ｃ The substituents may link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds. R １Ｄ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｄ Substituted or unsubstituted alkyl, R １２Ｄ Substituted or unsubstituted heteroalkyl groups, R １２Ｄ Substituted or unsubstituted cycloalkyl, R １２Ｄ Substituted or unsubstituted heterocycloalkyl, R １２Ｄ Substitutable or unsubstituted aryl, or R １２Ｄ It is a substituted or unsubstituted heteroaryl, R ２Ａ , R ２Ｂ , R ２Ｃ , R ２Ｄ , R ５Ａ , R ５Ｂ , R ５Ｃ , R ５Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , R ６Ｄ , R ７Ａ , R ７Ｂ , R ７Ｃ , R ７Ｄ , R １２Ａ , R １２Ｂ , R １２Ｃ , and R １２Ｄ These independently produce hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom ２Ｂ substituents and R ２Ｃ substituents and R ５Ｂ substituents and R ５Ｃ substituents and R ６Ｂ substituents and R ６Ｃ substituents and R ７Ｂ substituents and R ７Ｃ substituents and R ８Ｂ substituents and R ８Ｃ With substituents, or R １２Ｂ substituents and R １２Ｃ The substituents may link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds, X, X １．１ , X ２．１ , X ５．１ , X ６．１ , X ７．１ , and X １２．１ These are independently -Cl, -Br, -I, or -F. method.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof has the following structure: 【Transformation 5】 The method according to claim 1, comprising:

3. The compound of formula (II) or a pharmaceutically acceptable salt thereof has the following structure: 【Transformation 6】 The method according to claim 1, comprising:

4. The compound of formula (I-A) or a pharmaceutically acceptable salt thereof has the following structure: 【Transformation 7】 The method according to claim 1 or 2, comprising:

5. The method according to any one of claims 1, 2, or 4, wherein the pharmaceutical composition comprises a compound having the structure of a compound provided in Table 1 or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 or 3, wherein the pharmaceutical composition comprises a compound having the structure of a compound provided in Table 2 or a pharmaceutically acceptable salt thereof.

7. The method according to any one of claims 1, 2, 4, or 5, wherein the pharmaceutical composition comprises a compound having the structure of a compound provided in Table 3 or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1, wherein the neuroinflammatory disease is selected from Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), traumatic brain injury (TBI), complex regional pain syndrome (CRPS), optic neuritis (ON), neuromyelitis optica (NMO), chronic traumatic encephalopathy (CTE), ischemic stroke (IS), vascular dementia (VAD), anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD), transverse myelitis (TM), autoimmune encephalitis (AE), acute disseminated encephalomyelitis (ADEM), chronic meningitis (CM), central nervous system vasculitis (CNS), Hashimoto's encephalitis (HE), neurosarcoidosis (NS), multiple system atrophy (MSA), migraine, chemotherapy-induced pain, or dementia-related pain.

9. The method according to claim 1, wherein the neuroinflammatory disease is Alzheimer's disease.

10. The method according to claim 1, wherein the neuroinflammatory disease is Parkinson's disease.

11. The method according to claim 1, wherein the neuroinflammatory disease is amyotrophic lateral sclerosis (ALS).

12. The method according to claim 1, wherein the neuroinflammatory disease is multiple sclerosis (MS).

13. The method according to claim 1, wherein the neuroinflammatory disease is traumatic brain injury (TBI).

14. The method according to claim 1, wherein the neuroinflammatory disease is complex regional pain syndrome (CRPS).

15. The method according to claim 1, wherein the neuroinflammatory disease is optic neuritis.

16. The method according to claim 1, wherein the neuroinflammatory disease is neuromyelitis optica.

17. The method according to claim 1, wherein the neuroinflammatory disease is chronic traumatic encephalopathy (CTE).

18. The method according to claim 1, wherein the neuroinflammatory disease is ischemic cerebral infarction.

19. The method according to claim 1, wherein the neuroinflammatory disease is vascular dementia (VAD).

20. The method according to claim 1, wherein the neuroinflammatory disease is anti-myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

21. The method according to claim 1, wherein the neuroinflammatory disease is transverse myelitis (TM).

22. The method according to claim 1, wherein the neuroinflammatory disease is autoimmune encephalitis (AE).

23. The method according to claim 1, wherein the neuroinflammatory disease is acute disseminated encephalomyelitis (ADEM).

24. The method according to claim 1, wherein the neuroinflammatory disease is chronic meningitis (CM).

25. The method according to claim 1, wherein the neuroinflammatory disease is central nervous system (CNS) vasculitis.

26. The method according to claim 1, wherein the neuroinflammatory disease is Hashimoto's encephalitis (HE).

27. The method according to claim 1, wherein the neuroinflammatory disease is neurosarcoidosis (NS).

28. The method according to claim 1, wherein the neuroinflammatory disease is multiple system atrophy (MSA).

29. The method according to claim 1, wherein the neuroinflammatory disease is migraine.

30. The method according to claim 1, wherein the neuroinflammatory disease is chemotherapy-induced pain.

31. The method according to claim 1, wherein the neuroinflammatory disease is dementia-related pain.

32. The method according to any one of claims 8 to 31, wherein the pharmaceutical composition comprises a compound having the structure of a compound provided in Table 3 or a pharmaceutically acceptable salt thereof.

33. The method according to any one of claims 8 to 31, wherein the pharmaceutical composition comprises a compound having the structure of (Z)-6-((2-(aminomethyl)-3-fluoroallyl)oxy)-N-((2-methoxypyridine-4-yl)methyl)benzo[d]oxazole-2-amine or a pharmaceutically acceptable salt thereof.

34. The method according to any one of claims 8 to 31, wherein the pharmaceutical composition comprises a compound having the structure (Z)-6-((2-(aminomethyl)-3-fluoroallyl)oxy)-N-((6-methoxypyridine-3-yl)methyl)benzo[d]oxazole-2-amine or a pharmaceutically acceptable salt thereof.

35. The method according to any one of claims 8 to 31, wherein the pharmaceutical composition comprises a compound having the structure of (Z)-3-fluoro-2-(((2-morpholinobenzo[d]oxazole-6-yl)oxy)methyl)propa-2-en-1-amine or a pharmaceutically acceptable salt thereof.

36. The method according to any one of claims 8 to 31, wherein the pharmaceutical composition comprises a compound having the structure of a compound provided in Table 1 or a pharmaceutically acceptable salt thereof.

37. The method according to any one of claims 8 to 31, wherein the pharmaceutical composition comprises a compound having the structure of a compound provided in Table 2 or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition 【Chemistry 8-1】 【Chemistry 8-2】 【Chemistry 8-3】 【Chemistry 8-4】 【Chemistry 8-5】 The method according to any one of claims 8 to 31, comprising a compound having the structure of a compound selected from or an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; or a pharmaceutically acceptable salt thereof.

39. The compound of formula (I) is formula (III-A): 【Chemistry 9】 (In the formula, X １ ga-NR ８ -, -O-, or -S- Y is -O-, W is a bond, -O-, -S-, or -NH-, z1 and z2 are independent integers between 0 and 3. n1, n2, n5, n6, n7, n8, and n12 are independent integers from 0 to 4. m1, m2, m5, m6, m7, m8, m12, v1, v2, v5, v6, v7, v8, and v12 are independently 1 or 2, L １ The bonds are -O-, -S-, -NR １Ｌ -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, R １Ｌ is hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. R １ Hydrogen, halogen, -CX １．１ ３ EN-CHX １．１ ２ ien-CH ２ X １．１ -CN, -SO ｎ１ R １Ａ , -SO ｖ１ NR １Ｂ R １Ｃ ,-NHNR １Ｂ R １Ｃ , -ONR １Ｂ R １Ｃ , -NHC(O)NHNR １Ｂ R １Ｃ , -NHC(O)NR １Ｂ R １Ｃ , -N(O) ｍ１ , -NR １Ｂ R １Ｃ , -C(O)R １Ｄ , -C(O)OR １Ｄ , -C(O)NR １Ｂ R １Ｃ , -OR １Ａ , -NR １Ｂ SO ２ R １Ａ , -NR １Ｂ C(O)R １Ｄ , -NR １Ｂ C(O)OR １Ｄ , -NR １Ｂ OR １Ｄ , -OCX １．１ ３ , -OCHX １．１ ２ , R １２ Substituted or unsubstituted alkyl, R １２ Substituted or unsubstituted heteroalkyl groups, R １２ Substituted or unsubstituted cycloalkyl, R １２ Substituted or unsubstituted heterocycloalkyl, R １２ Substitutable or unsubstituted aryl, or R １２ A substituted or unsubstituted heteroaryl, or at least one amino acid, R ２ Hydrogen, halogen, -CX ２．１ ３ EN-CHX ２．１ ２ ien-CH ２ X ２．１ -CN, -SO ｎ２ R ２Ａ , -SO ｖ２ NR ２Ｂ R ２Ｃ , -NR ２Ｂ R ２Ｃ , -C(O)R ２Ｄ , -C(O)OR ２Ｄ , -C(O)NR ２Ｂ R ２Ｃ , -OR ２Ａ , -OCX ２．１ ３ , -OCHX ２．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ３ and R ４ These are independently hydrogen or -F, R ５ Hydrogen, halogen, -CX ５．１ ３ EN-CHX ５．１ ２ ien-CH ２ X ５．１ -CN, -N ３ , -SO ｎ５ R ５Ａ , -SO ｖ５ NR ５Ｂ R ５Ｃ ,-NHNR ５Ｂ R ５Ｃ , -ONR ５Ｂ R ５Ｃ , -NHC(O)NHNR ５Ｂ R ５Ｃ , -NHC(O)NR ５Ｂ R ５Ｃ , -N(O) ｍ５ , -NR ５Ｂ R ５Ｃ , -C(O)R ５Ｄ , -C(O)OR ５Ｄ , -C(O)NR ５Ｂ R ５Ｃ , -OR ５Ａ , -NR ５Ｂ SO ２ R ５Ａ , -NR ５Ｂ C(O)R ５Ｄ , -NR ５Ｂ C(O)OR ５Ｄ , -NR ５Ｂ OR ５Ｄ , -OCX ５．１ ３ , -OCHX ５．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ６ Hydrogen, halogen, -CX ６．１ ３ EN-CHX ６．１ ２ ien-CH ２ X ６．１ -CN, -N ３ , -SO ｎ６ R ６Ａ , -SO ｖ６ NR ６Ｂ R ６Ｃ ,-NHNR ６Ｂ R ６Ｃ , -ONR ６Ｂ R ６Ｃ , -NHC(O)NHNR ６Ｂ R ６Ｃ , -NHC(O)NR ６Ｂ R ６Ｃ , -N(O) ｍ６ , -NR ６Ｂ R ６Ｃ , -C(O)R ６Ｄ , -C(O)OR ６Ｄ , -C(O)NR ６Ｂ R ６Ｃ , -OR ６Ａ , -NR ６Ｂ SO ２ R ６Ａ , -NR ６Ｂ C(O)R ６Ｄ , -NR ６Ｂ C(O)OR ６Ｄ , -NR ６Ｂ OR ６Ｄ , -OCX ６．１ ３ , -OCHX ６．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ７ Hydrogen, halogen, -CX ７．１ ３ EN-CHX ７．１ ２ ien-CH ２ X ７．１ -CN, -SO ｎ７ R ７Ａ , -SO ｖ７ NR ７Ｂ R ７Ｃ , -NR ７Ｂ R ７Ｃ , -C(O)R ７Ｄ , -C(O)OR ７Ｄ , -C(O)NR ７Ｂ R ７Ｃ , -OR ７Ａ , -OCX ７．１ ３ , -OCHX ７．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R ８ Hydrogen, halogen, -CX ８．１ ３ EN-CHX ８．１ ２ ien-CH ２ X ８．１ -CN, -SO ｎ８ R ８Ａ , -SO ｖ８ NR ８Ｂ R ８Ｃ , -NR ８Ｂ R ８Ｃ , -C(O)R ８Ｄ , -C(O)OR ８Ｄ , -C(O)NR ８Ｂ R ８Ｃ , -OR ８Ａ , -OCX ８．１ ３ , -OCHX ８．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R １２ Hydrogen, halogen, -CX １２．１ ３ EN-CHX １２．１ ２ ien-CH ２ X １２．１ -CN, -SO ｎ１２ R １２Ａ , -SO ｖ１２ NR １２Ｂ R １２Ｃ , -NR １２Ｂ R １２Ｃ , -C(O)R １２Ｄ , -C(O)OR １２Ｄ , -C(O)NR １２Ｂ R １２Ｃ , -OR １２Ａ , -OCX １２．１ ３ , -OCHX １２．１ ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, R １Ａ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ａ Substituted or unsubstituted alkyl, R １２Ａ Substituted or unsubstituted heteroalkyl groups, R １２Ａ Substituted or unsubstituted cycloalkyl, R １２Ａ Substituted or unsubstituted heterocycloalkyl, R １２Ａ Substitutable or unsubstituted aryl, or R １２Ａ It is a substituted or unsubstituted heteroaryl, R １Ｂ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｂ Substituted or unsubstituted alkyl, R １２Ｂ Substituted or unsubstituted heteroalkyl groups, R １２Ｂ Substituted or unsubstituted cycloalkyl, R １２Ｂ Substituted or unsubstituted heterocycloalkyl, R １２Ｂ Substitutable or unsubstituted aryl, or R １２Ｂ It is a substituted or unsubstituted heteroaryl, R １Ｃ is hydrogen, halogen, -CF ３ , -CCl ３ , -CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｃ substituted or unsubstituted alkyl, R １２Ｃ substituted or unsubstituted heteroalkyl, R １２Ｃ substituted or unsubstituted cycloalkyl, R １２Ｃ substituted or unsubstituted heterocycloalkyl, R １２Ｃ substituted or unsubstituted aryl, or R １２Ｃ substituted or unsubstituted heteroaryl, or the R １Ｂ substituent and the R １Ｃ substituent may be linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl, R １Ｄ Hydrogen, halogen, -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , R １２Ｃ Substituted or unsubstituted alkyl, R １２Ｄ Substituted or unsubstituted heteroalkyl groups, R １２Ｄ Substituted or unsubstituted cycloalkyl, R １２Ｄ Substituted or unsubstituted heterocycloalkyl, R １２Ｄ Substitutable or unsubstituted aryl, or R １２Ｄ It is a substituted or unsubstituted heteroaryl, R ２Ａ , R ２Ｂ , R ２Ｃ , R ２Ｄ , R ５Ａ , R ５Ｂ , R ５Ｃ , R ５Ｄ , R ６Ａ , R ６Ｂ , R ６Ｃ , R ６Ｄ , R ７Ａ , R ７Ｂ , R ７Ｃ , R ７Ｄ , R ８Ａ , R ８Ｂ , R ８Ｃ , R ８Ｄ , R １２Ａ , R １２Ｂ , R １２Ｃ , and R １２Ｄ These independently produce hydrogen, halogen, and -CF ３ , -CCl ３ , - CBr ３ , -CI ３ , -COOH, -CONH ２ , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R bonded to the same nitrogen atom ２Ｂ substituents and R ２Ｃ substituents and R ５Ｂ substituents and R ５Ｃ substituents and R ６Ｂ substituents and R ６Ｃ substituents and R ７Ｂ substituents and R ７Ｃ substituents and R ８Ｂ substituents and R ８Ｃ With substituents, or R １２Ｂ substituents and R １２Ｃ The substituents may link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl compounds. X, X １．１ , X ２．１ , X ５．１ , X ６．１ , X ７．１ , X ８．１ , and X １２．１ is independently -Cl, -Br, -I, or -F) The method according to any one of claims 1 or 8 to 31, having the structure of an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

40. Structural formula (III-B): 【Chemistry 10】 or its alkene isomers, tautomers, or isotopic variants; or having pharmaceutically acceptable salts, solvates, or hydrates thereof, wherein X １ ga-NR ８ The compound according to claim 39, wherein it is -, -O-, or -S-.

41. Structural formula (III-C): 【Chemistry 11】 or its alkene isomers, tautomers, or isotopic variants; or having pharmaceutically acceptable salts, solvates, or hydrates thereof, wherein X １ ga-NR ８ The compound according to claim 39, wherein it is -, -O-, or -S-.

42. X １ The compound according to claim 39, wherein is -O-, or an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

43. The compound according to claim 39, or an alkene isomer, tautomer, or isotopic variant thereof, wherein z1 is 1; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

44. R ５ and R ６ These independently form hydrogen, -F, -Br, or -CH ３ The compound according to claim 39, or its alkene isomer, tautomer, or isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

45. R ３ ga-F de R ４ is hydrogen Compounds and R ３ is hydrogen R ４ is -F The compound according to claim 39, including a mixture with the compound, or its alkene isomers, tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, or hydrates thereof.

46. The compound according to claim 39, comprising a mixture of (E)- and (Z)-alkene isomers, or its alkene isomers, tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, or hydrates thereof.

47. R ２ The compound according to claim 39, wherein is hydrogen; or an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

48. L １ is combined, -NR １Ｌ - A compound according to claim 39, which is a substituted or unsubstituted alkylene, a substituted or unsubstituted heteroalkylene, a substituted or unsubstituted cycloalkylene, or a substituted or unsubstituted heterocycloalkylene; or an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

49. R １ ga-NR １Ｂ R １Ｃ , -C(O)NR １Ｂ R １Ｃ , -OR １Ａ , R １２ Substituted or unsubstituted alkyl, R １２ Substituted or unsubstituted heteroalkyl groups, R １２ Substituted or unsubstituted cycloalkyl, R １２ Substituted or unsubstituted heterocycloalkyl, R １２ Substitutable or unsubstituted aryl, or R １２ The compound according to claim 39, which is a substituted or unsubstituted heteroaryl, or an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

50. R １ R １２ Substitute or non-substitute C １ -C ６ The compound according to claim 39, which is alkyl, or an alkene isomer, tautomer, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

51. R １ が-(CH ２ ) ３ CH ３ 、-C(CH ３ ) ３ 、 【Chemistry 12】 The compound according to claim 39, or its alkene isomer, tautomer, or isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

52. R １ ga-NR １Ｂ R １Ｃ The compound according to claim 39, or its alkene isomer, tautomer, or isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

53. R １Ｂ is hydrogen, R １２Ｂ Substituted or unsubstituted alkyl, R １２Ｂ Substituted or unsubstituted heteroalkyl groups, R １２Ｂ Substituted or unsubstituted cycloalkyl, R １２Ｂ Substituted or unsubstituted heterocycloalkyl, R １２Ｂ Substitutable or unsubstituted aryl, or R １２Ｂ It is a substituted or unsubstituted heteroaryl, R １Ｃ is hydrogen, R １２Ｃ Substituted or unsubstituted alkyl, R １２Ｃ Substituted or unsubstituted heteroalkyl groups, R １２Ｃ Substituted or unsubstituted cycloalkyl, R １２Ｃ Substituted or unsubstituted heterocycloalkyl, R １２Ｃ Substitutable or unsubstituted aryl, or R １２Ｃ Whether it is a substituted or unsubstituted heteroaryl, Or R bonded to the same nitrogen atom １Ｂ substituents and R １Ｃ The substituents may link to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl groups. The compound described in claim 39, or its alkene isomer, tautomer, or isotopic variant; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

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