2-azabicyclo[2.1.1]hexane derivatives suitable for the treatment of mitochondrial diseases

Abstract

This invention relates to compounds of formula (1): (1) or their salts or tautomers; wherein: R 1 C(O)OR a ;R a Selected from hydrogen, optionally substituted methyl or C 2‑12 Hydrocarbon group and radical A-B-Cyc; A is selected from bond and C 1‑6 Alkylene linking group; B is absent, represented by -C(O)NR. D - or -NR D C(O)−, condition: B does not exist when A is a bond; R D Selected from hydrogen and C 1‑4 Hydrocarbon group; Cyc is an optionally substituted 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group R. 2 Selected from hydrogen, or optionally substituted C 1‑4 Hydrocarbon group and optionally substituted 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group; R 3 and R 4 One of them is selected from hydrogen and optionally substituted C. 1‑4 hydrocarbon group; and R 3 and R 4 The other component is hydrogen. The compound enhances mitochondrial function; therefore, the present invention also provides pharmaceutical compositions containing the compound and therapeutic uses of the compound, particularly in diseases caused by or affected by mitochondrial dysfunction.

Description

Technical Field

[0001] This invention relates to compounds that enhance mitochondrial function, pharmaceutical compositions containing said compounds, and the therapeutic use of said compounds, particularly in the treatment of diseases caused by or affected by mitochondrial dysfunction. Background Technology

[0002] Mitochondria are complex intracellular organelles that play a crucial role in cellular homeostasis. Mitochondria, responsible for coordinating cellular energy production, are essential for sustaining life [Osellame 2012]. Chemical energy is produced by mitochondria through oxidative phosphorylation (OXPHOS) and stored as adenosine triphosphate (ATP). ATP is produced by mitochondria through a variety of chemical reactions collectively known as the Krebs cycle, or tricarboxylic acid (TCA) cycle. This complex set of cellular reactions is driven by the proton gradient across the inner mitochondrial membrane [Papa 2012]. In addition to supplying energy, mitochondria are involved in a variety of other processes, such as cell signaling, calcium regulation, cell differentiation, and cell death regulation [Finkel et al., Circulation Research. 2015;116:1810-1819; McBride 2006].

[0003] Oxidative phosphorylation (OXPHOS) is a metabolic pathway responsible for producing most of the cell's energy. The human mitochondrial genome contains the genetic code for 13 proteins, all of which encode essential components of OXPHOS. The OXPHOS system consists of five multi-protein complexes, individual subunits of which are encoded by the mitochondrial or nuclear genome [Smeitink 2001]. This complex series of biochemical reactions converts the transmembrane electrochemical proton gradient energy into mechanical energy via ATP synthase, ultimately catalyzing the chemical bond between ADP and phosphate (P) to form ATP [Friedman 2014].

[0004] Free radicals generated during ATP synthesis can cause DNA damage, making mitochondrial DNA more susceptible to damage than DNA in other cells. Mitochondria lack all the protective mechanisms responsible for preventing DNA damage found in other cellular systems. Furthermore, gene mutations can lead to reduced mitochondrial production. All these factors contribute to decreased mitochondrial activity. Mitochondrial abnormalities, characterized by decreased mitochondrial function and the accumulation of damaged mitochondria, have been observed in various cell types and tissues. Some diseases may be caused by mutations or deletions in the mitochondrial genome, while others may be caused by disorders of the mitochondrial respiratory system or other mitochondrial functional impairments [Wallace 1999]. In patients with mtDNA mutations, genetic and clinical manifestations are further complicated by the presence of multiple mtDNA genomes in individual cells, resulting in a mixture of mutant and wild-type genomes (heterogeneity) in the same cell or tissue [Stewart 2015].

[0005] Mitochondrial disorders are common genetic disorders of energy metabolism, affecting approximately one in 5,000 people. These disorders are typically incurable and exhibit genetic and clinical heterogeneity [DiMauro 2008]. This heterogeneous group of disorders can manifest as encephalopathy, myopathy, or multiple organ syndrome in children or adults. The disorders are characterized by insufficient activity of one or more mitochondrial respiratory chain (RC) complexes involved in OXPHOS [complexes I (CI) to V] and / or reduced levels of OXPHOS complex homeostasis, leading to decreased ATP production [Nsiah-Sefaa 2016]. The disorders are most commonly caused by genetic mutations in the mitochondrial or nuclear genome, exhibiting clinical heterogeneity and phenotypic diversity, all of which involve OXPHOS deficiency and impaired ATP synthesis. Furthermore, the presence of mtDNA in all human tissues implies dysfunction in multiple organ systems. The most commonly affected organ systems are the nervous, muscular, cardiac, and endocrine systems. Regardless of phenotypic presentation, all mitochondrial disorders can be considered defects in energy metabolism and cellular function [Schaefer 2004].

[0006] Mitochondrial myopathy is a clinically heterogeneous disease that can affect multiple systems beyond skeletal muscle, and it is usually defined by morphological abnormalities of muscle mitochondria. These represent the largest subset of primary mitochondrial diseases, making them the most common congenital metabolic disorders [DiMauro 2008]. Mitochondrial myopathy associated with mitochondrial export dysfunction has been identified in several ways, including: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode (MELAS), one of the most common maternally inherited mitochondrial diseases [Lin 2014]; myoclonic epilepsy and ragged-red fibers (MERRF), in which 80-90% of patients carry mutations in the tRNALys gene in mtDNA, leading to low ATP production efficiency [Wu 2010]; and mitochondrial DNA-associated Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), which are part of a series of progressive neurodegenerative diseases caused by abnormal mitochondrial energy production [Thorburn 2017]. Lechner syndrome is a devastating neurodegenerative disease characterized by multiple pathogenic mutations in mitochondrial and nuclear genes encoding OXPHOS components [Baertling 2014]; mitochondrial dysfunction in fatty acid oxidation disorders (such as long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)) [Olpin 2005, Wajner 2016]; Maple syrup urine disease (MSUD) is a congenital metabolic disorder that leads to the accumulation of DNA damage and corresponding mitochondrial dysfunction [Strand 2014]; Luft disease is clinically characterized by hypermetabolism and is caused by extensive uncoupling of mitochondrial respiration in skeletal muscle tissue [Luft 1994]; Chronic progressive external ophthalmoplegia (CPEO), also known as progressive external ophthalmoplegia (PEO), is a disease characterized by slow, progressive paralysis of the external ophthalmoscopy muscles [Luft 1994, [Man 2005]; Charcot-Marie-Tooth disease type 2;CMT2), in which mutations in the mitochondrial fusion protein 2 gene (MFN2) may account for at least one-third of cases, and reduced oxidative phosphorylation efficiency in MFN2-associated CMT2 may contribute to the pathophysiology of axonal neuropathy [Züchner 2004, Loiseau 2007]; Leber hereditary optic neuropathy (LHON), a primary mtDNA disorder characterized by vision loss in young adults [Luft 1994]; hereditary conditions such as Kearns-Sayre syndrome (KSS) [Pieczenik 2007], myoneurogenic gastrointestinal encephalopathy (MNGIE) [Pieczenik 2007], and Barth syndrome (an X-linked cardiomyopathy caused by mutations in tafazzin) [Gonzalvez].

[2013] , all are related to mitochondrial dysfunction. Furthermore, mitochondrial DNA depletion syndrome (MDS) is a group of genetically and clinically heterogeneous autosomal recessive disorders characterized by a significant reduction in mtDNA content, leading to impaired energy production in affected tissues and organs. These disorders include TK2-related disorders and POLG-related disorders [El-Hattab 2013].

[0007] In addition, mitochondrial mutations are associated with mitochondrial dysfunction in the following areas: maternally inherited epilepsy / mitochondrial tubulointerstitial kidney disease (MITKD) [Connor 2017]; mitochondrial deafness (DEAF) [Kototas 2007]; ataxia, myoclonus, and deafness (AMDF) [Park 2014]; hypertrophic cardiomyopathy (HCM) [Lucas 2003]; diabetes mellitus with deafness (DMDF) [Hutchin 200]; maternally inherited diabetes mellitus with deafness (MIDD) [Tsang 2018]; mitochondrial syndrome-related sensorineural hearing loss (SNHL) [Forli 2007]; focal segmental glomerulosclerosis associated with mitochondrial disease (FSGS) [Lim 2017]; autism spectrum disorder (ASD)

[2012] ; and progressive encephalopathy (PEM) [Kollberg].

[2006] ; Bilateral striatal necrosis (BSN) [Solano 2003]; Leber's hereditary optic neuropathy and dystonia (LDYT)

[2021] ; Maternally inherited cardiomyopathy (MICM) [Casali 1999]; Motor neuron disease (MND)

[2020] ; Myoclonic epilepsy / spasmodic epilepsy [Lamperti 2016]; Mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA)

[2014] ; Familial bilateral striatal necrosis (FBSN) [Thyagarajan 1995]; Epilepsy, stroke, optic atrophy and cognitive decline (Epilepsy, stroke, optatrophy, and cognitive decline; ESOC)

[2001] .

[0008] Mitochondrial dysfunction is not only a hallmark of rare, inherited mitochondrial disorders, but it is also associated with age-related diseases, including neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease [Johri 2021]; metabolic disorders such as type 2 diabetes [Lowell 2005]; steatosis and non-alcoholic steatohepatitis (NASH) [Begriche 2006]; and obesity [Bournat 2010]. Furthermore, heart diseases (such as ischemia-reperfusion, ischemic preconditioning, cardiomyopathy, and heart failure) [Lesnefsky 2001], as well as muscular dystrophy [Ryu 2016] and aging [Cui 2012] are all associated with mitochondrial dysfunction.

[0009] Cellular energy deficiency caused by mitochondrial dysfunction is a hallmark of mitochondrial diseases. This increases the likelihood of pharmacologically increasing cellular mitochondrial content to enhance mitochondrial ATP production, as occurs in motor responses [Komen 2014]. A potential therapeutic approach to overcome impaired mitochondrial biogenesis is to effectively promote mitochondrial biogenesis through pharmacological means to compensate for OXPHOS deficiencies associated with mitochondrial respiratory dysfunction, thereby enriching the wild-type mitochondrial population [Wenz 2010, Moraes 2009]. Therefore, strategies aimed at improving mitochondrial function may provide an effective therapy for patients with mitochondrial diseases. It has been demonstrated that pharmacological stimulation of several proteins can improve mitochondrial biogenesis and function, such as pharmacological activation of transcriptional coactivator (peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)) [Sandoval-Acuna 2014]; agonist activation of a combination of peroxisome proliferator-activated receptor (PPAR) and deoxyribonucleoside (dN) has been shown to increase mtDNA copy number and mitochondrial mass, thereby improving mitochondrial respiratory function in a cellular MELAS model [Burgin 2020]; and AMPK-activating compounds have been shown to promote mitochondrial function by increasing the expression of genes involved in mitochondrial biogenesis [Herzig 2018]. Compounds such as nicotinamide nucleoside have been shown to increase mitochondrial biogenesis and systemic metabolism [Kahn 2014], and nicotinamide mononucleotide has been shown to improve age-related phenotypes in mice, including changes in energy metabolism and increased physical activity, by increasing NAD+ levels [Mills 2016]. Furthermore, compounds that enhance NAD, such as PARP inhibitors [Felici 2014] and CD38 inhibitors [Escande 2013], as well as compounds that interact with NAD(P)H:quinone oxidoreductase 1 (NQO1), have been shown to improve mitochondrial quality and OXPHOS in cellular models of mitochondrial dysfunction [Seo, Kang-Sik 2018]. These findings in cell and mouse models with different mitochondrial defects support strategies to improve diseases characterized by abnormal mitochondrial biology by increasing mitochondrial quality.

[0010] Therefore, it would be beneficial to develop compounds that can increase cellular mitochondrial activity, for example, by increasing mitochondrial mass. Summary of the Invention

[0011] This invention provides compounds of formula (1): (1) Compounds of formula (1) can be used to improve mitochondrial activity and / or increase mitochondrial quality.

[0012] Therefore, in the first embodiment of the present invention (Embodiment 1.1), a compound of formula (1) is provided: (1) or its salts or tautomers; wherein R 1 C(O)OR a ; R a Selected from: i) Hydrogen; ii) The group Hyd, wherein Hyd is a methyl group or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and said group Hyd may optionally be replaced by a hydroxyl, halogen, cyano, or oxo group; and iii) Group AB-Cyc; A is selected from keys and C. 1-6 alkylene linking group; B does not exist, so it is -C(O)NR D -or-NR D C(O)-, the condition is that B does not exist when A is a bond; R D Selected from hydrogen and C 1-4 hydrocarbon group; Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group of Cyc are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, oxo (as the case may be), cyano, SO2R. S C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups; R S C 1-4 Alkyl, hydroxyl, or fluorine; R 2 Selected from hydrogen, C ions optionally substituted with hydroxyl groups 1-4 Hydrocarbon group and 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group, wherein R 2 The cyclic aromatic groups and cyclic non-aromatic groups are optionally substituted by one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group; and R 3 and R 4 One of them is selected from hydrogen and C, which is optionally substituted with a 5-6 membered cyclic aromatic group. 1-4 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 alkoxy groups; and R 3 and R 4 The other one is hydrogen; The specific and preferred compounds of formula (1) are as defined in embodiments 1.2 to 1.112 below.

[0013] 1.2 The compound according to embodiment 1.1, wherein R a It is hydrogen.

[0014] 1.3 The compound according to embodiment 1.1, wherein R a Selected from: ii) The group Hyd, wherein Hyd is a methyl group or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and said group Hyd may optionally be replaced by a hydroxyl, halogen, cyano, or oxo group; and iii) Group AB-Cyc.

[0015] 1.4 The compound according to embodiment 1.3, wherein R a Methyl or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and wherein the methyl group and C 2-12 The hydrocarbon group may be optionally replaced by a hydroxyl group, a halogen group, a cyano group, or an oxo group.

[0016] 1.5 The compound according to embodiment 1.3, wherein R a It is the group AB-Cyc.

[0017] 1.6 The compound according to any one of embodiments 1.1 to 1.5, wherein when R a When is or is selected from Hyd, Hyd is an optionally substituted methyl group or C. 2-6 Hydrocarbon group, wherein the C 2-6 One of the carbon atoms in the hydrocarbon group may be optionally replaced by S, S(O) or S(O)2.

[0018] 1.7 The compound according to any one of embodiments 1.1 to 1.6, wherein when Ra When is or is selected from Hyd, Hyd is an optionally substituted methyl group or C. 2-6 Hydrocarbon group, wherein the C 2-6 One of the carbon atoms in the hydrocarbon group may be optionally replaced by S.

[0019] 1.8 The compound according to any one of embodiments 1.1 to 1.7, wherein when R a When is or is selected from Hyd, Hyd is an optionally substituted methyl group or C. 2-6 Hydrocarbon group.

[0020] 1.9 The compound according to any one of embodiments 1.1 to 1.8, wherein when R a When is or is selected from Hyd, Hyd is an optionally substituted methyl group or C. 2-4 Hydrocarbon group.

[0021] 1.10 The compound according to any one of embodiments 1.1 to 1.8, wherein when R a When is or is selected from Hyd, Hyd is optionally substituted methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0022] 1.11 The compound according to embodiment 1.10, wherein when R a When is or is selected from Hyd, Hyd is an optionally substituted methyl group.

[0023] 1.12 The compound according to embodiment 1.10, wherein when R a When is or is selected from Hyd, Hyd is an ethyl group that is optionally substituted.

[0024] 1.13 The compound according to embodiment 1.10, wherein when R a When is or is selected from Hyd, Hyd is an optional substituted isopropyl group.

[0025] 1.14 The compound according to any one of embodiments 1.1 to 1.13, wherein Hyd is optionally substituted with a substituent selected from hydroxyl, fluorine or cyano.

[0026] 1.15 The compound according to any one of embodiments 1.1 to 1.13, wherein Hyd is optionally substituted with a hydroxyl group.

[0027] 1.16 The compound according to any one of embodiments 1.1 to 1.13, wherein Hyd is optionally substituted with a fluorine group.

[0028] 1.17 The compound according to any one of embodiments 1.1 to 1.13, wherein Hyd is optionally substituted with a cyano group.

[0029] 1.18 The compound according to any one of embodiments 1.1 to 1.13, wherein Hyd is unsubstituted.

[0030] 1.19 The compound according to any one of embodiments 1.1 to 1.5, wherein when R a When A is selected from or is derived from the group AB-Cyc, A is a bond.

[0031] 1.20 The compound according to any one of embodiments 1.1 to 1.5, wherein when R a When A is or is selected from the group AB-Cyc, A is C. 1-6 Alkylene linking group.

[0032] 1.21 The compound according to any one of embodiments 1.1 to 1.5, wherein when R a When A is or is selected from the group AB-Cyc, A is C. 1-4 Alkylene linking group.

[0033] 1.22 The compound according to any one of embodiments 1.1 to 1.5, wherein when R a When A is or is selected from the group AB-Cyc, A is a methylene (-CH2-) or ethylene (-CH2CH2-) linking group.

[0034] 1.23 The compound according to any one of embodiments 1.1 to 1.5, wherein when R a When A is selected from or is derived from the group AB-Cyc, A is a methylene linking group (-CH2-).

[0035] 1.24 The compound according to any one of embodiments 1.19 to 1.23, wherein B is absent.

[0036] 1.25 The compound according to any one of embodiments 1.20 to 1.23, wherein B is -C(O)NR D -or-NR D C(O)-.

[0037] 1.26 The compound according to embodiment 1.25, wherein B is -C(O)NR D -

[0038] 1.27 The compound according to embodiment 1.25, wherein B is -NR D C(O)-.

[0039] 1.28 The compound according to any one of embodiments 1.1 to 1.27, wherein R D It can be hydrogen, methyl, or ethyl.

[0040] 1.29 The compound according to embodiment 1.28, wherein R D It is hydrogen.

[0041] 1.30 The compound according to embodiment 1.28, wherein R D It is a methyl group.

[0042] 1.31 The compound according to any one of embodiments 1.1 to 1.30, wherein when R a When Cyc is selected from or is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, the cyclic aromatic group and the cyclic non-aromatic group each contain 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.

[0043] 1.32 The compound according to any one of embodiments 1.1 to 1.31, wherein when R a When Cyc is or is selected from the group AB-Cyc, Cyc is an optionally substituted 5-6 membered cyclic aromatic group, wherein the cyclic aromatic group contains 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.

[0044] 1.33 The compound according to any one of embodiments 1.1 to 1.31, wherein when R a When Cyc is selected from or is a 3- to 6-membered cyclic non-aromatic group, the cyclic non-aromatic group contains 0, 1, or 2 heteroatom ring members selected from N, O, S, S(O), and SO2.

[0045] 1.34 The compound according to any one of embodiments 1.1 to 1.31, wherein when R a When Cyc is selected from or is a 5-6 membered cyclic aromatic group or a 4-6 membered cyclic non-aromatic group, the cyclic aromatic group and the cyclic non-aromatic group each contain 0, 1 or 2 heteroatom ring members selected from N, O, S, S(O) and SO2.

[0046] 1.35 The compound according to any one of embodiments 1.1 to 1.31, wherein when R a When Cyc is selected from or is a 5-6 membered cyclic aromatic group or a 4-6 membered cyclic non-aromatic group, the cyclic aromatic group and the cyclic non-aromatic group each contain 0 or 1 heteroatom ring member selected from N, O, S, S(O) and SO2.

[0047] 1.36 The compound according to any one of embodiments 1.1 to 1.31, wherein when R aWhen the 5-6 membered cyclic aromatic group is or is selected from the group AB-Cyc, the cyclic aromatic group is selected from optionally substituted phenyl, pyridinyl, pyrimidinyl, piperidinyl, pyrroloyl, oxazolyl, and imidazolyl.

[0048] 1.37 The compound according to any one of embodiments 1.1 to 1.36, wherein when R a When the 5-6 membered cyclic aromatic group is or is selected from the group AB-Cyc, the cyclic aromatic group is selected from optionally substituted phenyl, pyridyl, oxazolyl and imidazolyl.

[0049] 1.38 The compound according to any one of embodiments 1.1 to 1.37, wherein when R a When the 5-6 membered cyclic aromatic group is selected from AB-Cyc, the substituted phenyl and pyridyl groups are selected by choice.

[0050] 1.39 The compound according to any one of embodiments 1.1 to 1.38, wherein when R a When the 5-6 membered cyclic aromatic group is selected from or is chosen from the AB-Cyc group, the 5-6 membered cyclic aromatic group is selected from the optionally substituted phenyl group.

[0051] 1.40 The compound according to any one of embodiments 1.1 to 1.39, wherein when R a When the 5-6 membered cyclic aromatic group is selected from or is chosen from the AB-Cyc group, the 5-6 membered cyclic aromatic group is selected from the optionally substituted pyridyl group.

[0052] 1.41 The compound according to any one of embodiments 1.1 to 1.40, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is a 5-6 membered cyclic non-aromatic group with optional substitution of 0 or 1 heteroatom ring member selected from N, O, S, S(O) and SO2.

[0053] 1.42 The compound according to any one of embodiments 1.1 to 1.41, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is a 6-membered cyclic non-aromatic group with optional substitution of 0 or 1 heteroatom ring member selected from N, O, S, S(O) and SO2.

[0054] 1.43 The compound according to any one of embodiments 1.1 to 1.31 or 1.33 to 1.35, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is a 4-6 membered heterocyclic non-aromatic group containing one or two heteroatom ring members selected from N, O, S, S(O) and SO2 with optional substitution.

[0055] 1.44 The compound according to any one of embodiments 1.1 to 1.43, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is an optionally substituted 6-membered heterocyclic non-aromatic group containing one heteroatom ring member selected from N, O, S, S(O) and SO2.

[0056] 1.45 The compound according to any one of embodiments 1.1 to 1.40, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is optionally substituted cyclobutyl, cyclopropyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl-1-oxide or tetrahydrothiopyranyl-1,1-dioxide group.

[0057] 1.46 The compound according to any one of embodiments 1.1 to 1.45, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is optionally substituted cyclobutyl, cyclohexyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl-1-oxide or tetrahydrothiopyranyl-1,1-dioxide group.

[0058] 1.47 The compound according to any one of embodiments 1.1 to 1.46, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is an optionally substituted cyclohexyl, piperidinyl, tetrahydropyranyl or tetrahydrothiopyranyl-1,1-dioxide group.

[0059] 1.48 The compound according to any one of embodiments 1.1 to 1.47, wherein when R a When the cyclic non-aromatic group is or is selected from the group AB-Cyc, the cyclic non-aromatic group is an optionally substituted tetrahydrothiopyranyl-1,1-dioxide group.

[0060] 1.49 The compound according to any one of embodiments 1.1 to 1.48, wherein when R a When Cyc is selected from the group AB-Cyc, Cyc is substituted by one or two substituents selected from the following: hydroxyl, halogen, oxo (as the case may be), cyano, SO2R. S C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups.

[0061] 1.50 The compound according to any one of embodiments 1.1 to 1.49, wherein when R aWhen Cyc is selected from the group AB-Cyc, Cyc is substituted by one or two substituents selected from the following: hydroxyl, fluorine, oxo (as the case may be), cyano, SO2R. S Methyl, ethyl, methoxy, ethoxy, -C(O)CH3 and phenyl.

[0062] 1.51 The compound according to any one of embodiments 1.1 to 1.50, wherein when R a When Cyc is selected from or is composed of the group AB-Cyc, Cyc is substituted by one or two substituents selected from fluorine, methoxy, and methyl.

[0063] 1.52 The compound according to any one of embodiments 1.1 to 1.50, wherein R s Selected from methyl and fluorine.

[0064] 1.53 The compound according to embodiment 1.52, wherein R s It is fluorine.

[0065] 1.54 The compound according to any one of embodiments 1.1 to 1.53, wherein when R a When Cyc is selected from or is derived from the group AB-Cyc, Cyc is substituted by one substituent.

[0066] 1.55 The compound according to any one of embodiments 1.1 to 1.47, wherein when R a When the group is or is selected from AB-Cyc, Cyc is not substituted.

[0067] 1.56 The compound according to embodiment 1.1, wherein R a Groups selected from AA to BN in Table 1 below, where an asterisk marks the junction with -O (C=O):

[0068] 1.57 The compound according to embodiment 1.56, wherein R a Having the formula (AE): The asterisk marks the connection point with -O (C=O).

[0069] 1.58 The compound according to embodiment 1.56, wherein R a Having the formula (AO): Where R a C(O)ORa When, the asterisk marks the connection point with -O (C=O).

[0070] 1.59 The compound according to embodiment 1.56, wherein R a Having the formula (AP): Where R a C(O)OR a When, the asterisk marks the connection point with -O (C=O).

[0071] 1.60 The compound according to embodiment 1.56, wherein R a Having the formula (AQ): Where R a C(O)OR a When, the asterisk marks the connection point with -O (C=O).

[0072] 1.61 The compound according to any one of embodiments 1.1 to 1.60, wherein R 2 Selected from C14 cells that are optionally substituted with hydroxyl groups 1-4 A hydrocarbon group and a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group are optionally substituted by one or more substituents selected from: halogen, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group.

[0073] 1.62 The compound according to any one of embodiments 1.1 to 1.60, wherein R 2 Selected from hydrogen, C 1-4 Saturated hydrocarbon group and 5-6 membered cyclic aromatic group optionally substituted with one or more substituents selected from the following: halogen, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group.

[0074] 1.63 The compound according to any one of embodiments 1.1 to 1.62, wherein R 2 Selected from C 1-4 Saturated hydrocarbon group and 5-6 membered cyclic aromatic group optionally substituted with one or more substituents selected from the following: halogen, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group.

[0075] 1.64 The compound according to any one of embodiments 1.1 to 1.60 or 1.62, wherein R 2 Selected from hydrogen, C 1-4 Alkyl groups and phenyl groups optionally substituted with one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group.

[0076] 1.65 The compound according to any one of embodiments 1.1 to 1.64, wherein R 2 Selected from C 1-4 Alkyl groups and phenyl groups optionally substituted with one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group.

[0077] 1.66 The compound according to any one of embodiments 1.1 to 1.60, 1.62 or 1.64, wherein R 2 Selected from hydrogen, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups.

[0078] 1.67 The compound according to any one of embodiments 1.1 to 1.66, wherein R 2 Selected from C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups.

[0079] 1.68 The compound according to any one of embodiments 1.1 to 1.60, 1.62, 1.64 or 1.66, wherein R 2 Selected from hydrogen, C 1-4 Alkyl groups and unsubstituted phenyl groups.

[0080] 1.69 The compound according to any one of embodiments 1.1 to 1.68, wherein R 2 Selected from C 1-4 Alkyl groups and unsubstituted phenyl groups.

[0081] 1.70 The compound according to any one of embodiments 1.1 to 1.60, 1.62, 1.64, 1.66 or 1.68, wherein R 2 It is selected from hydrogen, methyl, ethyl and phenyl.

[0082] 1.71 The compound according to any one of embodiments 1.1 to 1.70, wherein R 2 Selected from methyl, ethyl, and phenyl.

[0083] 1.72 The compound according to any one of embodiments 1.1 to 1.60, 1.62, 1.64, 1.66, 1.68 or 1.70, wherein R 2 Selected from hydrogen and C 1-4 alkyl.

[0084] 1.73 The compound according to any one of embodiments 1.1 to 1.72, wherein R 2 C 1-4 alkyl.

[0085] 1.74 The compound according to any one of embodiments 1.1 to 1.60, 1.62, 1.64, 1.66, 1.68, 1.70 or 1.72, wherein R 2 Selected from hydrogen and C 1-3 alkyl.

[0086] 1.75 The compound according to any one of embodiments 1.1 to 1.74, wherein R 2 C 1-3 alkyl.

[0087] 1.76 The compound according to any one of embodiments 1.1 to 1.60, 1.62, 1.64, 1.66, 1.68, 1.70, 1.72 or 1.74, wherein R 2 Selected from hydrogen, methyl, and ethyl.

[0088] 1.77 The compound according to any one of embodiments 1.1 to 1.76, wherein R 2 Selected from methyl and ethyl.

[0089] 1.78 The compound according to any one of embodiments 1.1 to 1.60, 1.62, 1.64, 1.66, 1.68, 1.70, 1.72, 1.74 or 1.76, wherein R 2 It is hydrogen.

[0090] 1.79 The compound according to any one of embodiments 1.1 to 1.77, wherein R 2 It is a methyl group.

[0091] 1.80 The compound according to any one of embodiments 1.1 to 1.71, wherein R 2 It is a phenyl group.

[0092] 1.81 The compound according to any one of embodiments 1.1 to 1.80, wherein R 4 It is hydrogen.

[0093] 1.82 The compound according to any one of embodiments 1.1 to 1.81, wherein R3 Selected from hydrogen and C, optionally substituted with 5-6 membered cyclic aromatic groups. 1-4 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 Alkyl group.

[0094] 1.83 The compound according to any one of embodiments 1.1 to 1.82, wherein R 3 Selected from hydrogen and C, optionally substituted with 5-6 membered cyclic aromatic groups. 1-3 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 Alkyl group.

[0095] 1.84 The compound according to any one of embodiments 1.1 to 1.83, wherein R 3 Selected from hydrogen and C, optionally substituted with 5-6 membered cyclic aromatic groups. 1-3 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from the group consisting of cyano, C, ... 1-2 Alkyl and C 1-2 Alkyl group.

[0096] 1.85 The compound according to any one of embodiments 1.1 to 1.84, wherein R 3 Selected from hydrogen and C groups optionally substituted with phenyl or pyridyl groups 1-3 The alkyl group, wherein the phenyl or pyridyl group is optionally substituted with one or more substituents selected from cyano and methoxy.

[0097] 1.86 The compound according to any one of embodiments 1.1 to 1.85, wherein R 3 Selected from hydrogen and C groups optionally substituted with phenyl or pyridyl groups 1-3 The alkyl group, wherein the phenyl or pyridyl group is optionally substituted by one or more substituents selected from the following: cyano, C 1-2 Alkyl and C 1-2 Alkyl group.

[0098] 1.87 The compound according to any one of embodiments 1.1 to 1.86, wherein R 3 Selected from hydrogen and C244, optionally substituted with phenyl 1-3 The alkyl group, wherein the phenyl group is optionally substituted by one or more substituents selected from the group consisting of cyano, C, ... 1-2 Alkyl and C 1-2 Alkyl group.

[0099] 1.88 The compound according to any one of embodiments 1.1 to 1.87, wherein R 3 Selected from hydrogen and C244, optionally substituted with phenyl 1-3 The phenyl group is a hydrocarbon group, wherein the phenyl group is optionally substituted with one or more substituents selected from cyano and methoxy.

[0100] 1.89 The compound according to any one of embodiments 1.1 to 1.82, wherein R 3 Selected from hydrogen and C 1-4 Hydrocarbon groups (e.g., C) 1-4 (Saturated hydrocarbon group).

[0101] 1.90 The compound according to embodiment 1.89, wherein R 3 Selected from hydrogen and noncyclic C 1-4 Hydrocarbon group.

[0102] 1.91 The compound according to embodiment 1.90, wherein R 3 Selected from hydrogen and noncyclic C 1-3 Hydrocarbon group.

[0103] 1.92 The compound according to embodiment 1.91, wherein R 3 It is selected from hydrogen, methyl, ethyl, propyl, isopropyl and prop-2-enyl.

[0104] 1.93 The compound according to embodiment 1.92, wherein R 3 It is hydrogen.

[0105] 1.94 The compound according to any one of embodiments 1.1 to 1.93, having formula (1-A): (1-A) Where R 1 R 2 and R 3 As defined in any of Implementation Schemes 1.1 to 1.93.

[0106] 1.95 The compound according to any one of embodiments 1.1 to 1.93, having formula (1-B): (1-B) Where R 1 R 2 and R 3 As defined in any of Implementation Schemes 1.1 to 1.93.

[0107] 1.96 The compound according to any one of embodiments 1.1 to 1.93, having the formula (1-C): (1-C) Where R 1 R 2 and R 3 As defined in any of Implementation Schemes 1.1 to 1.93.

[0108] 1.97 The compound according to any one of embodiments 1.1 to 1.93, having the formula (1-D): (1-D) Where R 1 R 2 and R 3 As defined in any of Implementation Schemes 1.1 to 1.93.

[0109] 1.98 The compound according to any one of embodiments 1.1 to 1.97, wherein when R 2 When it is hydrogen, R 1 It is not C(O)OCH3.

[0110] 1.99 The compound according to any one of embodiments 1.1 to 1.97, wherein when R 2 It is hydrogen and R 1 When it is C(O)O, then R a It is not methyl.

[0111] 1.100 The compounds described in embodiment 1.1 or any of its dependent embodiments, but excluding compound (1R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylate.

[0112] 1.101 The compound according to embodiment 1.1 or any of its dependent embodiments, wherein the compound is not methyl (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylate.

[0113] 1.102 The compounds described in embodiment 1.1 or any of its dependent embodiments, but excluding one or more of the following compounds, for example, all of them: 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 4-methyltetrahydrofuran-3-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid tetrahydro-2H-pyran-4-yl ester; 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 1-methylpyrrolidine-3-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 1-methylpiperidin-4-yl ester; 2-azabicyclo[2.1.1]hexane-5-carboxylate oxetane-3-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid tetrahydrofuran-3-yl ester And its salt.

[0114] 1.103 The compounds described in embodiment 1.1 or any of its dependent embodiments, but excluding one or more of the following compounds, for example, all of them: 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 4-methyltetrahydrofuran-3-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid tetrahydro-2H-pyran-4-yl ester; 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 1-methylpyrrolidine-3-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 1-methylpiperidin-4-yl ester; 2-azabicyclo[2.1.1]hexane-5-carboxylate oxetane-3-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid tetrahydrofuran-3-yl ester; (1S,3S,4R,5R)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid tert-butyl ester; (1R,3R,4S,5S)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester; (1R,4S,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester; (1R,4S)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester; (1R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester; (1R,3R,4S,5S)-3-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester; (1R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid tert-butyl ester; (1R,4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester; (1R,4S,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid tert-butyl ester; (1R,4S,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester; (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester (1S,4R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester; (1S,4R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid tert-butyl ester; (1S,4R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester; (1R,4S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid 2-(prop-2-yn-1-yloxy)ethyl ester; (1R,4S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid 2-cyclopropylpropyl ester; (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester; (1S,4R,5R)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid tert-butyl ester; 1-Cyclobutylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 1-Ethylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclobutyl methyl ester; 1-Cyclopropylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-propyn-1-yl ester; 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-butyn-1-yl ester; 2,2-Dimethyl-3-buten-1-yl ester of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3-methyl-3-buten-1-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 5-methylhexyl ester; 1-Methyl-2-butyn-1-yl ester of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-fluoroethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3-buten-1-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 4-pentyn-1-yl ester; 1-Methyl-2-propyn-1-yl ester of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-propen-1-yl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-cyclopropylpropyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid (5-oxo-2-pyrrolidinyl) methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methylpentyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-(2-methylpropoxy)ethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methoxy-3-methylbutyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methoxy-2-methylpropyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-(1,1-dimethylethoxy)ethyl ester; 1-Methylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-propoxyethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-(dimethylamino)-1-methylethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid propyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid (tetrahydro-2H-pyran-4-yl) methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid hexyl ester; 2-azabicyclo[2.1.1]hexane-5-carboxylic acid (tetrahydro-2H-pyran-2-yl) methyl ester; 2-(2-thienyl)ethyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 1-(methoxymethyl)-2-methylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3-methoxypropyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylate; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methoxy-2-methylbutyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3-methoxy-3-methylbutyl ester; 2-Azabicyclo[2.1.1]hexane-5-carboxylic acid 2-ethoxy-1-methylethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-(1-methylethoxy)ethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclopentylmethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methylpropyl ester; 3,3-dimethyl butyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-cyclobutylethyl ester; 1-Methylpropyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclopropyl methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-cyclobutylpropyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 4-methylphenyl ester; 3-methylbutyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclohexylmethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-cyclopropylethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-butoxyethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methoxyethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methoxy-1-methylethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylate; 1,3-dimethyl butyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-ethylbutyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-thienyl methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid (tetrahydro-3-furanyl) methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid (tetrahydro-2-furanyl) methyl ester; 4,4-dimethylpentyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 1,2-dimethylpropyl hexane-5-carboxylic acid (2.1.1) 2-Azabicyclo[2.1.1]hexane-5-carboxylic acid 2-ethoxyethyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid pentyl ester; 1,1-Dimethylethyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid ethyl ester; 1-Methyl ethyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid phenyl methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3,3-difluorocyclobutyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3-methylcyclopentyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclopropyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 3-methylcyclohexyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 4-methylcyclohexyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid 2-methylcyclohexyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclohexyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclobutyl ester; 2-Zazabicyclo[2.1.1]hexane-5-carboxylic acid cyclopentyl ester; (1S,4R,5R)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid And its salt.

[0115] 1.104 The compound according to embodiment 1.1, wherein R 2 R 3 and R 4 One or more of them are substituents other than hydrogen.

[0116] 1.105 The compound according to embodiment 1.1, wherein R 2 Substituents other than hydrogen.

[0117] 1.106 A compound selected from the compounds of Examples 1 to 50 herein.

[0118] 1.107 The compound according to any one of embodiments 1.1 to 1.106, which is in salt form.

[0119] 1.108 The compound according to embodiment 1.107, wherein the salt is an acid addition salt.

[0120] 1.109 The compound according to embodiment 1.107 or embodiment 1.108, wherein the salt is a pharmaceutically acceptable salt.

[0121] 1.110 The compound according to any one of embodiments 1.1 to 1.106 is in the form of a non-salt (e.g., a free base).

[0122] 1.111 The compound according to any one of embodiments 1.1 to 1.110 is in the form of a solvate.

[0123] 1.112 The compound according to embodiment 1.111, wherein the solvate is a hydrate.

[0124] definition Unless the context otherwise indicates, references to “carbocyclic” and “heterocyclic” groups as used herein shall include both aromatic and non-aromatic systems. Thus, by way of example, the term “carbocyclic and heterocyclic groups” in its scope includes aromatic, non-aromatic, unsaturated, partially saturated, and fully saturated carbocyclic and heterocyclic systems.

[0125] The carbocyclic or heterocyclic group may be aryl or heteroaryl. Aryl or heteroaryl may be monocyclic or bicyclic as defined herein. As used herein, the term "aryl" refers to a carbocyclic group with aromatic characteristics, and the term "heteroaryl" is used herein to refer to a heterocyclic group with aromatic characteristics. Where the context permits, the terms "aryl" and "heteroaryl" may cover bicyclic systems in which both rings are aromatic, or one ring is non-aromatic and the other is aromatic. In such bicyclic systems containing one aromatic and one non-aromatic group, the group may be linked by an aromatic ring or by a non-aromatic ring.

[0126] The term "non-aromatic group" refers to unsaturated ring systems, partially saturated, and fully saturated carbocyclic and heterocyclic systems that do not possess aromatic characteristics. The terms "unsaturated" and "partially saturated" refer to ring structures containing atoms sharing more than one valence bond; for example, the ring contains at least one multiple bond, such as a C=C=C bond. The term "saturated" refers to a ring structure where no multiple bonds exist between the ring atoms. Saturated carbocyclic groups include cycloalkyl groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Partially saturated carbocyclic groups include cycloalkenyl groups: cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Non-aromatic heterocyclic groups include aziridine, pyrrolidine, piperidine, aziridine, piperazine, morpholine, thiomorpholine, thiomorpholine S-oxide and S,S-dioxide, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran, tetrahydrothiopyran, S-oxide, SS-dioxide, imidazoline, imidazolidinone, oxazoline, thiazoline, pyrazoline, and pyrazolidine.

[0127] Unless otherwise stated, the term "hydrocarbyl" as used herein refers to an aliphatic, alicyclic, aromatic, and acyclic group having an all-carbon backbone and consisting of carbon and hydrogen atoms. Examples of hydrocarbyl groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, ynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, arylenyl, and aryynyl. Such groups may be unsubstituted or, where specified, substituted with one or more substituents as defined herein. In some cases, as defined herein, one or more, but not all, of the carbon atoms in a hydrocarbyl group may be substituted with another atom or group of atoms. Hydrocarbyl groups may be saturated or unsaturated.

[0128] The claims of this application should be understood to cover only stable compounds. The claims are not intended to cover any combination of groups that would produce unstable compounds. For example, if the definition of protection covers a compound having OO or ON bonds, it should be understood that this compound is not intended to be protected because it is not a stable compound.

[0129] Salt The compounds of the present invention as defined in embodiments 1.1 to 1.109, 1.111 and 1.112 may be presented in the form of salts.

[0130] The salts mentioned above (and also defined in implementation schemes 1.107, 1.108 and 1.109) are generally acid addition salts.

[0131] It can be done through conventional chemical methods, such as Pharmaceutical Salts: Properties, Selection, and Use P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. The method described herein is for the synthesis of salts from affinistic compounds. Generally, such salts can be prepared by reacting a compound in its free base form with an acid in water or an organic solvent or a mixture thereof; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.

[0132] Alternatively, a salt may be formed during the synthesis and subsequent separation of the compound (1).

[0133] Acid addition salts (as defined in Embodiment 1.108) can be formed from a variety of acids (inorganic and organic acids). Examples of acid addition salts include salts formed from acids selected from the group consisting of: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+)camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactopyric acid, gentian acid, glucoheponic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxo- Glutamic acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethanesulfonic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid, undecenoic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[0134] The salt forms of the compounds of this invention are generally pharmaceutically acceptable salts (Embodiment 1.109), and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts". J. Pharm. Sci.,Volume 66, pp. 1-19. However, non-pharmaceutically acceptable salts can also be prepared as intermediates, which can then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, applicable for, for example, the purification or isolation of the compounds of the present invention, also form part of this invention.

[0135] The ability of a given compound of the present invention to form a stable acid addition salt will depend in part on the basicity of the free base form of the compound and the acidity of the acid. Preferably, although not necessarily required, there is a difference of at least two pKa units between the pKa of the acid and the pKa of the conjugate acid of the base. The acid may be selected from acids with a pKa of 3.5 or lower, for example, 3.0 or lower. Therefore, in another embodiment, the present invention provides: 1.113 The compound according to any one of embodiments 1.1 to 1.109, 1.111 and 1.112 is in the form of an acid addition salt formed with an acid having a pKa of 3.5 or lower (e.g. -7.0 to +3.5).

[0136] 1.114 The compound according to any one of embodiments 1.1 to 1.109, 1.111 and 1.112, which is in the form of an acid addition salt formed with an acid having a pKa of 3.0 or lower.

[0137] 1.115 The compound according to embodiment 1.113 or embodiment 1.114, wherein the acid forming the acid addition salt is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, malonic acid, maleic acid, and fumaric acid.

[0138] 1.116 The compound according to embodiment 1.115, wherein the acid forming the acid addition salt is selected from hydrochloric acid, sulfuric acid and methanesulfonic acid.

[0139] Crystalline form The hydrochloride salts of the compounds of formula (1) may exist in amorphous or crystalline form, as described in Example 1 of this document, and it is envisioned that other salt forms of the compounds will also exist in amorphous and crystalline forms.

[0140] Therefore, in another embodiment (Embodiment 1.117), the present invention provides an acid addition salt of the compound of formula (1) which is substantially crystalline.

[0141] The term “substantially crystalline” refers to the form of a compound of formula (1) in which it is 50% to 100% crystalline. Within this range, a compound of formula (1) may be at least 55% crystalline, or at least 60% crystalline, or at least 70% crystalline, or at least 80% crystalline, or at least 90% crystalline, or at least 95% crystalline, or at least 98% crystalline, or at least 99% crystalline, or at least 99.5% crystalline, or at least 99.9% crystalline.

[0142] Therefore, in another embodiment (embodiments 1.118 to 1.121), the present invention provides: 1.118 An acid addition salt of a compound of formula (1) that is substantially crystalline, wherein it is at least 90% crystalline.

[0143] 1.119 An acid addition salt of a compound of formula (1) that is substantially crystalline, wherein it is at least 95% crystalline.

[0144] 1.120 An acid addition salt of a compound of formula (1) that is substantially crystalline, being at least 99% crystalline.

[0145] 1.121 An acid addition salt of a compound of formula (1) that is substantially crystalline, being at least 99.9% crystalline.

[0146] The compounds of the present invention may be in crystalline form either solvated (e.g., hydrated) or non-solventized (e.g., anhydrous).

[0147] As used herein, the term "anhydrous" does not exclude the possibility that some water may be present on or within the compound (e.g., a compound crystal). For example, some water may be present on the surface of the compound (e.g., a crystal) or a small amount of water may be present in the bulk of the compound (e.g., a crystal). Typically, the anhydrous form contains less than 0.4 molecules of water per molecule of the compound, and more preferably less than 0.1 molecules of water per molecule of the compound, such as 0 molecules of water.

[0148] When hydrated in its crystalline form, it may contain, for example, up to three water molecules of crystallization, and more typically up to two water molecules, such as one or two water molecules. It may also form non-stoichiometric hydrates, in which the number of water molecules present is less than one, or otherwise non-integer. For example, when less than one water molecule is present, each molecule of compound (1) may contain, for example, 0.4, or 0.5, or 0.6, or 0.7, or 0.8, or 0.9 water molecules.

[0149] Crystallization can be characterized using a variety of techniques, including X-ray powder diffraction (XRPD), single-crystal X-ray diffraction (see Example 1), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The properties of crystals under different humidity conditions can be analyzed using gravimetric vapor adsorption studies (such as dynamic vapor adsorption (DVS)).

[0150] The crystalline structure of a compound can be analyzed using X-ray powder diffraction (XRPD) solid-state technology. XRPD can be performed using conventional methods, such as those described herein (see examples below) and those in "Introduction to X-ray Powder Diffraction," Ron Jenkins and Robert L. Snyder (John Wiley & Sons, New York, 1996). The presence of well-defined peaks in the XRPD diffraction pattern (relative to random background noise) indicates that the compound possesses a certain degree of crystallinity.

[0151] The X-ray powder pattern of the compound is characterized by the diffraction angle (2θ) and interplanar spacing (d) parameters of the X-ray diffraction pattern. These are related to Bragg's equation, nλ = 2d Sin θ, where n = 1; λ = wavelength of X-ray radiation; d = interplanar spacing; and θ = diffraction angle.

[0152] Alternatively, the crystalline structure of the salt form of compound (1) can be analyzed by single-crystal X-ray diffraction, as described in Example 1 below. The absolute stereochemical configuration of compound (1) has been determined using single-crystal X-ray diffraction studies.

[0153] Geometric isomers and tautomers The compounds of the present invention may exist in a variety of different geometric isomers and tautomers, and references to compounds of formula (1) as defined in embodiments 1.1 to 1.121 include all such forms.

[0154] Optical isomers can be classified by their optical activity (i.e., they exist as + and - isomers or...). d and l The optical isomers can be characterized and identified by their isomer forms, or they can be characterized by their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, Ingold, and Prelog. See [reference needed]. Advanced Organic Chemistry Jerry March, 6th edition, John Wiley & Sons, New Jersey, 2007, pp. 155-158; see also Cahn, Ingold, and Prelog. Angew. Chem. Int. Ed. Engl ., 1966, 5, 385-415.

[0155] Optical isomers can be separated by a variety of techniques, including chiral chromatography (via chiral support chromatography), and such techniques are well known to those skilled in the art.

[0156] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-xylyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid and (-)-camphorsulfonic acid, or chiral amines such as (+)-1-phenylethylamine or (+)-1-(1-naphthyl)ethylamine, and by preferentially separating the diastereomeric isomers and subsequently dissociating the salt to give individual enantiomers of the free base.

[0157] In each of embodiments 1.1 to 1.121, the compound of formula (1) is substantially optically pure; that is, it has an enantiomeric excess (ee) of at least 80% relative to any other optical isomer of the compound of formula (1).

[0158] As used herein, the term “enantiomer excess” is used in its conventional sense, referring to the percentage excess of the enantiomer of interest (compound (1) or compound (2)). When the enantiomer excess is 80%, this corresponds to a composition containing 90% of the desired enantiomer + 10% of other enantiomers = 100% (since 90% - 10% = 80%). More generally, the compound of formula (1) has an optical purity of at least 82%, or at least 84%, or at least 86%, or at least 88%, or at least 90%, or at least 92%, or at least 94%, or at least 96%, or at least 98%, or at least 99%, or 100% (enantiomer excess).

[0159] Therefore, in another embodiment (embodiments 1.122 to 1.125), the present invention provides: 1.122 The compound as defined in any one of embodiments 1.1 to 1.121, wherein the compound of formula (1) has, as appropriate, the following optical purity: (i) at least 80%; or (ii) At least 82%; or (iii) At least 84%, or (iv) At least 86%; or (v) At least 88%; or (vi) At least 90%; or (vii) At least 92%; or (viii) At least 94%; or (ix) At least 96%; or (x) At least 98%; or (xi) At least 99%; or (xii) 100%.

[0160] 1.123 The compound according to embodiment 1.122, wherein the compound of formula (1) has an optical purity of at least 98%, depending on the circumstances.

[0161] 1.124 The compound according to embodiment 1.122, wherein the compound of formula (1) has an optical purity of at least 99%, depending on the circumstances.

[0162] 1.125 The compound according to embodiment 1.122, wherein the compound of formula (1) has 100% optical purity as appropriate.

[0163] isotope In one embodiment, the compound of the invention as defined in any one of embodiments 1.1 to 1.125 is rich in deuterium at one or more sites.

[0164] Methods for deuterating organic compounds are known to those skilled in the art (see, for example, “Deuterium Discovery and Applications in Organic Chemistry”, Jaemoon Yang, 2016, Elsevier, and “The Organic Chemistry of Isotopic Labelling”, James R Hanson, 2019, RSC Publishing).

[0165] When the compounds of embodiments 1.1 to 1.125 are deuterated, the percentage of deuterium atoms in the total hydrogen atoms of the compounds of the present invention is less than 2%, more typically less than 1%, more usually less than 0.1%, preferably less than 0.05%, and most preferably not more than 0.02%.

[0166] solvates The compounds defined in any of the embodiments 1.1 to 1.125 may be solvated or non-solventized.

[0167] Preferred solvates are those formed by incorporating a non-toxic, pharmaceutically acceptable solvent molecule (hereinafter referred to as a solvating solvent) into the solid structure (e.g., crystal structure) of the compound of the present invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compound of the present invention with a solvent or a mixture of solvents containing a solvating solvent. Whether a solvate has been formed under any given condition can be determined by analyzing the crystals of the compound using well-known and standard techniques such as pyrolysis gravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography.

[0168] Solvents can be stoichiometric or non-stoichiometric.

[0169] The particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

[0170] For a more detailed discussion of solvates and methods for their preparation and characterization, see Bryn et al., Solid-State Chemistry of Drugs, 2nd Edition, SSCI Publication, Inc. of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0171] Complexes and crystal cage compounds In one embodiment, the compound of any one of embodiments 1.1 to 1.125 is a complex of the compound (e.g., an inclusion complex or cage compound with a compound such as cyclodextrin, or a complex with a metal).

[0172] Bioactivity The compounds defined in any of embodiments 1.1 to 1.125 can be used to enhance energy production in mitochondria. These compounds can be used to improve mitochondrial activity in vivo or in vitro.

[0173] The compound can be used to prevent (to reduce the likelihood of disease) or treat conditions or diseases involving components associated with mitochondrial dysfunction or abnormal activity.

[0174] For example, the compound may be suitable for the prevention or treatment of diseases and symptoms characterized by reduced mitochondrial activity. This reduced activity may be due to a decrease in the number of mitochondria produced by the body or due to reduced mitochondrial activity in the produced mitochondria.

[0175] As used herein, the term "treatment" generally refers to a beneficial therapeutic intervention. Such treatment can suppress symptoms caused by an underlying disease condition, even if the underlying disease condition persists; for example, the treatment can reduce or alleviate the symptoms of the disease, thereby making it easier for the patient to manage the symptoms.

[0176] As used in this article, the term "preventing" is generally used to refer to therapeutic interventions in which the onset of mitochondrial disease symptoms can be completely prevented or mitigated, even if the underlying cause of the disease (such as a genetic mutation) remains.

[0177] Therefore, in another embodiment (embodiments 2.1 to 2.7), the present invention provides: 2.1 The compound as defined in any one of embodiments 1.1 to 1.125, used in medicine or therapy.

[0178] 2.2 The compound as defined in any one of embodiments 1.1 to 1.125, which is used for the prevention or treatment of mitochondrial diseases.

[0179] 2.3 The compound as defined in any one of embodiments 1.1 to 1.125, used for the prevention or treatment of diseases characterized by reduced mitochondrial activity.

[0180] 2.4 Use of a compound as defined in any one of embodiments 1.1 to 1.125 for the treatment or prevention of mitochondrial diseases.

[0181] 2.5 Use of a compound as defined in any one of embodiments 1.1 to 1.125 for the treatment or prevention of diseases characterized by reduced mitochondrial activity.

[0182] 2.6 A method for treating mitochondrial disease in an individual in need, the method comprising administering to the individual an effective amount of a compound as defined in any one of embodiments 1.1 to 1.125.

[0183] 2.7 A method for treating a disease characterized by reduced mitochondrial activity in an individual in need, the method comprising administering to the individual an effective amount of a compound as defined in any one of embodiments 1.1 to 1.125.

[0184] Mitochondrial diseases can manifest as mitochondrial myopathy. Nerve cells in the brain and muscles utilize large amounts of chemical energy; therefore, mitochondrial dysfunction can cause a variety of neuromuscular diseases.

[0185] Examples of such conditions and diseases include: Karns-Sell syndrome (KSS); Leigh syndrome; Maternally inherited Leigh syndrome (MILS); Mitochondrial DNA deletion syndrome (MDS); Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); Myositis with fragmented red fibers (MERRF); Neuropathic ataxia and retinitis pigmentosa (NARP); and Pearson syndrome. Chlamydia syndrome or progressive extraocular muscle paralysis (PEO); CPEO Chuck-Maley-Duss disease type 2 (CMT2); fatty acid oxidation disorder, i.e., long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency; maple syrup urine disease (MSUD); Left disease and Leber's hereditary optic neuropathy (LHON); maternally inherited epilepsy / mitochondrial tubulointerstitial nephropathy (MITKD), mitochondrial deafness (DEAF); ataxia, myoclonus with deafness (AMDF); hypertrophic cardiomyopathy (HCM); diabetes mellitus with deafness (DMDF); maternally inherited diabetes mellitus with deafness (MIDD); mitochondrial... Sensory-neural hearing loss due to somatic syndromes (SNHL); focal segmental glomerulosclerosis associated with mitochondrial disease (FSGS); autism spectrum disorder (ASD); progressive encephalopathy (PEM); bilateral striatal necrosis (BSN); Leber hereditary optic neuropathy and dystonia (LDYT); maternally inherited cardiomyopathy (MICM); motor neuron disease (MND); myoclonic epilepsy / spasmodic epilepsy; mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA); familial bilateral striatal necrosis (FBSN); epilepsy, stroke, optic atrophy, and cognitive decline (ESOC).

[0186] Mitochondrial diseases can also be diabetes or deafness (DAD) and type 2 diabetes.

[0187] In addition to the diseases mentioned above, several other acquired conditions are believed to be related to mitochondrial dysfunction. These conditions include: ● Huntington's disease ● Cancer ● Alzheimer's disease Parkinson's disease ● Bipolar disorder ● Schizophrenia ● Aging and senescence ● Anxiety ● Cardiovascular diseases ● Sarcopenia ● Chronic fatigue syndrome Amyotrophic Lateral Sclerosis (ALS) ● Steatohepatitis and nonalcoholic steatohepatitis (NASH) ● Obesity ● Ischemia-reperfusion ● Ischemic preconditioning ● Cardiomyopathy ● Heart failure ● Muscular dystrophy.

[0188] Therefore, in another embodiment (embodiments 2.8 to 2.21), the present invention provides: 2.8 A compound as defined in any one of embodiments 1.1 to 1.125, used for the prevention or treatment of mitochondrial myopathy.

[0189] 2.9 Use of a compound as defined in any one of embodiments 1.1 to 1.125 for the treatment or prevention of mitochondrial myopathy.

[0190] 2.10 A method for treating mitochondrial myopathy in an individual in need, the method comprising administering to the individual an effective amount of a compound as defined in any one of embodiments 1.1 to 1.125.

[0191] 2.11 Use of the compound according to embodiment 2.8, the compound according to embodiment 2.9, or the method according to embodiment 2.10, wherein the mitochondrial myopathy is selected from: Karns-Sell syndrome (KSS); Leigh syndrome; maternally inherited Leigh syndrome (MILS); mitochondrial DNA deletion syndrome (MDS); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); mitochondrial neurogastrointestinal encephalomyopathy (MNGIE); myositis with broken red fibers (MERRF); neuropathic ataxia with retinitis pigmentosa (NARP); Pearson syndrome or progressive extraocular muscle palsy (PEO); CPEO Chuck-Maley-Dus disease type 2 (CMT2); fatty acid oxidation disorder, i.e., long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency; maple syrup urine disease (MSUD); Left disease and Leber hereditary optic neuropathy (LHON). Maternally inherited epilepsy / mitochondrial tubulointerstitial nephropathy (MITKD), mitochondrial deafness (DEAF); ataxia, myoclonus with deafness (AMDF); hypertrophic cardiomyopathy (HCM); diabetes mellitus with deafness (DMDF); maternally inherited diabetes mellitus with deafness (MIDD); mitochondrial syndrome-related sensorineural hearing loss (SNHL); focal segmental glomerulosclerosis associated with mitochondrial disease (FSGS); autism spectrum disorder (ASD); progressive encephalopathy (PEM); bilateral striatal necrosis (BSN); Leber's inherited optic neuropathy and dystonia (LDYT); maternally inherited cardiomyopathy (MICM); motor neuron disease (MND); myoclonic epilepsy / spasmodic epilepsy; mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA); familial bilateral striatal necrosis (FBSN); epilepsy, stroke, optic atrophy, and cognitive decline (ESOC).

[0192] 2.12 A compound as defined in any one of embodiments 1.1 to 1.125, used for the prevention or treatment of diabetes or deafness (DAD) and type 2 diabetes.

[0193] 2.13 Use of a compound as defined in any one of embodiments 1.1 to 1.125 for the treatment or prevention of diabetes or deafness (DAD) and type 2 diabetes.

[0194] 2.14 A method for treating diabetes or deafness (DAD) and type 2 diabetes in an individual in need, the method comprising administering to the individual an effective amount of a compound as defined in any one of embodiments 1.1 to 1.125.

[0195] 2.15 A compound as defined in any one of embodiments 1.1 to 1.125, used for the prevention or treatment of diseases selected from: Huntington's disease, cancer, Alzheimer's disease, Parkinson's disease, bipolar disorder, schizophrenia, aging and senility, anxiety disorders, cardiovascular disease, sarcopenia, chronic fatigue syndrome, amyotrophic lateral sclerosis, steatosis and non-alcoholic steatohepatitis (NASH), obesity, ischemia-reperfusion, ischemic preconditioning, cardiomyopathy, heart failure and muscular dystrophy.

[0196] 2.16 Use of a compound as defined in any one of embodiments 1.1 to 1.125 for the treatment or prevention of diseases selected from: Huntington's disease, cancer, Alzheimer's disease, Parkinson's disease, bipolar disorder, schizophrenia, aging and senility, anxiety disorders, cardiovascular diseases, sarcopenia, chronic fatigue syndrome, amyotrophic lateral sclerosis, steatosis and non-alcoholic steatohepatitis (NASH), obesity, ischemia-reperfusion, ischemic preconditioning, cardiomyopathy, heart failure and muscular dystrophy.

[0197] 2.17 A method of treating a disease in an individual in need, said disease being selected from Huntington's disease, cancer, Alzheimer's disease, Parkinson's disease, bipolar disorder, schizophrenia, aging and degeneration, anxiety disorders, cardiovascular disease, sarcopenia, chronic fatigue syndrome, amyotrophic lateral sclerosis, steatosis and nonalcoholic steatohepatitis (NASH), obesity, ischemia-reperfusion, ischemic preconditioning, cardiomyopathy, heart failure and muscular dystrophy, said method comprising administering to said individual an effective amount of a compound as defined in any one of embodiments 1.1 to 1.125.

[0198] 2.18 A method for treating an individual who has been diagnosed and found to have a disease or symptom characterized by reduced mitochondrial activity, the method comprising administering to the individual an effective amount of a compound as defined in any one of embodiments 1.1 to 1.125.

[0199] 2.19 A method for diagnosing and treating a disease condition or symptom characterized by reduced mitochondrial activity, the method comprising: (i) screening a patient to determine whether the patient has or may have a disease or symptom that is susceptible to treatment with a compound that increases mitochondrial activity; and (ii) subsequently administering to the patient a compound as defined in any one of embodiments 1.1 to 1.125, if the patient is indicated to be therefore susceptible to the disease or symptom.

[0200] 2.20 Use of a compound as defined in any one of embodiments 1.1 to 1.125 for the manufacture of an agent for the treatment or prevention of a disease condition or symptom in a patient who has been screened and identified as having or at risk of having a disease or symptom that is sensitive to treatment with a compound that increases mitochondrial activity.

[0201] 2.21 A compound as defined in any one of embodiments 1.1 to 1.125, used to treat or prevent a disease condition or symptom in a patient who has been screened and identified as having or at risk of having a disease or symptom that is sensitive to treatment with a compound that increases mitochondrial activity.

[0202] Diagnostic methods for determining whether a particular cancer is sensitive to treatment with the compounds of the present invention are described in the section entitled “Diagnostic Methods” below.

[0203] Determination of biological characteristics The ability of the compounds in implementation schemes 1.1 to 1.125 to increase mitochondrial activity can also be determined using the schemes described in the Examples section below.

[0204] Cell-based in vitro functional and phenotypic analyses can be used to simultaneously analyze mitochondrial parameters, thus obtaining a more comprehensive footprint of the effects of compounds on mitochondrial activity. Mitochondrial membrane potential (ΔψM) can be assessed using dyes that accumulate within mitochondria without affecting mitochondrial respiration. These dyes include, but are not limited to, acridine orange 10-nonyl bromide (NAO), MitoTracker™ Green FM, MITO-ID® Green, and MitoView™ Green. These dyes are widely used for imaging mitochondria to assess their intracellular localization and quantify mitochondrial abundance, thus providing indirect indicators of mitochondrial biogenesis and efficiency [Kitami 2012]. To assess mitochondrial biomass at the cellular level, reporter cell lines transfected with mitochondrial-targeting green fluorescent protein (GFP) can be used to quantify the expression of respiratory complex subunits (such as cytochrome c oxidase subunit IV (Cox8)) in living cells [Wang 2012, Nilsson 2015]. Furthermore, the development of oxygen-dependent fluorescence quenching systems and high-resolution respirometry (HRR) has enabled the direct quantification of mitochondrial respiration in high-throughput formats. By combining multiple test results for all compounds, it is possible to define a comprehensive set of mitochondrial signatures, thereby enabling the clustering of novel chemical entities based on their impact on mitochondrial function [Andreux 2016].

[0205] Preferred compounds in embodiments 1.1 to 1.125 are compounds having 102% or greater, preferably 105% or greater, mitochondrial-size activity (measured using the methods described above, such as in the Mitotracker assay or the Cox8 MTS reporter assay).

[0206] Therefore, in another embodiment (embodiments 2.22 to 2.26), the present invention provides: 2.22 The compound according to any one of embodiments 1.1 to 1.125 has 102% or greater mitochondrial-sized activity.

[0207] 2.23 The compound according to any one of embodiments 1.1 to 1.125 has 103% or greater mitochondrial-sized activity.

[0208] 2.24 The compound according to any one of embodiments 1.1 to 1.125 has 104% or greater mitochondrial-sized activity.

[0209] 2.25 The compound according to any one of embodiments 1.1 to 1.125 has 105% or greater mitochondrial-sized activity.

[0210] 2.26 The compound according to any one of embodiments 1.1 to 1.125, used in any one of embodiments 2.1 to 2.25 of the therapy, treatment, method or use.

[0211] Method for preparing the compounds of the present invention The present invention also provides a method for preparing the compound according to any one of embodiments 1.1 to 1.125.

[0212] Where R 1 C(O)OR a The compound of formula (1) (referred to herein as compound of formula (4)) can be prepared by reacting compound of formula (17) (where PG is a suitable nitrogen protecting group (e.g., N-Boc)) with an acid in a polar solvent in order to remove PG.

[0213] Therefore, in another embodiment (Embodiment 3.1), a method for preparing a compound as defined in any one of Embodiments 1.1 to 1.125 is provided, the method comprising: (a) Removal of protecting group PG from compound (17): To form compounds of formula (4); The following provides an alternative implementation scheme: 3.2 The method according to implementation scheme 3.1, wherein PG has the formula C(O)OR N , where R N C is an optional replacement 1-4 Hydrocarbon group.

[0214] 3.3 The method according to implementation scheme 3.2, wherein R N It is tert-butyl.

[0215] 3.4 The method according to any one of embodiments 3.1 to 3.3, wherein step (a) is carried out in the presence of an acid.

[0216] 3.5 The method according to embodiment 3.4, wherein the acid is selected from trifluoroacetic acid and hydrochloric acid.

[0217] 3.6 The method according to any one of embodiments 3.1 to 3.5, wherein step (a) is carried out in a polar aprotic solvent.

[0218] 3.7 The method according to any one of embodiments 3.1 to 3.6, wherein step (a) is carried out in dichloromethane or diethyl ether.

[0219] Or, where R 1 C(O)OR a (where R) a Compounds of formula (1) that are not hydrogen (referred to herein as compounds of formula (4)) can be prepared by reacting a compound of formula (18) with the following scheme: i) Having the formula R a Alcohols with -OH groups; or ii) Having the formula XR a Alkylating agents, wherein X is a suitable leaving group, such as halogen or arylsulfonyloxy (e.g., toluenesulfonate group).

[0220] Therefore, in another embodiment, the present invention provides: 3.8 A method for preparing a compound as defined in any one of embodiments 1.1 to 1.125, wherein R a The method, which is not hydrogen, comprises: (a) To make the compound of formula (18): With formula R a Alcohols with -OH groups or those having the formula XRa (where X is a suitable leaving group) alkylating agent reaction, To form compounds of formula (4); Protective base In the methods described above, it may be necessary to protect one or more functional groups to prevent reactions from occurring at undesirable positions on the molecule. Examples of protecting groups, as well as methods for protecting and deprotecting functional groups, can be found in [reference needed]. Protective Groups in Organic Synthesis (P. Wuts; 5th edition; Wiley, 2014).

[0221] The hydroxyl group can be protected as, for example, an ether (-OR) or an ester (-OC(=O)R), such as: tert-butyl ether; tetrahydropyranyl (THP) ether; anisole, benzhydryl / diphenylmethyl ether or triphenylmethyl ether; trimethylsilane ether or tert-butyldimethylsilane ether; or acetyl ester (-OC(=O)CH3, -OAc).

[0222] The aldehyde or ketone group can be protected, for example, as an acetal (R-CH(OR)2) or a ketal (R2C(OR)2), wherein the carbonyl group (>C=O) is converted to a diether (>C(OR)2) by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis with a large excess of water in the presence of an acid.

[0223] The amino group can be protected as, for example, an amide (-NRCO-R) or a carbamate (-NRCO-OR), such as: methylamide (-NHCO-CH3); benzoxyamide (-NHCO-OCH2C6H5, -NH-Cbz or NH-Z); tert-butoxyamide (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamide (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc); 9-fluorenylmethoxyamide (-NH-Fmoc); 6-nitroveratroloxyamide (-NH-Nvoc); 2-trimethylsilylethoxyamide (-NH-Teoc); 2,2,2-trichloroethoxyamide (-NH-Troc); allyloxyamide (-NH-Alloc); or 2(-phenylsulfonyl)ethoxyamide (-NH-Psec).

[0224] Other protecting groups of amines (such as cyclic amino groups and heterocyclic NH groups) include toluenesulphonyl / tosyl and methanesulphonyl / mesyl, benzyl (such as p-methoxybenzyl (PMB)) and tetrahydropyranyl (THP).

[0225] The carboxylic acid group can be protected to form an ester, for example: C 1-7 Alkyl esters (e.g., methyl esters; tert-butyl esters); C 1-7 Halogenated alkyl esters (e.g., C64) 1-7 Trihaloalkyl esters); Tri-C 1-7 Alkylsilyl-C 1-7 Alkyl ester; or C 5-20 Aryl-C 1-7 Alkyl esters (e.g., benzyl ester; nitrobenzene); or may be protected as amides, such as methylamides. Thiol groups may be protected as, for example, thioethers (-SR), such as benzyl thioether; acetamidomethyl ether (-S-CH2NHC(=O)CH3).

[0226] pharmaceutical preparations The compounds of the present invention are typically administered to patients in the form of pharmaceutical compositions. Therefore, in another embodiment of the invention (Embodiment 4.1), the present invention provides a pharmaceutical composition comprising a compound according to any one of Embodiments 1.1 to 1.125 and a pharmaceutically acceptable excipient.

[0227] In another implementation, the following is provided: 4.2 The pharmaceutical composition according to embodiment 4.1 comprises about 1% (w / w) to about 95% (w / w) of the compound as described in any one of embodiments 1.1 to 1.125 and 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient or combination of excipients, and optionally one or more additional therapeutically active ingredients.

[0228] 4.3 The pharmaceutical composition according to embodiment 4.2 comprises about 5% (w / w) to about 90% (w / w) of the compound as described in any one of embodiments 1.1 to 1.125 and 95% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients, and optionally one or more additional therapeutically active ingredients.

[0229] 4.4 The pharmaceutical composition according to embodiment 4.3 comprises about 10% (w / w) to about 90% (w / w) of the compound as described in any one of embodiments 1.1 to 1.125 and 90% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.

[0230] 4.5 The pharmaceutical composition according to embodiment 4.4 comprises about 20% (w / w) to about 90% (w / w) of the compound as described in any one of embodiments 1.1 to 1.125 and 80% (w / w) to 10% of a pharmaceutically acceptable excipient or combination of excipients.

[0231] 4.6 The pharmaceutical composition according to embodiment 4.5 comprises about 25% (w / w) to about 80% (w / w) of the compound as described in any one of embodiments 1.1 to 1.125 and 75% (w / w) to 20% of a pharmaceutically acceptable excipient or combination of excipients.

[0232] The pharmaceutical compositions of the present invention may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, ocular, ocular, rectal, vaginal, or percutaneous administration. If the composition is intended for parenteral administration, it may be formulated for intravenous, intramuscular, intraperitoneal, or subcutaneous administration, or for direct delivery to the target organ or tissue by injection, infusion, or other means of delivery.

[0233] Drug dosage forms suitable for oral administration include tablets, capsules, pouches, pills, lozenges, syrups, solutions, sprays, powders, granules, elixirs and suspensions, sublingual tablets, sprays, powder tablets or patches and buccal patches.

[0234] Pharmaceutical compositions containing any one of the compounds according to embodiments 1.1 to 1.125 of the present invention can be formulated according to known techniques, see example Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.

[0235] Therefore, tablet compositions may contain a unit dose of the active compound and an inert diluent or carrier, such as sugars or sugar alcohols, such as lactose, sucrose, sorbitol, or mannitol; and / or non-sugar-derived diluents, such as sodium carbonate, calcium phosphate, talc, calcium carbonate, or cellulose or its derivatives, such as methylcellulose, ethylcellulose, hydroxypropyl methylcellulose; and starch, such as corn starch. Tablets may also contain such standard ingredients as binders and granulating agents (e.g., polyvinylpyrrolidone), disintegrants (e.g., expandable crosslinking polymers, such as crosslinked carboxymethyl cellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and foaming agents (e.g., citrate / bicarbonate mixtures). Such excipients are well known and need not be discussed in detail here.

[0236] Capsule formulations can be made from hard or soft gelatin and may contain active ingredients in solid, semi-solid, or liquid form. Gelatin capsules may be formed from animal gelatin or its synthetic or plant-derived equivalents.

[0237] Solid dosage forms (e.g., tablets, capsules, etc.) may be coated or uncoated, but are typically coated, such as with a protective film (e.g., wax or varnish) or a release-controlling coating. The coating (e.g., an Eudragit™ type polymer) can be programmed to release the active ingredient at a desired location within the gastrointestinal tract. Therefore, coatings can be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach, ileum, or duodenum.

[0238] Alternatively, or in addition to coating, the drug may be present in a solid matrix containing a release controller, such as a release delay agent, which is adapted to selectively release the compound under varying acidity or alkalinity conditions in the gastrointestinal tract. Alternatively, the matrix material or release delay coating may be in the form of an erosive polymer (e.g., a maleic anhydride polymer) that is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.

[0239] In one particular embodiment, the pharmaceutical composition of embodiment 4.1 is an enteric-coated solid dosage form, such as a coated tablet or capsule, wherein the coating is selected to be resistant to acidic conditions and degrade under pH conditions prevalent in the duodenum or ileum, thereby selectively releasing the compound in the duodenum or ileum.

[0240] Topical compositions include ointments, creams, sprays, patches, gels, liquid drops, and inserts (e.g., intraocular inserts). Such compositions can be formulated according to known methods.

[0241] Compositions intended for parenteral administration are typically provided as sterile aqueous or oily solutions or fine suspensions, or as sterile powders that can be finely pulverized for temporary reconstitution with sterile water for injection.

[0242] Examples of preparations for rectal or vaginal administration include pessaries and suppositories, which may be formed, for example, from moldable or waxy materials containing active compounds.

[0243] Compositions administered by inhalation may be in the form of inhalable powder compositions, liquids, or powder sprays, and may be administered in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For inhalation administration, powder formulations typically contain an active compound along with an inert solid powdered diluent (such as lactose).

[0244] The compounds of the present invention will generally be presented in unit dosage forms and will therefore generally contain a compound sufficient to provide the desired level of biological activity. For example, according to embodiment 4.1, a composition intended for oral administration may contain 2 mg to 200 mg of the active ingredient, more typically 10 mg to 100 mg, such as 12.5 mg, 25 mg or 50 mg.

[0245] Combination therapy It is envisioned that the compounds of embodiments 1.1 to 1.125 will be available as therapeutic agents alone or in combination with other therapeutic agents.

[0246] The compounds of this invention, designed to enhance mitochondrial bioenergetics by increasing OXPHOS capacity, are intended to be used in combination with the following: ● Reagents to replenish the NAD+ pool; ● Inhibitors of pathways that deplete cellular and mitochondrial NAD+ pools; ● Regulators of mitochondrial biogenesis; ● Activator of retinoid X receptor-α (RXRα); ● SIRT1-activated compound (STAC); ● Mitochondrial-targeting protective compounds that reduce the production of toxic reactive oxygen species; ● Antioxidants; ● Vitamins and supplements; and ● Behavioral intervention.

[0247] Dosimetry The compounds of the present invention as defined in any one of embodiments 1.1 to 1.125 may be administered for a prolonged period to maintain a beneficial therapeutic effect, or may be administered for a short period of time. Alternatively, they may be administered in a pulsed or continuous manner.

[0248] The compounds of this invention will be administered in an effective amount, that is, an amount that effectively produces the desired therapeutic effect. For example, an "effective amount" may be the amount of a compound that improves disease symptoms and / or increases lifespan when administered to an individual.

[0249] The amount of the compound of the invention administered to an individual will depend on the type and severity of the disease or symptom, as well as the individual's characteristics (such as general health, age, sex, weight, and tolerance to the drug). Those skilled in the art will be able to determine the appropriate dosage based on these and other factors.

[0250] The compound is typically administered to an individual who requires such administration, such as a human or animal individual (patient), preferably a human.

[0251] Ultimately, the amount of compound applied and the type of composition used will be appropriate to the nature of the disease or physiological condition being treated, and will be determined by the physician.

[0252] Diagnostic methods Prior to administering any of the compounds in embodiments 1.1 to 1.125, patients may be screened to determine whether the patient has or may have a disease or condition that is sensitive to treatment with compounds that can increase mitochondrial activity. Such patients may then be treated according to the methods described above.

[0253] For example, biological samples taken from a patient can be analyzed to determine whether the patient's existing or potential condition or disease is characterized by a genetic abnormality that leads to mitochondrial dysfunction. The term mitochondrial dysfunction encompasses both reduced mitochondrial production and decreased mitochondrial activity.

[0254] Mitochondrial dysfunction can be caused by exposure to certain environmental factors, such as occupational chemical mutagens, air pollution, and cigarette smoke, or by genetic abnormalities in mitochondrial (mtDNA) and nuclear DNA (nDNA). Mitochondrial dysfunction can affect any organ system and can occur at any age.

[0255] Diagnosing mitochondrial myopathy from patient tissue, skin, or serum samples involves techniques such as histological and immunohistochemical analysis: for example, staining frozen sections of skeletal muscle with a modified Gomori trichrome staining method to indicate the presence of broken red fibers (RRF); succinate dehydrogenase (SDH, complex II) histochemistry, used to detect mitochondrial aggregates formed due to mitochondrial OXPHOS dysfunction; and sequential COX / SDH histochemistry, which can be used to detect cytochrome c oxidase (COX, complex IV) negative fibers. Biochemical enzyme analysis using spectrophotometry to assess OXPHOS complexes (such as NADH: ubiquinone oxidoreductase, complex I; succinate: cytochrome c oxidoreductase, complex II; ubiquinol cytochrome c oxidoreductase, complex III; cytochrome c oxidase, complex IV) and blue native acrylamide PAGE (BN-PAGE) can both be used to detect mitochondrial dysfunction in patient tissue, skin, or serum. Mutations leading to mitochondrial myopathy can be present in either mtDNA or nDNA, and these mutations can be detected using next-generation sequencing (NGS), whole-exome sequencing (WES), whole-genome sequencing (WGS), or a combination of multi-gene targeted detection of candidate genes via NGS. For some patients with mitochondrial myopathy, determining the mtDNA copy number in muscle tissue using real-time PCR is helpful, or long-range PCR can be used to detect large-scale or multiple mtDNA deletions. Furthermore, mtDNA heterogeneity and deletions can be determined using NGS, real-time PCR, pyrosequencing, and long-range PCR.

[0256] In particular, mutations in mtDNA have been identified and linked to mitochondrial dysfunction in the following diseases:

[0257] Other diagnostic tests for mitochondrial myopathy include: measuring lactate levels at rest or after exercise; serum fibroblast growth factor 21 (FGF-21); and serum growth differentiation factor 15 (GDF-15). Integrating the information from these tests can help diagnose most patients with mitochondrial myopathy [Ahmed 2018].

[0258] In vitro applications As described above, the compounds of embodiments 1.1 to 1.125 can be used to improve mitochondrial activity in isolated cells. Such ex vivo methods are envisioned for use in a variety of therapies involving the removal of cells from an individual, modification of the cells, and then reintroduction of the cells into the individual. Examples of such therapies include CAR-T and CAR-NK therapies.

[0259] Therefore, an in vitro method for improving cellular mitochondrial activity is also provided, the method comprising contacting an effective amount of a compound as described in any one of embodiments 1.1 to 1.125 with the cell.

[0260] Example Examples 1 to 50 The compounds in Examples 1 to 50 of Table 1 below are illustrative of the present invention.

[0261] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention as described herein. For convenience, the following common abbreviations are used herein: - ACN: Acetonitrile - Boc: tert-butoxycarbonyl - CV: cylinder volume - DCC: Dicyclohexylcarbodiimide - DCE: 1,2-Dichloroethane - DCM: Dichloromethane - DEAD: Diethyl azodicarbonate - DIAD: Diisopropyl azodicarbonate - DIBAL: Diisobutylaluminum hydride - DIPEA: N,N -Diisopropylethylamine, Hunig's base - DMA: N,N -Dimethylacetamide - DMAP: 4-(dimethylamino)pyridine - DMF: N,N -Dimethylformamide - DMSO: Dimethyl sulfoxide - EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide - h: hours - FCC: Fast Column Chromatography - HATU: N -[(dimethylamino)-1 H -1,2,3-Triazolo-[4,5-b]pyridin-1-ylmethylene]- N -Methylmethyleneimine hexafluorophosphate N-oxide - HBTU:(1 H -benzotriazine-1-yloxy)(dimethylamino)- N,N -Dimethylmethaneimine hexafluorophosphate - HOBT: N -Hydroxybenzotriazole - HPLC: High-performance liquid chromatography - LAH: Lithium Aluminum Hydrogen - IPA: Isopropyl alcohol - LCMS: Liquid Chromatography-Mass Spectrometry - LDA: Lithium diisopropylamino - Min: minutes - MTBE: Methyl tert-butyl ether - MW: Microwave - NBS: N - Bromosuccinamide - NCS: N chlorosuccinamide - NMR: Nuclear Magnetic Resonance - Rbf: Round-bottom flask - RT: Detention Time - SCX-2: A silicon-based adsorbent with chemically bonded propylsulfonic acid functional groups. - SFC: Supercritical Fluid Chromatography - SPE: Solid Phase Extraction - TFA: Trifluoroacetic acid - THF: Tetrahydrofuran General method: Analytical methods Liquid chromatography-mass spectrometry LCMS - Method 1 UPLC-MS was performed on a Waters DAD + Waters SQD2 single quadrupole UPLC-MS spectrometer: an Acquity UPLC HSS Shield RP18 1.7μm 100×2.1 mm (Plus guard column) was used, the temperature was maintained at 40℃, and the column was initially prepared with 5% acetonitrile (far UV grade) + 0.1% ( v / v Formic acid / water (high purity, obtained via PureLab Option device) (containing 0.1% formic acid) was maintained for 0.4 min, followed by a 5-95% linear gradient over 6.4 min, and then maintained for 1.2 min in 95% acetonitrile (F = 0.4 mL / min).

[0262] LCMS - Method 2 LC-MS was performed on an Agilent 1290 Infinity II UHPLC system equipped with an Agilent 1290 DAD and an Agilent Model 6125C single quadrupole mass spectrometer: an Acquity UPLC CSH C18 1.7μm 50×2.1mm column was used, the temperature was maintained at 40℃, and the column was initially prepared in high-purity water (Milli-Q) with 5% acetonitrile (LC-MS grade) + 0.1% ( v / v Hold in formic acid for 0.4 minutes, then perform a linear gradient of 5-95% acetonitrile over 1.5 minutes, and then hold in 95% acetonitrile for 0.5 minutes at a flow rate of 0.8 mL / min.

[0263] LCMS - Method 3 LC-MS was performed on an HPLC-ESI-MS instrument equipped with a UV-VIS (Nexera-I LC-2040C Plus) and an MS detector (LCMS2020 single quadrupole Shimadzu): a reversed-phase column (Halo C18®, C18, 2.7 µm, 50 × 4.6 mm) was used, the temperature was maintained at 40 °C, and the column was initially prepared in high-purity water (Milli-Q) with 5% acetonitrile (LC-MS grade) + 0.1% ( v / v Hold for 1 minute in formic acid, then perform a linear gradient of 5-95% acetonitrile over 2.5 minutes, followed by a constant concentration of 95% acetonitrile for 1.5 minutes at a flow rate of 0.7 mL / min.

[0264] LCMS - Method 4 LC-MS was performed on an Agilent UHPLC-ESI-MS instrument comprising a binary pump (Agilent G7120A), a mass spectrometer detector (Agilent single quadrupole G6125C), a diode array detector (Agilent G7117B), and an ELSD (Agilent 1260 Infinity II G4260B). A reversed-phase column (ACQUITY UPLC HSS T3, 100 Å, 1.8 µm, 2.1 mm × 100 mm) was used, maintained at 40 °C. The column was initially held for 0.4 min in 95% LC-MS grade water + NH4OAc (0.1% v / v), followed by a linear gradient of 5–95% acetonitrile over 1.5 min, and then held at an isoconcentration of 95% acetonitrile for 0.5 min at a flow rate of 0.8 mL / min.

[0265] LCMS - Method 5 LC-MS was performed on an Agilent 1290 series instrument equipped with a UV detector, an ELSD 1290 detector, and an Agilent 6120 detector: a Waters Atlantis T3 (4.6 × 100 mm; 3 μm) column was used, initially in 100% high-purity water (Milli-Q) + 0.05% ( v / v Hold in trifluoroacetic acid for 2 minutes, then perform a linear gradient of 0-90% acetonitrile (LC-MS grade) over 3 minutes, and then hold in 90% acetonitrile for 4 minutes at a flow rate of 1.0 mL / min.

[0266] LCMS - Method 6 LC-MS was performed on an Agilent UHPLC-ESI-MS instrument comprising a binary pump (Agilent G7120A), a mass spectrometer detector (Agilent single quadrupole G6125C), a diode array detector (Agilent G7117B), and an ELSD (Agilent 1260 Infinity II G4260B). A reversed-phase column (ACQUITY UPLC HSS T3, 100 Å, 1.8 µm, 2.1 mm × 100 mm) was used, and the temperature was maintained at 40 °C. The column was initially held for 0.4 min in 100% LC-MS grade water + NH4OAc (0.1% v / v), followed by a linear gradient of 0–50% acetonitrile over 1.5 min, and then held at an isoconcentration of 50% acetonitrile for 0.5 min at a flow rate of 0.8 mL / min.

[0267] NMR Unless otherwise stated, 11H nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker or Jeol resonance instrument operating at 400 MHz or 500 MHz, with the solvent used at approximately room temperature. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) were given in parts per million, using conventional abbreviations to denote the main peak: for example, s: singlet; d: doublet; t: triplet; q: quartet; dd: double doublet; dt: double triplet; m: multiplet; br: broad peak.

[0268] Chiral supercritical fluid chromatography (SFC) method 1 Enantiomer analysis of compounds was performed using supercritical fluid chromatography (SFC) on a Waters Acquity UPC2 system equipped with a UV detector and a QDA detector. The standard SFC method used a Daicel Chiralpak IC-3 (3.0 × 150 mm, 3 μm) column at 40 °C; a flow rate of 1.2 mL / min; and gradient conditions (2:98 methanol:CO₂ 0.0–4 min; 25:75 4–4.1 min; 98:2 4.1–5 min; 0.2%). v / v NH3), 125 bar back pressure, 1.0 μL injection volume, and analysis at 212 nm using SFC (Waters / Thar SFC system with Waters SQD).

[0269] Chiral supercritical fluid chromatography (SFC) method 2 Enantiomer analysis of compounds was performed using a Waters SFC system via supercritical fluid chromatography (SFC). The standard SFC method employed a Chiralpak IG (4.6 mm × 250 mm, 5 μm) column at 40 °C; a flow rate of 4 mL / min; and isostatic conditions (25:75 ethanol:CO2 (0.2%)). v / v NH3), 125 bar back pressure, 1.0 μL injection volume, and analysis at 210–400 nm using SFC (Waters / Thar SFC system with Waters SQD).

[0270] Purification methods Preparative reversed-phase HPLC conditions Preparative HPLC purification was performed by reversed-phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996 / 2998 UV / VIS detector, 2767 liquid processor) or an equivalent HPLC system (such as the Gilson Trilution UV-oriented system). The Waters 2767 liquid processor served as both the autosampler and fraction collector. The columns used for preparative purification of the compounds were either a YMC Triart C18 100×20 mm, 5 μm or a Chromatorex 18 SMB100-5T 100×19 mm, 5 μm. Appropriate focusing gradients were selected based on the acetonitrile and methanol solvent system under acidic or basic conditions. The modifiers used under acidic / basic conditions were trifluoroacetic acid (0.1%). v / v ) or NH4OH (0.1%) v / v Purification was controlled by Waters Fractionlynx software: the collection threshold was triggered at 260 nm by monitoring the 210–400 nm range, and the presence of the target molecular ion was observed under API conditions when using Fractionlynx. The collected fractions were analyzed by LCMS (Waters Acquity system with Waters SQD).

[0271] synthesis This document describes several methods for the chemical synthesis of the heterocyclic formamide compounds of this application. These and / or other well-known methods can be modified and / or adapted in various ways to facilitate the synthesis of additional compounds within the scope of this application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Therefore, the methods set forth in the following description, schemes, and examples are intended for illustrative purposes and should not be construed as limiting the scope of this disclosure.

[0272] Option 1 In one method (Scheme 1), by reacting allylamine of general formula (11) with (3) E Compounds of formula (13) are prepared by reacting 4-methoxybut-3-en-2-one (12) in a polar aprotic solvent (such as THF or dioxane). The reaction is carried out at ambient temperature, and the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization after post-reaction treatment (typically liquid-liquid extraction) to obtain secondary allylamine of general formula (13).

[0273] N-(14) of general formula (13) is prepared by reacting secondary allylamine of general formula (13) with di-tert-butyl dicarbonate in a polar aprotic solvent (such as THF or dioxane) in the presence of a sterically hindered base (such as potassium tert-butoxide). Boc Protected allylamine compounds. The reaction is preferably carried out at ambient temperature, and the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization after post-reaction treatment (usually liquid-liquid extraction) to obtain N- compounds of general formula (14). Boc Protected allylamine.

[0274] Bicyclic compounds of general formula (15) are prepared by photocyclization of compounds of general formula (14). Boc The protected amino compound undergoes photocyclization via irradiation in a polar aprotic solvent (such as ACN) using a UV radiation source, particularly UV light with a wavelength of 300-400 nm. The reaction is carried out at ambient temperature in a batch reactor or in a continuous flow reaction apparatus. Following post-reaction treatment (typically liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization to obtain a bicyclic N-[formula missing] of general formula (15). Boc Protected amino compounds.

[0275] In the haloform reaction, the bicyclic N- group of general formula (15) is oxidized by the reaction of bromine with a strong inorganic base (such as sodium hydroxide or potassium hydroxide). Boc The carboxylic acid derivative of general formula (16) is prepared by using a protected amino compound, and the reaction is preferably carried out at 0°C with H2O as the solvent. After post-treatment (usually by adding sodium sulfite solution, followed by acidification to pH 2 with NaHSO4 solution and liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC or recrystallization to obtain the carboxylic acid derivative of general formula (16).

[0276] Intermediate A: 2-[(tert-butoxy)carbonyl]-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid Step A synthesis( 3E )-4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one Add ( ) to a stirred solution of 2-methylprop-2-en-1-amine (20 g, 281 mmol, 26 mL, 1.05 eq.) in THF (500 mL) 3E )-4-methoxybut-3-en-2-one (27 g, 267 mmol). After stirring at room temperature for 18 h, the reaction mixture was concentrated under reduced pressure to give a pale yellow oil. 3E4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one (40.0 g, 97% yield) was used directly in the next step without further purification. LCMS (Method 1) RT = 0.85 min, m / z : [ESI + 140.2 (M+H) + .

[0277] Step B synthesis N -(2-Methylpropyl-2-en-1-yl)- N -[( 1E 3-O-But-1-en-1-yl]tert-butyl carbamate Towards( 3E 4-[(2-methylprop-2-en-1-yl)amino]but-3-en-2-one (40 g, 287 mmol) was added fractionally to a stirred solution cooled to 0°C in THF (1000 mL) with sodium tert-butoxide (27 g, 284 mmol, 1.1 eq.). After the addition was complete, di-tert-butyl dicarbonate (56 g, 258 mmol, 1.0 eq.) was added, and the mixture was stirred for another 3 h. After the reaction was complete, the solvent was removed under reduced pressure. MTBE (400 mL) was added, and the organic layer was washed with brine. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give a pale yellow oil. N -(2-Methylpropyl-2-en-1-yl)- N -[( 1E 3-O-But-1-en-1-yl]tert-butyl carbamate (52 g, 84% yield). LCMS (Method 1) RT = 1.29 min, m / z : [ESI + 140.2 (M+H-56) + . 1 H NMR (400 MHz, CDCl3): δ8.18 (d, 1H); 5.48 (d, 1H); 4.88 (s, 1H); 4.69 (s, 1H); 4.09 (s, 2H); 2.23(s, 3H); 1.71 (s, 3H); 1.53 (s, 9H).

[0278] Step C Synthesis of tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate Will N -(2-Methylpropyl-2-en-1-yl)- N -[( 1EA stirred solution of tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (10.0 g, 42 mmol) in ACN (1000 mL) was irradiated with a UV lamp (350 nm) for 3.3 h in a flow reactor at a flow rate of 2.5 mL / min. The reaction mixture was then concentrated under reduced pressure and purified by rapid column chromatography to give tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (4.0 g, 47% yield) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3): δ 4.55 (br d, 1H); 3.26 (br d, 1H); 2.99 (m, 1H); 2.40 (s, 1H); 2.05 (s, 3H); 1.48 (m, 2H); 1.43 (s, 9H); 1.37 (s, 3H).

[0279] Step D Synthesis of 2-[(tert-butoxy)carbonyl]-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid Bromine (1.67 g, 10 mmol, 5.0 eq.) was added dropwise to a stirred solution of sodium hydroxide (836 mg, 21 mmol, 10.0 eq.) in water (4 mL) at 0 °C. The reaction mixture was then stirred for 0.5 h, and a solution of tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid (500 mg, 2.1 mmol) in dioxane (2 mL) was carefully added. The solution was then stirred for another 4 h at room temperature. The reaction mixture was quenched with sodium sulfite solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated under reduced pressure to give 2-[(tert-butoxy)carbonyl]-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (400 mg, 93% yield) as a colorless solid. LCMS (Method 1) RT = 1.15 min, m / z: [ESI+] 240.2 (MH) - . 1 ¹H NMR (400 MHz, CDCl₃): δ 4.50 (br s, 1H); 3.36 (d, 1H); 3.05 (d, 1H); 2.48 (s, 1H); 1.56 (d, 1H); 1.43 (s, 9H); 1.43 (d, 1H); 1.35 (s, 3H), No exchangeable protons observed.

[0280] Option 2 Using procedure (Scheme 2), by reacting a carboxylic acid derivative of general formula (16) with a suitable Hal-R... a The compounds of formula (17) are prepared by reacting alkyl halides (where Hal is selected from Cl, Br, and I) in a polar aprotic solvent (such as DMF or DMA) with a suitable base (such as potassium carbonate or cesium carbonate). The reaction is carried out at ambient temperature or at high temperature depending on the reactivity. After post-reaction treatment (usually liquid-liquid extraction), the reaction products are purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization.

[0281] In R a In the example of methyl, compounds of formula (17) are prepared by reacting a carboxylic acid derivative of general formula (16) with a methylating agent (such as diazomethane) in a polar aprotic solvent (such as MTBE or THF), said reaction being carried out at 0°C or ambient temperature. Following post-reaction treatment (typically liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization.

[0282] Compounds of general formula (4) are obtained through general N- Boc The preparation involves a deprotection step, such as reaction with TFA or hydrochloric acid in a polar solvent (e.g., 1,4-dioxane) and a co-solvent (e.g., DCM or diethyl ether). Following post-reaction treatment (typically ion-exchange purification or liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization.

[0283] Example 1: ( 1R, 4S, 5S 2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester hydrochloride Step A synthesis( 1R, 4S, 5S )-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid Add 81.7 g, 0.35 mol of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS1279894-35-7, 81.7 g, 0.35 mol) to a stirred solution of 2-[tert-butoxy]carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid in 2000 mL of THF to a stirred solution at room temperature for 0.1 h. R -( + 1-Phenylacetylamine (47 mL, 0.37 mol, 1.1 eq.). The mixture was then filtered, the resulting solid was collected, and recrystallized from a minimal amount of THF and filtered. The resulting crystalline material was further recrystallized from a minimal amount of ACN and filtered. The filtered solid was suspended in ethyl acetate (200 mL) and treated with 2... N Dissolve separately in hydrochloric acid (200 mL). Extract the organic phase, dry (Na2SO4), and concentrate under reduced pressure to obtain a pale yellow oil (1... R 4S 5 S )-2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (20 g, 49% yield). 1 ¹H NMR (400 MHz, CDCl₃): δ 4.60 (d, 1H), 3.60 (d, 1H), 3.30 (d, 1H), 3.32 – 3.29 (m, 1H), 2.82 – 2.80 (m, 1H), 1.81 – 1.78 (m, 1H), 1.42 (d, 9H), 1.38 (m, 1H); Chiral SFC (Method 1) RT 3.28 min (99%) ee ).

[0284] Step B synthesis( 1R, 4S, 5S methyl 2-azabicyclo[2.1.1]hexane-5-carboxylate Towards( 1R, 4S, 5S 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS 615575-74-1, 20.0 g, 88 mmol) was added dropwise to a stirred suspension of thionyl chloride (19 mL, 260 mmol) in methanol (100 mL) at 0 °C. The mixture was then heated to room temperature and stirred overnight. The resulting solid was then collected by filtration and air-dried to give the title compound (15 g, 96% yield) as a colorless solid. LCMS (Method 1) RT = 0.69 min, m / z :[ESI + 142.12 (M+H) + Chiral SFC (Method 2) RT 1.77 min (98%) ee ); 1 H NMR (400 MHz, CDCl3): δ 10.42 (br s, 1H), 9.18 (br s, 1H), 4.47 – 4.44 (m, 1H), 3.72 (s,3H), 3.59 – 3.57 (m, 2H), 3.04 – 3.01 (m, 1H), 2.85 – 2.82 (m, 1H), 1.87 –1.85 (m, 1H), 1.68 – 1.62 (m, 1H).

[0285] X-ray crystallography analysis Single crystals of the compound of Example 1 were prepared and subjected to X-ray crystallography as described below.

[0286] experiment: The compound was obtained as a single, colorless, massive crystal by recrystallization from methanol. A suitable crystal size of 0.05 × 0.04 × 0.03 mm was selected. 3 The data were collected using a Hampton Research CryoLoop™ diffractometer mounted on a Rigaku XtaLAB Synergy-S diffractometer equipped with a HyPix-6000HE detector and an Oxford Cryosystems Cobra cooling unit. The crystal was kept constant at 100 K during data collection.

[0287] Data were generated using CuKα radiation. The maximum resolution achieved was θ = 69.977° (0.82 Å). Data simplification, scaling, and absorption correction were performed. The final integrity was 100% at θ 69.977°. A total of 8295 reflections (12.204° ≤ 2θ ≤ 139.954°) and 1619 unique reflections (Rint = 0.0306, Rsigma = 0.0204) were measured and used in all calculations. The absorption coefficient μ of the compound was determined to be 3.580 mm at wavelength (λ = 1.54184 Å). -1 .

[0288] Data was collected and processed using Rigaku CrysAlisPro software (Rigaku Oxford Diffraction, 2020), and the structure was analyzed using the ShelXTL (Sheldrick, 2013) structure parser with a direct method and Olex2 (Dolomanov et al., 2009) as the graphical interface. The model was improved using the 2014 / 6 version of ShelXL (Sheldrick, 2014) with least squares minimization.

[0289] All non-hydrogen atoms were anisotropically refined. The positions of hydrogen atoms were calculated geometrically and refined using a riding model.

[0290] Based on the collected data, the crystal structure of the compound was characterized as follows: Crystal system: Orthorhombic Space group P212121 Cell size a = 7.96499(16) Å a = 90° b = 9.35289(19)Å b = 90° c = 11.4872(2) Å g = 90° Volume = 855.75(3) Å 3 R factor = 2.04% Absolute stereochemistry: C2: S configuration; C4: R configuration; C5: S configuration.

[0291] Flack parameter(x) = -0.003(7) References: OV Dolomanov and LJ Bourhis and RJ Gildea and JAKHoward and H. Puschmann, Olex2: A complete structure solution, refinement and analysis program, J. Appl. Cryst., (2009), 42, 339-341. Sheldrick, GM, Crystal structure refinement with ShelXL, ActaCryst., (2015), C71, 3-8. Sheldrick, GM, ShelXT-Integrated space-group and crystal-structure determination, Acta Cryst., (2015), A71, 3-8. Example 2: 4-Methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester hydrochloride Step A Synthesis of 4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-(tert-butyl)5-methyl ester To a stirred suspension of 2-[(tert-butoxy)carbonyl]-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (3.7 g, 15.3 mmol) in MTBE (150 mL) at 0 °C, 100 mL of MTBE containing 1.2 eq. of diazomethane was added dropwise. The reaction mixture was stirred at room temperature for 0.5 h, followed by concentration under reduced pressure to give 2-(tert-butyl)-5-methyl 4-methyl-2,5-dicarboxylic acid (3.2 g, 95% yield) as a pale yellow oil. LCMS (Method 1) RT = 1.31 min, m / z : [ESI + 156.2 (M+H-100) + . 1H NMR (400 MHz, CDCl3): δ 4.48 (br d,1H); 3.59 (s, 3H); 3.30 (dd, 1H); 3.01 (br d, 1H); 2.43 (s, 1H); 1.51 (d,1H); 1.42 (s, 9H); (d, 1H); 1.34 (s, 3H).

[0292] Step B Synthesis of methyl 4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride Add 4 methyl ester (1.0 g, 3.92 mmol) of 2-tert-butyl 2,5-dicarboxylate to 4-methyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylate-5-methyl ester. N A solution of hydrogen chloride in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 18 h and filtered. The resulting solid was washed with diethyl ether to give methyl 4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride (447 mg, 69% yield) as a colorless solid. LCMS (Method 1) RT = 0.24 min, m / z : [ESI + 156.2 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6): δ 10.17 (br s, 1H); 8.79 (br s, 1H); 4.27 (s,1H); 3.61 (s, 1H); 3.06 (s, 2H); 2.95 (s, 1H); 1.73 (d, 1H); 1.51 (d, 1H);1.31 (s, 3H).

[0293] Example 3: 4-Phenyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester trifluoroacetate Step A Synthesis of 2-(tert-butyl)-5-methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid. TMS-diazomethane (2.8 mL, 2.0 M in diethyl ether, 5.5 mmol, 1.2 eq.) was added dropwise to a stirred solution of 2-(tert-butoxycarbonyl)-4-phenyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (1.4 g, 4.6 mmol, 1.0 eq.) in toluene (46 mL) and methanol (23 mL). The mixture was then stirred at room temperature for 20 h. Subsequently, the reaction mixture was concentrated under reduced pressure and purified by rapid column chromatography to give 2-(tert-butyl)-5-methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid as a colorless oil (1.09 g, 74% yield). 1 H NMR (400 MHz, CDCl3)δ 7.36 – 7.30 (m, 3H), 7.23 – 7.20 (m, 2H), 4.60 (d, J = 2.03 Hz, 1H) 3.68 (dd, J = 8.8, 1.6 Hz, 1H), 3.48 (d, J = 8.84, 3H), 3.19 (dt, J = 7.7, 1.9 Hz, 1H), 3.06(d, J = 7.2, 1.8 Hz, 1H), 1.97 (t, J = 7.7, 1H) 1.99 – 1.95 (m, 1H), 1.49 (s, 9H).

[0294] Step B Synthesis of methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-5-carboxylate trifluoroacetate TFA (485 µL, 6.30 mmol, 10.0 eq.) was added to a stirred solution of 2-(tert-butyl)-5-methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid (100 mg, 0.32 mmol, 1.00 eq.) in DCM (9.2 mL), and the mixture was stirred at room temperature for 3 h. The mixture was then concentrated under reduced pressure. The resulting residue was dissolved in methanol, and the mixture was stirred overnight at 40 °C. The solution was concentrated under reduced pressure to give methyl 4-phenyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid trifluoroacetate (71 mg, 68% yield) as a yellow oil. LCMS (Method 3) RT 2.94 min, m / z :[ESI + 218 (M+H) + . 1H NMR (400 MHz, CDCl3) δ 11.67 (s, 1H), 8.69 (s, 1H), 7.42– 7.32 (m, 3H), 7.32 – 7.27 (m, 2H), 4.52 (t, J = 1.8 Hz, 1H), 3.87 – 3.81 (m,1H), 3.78 (s, 3H), 3.75 – 3.68 (m, 1H), 3.14 – 3.10 (m, 1H), 2.27 (dd, J = 9.0, 1.0 Hz, 1H), 2.15 (dt, J = 9.0, 1.9 Hz, 1H).

[0295] Option 3 Using procedure (Scheme 3), compounds of formula [F3-1] are prepared by reacting carboxylic acid derivatives of general formula [F1-5] with alcohol derivatives of formula [F3-2] using a chlorinating agent (such as thionyl chloride). The reaction is carried out at 0°C or ambient temperature. After post-reaction treatment (typically liquid-liquid extraction), the reaction products are purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization.

[0296] Example 4: Ethyl 2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride A solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (50 mg, 0.22 mmol) in ethanol (1 mL) at 0 °C was added with thionyl chloride (16 µL, 0.22 mmol, 1 eq.). The mixture was heated to room temperature and stirred overnight. The crude reaction mixture was then concentrated under reduced pressure to give ethyl 2-azabicyclo[2.1.1]hexane-5-carboxylic acid hydrochloride (35.9 mg, 86% yield) as a grayish-white solid. LCMS (Method 2) RT = 0.15 min, m / z :[ESI + 156.0 (M+H) + . 1 H NMR (400 MHz, DMSO- d6): δ 9.98 (br s, 1H), 8.76 (br s,1H), 4.38 – 4.32 (m, 1H), 4.19 – 4.11 (m, 2H), 3.46 – 3.39 (m, 2H), 3.24 –3.15 (m, 1H), 3.12 – 3.04 (m, 1H), 1.97 – 1.91 (m, 1H), 1.75 – 1.70 (m, 1H), 1.39 – 1.31 (m, 3H).

[0297] According to Scheme 3, the following compounds were prepared using the method described above:

[0298] Example 9: (1R,4S,5S)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester hydrochloride Step A synthesis( E 2-Methylallyl)(3-oxobut-1-en-1-yl)tert-butyl carbamate A solution of butyninone (147 g, 2.16 mol, 1.03 eq.) in DCM (400 mL) was added dropwise to a stirred solution of methylallylamine (147 g, 2.1 mol) in DCM (1500 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 16 h. Subsequently, the mixture was concentrated under reduced pressure, dissolved in DCM, and cooled to 0 °C. Boc Acid anhydride (450 g, 2.07 mol, 1.0 eq.) was added, followed by the addition of DMAP (3 g, 0.02 mol, 0.001 eq.). The mixture was then stirred at room temperature for 80 h. Subsequently, the reaction mixture was concentrated under reduced pressure and filtered through a silica gel stopper, eluting with a mixture of ethyl acetate / DCM to give a dark syrup. E 3-(2-methylallyl)(3-oxobut-1-en-1-yl)carbamate tert-butyl ester (385 g, 78% yield). This substance was used directly in step B without further purification.

[0299] Step B Synthesis of tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate Towards( E 41 g (170 mmol) of tert-butyl 2-(2-methylallyl)(3-oxobut-1-en-1-yl)carbamate was added to a stirred solution of 2-butanone (900 mL) to a stirred solution of tris[2-(4,6-difluorophenyl)pyridinyl-C] 2 , NIridium(III) (1.2 g, 1.6 mmol, 0.01 eq.). The mixture was transferred to a photoreactor, exposed to two light sources (UV light + blue light), and passed through the reactor. After completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylate, which was used in the next step without further purification.

[0300] Step C Synthesis of 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid A sodium hypochlorite solution (approximately 14%, 400 mL) was added to a round-bottom flask and cooled to 15°C. ACN (200 mL) containing tert-butyl 5-acetyl-4-methyl-2-azabicyclo[2.1.1]hexane-2-carboxylic acid was added to the solution. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. Subsequently, the mixture was aliquoted with MTBE (200 mL), and the aqueous phase was acidified to pH 2 and extracted with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give 31 g (50% yield, in two steps) of syrupy 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid.

[0301] Step D synthesis( 1R, 4S, 5S )-2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid The stirred suspension of 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (302 g, 0.68 mol) in ACN (2 L) was refluxed. S A stirred solution of phenylglycine (94 g, 0.69 mol, 1.01 eq.) was dissolved in ACN (2 L) and added dropwise to the reflux mixture. The reaction mixture was stirred under reflux for 0.5 h and then cooled to room temperature. The resulting suspension was filtered, and the filter cake was washed with ACN to give (1 eq.) in the form of phenylglycine salt. R 4 S 5 S 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (110 g, 85% yield). Chiral HPLC: 99.4% ee .

[0302] To (1) R 4 S 5 S51 g, 0.13 mol of glycanol salt of hexane-5-carboxylic acid (2.1.1) in a stirred suspension in DCM (1 L) was mixed with an aqueous solution of KHSO4 (21 g, 0.15 mol, 500 mL). The two-phase mixture was stirred for 0.2 h, and then each phase was extracted. The aqueous layer was extracted with DCM, and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain a grayish-white solid. 1R, 4S, 5S 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (30 g, 90% yield). LCMS (Method 3) RT = 1.65 min, m / z :[ESI + 242.2 (M+H) + .

[0303] X-ray crystallography analysis Preparation of intermediates in the form of phenylglycine salts ( 1R, 4S, 5S Single crystals of 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid were obtained and subjected to X-ray crystallographic studies as described below.

[0304] experiment: Data collection. Single colorless, bulky single crystals of the compound were obtained by recrystallization from methanol / ACN. The measured crystals were prepared under inert conditions and immersed in a perfluoropolyether as a protective oil for operation. Crystal structure determination was performed using an Apex DUO Kappa 4-axis goniometer equipped with an APPEX2 4K CCD area detector, a Microfocus Source E025 IuS using CuKα radiation (1.54178 Å), a Quazar MX multilayer optics as a monochromator, and an Oxford Cryosystems Cryostream 700+ cryogenic apparatus (T=-173℃). Global surface data collection was combined with both ᵚ and ᵠ scans. Procedure used: Data collection APEX-2 1 Data simplification Bruker Saint 2 V / .60A and absorption correction SADABS 3 .

[0305] Structural analysis and refinement. Using tools such as SHELXT. 4 The direct method implemented in the paper achieves crystal structure resolution, and the program SHELXe is used. 5Visualization was then performed. Missing atoms were then located using difference Fourier synthesis and added to the atom list. This was done using the SHELXL program. 6 Perform intensity measurements on F using all measured values. 2 The least squares method is used for refinement. Refinement is performed on all non-hydrogen atoms, including anisotropic shift parameters.

[0306] Structural description. This compound is in monoclinic chiral space group. P Crystallization in 21. The absolute configuration is determined relative to the known chiral centers S(C7A), S(C1B), R(C4B), and S(C5B). Alternatively, the absolute configuration can be directly specified based on the anomalous dispersion effect. It can be determined using Parsons' quotient 0.11(10). 7 The Flack value reliably determines the absolute structure. The Flack parameter value used to determine whether the absolute structure is correct should be 0; if the structure is flipped, the value should be 1; the standard deviation should always be considered. The measured structure has excellent quality (no Class A or Class B alarms), where R 1 The value is 3.38%.

[0307] Based on the collected data, the crystal structure of the compound was characterized as follows: Crystal system: Monoclinic Space Group: P twenty one Cell size a = 11.922(3) Å α = 90 ° b = 6.0887(18)Å β = 110.765(7) ° c = 15.212(4) Å γ = 90 ° Volume = 1032.5(5) Å 3 References 1 Data collection with APEX II versions v2013.4-1. Bruker (2007). Bruker AXS Inc., Madison, Wisconsin, USA. 2 Data reduction with Bruker SAINT versions V8.30c. Bruker (2007). Bruker AXS Inc., Madison, Wisconsin, USA. 3 SADABS: V2012 / 1 Bruker (2001). Bruker AXS Inc., Madison, Wisconsin, USA. Blessing, Acta Cryst. (1995) A51 33-38. 4 SHELXT V2014 / 4 (Sheldrick 2014). Sheldrick, GM Acta Cryst. 2015,A71, 3-8. 5 SHELXle; CB Huebschle, GM Sheldrick&B. Dittrich; J. Appl. Cryst.2011, 44, 1281-1284. 6 SHELXL; SHELXL-2014 / 7 (Sheldrick 2014). Sheldrick, GM Acta Cryst.2015, C71, 3-8. 7 Flack HD, Acta Cryst. A39 (1983) 876, Parsons S.;, Flack H., Acta Cryst. A39 (2004) S61, Parson, Flack and Wagner, Acta Cryst. B69 (2013) 249-259; (2014)B70, 660-668; Flack X determined using 1202 quotients [(I+)-(I-)] / [(I+)+(I-)]) Step E synthesis( 1R, 4S, 5S Synthesis of methyl 4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride Towards( 1R, 4S, 5S 2-(tert-butoxycarbonyl)-4-methyl-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (160 mg, 0.66 mmol, 1 eq.) was added to a stirred 0°C solution of methanol (5 mL) to a solution containing thionyl chloride (150 mL, 2.1 mmol, 3 eq.). The reaction mixture was heated to room temperature and stirred for 1 h. The mixture was then concentrated under reduced pressure to give a brown syrup. 1R, 4S, 5S 4-Methyl-2-azabicyclo[2.1.1]hexane-5-carboxylate hydrochloride (125 mg, 99% yield). LCMS (Method 3) RT = 0.34 min, m / z : [ESI + 156.40 (M+H) + . 1 H NMR (400 MHz, CD3OD): δ 4.40 (t, J = 1.6 Hz, 1 H), 3.80 (s, 3H), 3.28 – 3.35 (m, 3H), 1.98(d, J = 8.9 Hz, 1H), 1.64 (dd, 3J = 8.9 Hz, 4J = 0.8 Hz, 1H), 1.50 (s, 3H).

[0308] Option 4 In one method (Scheme 4), compounds of formula [F3-1] are prepared by reacting carboxylic acid derivatives of general formula [F1-5] with amines of general formula [F4-3] in the presence of a tertiary amine base (such as triethylamine, DIPEA, or NMM) in a polar aprotic solvent (such as DMA or DMF) using a suitable coupling agent (such as HBTU or HATU). After post-reaction treatment (typically liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization to obtain amide heterocyclic compounds of general formula [F3-1]. Compounds of general formula [F3-3] are purified by general N- Boc The preparation involves a deprotection step, such as reaction with TFA or HCl in a polar solvent (e.g., DCM or diethyl ether). Following post-treatment (typically ion exchange purification or liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization. Compounds of general formula [F3-4] are prepared from compounds of general formula [F3-3] by treatment with a base (e.g., aminopolystyrene resin) in a halogenated solvent (e.g., DCM). The reaction is carried out at ambient temperature, and the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization after post-treatment (typically filtration). In some instances, compounds of general formula [F3-4] are prepared by general N- BocThe deprotection step (such as reaction with TFA or HCl in a polar solvent (such as DCM or diethyl ether)) is performed directly from a compound of general formula [F3-1]. Following post-reaction treatment (typically with a weak base (such as a saturated aqueous solution of NaHCO3), followed by liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization.

[0309] Example 10: ( 1S, 4R, 5R 2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester hydrochloride Step A synthesis( 1S, 4R, 5R )-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid Add to a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (CAS1279894-35-7, 290 g, 1.28 mol) in 1500 mL of THF at room temperature for 0.1 h. S -(-)-1-Phenylacetamine (75 g, 0.62 mol, 0.5 eq.). The mixture was then filtered, the resulting solid was collected, and recrystallized from a minimal amount of THF and filtered. The resulting crystalline material was further recrystallized from a minimal amount of ACN and filtered. The filtered solid was suspended in ethyl acetate (200 mL) and 2... N HCl (600 mL). Separate the organic phase, dry (Na2SO4), filter and concentrate under reduced pressure to obtain a yellow oily substance. 1S, 4R, 5R 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (42 g, 28% yield). Chiral SFC (Method 1) RT 4.06 min (99%) ee ). 1 H NMR (400 MHz, CDCl3): δ 4.60(d, 1H), 3.60 (d, 1H), 3.30 (d, 1H), 3.30 – 3.26 (m, 1H), 2.85 – 2.74 (m,1H), 1.83 – 1.79 (m, 1H), 1.42 (d, 9H), 1.40 – 1.37 (m, 1H).

[0310] Step B synthesis( 1S, 4R, 5R 2-azabicyclo[2.1.1]hexane-5-carboxylic acid methyl ester hydrochloride Towards( 1S, 4R, 5R40 g (0.18 mmol) of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid was added dropwise to a stirred suspension in methanol (240 mL) at 0 °C. The mixture was then heated to room temperature and stirred for 16 h. The resulting solid was then collected by filtration and air-dried to obtain a colorless solid (…). 1S, 4R, 5R 2-azabicyclo[2.1.1]hexane-5-carboxylate methyl hydrochloride (25 g, 80% yield). LCMS (Method 1) RT = 0.69 min, m / z : [ESI + 142.12 (M+H) + Chiral SFC (Method 2) RT 2.63 min (98%) ee ). 1 HNMR (400 MHz, CDCl3): δ 10.42 (br s, 1H), 9.18 (br s, 1H), 4.49 – 4.38 (m,1H), 3.72 (s, 3H), 3.63 – 3.55 (m, 2H), 3.09 – 3.00 (m, 1H), 2.86 – 2.81 (m,1H), 1.91 – 1.79 (m, 1H), 1.69 – 1.62 (m, 1H).

[0311] Option 5 In one method (Scheme 5), compounds of formula [F5-2] are prepared by reacting a carboxylic acid derivative of general formula [F1-5] with an alcohol of general formula [F5-1] in a polar aprotic solvent (such as THF or DMF), in the presence of a nucleophilic catalytic base (such as DMAP), using a suitable carbodiimide coupling agent (such as DCC). After post-reaction treatment (typically liquid-liquid extraction), the reaction product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization to obtain the azabicyclic ester compound of general formula [F5-2]. Compounds of general formula [F5-3] are purified by general N- Boc The product is prepared by removing protecting groups, such as reacting with TFA or HCl in a polar solvent (e.g., DCM or diethyl ether). Following post-reaction treatment (typically ion exchange purification or liquid-liquid extraction), the product is purified by rapid column chromatography, reversed-phase preparative HPLC, or recrystallization.

[0312] Example 11: 1,1-dioxatetrahydro-2-(2-azabicyclo[2.1.1]hexane-5-carboxylic acid) H -Thiopyran-4-yl ester hydrochloride Step A Synthesis of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-(tert-butyl)5-(1,1-dioxotetrahydro-2H-thio) (4-pyranyl ester) To 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (600 mg, 2.64 mmol) and 4-hydroxytetrahydro-2 H 1,1-thiopyran dioxide (360 mg, 2.4 mmol, 0.9 eq.) was slowly added to a stirred solution of anhydrous DCM at 0 °C, along with DCC (594 mg, 2.88 mmol, 1.2 eq.) and DMAP (87.9 mg, 0.72 mmol, 0.35 eq.). The mixture was stirred overnight at room temperature. The resulting precipitate was then filtered. The organic phase was washed with water, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-(tert-butyl)-5-(1,1-dioxotetrahydro-2-) H -Thiopyran-4-yl ester) (280 mg, 36% yield). LCMS (Method 1) RT 1.04 min, m / z : [ESI + 360.16 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6) δ 4.92(s, 1H), 4.42 (s, 1H), 3.24 – 3.05 (m, 5H), 3.01 (s, 2H), 2.20 – 1.91 (m,5H), 1.81 (d, J = 7.2 Hz, 1H), 1.37 (s, 9H), 1.19 (d, J = 7.4 Hz, 1H).

[0313] Step B Synthesis of 1,1-dioxatetrahydro-2-(2-azabicyclo[2.1.1]hexane-5-carboxylic acid) H -Thiopyran-4-yl ester hydrochloride Salt To 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-(tert-butyl)5-(1,1-dioxotetrahydro-2 HAcetyl chloride (122 mg, 1.56 mmol, 2.0 eq.) was added to a stirred solution of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid (4-yl thiopyran) (280 mg, 0.78 mmol) in methanol at 0 °C. The mixture was stirred for 16 h and then concentrated under reduced pressure. MTBE was added to the residue, and the mixture was stirred for 15 min. The precipitate was collected by filtration and air-dried to give 1,1-dioxatetrahydro-2-(2-azadicyclo[2.1.1]hexane-5-carboxylic acid) as a pale yellow solid. H -Thiopyran-4-yl ester hydrochloride (167 mg, 72% yield). LCMS (Method 1) RT = 0.18 min, m / z : [ESI + 260.1 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.25 (s,1H), 8.50 (s, 1H), 5.12 - 4.93 (m, 1H), 4.42 (d, J = 6.0 Hz, 1H), 3.33 – 3.07(m, 8H), 2.19 – 2.05 (m, 4H), 1.95 (d, J = 8.7 Hz, 1H), 1.26 (d, J = 8.6 Hz, 1H).

[0314] According to Scheme 5, the following compounds were prepared using the method described above:

[0315] Example 47: 3-hydroxypropyl 2-hexane-5-carboxylic acid trifluoroacetate of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid Step A Synthesis of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-tert-butyl ester and 5-(3-hydroxypropyl ester) DCC (830 mg, 4.0 mmol) and DMAP (21 mg, 0.17 mmol) were slowly added to a stirred solution of 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (700 mg, 3.1 mmol) and propane-1,3-diol (270 mg, 3.5 mmol, 1.1 eq.) in anhydrous DCM at 0 °C. The mixture was stirred overnight at room temperature. The resulting precipitate was then filtered. The organic phase was washed with water, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-tert-butyl 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-(3-hydroxypropyl) (316 mg, 40% yield). LCMS (Method 1) RT = 1.04 min, m / z : [ESI + 186.2 (M+H-100) + .

[0316] Step B Synthesis of 3-hydroxypropyl 2-hexane-5-carboxylic acid trifluoroacetate salt of azirbicyclo[2.1.1]hexane-5-carboxylic acid TFA (288 mg, 2.5 mmol, 30 eq.) was added to a stirred solution of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-tert-butyl ester 5-(3-hydroxypropyl ester) (240 mg, 0.8 mmol) in DCM at 0 °C. The solution was then stirred overnight at room temperature. Subsequently, the mixture was concentrated under reduced pressure, and the residue was lyophilized to give a brown oily substance of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-hydroxypropyl trifluoroacetate (175 mg, 95% yield). LCMS (Method 6) RT = 1.53 min, m / z : [ESI + 186.3 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.34 (s, 1H), 8.56 (s, 1H), 4.38 (d, J = 5.8 Hz, 1H), 4.20 – 4.00 (m, 2H), 3.46 (t, J = 6.1 Hz, 2H),3.28 (s, 2H), 3.20 (d, J = 2.9 Hz, 1H), 3.10 (dt, J= 6.3, 3.2 Hz, 1H), 1.96 (d, J = 8.6 Hz, 1H), 1.75 – 1.72 (m, 2H), 1.35 – 1.19 (m, 1H).

[0317] Example 48: 3-((cyclopentanecarbonyl)oxy)propyl trifluoroacetate of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid Step A Synthesis of 2-tert-butyl 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-(3-((cyclopentanecarbonyl)oxy)propane ester) To a stirred solution of 2-tert-butyl 5-(3-hydroxypropyl)-2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid (460 mg, 1.62 mmol) and cyclopentanecarboxylic acid (185 mg, 1.62 mmol, 1.0 eq.) in anhydrous DCM at 0 °C, DCC (401 mg, 1.95 mmol, 1.2 eq.) and DMAP (10 mg, 0.08 mmol) were slowly added. The mixture was stirred overnight at room temperature. The resulting precipitate was then filtered. The organic phase was washed with water, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-tert-butyl 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-(3-((cyclopentanecarbonyl)oxy)propyl ester) (242 mg, 43% yield). LCMS (Method 1) RT = 1.28 min, m / z : [ESI + 282.2 (M-100+H) + .

[0318] Step B Synthesis of 3-((cyclopentanecarbonyl)oxy)propyl trifluoroacetate of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid TFA (72 mg, 1.2 mmol) was added to a stirred solution of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-tert-butyl ester 5-(3-((cyclopentanecarbonyl)oxy)propyl ester) (242 mg, 0.64 mmol) in DCM at 0 °C. The solution was then stirred overnight at room temperature. The mixture was subsequently concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-((cyclopentanecarbonyl)oxy)propyl ester trifluoroacetic acid (54 mg, 22% yield) as a yellow oil. LCMS (Method 1) RT = 0.92 min, m / z : [ESI + 282.19 (M+H) + .1 H NMR (400MHz, DMSO- d 6) δ 9.40 (s, 1H), 8.62 (s, 1H), 4.38 (d, J = 6.0 Hz, 1H), 4.21 –3.97 (m, 4H), 3.25 - 3.20 (m, 3H), 3.10 (dt, J = 6.1, 3.2 Hz, 1H), 2.73 – 2.70(m, 1H), 2.02 – 1.73 (m, 6H), 1.73 – 1.44 (m, 5H), 1.27 (d, J = 8.5 Hz, 1H).

[0319] Example 49: 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-acetoxypropyl trifluoroacetate Step A Synthesis of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-(3-acetoxypropyl) 2-tert-butyl ester Acetyl chloride (32 mg, 0.41 mmol, 1.2 eq.) was added to a stirred solution of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-tert-butyl ester 5-(3-hydroxypropyl ester) (97 mg, 0.34 mmol) and triethylamine (0.41 mmol, 57 µL, 1.2 eq.) in anhydrous DCM at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction mixture was then quenched with water and extracted with DCM. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-(3-acetoxypropyl ester) 2-tert-butyl ester (83 mg, 75% yield). LCMS (Method 1) RT = 1.14 min, m / z : [ESI + 228.19 (M-100+H) + .

[0320] Step B Synthesis of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-acetoxypropyl ester trifluoroacetate salt TFA (30 mg, 0.51 mmol, 2 eq.) was added to a stirred 0°C solution of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-(3-acetoxypropyl) 2-tert-butyl ester (83 mg, 0.25 mmol) in DCM. The reaction mixture was then stirred overnight at room temperature. The solvent was then evaporated, and the residue was purified by preparative HPLC to give 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-acetoxypropyl trifluoroacetate as a colorless oil (23.5 mg, 27% yield). LCMS (Method 1) RT = 0.62 min, m / z : [ESI + 228.13 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6)δ 9.31 (s, 1H), 8.57 (s, 1H), 4.38 (dt, J = 6.1, 1.7 Hz, 1H), 4.13 - 4.10 (m,4H), 3.28 (s, 2H), 3.22 (d, J = 3.2 Hz, 1H), 3.11 (dt, J = 6.3, 3.2 Hz, 1H), 2.07– 1.81 (m, 6H), 1.26 (d, J = 8.6 Hz, 1H).

[0321] Example 50: 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-(4-(fluorosulfonyl)benzamido)propyl ester trifluoro Acetate Step A Synthesis of 4-[(3-hydroxypropyl)carbamoyl]benzene-1-sulfonyl fluoride HOBT (120 mg, 0.89 mmol, 0.2 eq.) and DIPEA (1.1 g, 5.3 mmol) were added to a stirred solution of 4-(fluorosulfonyl)benzoic acid (1.0 g, 4.9 mmol) and 3-aminoprop-1-ol (334 mg, 4.5 mmol, 0.9 eq.) in anhydrous DCM at 0 °C. The mixture was stirred overnight at room temperature. The resulting precipitate was then filtered. The organic phase was washed with water, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography to give 4-[(3-hydroxypropyl)carbamoyl]benzene-1-sulfonyl fluoride (362 mg, 31% yield). LCMS (Method 2) RT = 0.80 min, m / z : [ESI+ 262.2 [M+H] + .

[0322] Step B Synthesis of 2-tert-butyl 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 5-{3-[(4-fluorosulfonylbenzoyl] [amino]propyl ester DCC (343 mg, 1.7 mmol, 1.2 eq.) and DMAP (51 mg, 0.42 mmol, 0.33 eq.) were slowly added to a stirred solution of 4-[(3-hydroxypropyl)carbamoyl]benzene-1-sulfonyl fluoride (362 mg, 1.4 mmol) and 2-[(tert-butoxy)carbonyl]-2-azabicyclo[2.1.1]hexane-5-carboxylic acid (346 mg, 1.5 mmol, 1.1 eq.) in anhydrous DCM at 0 °C. The mixture was stirred overnight at room temperature. The resulting precipitate was then filtered. The organic phase was washed with water, dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give... 2-Zazabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-tert-butyl ester 5-{3-[(4-fluorosulfonyl) [benzoyl)amino]propyl ester} (549 mg, 91% yield). LCMS (Method 2) RT = 1.23 min, m / z : [ESI + 371.2 (M-100+H) + .

[0323] Step C Synthesis of 3-(4-(fluorosulfonyl)benzamido)propyl ester of 2-azabicyclo[2.1.1]hexane-5-carboxylic acid trifluoroethyl Salt TFA (2.7 g, 23.3 mmol, 20.0 eq.) was added to a stirred 0°C solution of 2-azabicyclo[2.1.1]hexane-2,5-dicarboxylic acid 2-tert-butyl ester 5-{3-[(4-fluorosulfonylbenzoyl)amino]propyl ester} (549 mg, 1.2 mmol) in DCM. The solution was then stirred overnight at room temperature. Subsequently, the mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give a yellow oily substance, 2-azabicyclo[2.1.1]hexane-5-carboxylic acid 3-(4-(fluorosulfonyl)benzoamide)propyl trifluoroacetate (138 mg, 26% yield). LCMS (Method 2) RT = 0.73 min, m / z : [ESI + 371.0 (M+H) + . 1 H NMR (400 MHz, DMSO- d 6) δ 9.29 (s, 1H), 8.94 (t, J= 5.8 Hz, 1H),8.49 (s, 1H), 8.27 (d, J = 8.3 Hz, 2H), 8.16 (d, J = 8.3 Hz, 2H), 4.38 (d, J = 5.9Hz, 1H), 4.16 – 4.04 (m, 2H), 3.43 – 3.23 (m, 4H), 3.21 (s, 1H), 3.10 (dt, J =6.5, 3.2 Hz, 1H), 1.96 (d, J = 8.9 Hz, 1H), 1.89 – 1.85 (m, 2H), 1.26 (d, J = 8.7Hz, 1H).

[0324] Example 51 – Bioactivity Mitotracker analysis (MTR) On day 1, 25,000 U937 cells were seeded into each well of a 96-well plate containing either the compound of interest or a DMSO control, and incubated at 37°C and 5% CO2 for 48 h. On day 3, Mitotracker Red CMXRos was added to each well to a final concentration of 200 nM, and the plate was incubated at 37°C for 1 h in a CO2 incubator. After incubation, the fluorescence of the dye was collected using Quantron with the following parameters: yellow laser gain of 300 and emission channel PE-Cy5-H. Reagents: RPMI (Gibco, reference number 61870-010), FBS (Gibco, Brazil origin, reference number 10270-106), Pen-Strep (Gibco™ 15140122), MitoTracker RedCMXRos (ThermoFisher Scientific, reference number M7512). Data analysis included median PC5.5 fluorescence of viable cells, percentage of viable cells, and number of cells per microliter. All data points were normalized relative to the mediator CTL. Results are presented as the percentage increase in MTR signal relative to the control at a given test concentration (A = 101% - 104.9%; B = 105% - 108.9%; C = 109% - 112.9%; D = ≥ 113%).

[0325] Fluorescently labeled mitochondrial protein Cox8 MTS reporter assay The fully described prosecutory sequence of cytochrome oxidase subunit 8 (COX8) was fused to the N-terminus of a reporter fluorescent protein (codon-optimized versions of Dasher, Twinkle, and Rudolph (ATUM Bio)) to enable the reporter fluorescent protein to be transported into mitochondria. This construct was cloned into a plasmid under the constitutive promoter of EF1α and co-expressed with a puromycin resistance gene for mammalian cell selection. K562 cells were transfected and selected for stable expression of Cox8-dasherGFP. On day 1, 25,000 K562 Cox8-dasherGFP cell plates were seeded into each well of a 96-well plate containing either the compound of interest or a DMSO control and incubated at 37°C and 5% CO2 for 48 h. On day 3, fluorescence of the reporter DasherGFP located in the mitochondria was collected using a NovoCyte Quanteon flow cytometer. Data analysis included median fluorescence of viable cells, percentage of viable cells, and number of cells per μL. All data points were normalized relative to the median cytokine (CTL). The results are presented as the percentage increase in Cox8 signal relative to the control at a given test concentration (A = 101% - 104.9%; B = 105% - 108.9%; C = 109% - 112.9%; D = ≥ 113%).

[0326] High-resolution breathalyzer (HRR) Mitochondrial oxygen dynamics were measured using the high-resolution respiration assay OROBOROS Oxygraph-2k. On day 1, 235,000 U937 cells per mL (grown in RPMI / 10% FBS / PS) plates were seeded in RPMI / 10% FBS / PS containing either the test compound or DMSO control and incubated at 37°C and 5% CO2 for 48 h.

[0327] 1. Before starting the experiment, warm the culture medium (RPMI / 10% FBS / PS) to room temperature. 2. Remove 70% of the ethanol from the stopper and chamber, and rinse three times with HCl water. 3. Add 2.5 mL of culture medium (RPMI / 10% FBS / PS) to each chamber to flush the stopper. Aspirate the chamber and add 2.5 mL of fresh culture medium. 4. Remove the culture medium from the chamber and replace it with 2.5 mL of culture medium (RPMI / 10% FBS / PS). Perform air calibration on the instrument and save the file for calibration during sample runs. 5. Remove the culture medium from the chamber and replace it with 2.5 mL of cell-containing medium (RPMI / 10% FBS / PS), which has been treated with the test compound or DMSO control and counted before the experiment. 6. Add 5 μL of 20 μM oligomycin solution and continue reading until stable. 7. Add 5 μL of 250 μM CCCP solution until the maximum reading is reached. For U937 cells, the maximum reading was reached after the second injection of 5 μL of 250 μM CCCP. Perform a third injection to confirm that the reading is lower than the previous reading. 8. Add 4 μL of 1 mM rotenone solution, followed by 3 μL of 2.5 mM antimycin A solution to inhibit mitochondrial respiration. 9. After the experiment, save the file, rinse the chamber three times with 100% ethanol, three times with 70% ethanol, and three times with HCl water. 10. For analysis, use the DatLab program to select the longest stable reading range for quantization. Data are presented as percentage increases in ATP-related respiration caused by the compounds at given test concentrations (A = 101% - 104.9%; B = 105% - 108.9%; C = 109% - 112.9%; D = ≥ 113%).

[0328] Data table

[0329] Example 52 – Pharmaceutical Preparations (i) Tablet formulations A tablet composition containing the compound as defined in any one of embodiments 1.1 to 1.125 can be prepared by mixing 50 mg of the compound with 197 mg of lactose (BP) as a diluent and 3 mg of magnesium stearate as a lubricant and compressing in a known manner to form a tablet.

[0330] (ii) Capsule formulations A capsule formulation was prepared by mixing 100 mg of a compound as defined in any one of embodiments 1.1 to 1.125 with 100 mg of lactose and filling the resulting mixture into a standard opaque hard gelatin capsule.

[0331] (iii) Injectable formulation I A parenteral composition for injection can be prepared by dissolving a compound as defined in any one of embodiments 1.1 to 1.125 in water containing 10% propylene glycol to obtain an active compound concentration of 1.5% by weight. The solution is then sterilized by filtration, filled into ampoules, and sealed.

[0332] (iv) Injectable formulation II The parenteral composition for injection is prepared by dissolving a compound (2 mg / mL) as defined in any one of embodiments 1.1 to 1.125 and mannitol (50 mg / mL) in water, sterilely filtering the solution and filling it into a sealable 1 ml vial or ampoule.

[0333] v) Injectable formulation III A formulation for intravenous (iv) delivery by injection or infusion can be prepared by dissolving a compound (e.g., in salt form) as defined in any one of embodiments 1.1 to 1.125 in water at a concentration of 20 mg / ml. The vial is then sealed and sterilized by autoclaving.

[0334] vi) Injectable formulations IV A formulation for intravenous delivery by injection or infusion can be prepared by dissolving a compound (e.g., in salt form) as defined in any one of embodiments 1.1 to 1.125 at a concentration of 20 mg / ml in water containing a buffer solution (e.g., 0.2 M acetate, pH 4.6). The vial is then sealed and sterilized by autoclaving.

[0335] (vii) Subcutaneous injection preparations A composition for subcutaneous administration is prepared by mixing a compound as defined in any one of embodiments 1.1 to 1.125 with pharmaceutical-grade corn oil to obtain a concentration of 5 mg / ml. The composition is sterilized and filled into a suitable container.

[0336] viii) Lyophilized preparations Aliquots of the compound prepared as defined in any one of embodiments 1.1 to 1.125 were placed in 50 ml vials and lyophilized. During lyophilization, the composition was frozen at -45°C using a one-step freezing protocol. The temperature was raised to -10°C for annealing, then lowered to -45°C for freezing, followed by primary drying at +25°C for approximately 3400 minutes, and then secondary drying, during which the temperature was gradually increased to 50°C. The pressure during both primary and secondary drying was set to 80 mTorr.

[0337] equivalent The foregoing examples are presented for illustrative purposes and should not be construed as imposing any limitation on the scope of the invention. It will be readily apparent that many modifications and alterations can be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the fundamental principles of the invention. This application is intended to cover all such modifications and alterations.

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Claims

1. A compound of formula (1): (1) or its salts or tautomers; wherein R 1 is C(O)OR a ; R a Selected from: i) Hydrogen; ii) The group Hyd, wherein Hyd is a methyl group or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and said group Hyd may optionally be replaced by a hydroxyl, halogen, cyano, or oxo group; and iii) Group AB-Cyc; A is selected from the bond and C. 1-6 alkylene linking group; B does not exist, so it is -C(O)NR D -or-NR D C(O)-, the condition is that B does not exist when A is a bond; R D Selected from hydrogen and C 1-4 hydrocarbon group; Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group of Cyc are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, oxo (as the case may be), cyano, SO2R. S C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups; R S C 1-4 Alkyl, hydroxyl, or fluorine; R 2 Selected from hydrogen, C ions optionally substituted with hydroxyl groups 1-4 Hydrocarbon group and 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group, wherein R 2 The cyclic aromatic groups and cyclic non-aromatic groups are optionally substituted by one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group; and R 3 and R 4 One of them is selected from hydrogen and C, which is optionally substituted with a 5-6 membered cyclic aromatic group. 1-4 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 alkoxy groups; and R 3 and R 4 The other one is hydrogen; Excluding compounds (4S,5S)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid and (1S,4R,5R)-2-azabicyclo[ 2.1.1] Methyl hexane-5-carboxylate.

2. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (1): (1) or its salts or tautomers; wherein R 1 is C(O)OR a ; R a Selected from: i) Hydrogen; ii) The group Hyd, wherein Hyd is a methyl group or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and said group Hyd may optionally be replaced by a hydroxyl, halogen, cyano, or oxo group; and iii) Group AB-Cyc; A is selected from the bond and C. 1-6 alkylene linking group; B does not exist, so it is -C(O)NR D -or-NR D C(O)-, the condition is that B does not exist when A is a bond; R D Selected from hydrogen and C 1-4 hydrocarbon group; Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group of Cyc are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, oxo (as the case may be), cyano, SO2R. S C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups; R S C 1-4 Alkyl, hydroxyl, or fluorine; R 2 Selected from hydrogen, C ions optionally substituted with hydroxyl groups 1-4 Hydrocarbon group and 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group, wherein R 2 The cyclic aromatic groups and cyclic non-aromatic groups are optionally substituted by one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group; R 3 and R 4 One of them is selected from hydrogen and C, which is optionally substituted with a 5-6 membered cyclic aromatic group. 1-4 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 alkoxy groups; and R 3 and R 4 The other one is hydrogen.

3. A compound for medicinal use, said compound being a compound of formula (1): (1) or its salts or tautomers; wherein R 1 is C(O)OR a ; R a Selected from: i) Hydrogen; ii) The group Hyd, wherein Hyd is a methyl group or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and said group Hyd may optionally be replaced by a hydroxyl, halogen, cyano, or oxo group; and iii) Group AB-Cyc; A is selected from the bond and C. 1-6 alkylene linking group; B does not exist, so it is -C(O)NR D -or-NR D C(O)-, the condition is that B does not exist when A is a bond; R D Selected from hydrogen and C 1-4 hydrocarbon group; Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group of Cyc are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, oxo (as the case may be), cyano, SO2R. S C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups; R S C 1-4 Alkyl, hydroxyl, or fluorine; R 2 Selected from hydrogen, C ions optionally substituted with hydroxyl groups 1-4 Hydrocarbon group and 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group, wherein R 2 The cyclic aromatic groups and cyclic non-aromatic groups are optionally substituted by one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group; R 3 and R 4 One of them is selected from hydrogen and C, which is optionally substituted with a 5-6 membered cyclic aromatic group. 1-4 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 alkoxy groups; and R 3 and R 4 The other one is hydrogen.

4. A compound for treating mitochondrial diseases, said compound being a compound of formula (1): (1) or its salts or tautomers; wherein R 1 is C(O)OR a ; R a Selected from: i) Hydrogen; ii) The group Hyd, wherein Hyd is a methyl group or C 2-12 Hydrocarbon group, wherein the C 2-12 One carbon atom in the hydrocarbon group may optionally be replaced by O, N, S, S(O) or S(O)2, and said group Hyd may optionally be replaced by a hydroxyl, halogen, cyano, or oxo group; and iii) Group AB-Cyc; A is selected from keys and C. 1-6 alkylene linking group; B does not exist, so it is -C(O)NR D -or-NR D C(O)-, the condition is that B does not exist when A is a bond; R D Selected from hydrogen and C 1-4 hydrocarbon group; Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group of Cyc are each optionally substituted by one or more substituents selected from the following: hydroxyl, halogen, oxo (as the case may be), cyano, SO2R. S C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl groups and 5-6 membered cyclic aromatic groups; R S C 1-4 Alkyl, hydroxyl, or fluorine; R 2 Selected from hydrogen, C ions optionally substituted with hydroxyl groups 1-4 Hydrocarbon group and 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group, wherein R 2 The cyclic aromatic groups and cyclic non-aromatic groups are optionally substituted by one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group; R 3 and R 4 One of them is selected from hydrogen and C, which is optionally substituted with a 5-6 membered cyclic aromatic group. 1-4 The hydrocarbon group, wherein the cyclic aromatic group is optionally substituted by one or more substituents selected from: halogen, cyano, hydroxyl, C 1-4 Alkyl and C 1-4 alkoxy groups; and R 3 and R 4 The other one is hydrogen.

5. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 4, wherein R a Selected from: i) The group Hyd, wherein Hyd is methyl or C 2-6 Hydrocarbon group, wherein the C 2-6 One, but not all, of the carbon atoms in the hydrocarbon group may optionally be replaced by O, N, S, S(O), or S(O)2, and wherein the C 1-6 The hydrocarbon group may be optionally substituted with a hydroxyl, halogen, cyano, or oxo group; and ii) Group AB-Cyc; A is selected from key, C 1-6 alkylene linking group; B does not exist, so it is -C(O)NR D -or-NR D C(O), the condition is that B does not exist when A is a bond; Cyc is a 5-6 membered cyclic aromatic group or a 3-6 membered cyclic non-aromatic group, wherein the cyclic aromatic group and the cyclic non-aromatic group of Cyc are each optionally substituted by one or more substituents selected from: hydroxyl, halogen, C 1-4 Alkyl and C 1-4 Alkyl group.

6. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 5, wherein A is a bond or a methylene linking group, and B is absent.

7. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 6, wherein Cyc is a 4-6 membered cyclic non-aromatic group containing one or two heteroatoms or heteroatom groups selected from O, N, S, S(O), and SO2, wherein the 4-6 membered cyclic non-aromatic group of Cyc is optionally substituted by one or more substituents selected from: hydroxyl, halogen, C 1-4 Alkyl and C 1-4 Alkyl group.

8. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 7, wherein Cyc is a 6-membered cyclic non-aromatic group containing a heteroatom or heteroatomic group selected from N, O, S, S(O), and SO2, wherein the 4-6-membered cyclic non-aromatic group of Cyc is optionally substituted by one or more substituents selected from: hydroxyl, halogen, C 1-4 Alkyl and C 1-4 Alkyl group.

9. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 8, wherein R a It has the following formula: in Instructions and R a The connection point of the oxygen atoms.

10. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 9, wherein R 2 Selected from hydrogen, methyl, and phenyl.

11. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 9, wherein R 2 Selected from C14 cells that are optionally substituted with hydroxyl groups 1-4 Hydrocarbon group and 5-6 membered cyclic aromatic group or 3-6 membered cyclic non-aromatic group, wherein R 2 The cyclic aromatic groups and cyclic non-aromatic groups are optionally substituted by one or more substituents selected from the following: halogens, C 1-4 Alkyl, hydroxyl, C 1-4 Alkoxy and C 1-4 Alkyl group.

12. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 11, wherein R 3 and R 4 It is hydrogen.

13. The compound, pharmaceutical composition, or compound for use according to any one of claims 1 to 12, wherein the compound has the formula (1-A): (1-A) Where R 1 R 2 and R 3 As defined in any one of claims 1 to 12.

14. A compound selected from any of Examples 1-50 in Table 1, and its salts and tautomers.

15. The pharmaceutical composition or compound for use according to any one of claims 2 to 13, wherein the compound is selected from any one of Examples 1-50 of Table 1 and its salts and tautomers.

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