Lactic acid enhancing compounds and uses thereof

Abstract

The invention relates to a novel drug which can be used for stimulating astrocyte to uptake glucose and release lactic acid. The invention also relates to a preparation method, a preparation and a treatment application of the medicines, and particularly relates to the medicines for preventing and / or treating nervous system diseases with low brain energy metabolism, particularly neurodegenerative, neurometabolic and mental diseases, or improving cognitive and memory functions.

Description

Field of the Invention

[0001] The present invention generally relates to the field of lactate enhancers, and in particular to the use of lactate enhancers in treating nervous system diseases including neurodegenerative diseases and psychiatric diseases. Background of the Invention

[0003] Neurological disorders represent some of the diseases with the highest unmet need. They are predicted to become the number one cause of death by 2050. These diseases are complex and difficult to treat. Finding treatments has been a challenge for the pharmaceutical industry over the past few decades, but progress in this field has been limited. To date, most treatment strategies have been aimed at directly targeting neurons using a "neurocentric" approach, largely ignoring the important role of other cell types of the nervous system, including astrocytes.

[0004] Astrocytes outnumber neurons in the brain and, together with oligodendrocytes and microglia, form a class of cells called glial cells that support neuronal activity and survival. Over the past decade, there has been a great deal of interest in the role of astrocytes in physiological processes and their significance in the development of neurological disorders such as neurodegenerative diseases, age-related cognitive impairment, and psychiatric disorders. While glial cells were for a long time only important for structural support of neural tissue (a type of brain glue), their more important role in controlling fundamental processes is now widely recognized. In particular, astrocytes play an important role by providing energy to neurons, which is required for neuronal function (transmitting electrical information) and survival. As a result, astrocytes have been found to be key to many physiological processes in the brain, including neuronal protection, neuronal function, synaptic plasticity, and memory consolidation (Magistretti et al., 2018, Nat. Rev. Neurosci., 19(4):235-249).

[0005] Although neurological diseases have traditionally been considered to be pathologies caused entirely by neuronal dysfunction and death, it is clear that other cell types, such as astrocytes, can also contribute to these pathologies. A large body of evidence suggests that astrocyte activity is associated with mild cognitive impairment (MCI), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), depression, and the like. For example, in AD patients, activated astrocytes are preferentially located near amyloid plaques, where they exhibit abnormal morphology and mitochondrial function. In the early stages of the disease, activated astrocytes have a neuroprotective effect by internalizing and degrading amyloid plaques, while as the disease progresses, the deposition of amyloid plaques leads to astrocyte death, which in turn leads to further accumulation of amyloid proteins (Nagele et al. 2004, Neurobiol. Aging, 25(5): 663-74). There are clear indications that age-related changes in astrocytes play an important role in the development of age-related neurodegenerative diseases such as MCI and AD (Cai et al., 2017, J. Neurol. 264(10):2068-74). Astrocytosis is a typical morphological feature of the Alzheimer's disease brain and represents the proliferation of astrocytes to support dying neurons or a response to degrade the increasing amount of toxic β-amyloid peptide. Of particular interest, exposure of astrocytes to β-amyloid in vitro alters their metabolic activity, resulting in a reduced protection of neurons against oxidative stress (Allaman et al., 2010, J. Neurosci 30(9):3326-38).

[0006] Disorders of brain energy metabolism are an important cause of several neurological diseases and age-related cognitive decline. These diseases are associated with reduced mitochondrial activity, increased oxidative stress, and decreased brain glucose metabolism. For example, reduced glucose metabolism in the brain appears early in the development of AD and actually represents a common phenomenon in other neurodegenerative diseases (Yin et al, 2016, Free Radic. Biol. Med., 100:108-22; Fu et al., 2014, Biogerontology, 15(6):579-86; Demetrius et al, 2013, Biogerontology, 14(6):641-9; Demetrius et al., 2014, front Physiol 5:522; Tomi et al., 2013, Brain Res., 1495:61-75; Ferreira et al., 2010, Curr Drug Targets, 11(10):1193-2016). Mitochondrial dysfunction is associated with age-related neurodegenerative diseases and is particularly prevalent in AD (Beal, 2005, Neurobiol Aging, 26(5):585-6; Yao et al., 2011, Curr Pharm Des 17(31):3474-9). Studies in AD patients and mouse models have highlighted the downregulation of several brain genes involved in energy regulation (Liang et al., 2008, Proc. Natl. Acad. Sci. USA, Mar 18; 105(11):4441-6). Thus, there is a significant correlation between reduced brain glucose metabolism and cognitive ability in Alzheimer's disease patients (Thomas et al., 2015, J. Nutr. Health Aging, 19(1):58-63; Woo et al, 2010, Int. J. Geriatr. Psychiatry, 25(11):1150-8):1150-8). In summary, these data suggest that impaired astrocyte activity and metabolic coupling in MCI and AD may lead to the characteristic accumulation of amyloid plaques and neuronal degeneration in specific brain regions.

[0007] In ALS, defects in mitochondrial activity and energy production were found to be at least partially responsible for the degeneration of motor neurons (Boillee et al., 2006, Neuron, 52:39-59). Astrocytes may also play an important role by regulating glutamate uptake, which is severely impaired in ALS (Rothstein et al., 1990, Ann. Neurol., 28:18-25; Spreux-Varoquaux et al., 2002, J. Neurol. Sci., 193:73-78).

[0008] Other neurological diseases, including psychiatric disorders such as depression, also show impaired brain energy metabolism (Elsayed and Magistretti, 2015, Front Cell Neurosci, 9: 468). In addition, increasing evidence suggests that changes in glial cells also contribute to the pathophysiology and treatment of major depression (Rajkowska and Stockmeier, 2013, Curr Drug Targets 14, 1225-1236; Czéh et al., 2006, Neuropsychopharmacology 31, 1616-1626; Banasr et al., 2010, Mol Psychiatry 15, 501-511; Banasr and Duman, 2008, Biol Psychiatry 64, 863-870).

[0009] Other neurological diseases show typical low brain energy metabolism, such as glucose transporter 1-deficiency syndrome (GLUT1-DS), also known as De Vivo disease. GLUT1-DS is a genetic disease caused by mutations in the GLUT1 gene, also known as solute carrier family 2, facilitator glucose transporter member 1 (SLC2A1). Patients carrying GLUT1 hemizygous and nonsense mutations that cause truncation of the GLUT1 protein have normal circulating blood glucose but low cerebrospinal fluid (CSF) lactate, persistent hypoglycemia (low CSF glucose), and reduced hexose transport to isolated red blood cells (De ViVo et al., 1991, N. Engl. J. Med., 325, 703-709). The severity of the symptoms of GLUT1-DS may vary depending on the SLC2A1 gene mutation. They include, but are not limited to, mental retardation, cognitive impairment, epilepsy, and motor problems (including ataxia, gait disorders, dystonia, dysarthria, abnormal saccades, spasticity, and other paroxysmal neurological phenomena) (Gras et al, 2014, Revue Neurologoqique 170:91-99).

[0010] Interestingly, a specific metabolite of glucose, lactate, appears to play a particularly important role in astrocyte-neuron metabolic coupling. In fact, lactate produced by astrocytes is used by neurons as a preferential energy source for neuronal activity via the so-called astrocyte-neuron lactate shuttle (ANLS) (Pellerin et al., 2012, J, Cereb Blood Flow Metab., 32(7): 1152-66). Lactate is produced in astrocytes by aerobic glycolysis, i.e., the conversion of glucose to lactate in the presence of oxygen, a process that normally occurs in the absence of oxygen (e.g., in muscles during physical activity). The source of glucose in the brain can come from the circulation (astrocyte terminals are in close contact with capillaries) or from internal stores of glycogen (brain glycogen is only present in astrocytes). After synaptic activity, lactate is produced by astrocytes and transferred to neurons, where it is converted to pyruvate, enters the tricarboxylic acid (TCA) cycle and produces ATP. In this context, lactate has been shown to be a neuroprotective agent against glutamate-mediated excitotoxicity (Jourdain et al., 2016, Sci. Rep., 6:21250), as well as against cerebral ischemia in vivo (Berthet et al., 2012, Cerebrovasc Dis., 34(5-6):329-35). In addition to its neuroprotective effects, ANLS has been found to be key in regulating long-term memory consolidation (Suzuki et al., 2011, Cell 144(5):810-23), as well as in regulating the expression of genes that regulate synaptic function and plasticity (Yang et al., 2014, Proc Natl Acad Sci USA, 111(33):12228-33; Tadi et al. 2015, PLoS One, 10(10):e0141568). Lactate not only plays a key role in providing energy to neurons, but also acts as a regulator of synaptic plasticity through signal transduction activities (Magistretti and Allaman, 2018, Nat Rev Neurosci 19 (4): 235-249). In addition, the transport of lactate was found to be impaired in the nervous system of ALS mouse models and ALS patients (Lee et al., 2012, Nature, 487 (7408): 443-8), providing additional evidence for the role of lactate in neurodegenerative diseases. In addition, in many animal models of depression, it was found that the administration of lactate produced antidepressant-like effects (Carrard et al., 2018, Mol Psychiatry, 23 (2): 488).Based on these recent studies, lactate (previously misunderstood as a waste byproduct of glycolysis) is considered a key signaling molecule that regulates exercise-induced beneficial brain adaptations and is thought to be a core protective mechanism for exercise-induced cognitive benefits. For those who are physically unable to enjoy the benefits of such high-intensity exercise, it is believed that lactate enhancement can partially mimic the benefits of exercise and help more people maintain the impact of exercise on physical and brain health in a low-cost way (Huang et al., 2021, Front. Physiol., 12:538962). In addition, recent findings on lactate-related mechanisms that promote brain health in exercise and cognitive function provide additional new perspectives for health-promoting aging strategies by increasing lactate (Xue et al., 2022, Nutrition & Metabolism, 19:52).

[0011] WO 99 / 62885 describes the preparation of N-(pyrazolylphenyl)alkanamides as inhibitors of IL-2 production.

[0012] Given the key role of ANLS in neuronal protection and cognition, as well as the impairment of astrocyte function and brain energy metabolism observed in many neurological diseases including MCI, AD, ALS, GLUT1-DS, and depression, there is an increasing need to develop lactate-enhancing drugs. Summary of the Invention

[0014] The present invention is based on the unexpected discovery of new molecules that stimulate lactate release and glucose uptake in primary astrocyte cultures in vitro and in mice in vivo, and have therapeutic effects in a hypometabolic GLUT1-DS prototype mouse model as well as in aging and AD mouse models.

[0015] A first aspect of the present invention provides a compound of the present invention, and its pharmaceutically acceptable salts, its hydrates, its solvates, or its polymorphs, its tautomers, its optically active forms, its enantiomeric mixtures, its pharmaceutically active derivatives, and mixtures thereof.

[0016] According to another aspect of the present invention, there is provided the use of a compound as described in the present invention in the use as a drug.

[0017] According to another aspect of the present invention, there is provided a pharmaceutical composition, which comprises at least one compound as described in the present invention and a pharmaceutically acceptable carrier, diluent or excipient as defined herein.

[0018] According to another aspect, the present invention provides a compound of the present invention for use in preventing and / or treating a nervous system disease or any disease characterized by a low metabolic state and / or dysfunction of the central or peripheral nervous system, which is a disease associated with abnormally low energy metabolism or in the central or peripheral nervous system; or for use in treating or stabilizing a nervous system disease with low brain metabolism or related symptoms (including cognitive impairment, motor function and movement disorders, or epileptic seizures).

[0019] According to another aspect, the present invention provides a compound of the present invention for use in preventing and / or treating cognitive disorders associated with aging, such as but not limited to age-related cognitive decline and age-related memory impairment, and for enhancing cognitive and memory functions in healthy subjects.

[0020] According to another aspect, the present invention provides the use of the compound described in the present invention, its pharmaceutically acceptable salt, its hydrate, its solvate, or its polymorph, its tautomer, its optically active form, its enantiomeric mixture, its pharmaceutically active derivative, and its mixture in preparing a pharmaceutical composition, wherein the pharmaceutical composition is used to prevent and / or treat diseases or conditions and / or nervous system diseases related to abnormally low brain energy metabolism or in the central nervous system; or to treat or stabilize nervous system diseases with low brain metabolism or related symptoms.

[0021] According to another aspect, the present invention provides a method for preventing or treating diseases or conditions and / or nervous system diseases associated with abnormally low energy metabolism or in the central nervous system; or for treating or stabilizing nervous system diseases with low brain metabolism or related symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, its tautomer, its geometric isomer, its optically active form, its enantiomeric mixture, its pharmaceutically acceptable salt, its pharmaceutically active derivative, or a mixture thereof.

[0022] According to another aspect, the present invention provides a method for increasing the level of glucose and / or lactate in the brain of a subject, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, a tautomer thereof, an optically active form thereof, a mixture of enantiomers thereof, a pharmaceutically active derivative thereof, and a mixture thereof, to induce an increase in the level of glucose and / or lactate in the brain.

[0023] A method for enhancing cognitive and memory function of a subject, the method comprising administering an effective amount of the compound of the present invention, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, a tautomer thereof, an optically active form thereof, a mixture of enantiomers thereof, a pharmaceutically active derivative thereof, and a mixture thereof.

[0024] According to another aspect, a method for preparing a compound of formula (I) is provided, the method comprising the step of reacting an intermediate of formula (II) with an intermediate of formula (III) in a polar solvent, wherein the compound of formula (I) is a compound of formula (Ia).

[0025] According to another aspect, a method for preparing a compound of formula (I) is provided, the method comprising the step of reducing an intermediate of formula (IV), wherein the compound of formula (I) is a compound of formula (Ib). BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Glucose uptake by astrocytes in primary culture measured 90 min after stimulation with compounds (1) to (5) according to the invention at concentrations ranging from 100 nM to 10 μM as described in Example 2 is shown as percentage of Vehicle treatment + SEM, n=6.

[0027] Figure 2 The in vitro mitochondrial activity of primary astrocytes measured 1.5 h and 24 h after treatment with compounds (1) to (7) according to the present invention at concentrations ranging from 100 nM to 100 μM as described in Example 2 is shown, expressed as absorbance (%) + SEM of MTT colorimetric assay for Vehicle treatment; n=8.

[0028] Figure 3 The mitochondrial activity of primary neurons treated with compound (2) of the present invention (10 μM) alone or in the presence of astrocytes as described in Example 2 is shown as percentage of Vehicle treatment ± SEM, n=6.

[0029] Figure 4 Shown are glucose uptake and lactate release by human induced pluripotent stem cell (iPSC)-derived astrocytes treated with compound (2) of the invention at concentrations ranging from 10 nM to 10 μM as described in Example 2, expressed as percentage of Vehicle treatment + SEM, n=6.

[0030] Figure 5As described in Example 3, the extracellular levels of glucose and lactate in the brain of freely moving mice were detected using glucose and lactate biosensors, respectively, 3 hours after oral administration of compounds (1) to (4) of the present invention (10-30 mg / kg) or vehicle, expressed as the mean + SEM of the AUC ratio of Veh or compounds (1) to (4) of the present invention to Veh in the same mouse, n = 4-8.

[0031] Figure 6 The graph shows the glucose uptake in the brain of mice detected by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) after oral administration of the compound (1) or (2) of the present invention (30 mg / kg each) or vehicle as described in Example 3, expressed as the mean ± SEM of FDG accumulation (BQML / vol), n=6.

[0032] Figure 7 As described in Example 4, the extracellular levels of glucose and lactate in the brain of freely moving GLUT1-DS mice were detected using glucose and lactate biosensors, respectively, 3 hours after oral administration of the compound (2) of the present invention (10 mg / kg) or vehicle, expressed as the mean + SEM of the AUC ratio of Veh or the compound (2) of the present invention to Veh in the same mouse, n = 4-8.

[0033] Figure 8 The data represent the latency before wild-type (WT) or GLUT1-DS mice fall from a rotating rod accelerated from 4 rpm to 40 rpm in 300 sec, 20 min after oral administration of the compound (1) or (2) described in the present invention (10 mg / kg) or vehicle (vehicle) as described in Example 4 (AB). The data are shown as the mean + SEM of n = 16 (n = 8 males, n = 8 females). (CD) The data represent the grip strength (Newtons) of the four paws of WT and GLUT1-DS mice using the grip strength test, 20 min after oral administration of the compound (1) or (2) described in the present invention (10 mg / kg) or vehicle (vehicle) as described in Example 4. The data are shown as the mean + SEM of n = 16.

[0034] Fig. 9 Shown are the distances reached to the target location in the Morris water maze by young (3 months old) and aged (16 months old) wild-type mice after 1 day of training following oral administration of vehicle or compound (2) of the invention (10 mg / kg and 30 mg / kg) as described in Example 5. Data are shown as mean + SEM of distance (cm) for n=5.

[0035] Fig.10 The distance reached by 3-month-old APOE3(+) and APOE4(+) female and male mice to the target location in the Morris water maze after 7 days of training following oral administration of vehicle or compound (2) of the present invention (10 mg / kg and 30 mg / kg) as described in Example 5. Data are shown as mean + SEM of distance (cm) for n=20 (n=10 males, n=10 females).

[0036] Fig.11 The memory of mice injected intracerebroventricularly with saline (CTL) or streptozotocin (STZ) and treated orally with vehicle or compound (2) of the present invention (10 mg / kg and 30 mg / kg) as described in Example 5 was evaluated by distance to the target location in Morris water maze (A) after 1 day of training, preference index for novel objects over known objects in novel object recognition task (B) after 1 day of training, and latency to enter the dark compartment in inhibitory avoidance task (C) after 1 day of training. Data are shown as mean + SEM of distance (cm) (A), preference index (%) (B) or latency (seconds) (C) for n=13-16 (n=5-8 males, n=8 females).

[0037] Detailed description

[0038] As used herein, "treatment" and the like generally refer to obtaining the desired pharmacological and physiological effects. The effect may be preventive in terms of preventing or partially preventing a disease, symptom or condition, and / or the effect may be therapeutic in terms of partially or completely curing a disease or a condition, symptom or adverse reaction attributable to the disease. The term "treatment" as used herein covers any treatment of a mammal, particularly a human disease, including: (a) preventing the disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed with the disease, such as preventive early asymptomatic intervention; (b) inhibiting the disease, i.e., stopping the development of the disease; or alleviating the disease, i.e., causing the regression of the disease and / or its symptoms or conditions, such as improvement or remediation of the injury. In particular, the methods, uses, preparations and compositions of the present invention can be used to enhance lactate, in particular for treating abnormal energy metabolism in the central nervous system.

[0039] The term "subject" as used herein refers to a mammal. For example, mammals contemplated by the present invention include humans, primates, domestic animals such as cattle, sheep, pigs, horses, laboratory rodents, other pets, and the like.

[0040] The term "a subject at risk for a disease associated with defects in energy metabolism in the brain or in the central nervous system (CNS)" refers to a subject with abnormal CNS energy metabolism, such as a neurological disease.

[0041] According to the present invention, the term "neurological disease" includes a neurological disease or any medical disease characterized by a hypometabolic state and / or dysfunction of the central or peripheral nervous system, such as motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS); dementias, such as Alzheimer's disease, frontotemporal dementia (FTD), Lewy body dementia (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA); movement disorders, such as Parkinson's disease including levodopa-induced dyskinesias, Huntington's disease, spinocerebellar ataxia, essential tremor, dystonia and related neurodegenerative diseases; various multiple sclerosis; various types of retinopathy; stroke, traumatic brain injury, intracerebral and subarachnoid hemorrhage; neuropsychiatric diseases, such as depression of any endophenotype, schizophrenia, anxiety disorders, attention deficit syndrome, autism; neurometabolic disorders, such as glucose transporter 1 deficiency syndrome (GLUT1-DS), Lafora disease and other glycogen storage disorders; Down syndrome; all types of epilepsy, migraine and cognitive impairment in type 2 diabetes (T2D); cerebral hypometabolic states caused by viral infections such as HIV or COVID-19, prion infections such as Creutzfeldt-Jakob disease, primary and secondary encephalitis; any cerebral hypometabolic state after anesthesia or postoperative care.

[0042] According to the present invention, the term "GLUT1-DS" includes GLUT1 deficiency syndrome, glucose transporter 1 deficiency syndrome, GLUT1 deficiency disease, also known as De Vivo syndrome, De Vivo disease or De Vivo syndrome disease.

[0043] The term "effective amount" as used herein refers to the amount of at least one compound of the present invention or its pharmaceutical preparation that induces a biological or medical response in the tissue, system, animal or human being sought. In one embodiment, the effective amount is a "therapeutically effective amount" for alleviating the symptoms of the disease or condition being treated. In another embodiment, the effective amount is a "prophylactic effective amount" for preventing the symptoms of the disease or condition being prevented. The term also includes the amount of the compound of the present invention sufficient to reduce the progression of the disease, particularly to reduce or inhibit the progression of neurodegenerative diseases, thereby inducing the response sought (i.e., "effective amount").

[0044] The "effectiveness" of a treatment according to the invention can be determined based on changes in the disease process in response to the uses or methods of the invention. For example, the effectiveness of a treatment can be determined by an increase in glucose or lactate levels in the central nervous system, or by imaging techniques, including the use of fluorine-18 ( 18F) labeled 2-fluoro-2-deoxy-D-glucose as a tracer or carbon-11, ( 11 C) Pittsburgh Compound B (PIB), Carbon-13 ( 13 C), phosphorus-31 ( 31 Positron emission tomography (PET), proton magnetic resonance spectroscopy ( 1 H) MRS to assess bioenergetic status in the brain.

[0045] Effective treatment is demonstrated by improvements in cognitive abilities (e.g., memory, reasoning tests), preservation of neuronal activity, which in the case of motor dysfunction can be measured by muscle activity, and clinical diagnosis relevant to the specific indication.

[0046] When used alone or in combination with other terms, the term “C 1 -C 6 "Alkyl" includes straight or branched chain C 1 -C 6 Alkyl, which refers to a monovalent alkyl group having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and the like.

[0047] When used alone or in combination with other terms, the term "C2-C6 alkenyl" includes straight or branched C2-C6 alkenyl groups, which may have any available number of double bonds in any available position, and the configuration of the double bonds may be (E) or (Z). The term is illustrated by groups such as vinyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.

[0048] The term "C3-C8 heterocycle" includes "C3-C8 heterocycloalkyl" and "heteroaryl".

[0049] The term "C3-C8 heterocycloalkyl" refers to a C3-C8 cycloalkyl group in which up to 3 carbon atoms are substituted by heteroatoms selected from O, S, NR (R is hydrogen or methyl). Heterocycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and the like.

[0050] The term "heteroaryl" refers to a monocyclic heteroaryl, or a bicyclic or tricyclic fused ring heteroaryl. Specific examples of heteroaryl include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuranyl, [2,3-dihydro]benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indole, 1,2,3-tri ...2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazinyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuranyl, [2,3-dihydro]benzofuranyl, isobenzofuranyl, benzothienyl, benzotriazolyl, isobenzothienyl, indole, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,3-triaz indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridinyl, benzothiazolyl, benzoxazolyl, quinolinazinyl, quinazolinyl, phthalazinyl, quinoxalinyl, cinnamyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, pyrido[4,3-b]pyridinyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

[0051] Unless otherwise limited by the definition of individual substituents, the term "substituted" refers to a group substituted with 1 to 5 substituents selected from C 1 -C 6 Alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C 1 -C 6 Alkyl aryl, C 1 -C 6 Alkyl heteroaryl, C 1 -C 6 Alkylcycloalkyl, C 1 -C 6 Alkylheterocycloalkyl, cycloalkylC 1 -C 6 Alkyl, heterocycloalkyl C 1 -C 6 Alkyl, amino, aminosulfonyl, ammonium, alkoxy, acylamino, aminocarbonyl, aryl, arylC 1 -C 6 Alkyl, heteroaryl, heteroarylC 1 -C 6 Alkyl, sulfinyl, sulfonyl, sulfonamide, alkoxy, alkoxycarbonyl, carbamate, sulfanyl, halogen, carboxyl, trihalomethyl, cyano, hydroxyl, mercapto, nitro, trihalomethoxy, trihalomethylthio and the like.

[0052] "Pharmaceutically active derivative" means any compound that, upon administration, is capable of directly or indirectly providing the activities disclosed herein. The term "indirectly" also includes prodrugs that can be converted to a pharmaceutically active form by endogenous enzymes or metabolism. A prodrug is a derivative of a compound described in the present invention, having enhanced activity of a lactic acid with a chemically or metabolically decomposable group, and a compound that can be converted in vivo to a pharmaceutically active compound under physiological conditions.

[0053] Prodrugs are converted to the compounds described in the present invention by reacting with enzymes, gastric acid, etc. under in vivo physiological conditions, for example, by oxidation, reduction, hydrolysis, etc., and each reaction is enzymatic.

[0054] These compounds can be prepared from the compounds of the present invention according to known methods. The term "indirectly" also includes metabolites of the compounds described in the present invention.

[0055] The term "metabolite" means all molecules derived from any compound of the present invention in a cell or an organism, preferably a mammal.

[0056] In the context of the present invention, it includes pharmaceutically acceptable salts, their hydrates, their solvates, or their polymorphs, their tautomers, their optically active forms, their enantiomeric mixtures, and their mixtures, as well as pharmaceutically active derivatives of the compounds described in the present invention. Unless otherwise specified, the present invention includes all possible diastereomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Also included are mixtures of stereoisomers and isolated specific stereoisomers. During the synthesis of such compounds, or during the racemization or epimerization processes known to those skilled in the art, the products of such processes can be mixtures of stereoisomers. Many organic compounds exist in optically active forms and have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule around its chiral center.

[0057] In the context of the present invention, "its pharmaceutically acceptable salt" means an acid addition salt formed with an acid, and the acid can be an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) or an organic acid such as acetic acid, fumaric acid, oxalic acid, tartaric acid, succinic acid, malic acid, malonic acid, fumaric acid, maleic acid, ascorbic acid, lactic acid or benzoic acid.

[0058] The pharmaceutically acceptable salts for use in the present disclosure can be selected from salts formed with acids such as hydrochloric acid.

[0059] The term "pharmaceutical preparation" means a preparation that allows the biological activity of the active ingredient to be clearly effective and does not contain other ingredients that are toxic to the subject to which the preparation is administered.

[0060] Compounds used in the present invention

[0061] According to a specific aspect of the present invention, there is provided a compound represented by formula (I):

[0062]

[0063] in,

[0064] Y is selected from NH and CH 2 ; R1 is selected from H, halogen, and is optionally selected from halogen, OR 12 and NR 13 R 14 The group substituted C 1 -C 6 Alkyl; R2 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, OR 12 NR 13 R 14 , cyano, or an optionally substituted heterocycle (eg, optionally substituted 6-pyrimidine, optionally substituted azetidine); R3 is selected from H, halogen (eg, Br), optionally selected from halogen, OR 12 and NR 13 R 14 The group substituted C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, OR 12 、NHR 13 , optionally substituted heterocycle or cyano; R4 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 alkyl, optionally substituted heterocycle and cyano; R5 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 Alkyl, OR 12 , or NR 13 R 14 ; R6 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 Alkyl, OR 12 , or NHR13 ; R7 and R8 are each independently selected from H and halogen; R9 is selected from SO-C 1 -C 6 Alkyl, SO 2 -C 1 -C 6 Alkyl, SO 2 -C3-C6 cycloalkyl, or an optionally substituted heterocycle selected from optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrrolidinone (e.g., pyrrolidin-2-one) and optionally substituted oxetane; R10 and R11 are each independently selected from H and halogen; R12, R13 and R14 are each independently selected from H, C(O)-C 1 -C 6 Alkyl (eg CO-methyl) and optionally substituted C 1 -C 6C3-C6 alkyl or C3-C6 cycloalkyl (e.g. optionally substituted ethyl, such as fluoroethyl, ethylphenylethyl, cyclopropylmethyl, optionally substituted propyl); any pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, or polymorph thereof, tautomer thereof, optically active form thereof, enantiomeric mixture thereof, and mixture thereof for preventing, inhibiting or treating a nervous system disease or any disease characterized by a low metabolic state and / or dysfunction of the central or peripheral nervous system, in particular motor neuron disease diseases (MNDs) such as amyotrophic lateral sclerosis (ALS), dementias, especially Alzheimer's disease, frontotemporal dementia (FTD), Lewy body dementia (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), movement disorders such as Parkinson's disease, including levodopa-induced dyskinesias, Huntington's disease, spinocerebellar ataxias, essential tremor, dystonia and related neurodegenerative diseases, multiple sclerosis , retinopathy, stroke, traumatic brain injury, intracerebral and subarachnoid hemorrhage, neuropsychiatric disorders such as depression of any endophenotype, schizophrenia, anxiety disorders, attention deficit syndrome, autism, neurometabolic disorders such as glucose transporter 1 deficiency syndrome (GLUT1-DS), Lafora disease and other glycogen storage disorders, Down syndrome, all types of epilepsy, migraine and cognitive impairment in type 2 diabetes (T2D), brain hypometabolism caused by viral infection (such as HIV or COVID-19), prion infection such as Creutzfeldt-Jakob disease, primary and secondary encephalitis, or abnormal protein processing and accumulation (such as all types of amyloidosis, synucleinopathy, Tauopathy, TD43 disease and other proteinopathy), brain hypometabolism after anesthesia or postoperative care; or for the treatment or stabilization of neurological diseases with brain hypometabolism or related symptoms, including cognitive impairment, motor function, psychiatric symptoms, movement disorders or epileptic seizures; and for enhancing cognitive and memory function.

[0065] According to a specific embodiment, there is provided a compound represented by formula (I), wherein Y is CH 2 .

[0066] According to a specific embodiment, a compound represented by formula (I) is provided, wherein Y is NH.

[0067] According to a specific embodiment, a compound of formula (I) is provided, wherein R1, R5, R4 and R6 are H.

[0068] According to a specific embodiment, there is provided a compound represented by formula (I), wherein R2 is OR 12 .

[0069] According to a specific embodiment, a compound of formula (I) is provided, wherein R3 is OR 12 .

[0070] According to a specific embodiment, a compound of formula (I) is provided, wherein R3 is NHR 13 .

[0071] According to a specific embodiment, a compound of formula (I) is provided, wherein R3 is a halogen.

[0072] According to a specific embodiment, a compound of formula (I) is provided, wherein R3 is H.

[0073] According to a specific embodiment, a compound of formula (I) is provided, wherein R3 is optionally substituted C 1 -C 6 alkyl (such as optionally substituted propyl).

[0074] According to a specific embodiment, a compound of formula (I) is provided, wherein R12 is optionally substituted C 1 -C 6 alkyl (such as optionally substituted methyl, ethyl (such as ethyl or fluoroethyl), isopropyl, optionally substituted aryl C 1 -C 6 alkyl such as optionally substituted phenyl C 1 -C 6 alkyl, such as fluorophenylmethyl).

[0075] According to a specific embodiment, a compound of formula (I) is provided, wherein R12 is H.

[0076] According to a specific embodiment, a compound of formula (I) is provided, wherein R13 is optionally substituted C 1 -C 6 alkyl (such as optionally substituted ethyl, such as fluoroethyl, ethylphenylethyl, cyclopropylmethyl, optionally substituted propyl).

[0077] According to a specific embodiment, a compound of formula (I) is provided, wherein R10 and R11 are H.

[0078] According to a specific embodiment, a compound of formula (I) is provided, wherein R10 is a halogen, such as fluorine.

[0079] According to a specific embodiment, a compound of formula (I) is provided, wherein R11 is a halogen, such as fluorine.

[0080] According to a specific embodiment, a compound of formula (I) is provided, wherein R7, R8, R10 and R11 are H.

[0081] According to a specific embodiment, there is provided a compound represented by formula (I), wherein R9 is selected from SO 2 -C 1 -C 6 Alkyl groups, such as SO 2 -CH 3 Or from SO 2 -CH 2 CH 3 .

[0082] According to a specific embodiment, there is provided a compound represented by formula (I), wherein R9 is selected from the following groups:

[0083]

[0084] According to a specific embodiment, a compound represented by formula (I) is provided, wherein R9 is an optionally substituted pyrrolidin-2-one.

[0085] According to a specific embodiment, a compound represented by formula (I) is provided, wherein R9 is an optionally substituted oxetane.

[0086] According to a specific embodiment, a compound of formula (I) is provided, wherein R9 is an optionally substituted isoxazole.

[0087] According to a specific embodiment, a compound of formula (I) is provided, wherein R9 is optionally substituted with SO 2 -cyclopropyl.

[0088] In a more specific embodiment, the compound of the present invention is selected from the group consisting of:

[0089] 1-[4-[(6,7-dimethoxy-1-isoquinolyl)methyl]phenyl]pyrrolidin-2-one;

[0090] 6,7-Dimethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0091] 6-methoxy-1-(4-methylsulfonylanilino)isoquinolin-7-ol;

[0092] 7-methoxy-1-(4-methylsulfonylanilino)isoquinolin-6-ol;

[0093] 1-(4-Methylsulfonylanilino)isoquinoline-6,7-diol;

[0094] 6-ethoxy-1-(4-methylsulfonylanilino)isoquinolin-7-ol;

[0095] 7-ethoxy-1-(4-methylsulfonylanilino)isoquinolin-6-ol;

[0096] 6,7-diethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0097] 1-[4-[(6,7-dimethoxy-1-isoquinolyl)amino]phenyl]pyrrolidin-2-one;

[0098] N-(4-methylsulfonylphenyl)-6-vinyloxy-isoquinolin-1-amine;

[0099] 6-isopropoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0100] N-(4-methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine;

[0101] N-[1-(4-methylsulfonylanilino)-7-isoquinolinyl]acetamide;

[0102] N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine;

[0103] 6-methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine;

[0104] 7-ethyl-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0105] 7-Bromo-1-(4-methylsulfonylanilino)isoquinolin-6-ol;

[0106] N7-Benzyl-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine;

[0107] N7-(cyclopropylmethyl)-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine;

[0108] 6-Methoxy-N1-(4-methylsulfonylphenyl)-N7-propyl-isoquinoline-1,7-diamine;

[0109] N6-(cyclopropylmethyl)-7-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,6-diamine;

[0110] 6-(azetidin-1-yl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0111] 6-ethyl-1-[(4-methylsulfonylphenyl)amino]isoquinolin-7-ol;

[0112] N-[4-(ethylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine;

[0113] 6,7-diethoxy-N-[4-(oxetan-3-yl)phenyl]isoquinolin-1-amine;

[0114] 6,7-diethoxy-N-[4-(1,2-oxazol-3-yl)phenyl]isoquinolin-1-amine;

[0115] 6,7-diethoxy-N-[4-(1,2-oxazol-5-yl)phenyl]isoquinolin-1-amine;

[0116] 6,7-diethoxy-N-(3-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine;

[0117] 6,7-diethoxy-N-(2-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine;

[0118] N-[4-(Cyclopropylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine;

[0119] 6-ethoxy-7-(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0120] 6,7-Bis(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine;

[0121] 1-[(4-Methylsulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline;

[0122] 6-[(4-fluorophenyl)methoxy]-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; and

[0123] 6-ethoxy-N-(4-methylsulfonylphenyl)-7-propylisoquinolin-1-amine;

[0124] Any pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, or polymorph thereof, tautomer thereof, optically active form thereof, enantiomeric mixture thereof, and mixture thereof.

[0125] According to another specific aspect of the present invention, there is provided a compound represented by formula (I), any pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, a tautomer thereof, an optically active form thereof, a mixture of enantiomers thereof, and a mixture thereof, provided that the compound is not selected from the following compounds:

[0126] N-[4-[5-ethyl-3-(1-methylethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-63-4;

[0127] N-[4-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-99-5;

[0128] N-[4-[5-ethyl-3-(3-pyridyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-04-5;

[0129] N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-94-0;

[0130] N-[4-[3-(tetrahydro-2-furyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-82-7;

[0131] N-[4-[3-(3-pyridinyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-03-4;

[0132] 3-Methyl-N-[4-(4-pyridyl)phenyl]-1-isoquinolinamine, RN: 1368370-93-7;

[0133] 1-[[4-(4-pyridyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN: 1368269-53-7;

[0134] 8-Methyl-N 1 -[4-(4-pyridyl)phenyl]-1,5-isoquinolinediamine, RN: 1369288-67-4;

[0135] 5-Nitro-N-[4-(4-pyridyl)phenyl]-1-isoquinolinamine, RN: 1368370-43-7;

[0136] N-[4-(4-pyridyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and

[0137] 4-Bromo-N 1 -[4-(4-pyridyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1.

[0138] The compounds described herein have been named according to the IUPAC standards used in ChemAxon Marvin Sketch version 20.11.0.

[0139] According to another aspect of the present invention, the method for preparing the compound represented by formula (I) comprises the step of reacting the aniline intermediate represented by formula (III) with the intermediate represented by formula (II) in a polar solvent to form a compound represented by formula (Ia) (Scheme 1), wherein Z is selected from the leaving group of iodide, bromide, chloride, O-triflate, etc.:

[0140] Solution 1

[0141]

[0142] According to another aspect, the method for preparing the compound of formula (I) comprises a reduction step of the carbonyl intermediate of formula (IV) (e.g., in ZnCl 2 In the presence of NaBH 3 CN or by catalytic hydrogenation (in the presence of Pd / C and trace amounts of acid by H 2 ), to obtain a compound represented by formula (Ib) (Scheme 2):

[0143] Solution 2

[0144]

[0145] Compositions of the present invention

[0146] The present invention provides pharmaceutical or therapeutic agents as compositions and methods for treating a subject, preferably a mammalian subject, most preferably a human patient suffering from a medical condition, particularly a disease or disorder described herein.

[0147] According to another specific aspect of the present invention, a drug is provided, wherein the drug comprises at least one compound represented by formula (I), provided that the compound is not selected from the following compounds:

[0148] N-[4-[5-ethyl-3-(1-methylethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-63-4;

[0149] N-[4-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-99-5;

[0150] N-[4-[5-ethyl-3-(3-pyridyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-04-5;

[0151] N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-94-0;

[0152] N-[4-[3-(tetrahydro-2-furyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-82-7;

[0153] N-[4-[3-(3-pyridinyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-03-4.

[0154] The medicament of the present invention or its preparation can be administered as a pharmaceutical preparation, which can include one or more medicaments of the present invention in any form as described herein. The composition of the present invention can be used in the form of a pharmaceutical composition and its unit dosage form together with conventionally used adjuvants, carriers, diluents or excipients, and can be used in solid form, such as tablets or filled capsules, or in liquid form, such as solutions, suspensions, emulsions, elixirs or capsules filled with them, all for oral administration, or in the form of sterile injection solutions, for parenteral (including subcutaneous) use for injection or continuous infusion. Injectable compositions are generally based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. Such pharmaceutical compositions and their unit dosage forms can include ingredients in conventional proportions, may contain or not contain other active compounds, and such unit dosage forms can contain any suitable effective amount of active ingredients commensurate with the expected daily dosage range.

[0155] The composition of the present invention can be a liquid preparation, including but not limited to aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. The composition can also be made into a dry product for reconstitution with water or other suitable carriers before use. Such liquid preparations may contain additives, including but not limited to suspending agents, emulsifiers, non-aqueous vehicles and preservatives. Suspending agents include but are not limited to sorbitol syrup, methylcellulose, glucose / syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and hydrogenated edible fats. Emulsifiers include but are not limited to lecithin, sorbitan monooleate and gum arabic. Preservatives include but are not limited to methyl or propyl paraben and sorbic acid. Dispersants or wetting agents include but are not limited to polyethylene glycol, glycerol, bovine serum albumin, Tween Span

[0156] The compositions of the present invention may also be formulated as long-acting preparations, which may be administered by implantation or intramuscular injection.

[0157] The solid compositions of the present invention may be in the form of tablets or lozenges formulated in a conventional manner. For example, oral tablets and capsules may contain conventional excipients, including but not limited to binders, fillers, lubricants, disintegrants and wetting agents. Binders include but are not limited to syrups, gum arabic, gelatin, sorbitol, tragacanth, starch mucus and polyvinyl pyrrolidone. Fillers include but are not limited to lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate and sorbitol. Lubricants include but are not limited to magnesium stearate, stearic acid, talc, polyethylene glycol and silicon dioxide. Disintegrants include but are not limited to potato starch and sodium starch glycolate. Wetting agents include but are not limited to sodium lauryl sulfate. Tablets may be coated according to methods well known in the art.

[0158] The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system.

[0159] According to a particular embodiment, the composition of the invention is for intravenous use.

[0160] According to a particular aspect, the formulation of the invention is an oral formulation.

[0161] In another specific aspect, the compositions of the invention are suitable for delivery by repeated administration.

[0162] According to a particular embodiment, the composition of the invention is a veterinary composition.

[0163] Other materials and preparation techniques are described in Remington: The Science & Practice of Pharmacy, 23 rd Edition, 2020, Ed. Adeboye Adejare, which is incorporated herein by reference.

[0164] Dosage

[0165] The compounds of the present invention and their preparations can be administered in any manner, including oral, nasal, parenteral, intravenous, intrathecal, rectal, ophthalmic, etc. or a combination thereof. The compounds of the present invention and their preparations can also be administered by inhalation or intradermal administration. Parenteral administration includes but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous and intramuscular administration. The compositions of the present invention can also be administered in the form of implants, which allows slow release of the composition and slow controlled intravenous infusion.

[0166] According to a particular embodiment, the compounds of the invention and their formulations are administered by oral route.

[0167] combination

[0168] According to the invention, the compounds and pharmaceutical preparations can be administered alone or in combination with adjuvants for the treatment and / or stabilization of a neurological disease or any disease characterized by a hypometabolic state and / or dysfunction of the central or peripheral nervous system, such as motor neuron diseases (MNDs), in particular amyotrophic lateral sclerosis (ALS), dementias, in particular Alzheimer's disease, frontotemporal dementia (FTD), Lewy body dementia (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), movement disorders such as Parkinson's disease, Huntington's disease, spinocerebellar ataxia, essential tremor, dystonia and Related neurodegenerative diseases, multiple sclerosis, retinopathy, stroke, traumatic brain injury, intracerebral and subarachnoid hemorrhage, neuropsychiatric disorders such as depression of any endophenotype, schizophrenia, anxiety disorders, attention deficit syndrome, autism, neurometabolic disorders such as GLUT1-DS, Lafora disease and other glycogen storage disorders, Down syndrome, all types of epilepsy, migraine and cognitive impairment in type 2 diabetes (T2D), brain hypometabolic state caused by viral infection (such as HIV or COVID-19), brain hypometabolic state caused by prion infection (such as Creutzfeldt-Jakob disease, primary and secondary encephalitis), brain hypometabolic state after anesthesia or postoperative care.

[0169] According to the present invention, the compound and its pharmaceutical preparation can be administered alone or in combination with a co-agent or co-therapy for treating and / or stabilizing a neurological disease with low brain metabolism or related symptoms, including cognitive impairment, motor function and movement disorders or epileptic seizures. Such co-agents or co-therapy will include, but are not limited to, at least co-agents that can be used to treat and / or stabilize a neurological disease with low brain metabolism or related symptoms, including gene therapy for restoring the expression of genes involved in brain energy metabolism, ketogenic diets, or pharmaceutical compounds that regulate ketone body synthesis, such as triheptanone.

[0170] The present invention includes the administration of the compounds of the present invention or formulations thereof, wherein the compounds are administered to a subject prior to, simultaneously with, or sequentially with other therapeutic regimens or adjuncts useful for preventing and / or treating mental disorders or improving cognitive and memory functions.

[0171] Examples of co-agents that can be used in combination with the compounds of the invention and their pharmaceutical formulations include drug therapies that can be used to treat cognitive symptoms of Alzheimer's disease (memory loss, confusion, and thinking and reasoning problems), such as cholinesterase inhibitors, memantine, and amyloid targeting agents. Non-limiting examples of cholinesterase inhibitors include donepezil, rivastigmine, and galantamine. Non-limiting amyloid targeting agents include aducanumab.

[0172] The co-dosage of the present invention may include donepezil and memantine in a single dosage form.

[0173] Examples of co-agents used in combination with the compounds and pharmaceutical formulations described herein include drug therapies useful for treating amyotrophic lateral sclerosis, such as riluzole, edaravone, AMX0035 (sodium phenylbutyrate and tauroursodeoxycholic acid), and Nuedexta (dextromethorphan and quinidine).

[0174] Examples of co-agents used in combination with the compounds of the present invention include drugs for behavioral changes that serve as adjunctive therapy but do not directly treat the symptoms of Alzheimer's disease, such as one or more antidepressants, antianxiety drugs, or antipsychotics. Non-limiting examples of suitable antidepressants include citalopram, fluoxetine, paroxetine, sertraline, trazodone, and estamine. Non-limiting examples of suitable antianxiety drugs include lorazepam and oxazepam. Non-limiting examples of suitable antipsychotics include aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone.

[0175] The compound or preparation of the present invention administered simultaneously with the co-agent may be administered in the same or different compositions via the same or different administration routes.

[0176] According to one embodiment, a pharmaceutical formulation is provided, which comprises a combination of a compound according to the present invention and at least one co-agent for treating and / or stabilizing a neurodegenerative disease and at least one pharmaceutically acceptable carrier.

[0177] Other combinations will be readily appreciated by those skilled in the art.In some embodiments, the compounds of the invention can be used to attenuate or reverse the activity of drugs useful for treating the neurological diseases described herein, and / or to limit the adverse effects of such drugs.

[0178] Those skilled in the art will readily appreciate that, according to at least some embodiments of the present invention, the combination may include a therapeutic agent and / or a pharmaceutical composition comprising a therapeutic agent and one other drug; as described herein, a therapeutic agent and / or a pharmaceutical composition comprising it and two other drugs, as shown herein, a therapeutic agent and / or a pharmaceutical composition comprising it and three other drugs. The determination of the optimal combination and dosage can be determined and optimized using methods well known in the art.

[0179] The therapeutic agents of the invention and one or more other therapeutic agents may be administered sequentially or simultaneously.

[0180] Uses of the compounds of the present invention

[0181] According to another aspect, the present invention provides compounds and methods useful for preventing or treating diseases associated with defective energy metabolism in the central nervous system.

[0182] According to another aspect, the present invention provides compounds and methods useful for preventing and / or treating neurodegenerative diseases.

[0183] According to another aspect, the present invention provides compounds and methods useful for preventing and / or treating neuropsychiatric disorders.

[0184] According to another aspect, the present invention provides compounds and methods useful for increasing astrocyte lactate secretion.

[0185] The dosage for individual single or multiple administrations will vary depending on a variety of factors, including pharmacokinetic properties, patient condition and characteristics (sex, age, weight, health status, size), degree of symptoms, concurrent treatment, frequency of treatment, and desired effect.

[0186] In another embodiment, the present invention provides a pharmaceutical composition comprising at least one compound described herein and a pharmaceutically acceptable carrier, diluent or excipient.

[0187] Synthesis of the compounds of the present invention

[0188] The novel derivative shown in formula (I) can be prepared from readily available starting materials using the following general method and process. It should be understood that, in the case of typical or preferred experimental conditions (i.e. reaction temperature, time, reagent mole number, solvent, etc.), other experimental conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary due to the specific reactants or solvents used, but those skilled in the art can determine these conditions using conventional optimization processes. The general synthetic method of the compound shown in the preparation formula (I) is described in the above schemes 1 and 2.

[0189] patient

[0190] In one embodiment, the patient of the present invention is a subject suffering from a disease associated with defective energy metabolism in the central nervous system.

[0191] In a specific embodiment, the patient described herein suffers from a neurodegenerative disease.

[0192] In a specific embodiment, the patient according to the present invention suffers from a neuropsychiatric disease.

[0193] In a specific embodiment, the patient according to the present invention suffers from a neurometabolic disorder.

[0194] In one embodiment, the patient of the present invention is a subject suffering from a neurometabolic disorder associated with GLUT1-DS.

[0195] In a specific embodiment, the patient according to the present invention suffers from GLUT1-DS.

[0196] In one embodiment, the patient according to the present invention is a patient at risk for GLUT1-DS.

[0197] In a specific embodiment, the patient of the present invention is a subject having a genetic predisposition to a disease selected from the group consisting of mild cognitive impairment, Parkinson's disease, multiple sclerosis, schizophrenia, stroke, traumatic brain injury, and epilepsy.

[0198] According to a particular aspect, the compounds and methods of the present invention are useful for preventing and / or treating neurodegenerative diseases.

[0199] According to another aspect, the neurodegenerative disease is Alzheimer's disease.

[0200] According to another aspect, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).

[0201] According to another aspect, the neuropsychiatric disorder is depression.

[0202] According to another specific aspect, the patient suffers from mild cognitive impairment due to aging, such as age-related cognitive decline and age-related memory impairment.

[0203] According to another specific aspect, the method of the present invention can be used to enhance cognitive and memory function in healthy subjects.

[0204] Having described the invention, the following examples are presented by way of illustration and not limitation. Example

[0205] The following studies were performed to support the effectiveness of the compounds described in this invention.

[0206] Example 1: Synthesis of the compounds described in the present invention

[0207] All synthetic reagents and solvents were used as received. If necessary, the solvents used in the reactions were previously dried and / or distilled according to the latest technology. Some solvents are commercially available in anhydrous state and were used as received.

[0208] Reaction conditions

[0209] When anhydrous conditions were required, glassware was first dried in an oven (>100 °C). All reactions were performed under N 2 or argon atmosphere. Ambient temperature (rt) refers to 20 to 25°C. A temperature of -78°C can be obtained by freezing an acetone bath with carbon dioxide or liquid nitrogen. A temperature of 0°C corresponds to the use of a water / ice bath. For heating, an oil bath with a temperature sensor is used for temperature control.

[0210] The progress of the reaction is followed by thin layer chromatography (CCM) with the help of a UV indicator on the plate and can be enhanced by oxidizing developers such as phosphomolybdic acid solution.

[0211] Purification Technology

[0212] Flash chromatography:

[0213] Silica gel (Kieselgel 60 from MN, 15-40 μm from Macherey-Nagel) was used to purify the crude product by flash chromatography. The sample was either applied directly on the column head or used as a solution in a silica gel suspension.

[0214] Automatic flash color spectrum

[0215] The purification system used was the Combiflash Companion from Teledyne Isco TM The original sample is dissolved in a small amount of a suitable solvent and then applied to the pretreated These columns are placed in the Combiflash Companion purification system TM The system is used with an automatic collector. Detection is by UV or by collecting all fractions analyzed by HPLC.

[0216] Nuclear Magnetic Resonance (NMR) Spectroscopy:

[0217] Used at 400MHz( 1 H) and 100MHz( 13 NMR spectra were recorded on a Bruker UltraShield spectrometer operated at 40 °C. Spectral calibration was performed by adding tetramethylsilane (TMS) as an internal reference to deuterated solvents. Calibration was obtained by setting the TMS signal to 0.

[0218] For fluorine-19, CFCl3 was used as an external reference. Chemical shifts are expressed in parts per million (ppm) and coupling constants are expressed in Hertz (Hz). Abbreviations for the multiplicities of proton and carbon signals are: s: singlet; d: doublet; dd: doublet of doublet; dt: triplet of doublet; ddt: triplet of doublet; t: triplet of triplet; tt: triplet of triplet; q: quintuplet; m: multiplet.

[0219] Mass Spectrometry (SM):

[0220] The Bruker Q-TOF maXis was coupled to a Dionex Ultimate 3000 RSLC chain used in FIA (flow injection analysis = no column) with ACN / H 2O + 0.1% formic acid mixture 65 / 35 to 200 μL / min was used as solvent for mass spectrometry analysis. The injection volume was 0.2 μL. Most of the time, the analysis was performed in the positive mode of the ESI source (electrospray ionization).

[0221] Sample preparation:

[0222] The sample is sampled with solvent at a concentration of about 1 mg / mL and then diluted about 500 times (≈2 ng / μL) in methanol (sometimes depending on the structure of the compound to be analyzed, another solvent is more suitable: water, acetonitrile...). If the obtained signal is insufficient, increase the sample concentration.

[0223] Melting point determination:

[0224] Melting points were determined using a STUART SMP3.

[0225] High Performance Liquid Chromatography (HPLC):

[0226] HPLC analysis was performed on a Waters analytical HPLC system (Waters Delta 600 multisolvent pump, Waters 600 system controller, Rheodyne 7725i injector with 20 μl sample loop), controlled by Empower software and equipped with appropriate analytical columns. Detection was performed using a UV detector with a photodiode strip (Waters 2996) and / or a refractometer.

[0227] 1-[4-[(6,7-Dimethoxy-1-isoquinolyl)methyl]phenyl]pyrrolidin-2-one (1)

[0228] The above compounds were prepared according to Scheme 3 under the following specific conditions:

[0229] Solution 3

[0230]

[0231] To a solution of 6,7-dimethoxyisoquinoline (2 g, 10.57 mmol) in dichloroethane (4 mL) was added trifluoroacetic acid (1.21 g, 10.57 mmol / L, 782.61 uL), 4-bromobenzaldehyde (5.87 g, 31.71 mmol) and 2-hydroperoxide-2-methylpropane (5 M, 6.34 mL). The mixture was stirred at 110 ° C for 16 h. LCMS showed that 50% of the starting material remained and the desired Ms was detected. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (40 ml). The organic phase was washed with Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2 The organic matter was concentrated under reduced pressure to obtain a pale yellow solid (4-bromophenyl)-6,7-dimethoxy-1-isoquinoline-methanone i (800 mg, 19.32% yield).

[0232] 1 H NMR (400MHz DMSO-d 6 ): δ8.42(d,J=5.38Hz,1H)7.91(d,J=5.50Hz,1H)7.73-7.82(m,4H)7.53(d,J=7.25Hz,2H)3.97(s,3H)3.85(s,3H).

[0233] To a solution of i (600 mg, 1.53 mmol) in methanol (6 mL) was added NaBH 4 (63.73 mg, 1.68 mmol). The mixture was then stirred at 25 °C for 3 h. LCMS showed that the starting material had been consumed and the desired Ms was detected. The reaction was cooled to 0 °C and quenched with ice water (20 mL). The solution was stirred at 25 °C for 10 min, and then the pH was adjusted to 7 with 1N HCl. The reaction solution was extracted with ethyl acetate (40 mL). The organic phase was washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave crude product ii (460 mg, 76.25% yield) as a grey solid.

[0234] 1 H NMR (400MHz DMSO-d 6 ): δ8.31(d,J=5.50Hz,1H)7.59-7.66(m,2H)7.44-7.52(m,2H)7.39(d,J=8.50Hz,2H )7.34(s,1H)6.42(d,J=5.50Hz,1H)6.33(d,J=5.38Hz,1H)3.89(s,3H)3.80(s,3H).

[0235] At 20 °C, H 2 SO 4 Triethylsilane (1.36 g, 11.68 mmol, 1.87 mL) was added to the (2 mL) solution. The mixture was stirred at 50 °C for 16 h. LCMS showed that 33% of the starting material remained and the desired Ms was detected. The reaction was poured into 50 mL of ice water and washed with Na 2 CO 3 The pH was adjusted to 8. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with Na2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was analyzed by preparative TLC (SiO 2 , petroleum ether:ethyl acetate=1:1) The mixture was filtered and concentrated under reduced pressure to obtain a white solid iii (220 mg, 47.33% yield).

[0236] 1 H NMR (400MHz DMSO-d 6 ): δ8.24(d,J=5.63Hz,1H)7.55(d,J=5.63Hz,1H)7.44-7.48(m,2H)7.42-7.44 (m,1H)7.33(s,1H)7.28(d,J=8.38Hz,2H)4.53(s,2H)3.90(s,3H)3.87(s,3H).

[0237] To a solution of iii (150 mg, 376.85 μmol) in dioxane (1 mL) were added pyrrolidin-2-one (38.49 mg, 452.23 μmol, 34.67 uL), Pd 2 (dba) 3 (17.25 mg, 18.84 μmol), Cs 2 CO 3 (368.36 mg, 1.13 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (21.81 mg, 37.69 μmol), degassed and heated with N 2 Purge 3 times. The reaction mixture was stirred at 110 °C for 12 h. LCMS showed that the starting material had been consumed and the desired Ms was detected. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the crude product. The product was purified by preparative TLC (SiO 2 The crude product was purified by HPLC-MS / MS (MS / MS): 40.4474 / 0.71444 (0.1040 mmol, 100.40 mmol, 30.70 mmol, 40.70 mmol, 3 ... 1 H NMR(400MHz CDCl3): δ8.37(d,J=5.63Hz,1H)7.48-7.54(m,2H)7.43(d,J=5.75Hz,1H)7.29(d,J=3.63Hz,2H)7.25-7.27(m, 1H)7.05(s,1H)4.58(s,2H)4.01(s,3H)3.90(s,3H)3.81(t,J=7.07Hz,2H)2.58(t,J=8.07Hz,2H)2.13(m,2H).

[0238] 6,7-Dimethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (2)

[0239] The above compounds were prepared according to the above general scheme 1 and the specific conditions of the following scheme 4:

[0240] Solution 4

[0241]

[0242] To a solution of 1-chloro-6,7-dimethoxy-isoquinoline (1 g, 4.47 mmol, 1 eq) and 4-methylsulfonylaniline (765.54 mg, 4.47 mmol, 1 eq) in dioxane (20 mL) was added Cs 2 CO 3 (2.91 g, 8.94 mmol, 2 eq) and SPhos (183.55 mg, 447.12 μmol, 0.1 eq), N 2 Bubble through the mixture for 1 min and then 2 Pd 2 (dba) 3 (204.72 mg, 223.56 μmol, 0.05 eq), N 2 The mixture was bubbled through for 1 min and stirred at 100 ° C for 16 h. TLC showed that both starting materials were consumed and a new spot was detected. The reaction mixture was filtered through a pad of celite, the filter cake was washed with methanol (3 x 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with methanol in dichloromethane from 0% to 4%, and the eluted fractions containing the product were concentrated under reduced pressure. The residue was treated with ethyl acetate (10 mL), and the solid was collected by filtration and dried under high vacuum to obtain the target compound (2) as a white solid (1.27 g, 79.46% yield). 1 H NMR400MHz (d6-DMSO): δ = 9.36 (s, 1H), 8.04 (d, J = 8.9Hz, 2H), 7.95 (d, J = 5.6Hz, 1H), 7.87 -7.75(m,3H),7.31(s,1H),7.24(d,J=5.8Hz,1H),3.98(s,3H),3.92(s,3H),3.16(s,3H).

[0243] 6-Methoxy-1-(4-methylsulfonylanilino)isoquinolin-7-ol (3), 7-methoxy-1-(4-methylsulfonylanilino)isoquinolin-6-ol (4) and 1-(4-methylsulfonylanilino)isoquinoline-6,7-diol (5)

[0244] The above compounds were prepared according to Scheme 5 under the following specific conditions:

[0245] Solution 5

[0246]

[0247] A mixture of 47% HBr aqueous solution (20 mL) of compound 2 (1 g, 2.80 mmol) was stirred at 100 ° C for 7 h. LCMS showed that the starting material had been consumed and the required demethylated Ms was detected. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (TFA conditions) and freeze-dried to obtain compounds (3), (4) and (5) (TFA salt). The products were ground in HCl (4N) / MTBE (2 mL) respectively, and the solid was collected by filtration. The filter cake was washed with MTBE (2 ml), dissolved in 10 mL water and 10 mL acetonitrile, and then freeze-dried to obtain white solid (3) (66.4 mg, 6.02% yield, HCl salt), white solid (4) (36.7 mg, 3.4% yield, HCl salt) and white solid (5) (72.1 mg, 6.8% yield, HCl salt).

[0248] (3): 1 H NMR (400MHz DMSO-d 6 ): δ10.09-10.78(m,2H)7.98(br d,J=7.88Hz,2H)7.91(s,1H)7.81(br d,J=7.75Hz,2H)7.60-7.71(m,1H)7.51(br s,1H)7.38(br d,J=6.50Hz,1H)4.02(s,3H)3.24(s,3H).(4): 1 H NMR (400MHz DMSO-d 6 ): δ10.75-11.27(m,1H)8.13(br s,1H)8.03(br d,J=8.26Hz,2H)7.83(br d,J=8.25Hz,2H)7.59(br d,J=5.00Hz,1H)7.32(br d,J=6.50Hz,1H)7.29(s,1H)4.02(s,3H)3.26(s,3H).(5): 1 H NMR (400MHz DMSO-d 6): δ12.71-13.50(m,1H)11.14-11.51(m,1H)10.51-10.94(m,1H)10.02-10.44(m,1H)8.00(br d,J=8.50Hz,2H)7.93(s,1H)7.75(br d,J=8.50Hz,2H)7.53(br d,J=6.50Hz,1H)7.34(d,J=6.63Hz,1H)7.31(s,1H)3.25(s,3H).

[0249] 6-Ethoxy-1-(4-methylsulfonylanilino)isoquinolin-7-ol, (6), 7-ethoxy-1-(4-methylsulfonylanilino)isoquinolin-6-ol (7) and 6,7-diethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (8)

[0250] The above compounds were prepared according to Scheme 6 under the following specific conditions:

[0251] Solution 6

[0252]

[0253] To a solution of iodoethane (240.78 mg, 1.54 mmol) in DMF (12 mL) was added K 2 CO 3 (640.10 mg, 4.63 mmol) and compound (5) (600 mg, 1.54 mmol). The mixture was then stirred at 60 ° C for 3 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC. The mobile phase was concentrated under high vacuum to obtain a brown solid (7) (54.5 mg, 9.33% yield), a brown solid (6) (73.6 mg, 13.04% yield) and a brown solid (8) (22.1 mg, 3.64% yield). (6): 1 H NMR (400MHz DMSO-d 6 ): δ9.52(s,1H)9.35(s,1H)8.03(br d,J=8.76Hz,2H)7.89(d,J=5.63Hz,1H)7.79(br d,J=9.26Hz,3H)7.27(s,1H)7.19(br d,J=5.63Hz,1H)4.21(m,2H)3.14(s,3H)1.44(br t,J=6.88Hz,3H).(7): 1 H NMR (400MHz DMSO-d 6): δ10.05(br s,1H)9.31(br s,1H)8.04(br d,J=8.63Hz,2H)7.74-7.92(m,4H)7.06-7.16(m,2H)4.25(m,2H)3.16(s,3H)1.45(br t,J=6.88Hz,3H).(8): 1 H NMR (400MHz DMSO-d 6 ): δ9.32(s,1H)8.04(d,J=8.88Hz,2H)7.94(d,J=5.63Hz,1H)7.82(d,J=8.88Hz,2H) 7.78(s,1H)7.29(s,1H)7.21(d,J=5.63Hz,1H)4.22(m,4H)3.16(s,3H)1.43(m,6H)-.

[0254] 1-[4-[(6,7-Dimethoxy-1-isoquinolyl)amino]phenyl]pyrrolidin-2-one (9)

[0255] The above compounds were prepared according to the general scheme 1 and the specific conditions of the following scheme 7:

[0256] Solution 7

[0257]

[0258] To a solution of 1-chloro-6,7-dimethoxy-isoquinoline (150 mg, 670.68 μmol, 1 eq) and 1-(4-aminophenyl)pyrrolidin-2-one (118.18 mg, 670.6 μmol, 1 eq) in dioxane (3 mL) was added Cs 2 CO 3 (437.04 mg, 1.34 mmol, 2 eq) and SPhos (27.53 mg, 67.07 μmol, 0.1 eq), N 2 Bubble through the mixture for 1 min and then 2 Pd 2 (dba) 3 (30.71 mg, 33.53 μmol, 0.05 eq), N 2 The mixture was bubbled for 1 min. The reaction mixture was stirred at 100 ° C for 16 h. TLC showed that the two starting materials had been consumed and a new spot was detected. The reaction mixture was filtered through a diatomaceous earth pad, the filter cake was washed with methanol (3 x 5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under neutral conditions, and freeze-dried to give a white solid (9) (130.7 mg, 52.77% yield). 1H NMR (400MHz DMSO-d 6 ): δ=8.88(s,1H),7.84-7.75(m,4H),7.61-7.57(m,2H),7.23(s,1H),7.05(d,J=5.7Hz,1H ),3.96(s,3H),3.90(s,3H),3.84(t,J=7.0Hz,2H),2.49-2.46(m,2H),2.12-2.01(m,2H).

[0259] N-(4-Methylsulfonylphenyl)-6-vinyloxy-isoquinolin-1-amine (10)

[0260] The above compounds were prepared according to the following specific conditions of General Scheme 1 and Schemes 8 to 12:

[0261] Step 1:

[0262] Solution 8

[0263]

[0264] To a suspension of 6-bromo-1-chloroisoquinoline (3 g, 12.37 mmol, 1 eq) and 4-methylsulfonylanilide (2.12 g, 12.3.7 mmol, 1 eq) in i-PrOH (60 mL) was added HCl / dioxane (6 M, 3.09 mL, 1.5 eq) at 20 °C and the reaction mixture was stirred at 90 °C for 16 h. LCMS showed that most of the starting material had been consumed and the product with the desired MS was detected. The reaction mixture was filtered, the filter cake was washed with i-PrOH (10 mL), then suspended in ethyl acetate (30 mL), cooled to 0 °C, and washed with saturated NaHCO 3 The aqueous solution was adjusted to pH 8, the two phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 20 mL), the combined organic layer was washed with saturated brine (20 mL), and dried under reduced pressure. The residue was treated with a mixture of ethanol and water (15 mL, 1:1), and the solid was collected by filtration. The process was repeated 2 times to obtain the pure product. The filter cake was dried under high vacuum to give 6-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine iv (2 g, 42.85% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ=9.72(s,1H),8.52(d,J=9.0Hz,1H),8.19(d,J=1.8Hz,1H),8.16-8.10(m,3H),7.88-7.81(m,3H),7.32(d,J=5.7Hz,1H),3.17(s,3H).

[0265] Step 2:

[0266] Solution 9

[0267]

[0268] To a solution of 6-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine iv (300 mg, 795.22 μmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (242.32 mg, 954.26 μmol, 1.2 eq) in dioxane (6 mL) was added KOAc (156.09 mg, 1.59 mmol, 2 eq) at 20°C. 2 Bubble through the mixture for 1 min and then 2 Pd(dppf)Cl 2 (64.94 mg, 79.52 μmol, 0.1 eq), N 2 The mixture was bubbled through for 1 min and the reaction mixture was stirred at 80 °C for 12 h. LCMS showed that the desired product (boric acid) was detected. The reaction mixture was filtered through a pad of celite, the filter cake was washed with ethyl acetate (2 x 5 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether from 0% to 50% to give N-(4-methylsulfonylphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine v (330 mg, 97.80% yield) as a white foam. 1 H NMR (400MHz DMSO-d 6 ): δ=9.69(s,1H),8.55(d,J=8.5Hz,1H),8.25(s,1H),8.20-8.08(m,3H),7.90-7.80(m,3H),7.44(d,J=5.8Hz,1H),3.17(s,3H),1.35(s,12H).

[0269] Step 3:

[0270] Solution 10

[0271]

[0272] To a solution of N-(4-methylsulfonylphenyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine v (330 mg, 777.72 μmol, 1 eq) in THF (6 mL) and water (3 mL) was added sodium 3-dioxaborol tetrahydrate (358.98 mg, 2.33 mmol, 3 eq) in portions at 20°C and the reaction mixture was stirred at 20°C for 12 h. LCMS showed that the desired product was detected. Cold water (18 mL) was added to the reaction mixture, the resulting solid was collected by filtration, the filter cake was washed with water (2 mL), and dried under high vacuum to give 1-(4-methylsulfonylanilino)isoquinolin-6-ol vi (200 mg, 81.81% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ):δ=10.31(br s,1H),9.48(s,1H),8.40(d,J=9.0Hz,1H),8.11(d,J=8.9Hz,2H),7.95(d,J=5.8Hz,1 H), 7.82 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 5.9 Hz, 2H), 7.07 (d, J = 2.3 Hz, 1H), 3.16 (s, 3H).

[0273] Step 4:

[0274] Solution 11

[0275]

[0276] To a solution of 1-(4-methylsulfonylanilino)isoquinolin-6-ol vi (180 mg, 572.59 μmol, 1 eq) in DMF (5 mL) was added 1,2-dibromoethane (537.84 mg, 2.86 mmol, 216.00 μL, 5 eq) and K at 20 °C. 2 CO 3 (158.27 mg, 1.15 mmol, 2 eq), the reaction mixture was stirred at 60 ° C for 12 h. LCMS showed that the desired product was detected. The reaction mixture was filtered to remove salts, the filter cake was washed with ethyl acetate (2 x 10 mL), the filtrate was washed with brine (5 mL), and anhydrous Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was treated with petroleum ether and ethyl acetate (5 mL, 5:1), and the solid was collected by filtration, washed with petroleum ether and ethyl acetate (2 mL, 5:1), and dried under high vacuum to obtain a white solid 6-(2-bromoethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine vii (120 mg, 49.74% yield). vii:1 H NMR (400MHz CDCL3): δ=8.14(d,J=5.8Hz,1H),7.99-7.82(m,5H),7.34-7.29(m,1H),7.27(br d,J=2.4Hz,1H),7.21(br d,J=5.6Hz,1H),7.10(d,J=2.4Hz,1H),4.48(t,J=6.2Hz,2H),3.75(t,J=6.1Hz,2H),3.07(s,3H).

[0277] Step 5:

[0278] Solution 12

[0279]

[0280] To a solution of 6-(2-bromoethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine vii (110 mg, 261.09 μmol, 1 eq) in DMSO (3 mL) was added t-BuOK (1 M, 652.73 μL, 2.5 eq) at 20 °C and the reaction mixture was stirred at 20 °C for 1 h. LCMS showed that the starting material had been consumed and the desired product was detected. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 x 5 mL), washed with water (3 mL), and washed with anhydrous Na 2 SO 4 The residue was treated with petroleum ether and ethyl acetate (5 mL, 5:1), the solid was collected by filtration, washed with petroleum ether and ethyl acetate (2 mL, 5:1), and dried under high vacuum to obtain a white solid compound (10) (25 mg, 28.13% yield). 1 H NMR (400MHz DMSO-d 6 ): δ=9.62(s,1H),8.55(d,J=9.3Hz,1H),8.12(d,J=9.0Hz,2H),8.06(d,J=5.8Hz,1H),7.83(d,J=8.9Hz,2H),7.48(d,J=2.5Hz,1H),7.41(dd,J =2.6, 9.1Hz, 1H), 7.29 (d, J = 5.8Hz, 1H), 7.11 (dd, J = 6.0, 13.5Hz, 1H), 4.94 (dd, J = 1.6, 13.5Hz, 1H), 4.68 (dd, J = 1.6, 6.0Hz, 1H), 3.16 (s, 3H).

[0281] 6-Isopropoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (11)

[0282] The above compounds were prepared according to Scheme 13 under the following specific conditions:

[0283] Solution 13

[0284]

[0285] To a solution of 1-(4-methylsulfonylanilino)isoquinolin-6-ol vi (170 mg, 540.78 μmol, 1 eq) in DMF (5 mL) was added 2-iodopropane (459.64 mg, 2.70 mmol, 270.38 μL, 5 eq) and K 2 CO 3 (149.48 mg, 1.08 mmol, 2 eq), the reaction mixture was stirred at 60 ° C for 6 h. LCMS showed that the desired product was detected. The reaction mixture was quenched with ice water (15 mL), the resulting solid was collected by filtration, the filter cake was dried under high vacuum, and then treated with petroleum ether and ethyl acetate (3 mL, 2: 1), the solid was collected by filtration, washed with petroleum ether and ethyl acetate (1 ml, 2: 1), and dried in high vacuum to obtain white solid compound (11) (111.8 mg, 55.39% yield). 1 H NMR (400MHz DMSO-d 6 ): δ=9.53(s,1H),8.44(d,J=9.3Hz,1H),8.11(d,J=8.9Hz,2H),8.00(d,J=5.8Hz,1H),7.81(d,J=8.9Hz,2 H),7.29(d,J=2.4Hz,1H),7.26-7.20(m,2H),4.83(spt,J=6.0Hz,1H),3.15(s,3H),1.35(d,J=6.0Hz,6H).

[0286] N-(4-Methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine (12)

[0287] The above compounds were prepared according to Scheme 14 under the following specific conditions:

[0288] Solution 14

[0289]

[0290] To a solution of 6-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine iv (200 mg, 530.15 μmol, 1 eq) and tert-butyl(pyrimidin-2-yl)stannane (293.54 mg, 795.22 μmol, 1.5 eq) in dioxane (8 mL) was added CsF (161.06 mg, 1.06 mmol, 39.09 μL, 2 eq) at 20°C. 2 Bubble through the mixture for 1 min and then 2 CuI (20.19 mg, 106.03 μmol, 0.2 eq) and Pd(PPh 3 ) 4 (61.26 mg, 53.02 μmol, 0.1 eq), N 2 The mixture was bubbled through for 1 min, and the reaction mixture was stirred at 100 ° C for 12 h. LCMS showed that the desired product was detected. The reaction mixture was filtered through a diatomaceous earth pad, the filter cake was washed with methanol (5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under neutral conditions and freeze-dried to give white solid compound (12) (75.8 mg, 37.37% yield). 1 H NMR (400MHz DMSO-d 6 ): δ=9.76(s,1H),9.02(d,J=4.9Hz,2H),8.93(d,J=1.4Hz,1H),8.71(d,J=8.9Hz,1H),8.62(dd ,J=1.6,8.9Hz,1H),8.20-8.15(m,3H),7.86(d,J=8.9Hz,2H),7.58-7.53(m,2H),3.18(s,3H).

[0291] N-(4-Methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine (13)

[0292] The above compounds were prepared according to Schemes 15 to 18 and under the following specific conditions:

[0293] Step 1:

[0294] Solution 15

[0295]

[0296] To a solution of 7-methoxyisoquinoline (2 g, 12.56 mmol) in dichloromethane (20 mL) at 0°C was added meta-chloroperbenzoic acid (3.06 g, 15.08 mmol). The mixture was stirred at 20°C for 1 h. LCMS showed that the starting material had been consumed and the desired Ms was detected. The reaction was quenched with 4N HCl in methyl tert-butyl ether (5 mL), filtered, and the filter cake was concentrated under reduced pressure to give a crude product. The crude product was triturated with methyl tert-butyl ether (10 mL) at 20°C for 10 min. The mixture was filtered and the filter cake was concentrated under reduced pressure to give 7-methoxy-2-oxido-isoquinolin-2-ium viii (1.97 g, 85.03% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6 ): δ9.48(s,1H),8.45(dd,J=1.6,7.0Hz,1H),8.25(d,J=7.0Hz,1H),8.12(d,J =9.0Hz, 1H), 7.67 (d, J = 2.1Hz, 1H), 7.59 (dd, J = 2.4, 8.9Hz, 1H), 3.94 (s, 3H).

[0297] Step 2:

[0298] Scheme 16

[0299]

[0300] A mixture of 7-methoxy-2-oxido-isoquinolin-2-ium viii (1.9 g, 10.30 mmol) in phosphorus oxychloride (20 mL) was stirred at 80 ° C for 2 h. LCMS showed that the starting material had been consumed and the desired Ms was detected. The reaction mixture was quenched by adding 50 mL of water at 20 ° C and extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluted with ethyl acetate in petroleum ether from 15% to 50%) to give 1-chloro-7-methoxy-isoquinoline ix (1.1 g, 52.38% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ8.18(d,J=5.5Hz,1H),8.02(d,J=9.0Hz,1H),7.84(d,J=5.4Hz,1H),7.54(dd,J=2.5,8.9Hz,1H),7.49(d,J=2.4Hz,1H),3.96(s,3H).

[0301] Step 3:

[0302] Solution 17

[0303]

[0304] To a solution of 1-chloro-7-methoxy-isoquinoline ix (0.5 g, 2.45 mmol) in 1,4-dioxane (10 mL) at 25°C, 4-methylsulfonylanilide (420.02 mg, 2.45 mol) and dicesium carbonate (1.60 g, 4.91 mmol) were added. A flask was filled with N 2 The mixture was vacuumed (3×). SPhos (100.71 mg, 245.31 μmol) and Pd 2 (dba) 3 (112.32 mg, 122.66 μmol), and the flask was filled with N 2 The mixture was stirred at 110 °C for 12 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was triturated at 25 °C and in ethyl acetate (1 mL) for 30 min and filtered. The filter cake was concentrated under reduced pressure to give 7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine x (0.5 g, 62.07% yield) as a gray solid. 1 H NMR (400MHz DMSO-d 6 ): δ9.73-9.35(m,1H),8.07(d,J=8.8Hz,2H),7.96(d,J=5.5Hz,1H),7.91(d,J=1.8Hz,1H),7.81(dd,J= 2.9, 9.0Hz, 3H), 7.40 (dd, J = 2.1, 8.9Hz, 1H), 7.25 (brd, J = 5.4Hz, 1H), 3.97 (s, 3H), 3.21-3.07 (m, 3H).

[0305] Step 4:

[0306] Scheme 18

[0307]

[0308] To a solution of 7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (300 mg, 913.56 μmol) in AcOH (6 mL) was added HBr (335.99 mg, 1.37 mmol) at 20°C. The reaction solution was slowly heated to 100°C and stirred for 5 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was concentrated under reduced pressure and then washed with NaHCO 3The aqueous solution was adjusted to pH 8. The mixture was filtered and the filter cake was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC and lyophilized to give 1-(4-methylsulfonylanilino)isoquinolin-7-ol (13) (112.3 mg, 39.10% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ10.04(br s,1H),9.43(s,1H),8.08(br d,J=8.5Hz,2H),7.91(br d,J=5.5Hz,1H),7.85-7.71(m,4H),7.34(br d,J=8.8Hz,1H),7.25(br d,J=5.5Hz,1H),3.15(s,3H).

[0309] N-[1-(4-methylsulfonylanilino)-7-isoquinolinyl]acetamide (14) and N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (15)

[0310] The above compounds were prepared according to the general scheme 1 and the specific conditions of the following schemes 19 to 20:

[0311] Step 1:

[0312] Solution 19

[0313]

[0314] To a mixture of 7-bromo-1-chloro-isoquinoline (2.10 g, 12.27 mmol) in isopropanol (60 mL) was added 4-methylsulfonylaniline (3 g, 12.27 mmol) and 6M HCl / dioxane (3.07 mL) at 20°C. The mixture was stirred at 90°C for 12 h. LCMS showed that the starting material had been consumed and the desired Ms was detected. The reaction mixture was filtered, the filter cake was washed with isopropanol (10 mL), then suspended in ethyl acetate (30 mL), cooled to 0°C, and washed with saturated NaHCO 3 The aqueous solution was adjusted to pH 8. The mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was ground with ethanol and water (15 mL, 1:1) at 80 ° C for 0.5 h, and the solid was collected by filtration. The process was repeated 2 times to give 7-bromo-N-(4-methylsulfonylphenyl)isoquinoline-1-amine xi (1.4 g, 27.22% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6): δ9.68(s,1H),8.86(s,1H),8.18-8.10(m,3H),7.93-7.81(m,4H),7.36(d,J=5.6Hz,1H),3.17(s,3H).

[0315] N-[1-(4-Methylsulfonylanilino)-7-isoquinolyl]acetamide (14)

[0316] Solution 20

[0317]

[0318] To a solution of 7-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xi (1.4 g, 3.34 mmol) in 1,4-dioxane (28 mL) was added acetamide (256.46 mg, 4.34 mol) and K 3 PO 4 (2.13 g, 10.02 mmol). A flask was filled with N 2 The mixture was vacuumed (3×). Pd 2 (dba) 3 The flask was charged with N 2 The mixture was stirred at 100 °C for 12 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluting with ethyl acetate in petroleum ether from 0% to 50%) to give N-[1-(4-methylsulfonylanilino)-7-isoquinolinyl]acetamide (14) (0.75 g, 60.02% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d 6 ): δ10.29(s,1H),9.63(s,1H),8.60(s,1H),8.04-7.93(m,3H),7.89-7.78(m,4H),7.32(d,J=5.7Hz,1H),3.16(s,3H),2.12(s,3H).

[0319] N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (15)

[0320] The above compounds were prepared according to Scheme 21 under the following specific conditions:

[0321] Solution 21

[0322]

[0323] A solution of N-[1-(4-methylsulfonylanilino)-7-isoquinolyl]acetamide (14) (300 mg, 801.89 μmol) in tetrahydrofuran (6 mL) was prepared at 25°C. A flask was filled with N 2 The reaction mixture was then cooled to 0°C and BH 3 -Me 2 S (10M, 160.38 μL). The mixture was stirred at 0 ° C for 30 min. The reaction mixture was then heated to 20 ° C and stirred for 30 min, then slowly heated to 60 ° C and stirred for 12 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The residue was quenched with methanol (5 mL) and stirred at 20 ° C for 30 min. The mixture was then concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (15) (76.2 mg, 27.41% yield). 1 H NMR (400MHz DMSO-d 6 ): δ10.29(s,1H),9.63(s,1H),8.60(s,1H),8.04-7.93(m,3H),7.89-7.78(m,4H),7.32(d,J=5.7Hz,1H),3.16(s,3H),2.12(s,3H).

[0324] Intermediate 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine XXVII

[0325] Step 1:

[0326] Solution 22

[0327]

[0328] To a solution of 1-bromo-4-iodo-2-methoxy-benzene (10 g, 31.96 mmol) and acrylic acid (2.86 g, 39.63 mmol, 2.72 mL) in MeCN (30 mL) was added TEA (8.08 g, 79.89 mmol) and Pd(OAc) at 20 °C. 2 (215.23 mg, 958.68 μmol). 2Under atmosphere, the mixture was stirred at 90 ° C for 1 h. TLC showed that the starting material was completely consumed and a new spot was detected. The reaction was cooled to 20 ° C and poured into an ice-water solution of HCl (50 mL, 1N). After stirring for 10 min, the mixture was filtered to obtain a crude product. The crude product was ground with ethanol: hexane (50 mL) = 1: 1 at 20 ° C and stirred for 20 min, then the mixture was filtered and the filter cake was dried with high vacuum to obtain a gray solid (E)-3-(4-bromo-3-methoxy-phenyl)prop-2-enoic acid xii (6 g, 70.11% yield).

[0329] Step 2:

[0330] Solution 23

[0331]

[0332] To a solution of (E)-3-(4-bromo-3-methoxy-phenyl)prop-2-enoic acid xii (20 g, 71.57 mmol, 92% purity, 1 eq) in toluene (160 mL) was added DPPA (19.70 g, 71.57 mmol, 15.51 mL, 1 eq) and TEA (10.14 g, 100.20 mmol, 13.95 mL, 1.4 eq) at 20°C. The mixture was stirred at 20°C for 1 h. TLC showed that the starting material was completely consumed and a new spot was formed. The mixture was filtered through a silica gel pad and eluted with 1500 mL of toluene, diphenyl ether (150 mL) was added to the filtrate, and then the mixture was concentrated under reduced pressure to give a diphenyl ether solution (150 mL) of the crude product (about 20 g). Then a solution of (E)-3-(4-bromo-3-methoxy-phenyl)prop-2-enoyl azide (20.19 g, 71.57 mmol) in diphenyl ether (300 mL) was stirred at 230 ° C for 1 h. TLC showed that the starting material was completely consumed and a new spot was formed. The reaction mixture was cooled to 20 ° C, and then petroleum ether (500 mL) was added to the mixture. After 10 min, a solid precipitated and the crude product was filtered. The crude product was triturated with petroleum ether / ethyl acetate = 5:1 and stirred for 20 min, then the mixture was filtered, and the filter cake was dried under high vacuum to obtain 7-bromo-6-methoxy-isoquinolin-1-one xiii (7.5 g, 23.61 mmol, yield 32.99%, purity 80%) as a brown solid.

[0333] Step 3:

[0334] Solution 24

[0335]

[0336] 7-Bromo-6-methoxy-isoquinolin-1-one xiii (6 g, 13.22 mmol) was dissolved in POCl 3 The solution was stirred at 100 °C for 2 h. LC-MS showed that the starting material was completely consumed and the desired substance was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate (200 mL) and washed with saturated NaHCO 3 The mixture was adjusted to pH = 9 with aqueous solution and then extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with water and brine (2 x 100 mL) and washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a crude product. The crude product was chromatographed on silica gel (petroleum ether / ethyl acetate = 1:0 to 5:1) to give 7-bromo-1-chloro-6-methoxy-isoquinoline xiv (1.5 g, 34.13% yield) as a pale yellow solid.

[0337] Step 4:

[0338] Solution 25

[0339]

[0340] To a solution of 7-bromo-1-chloro-6-methoxy-isoquinoline xiv (1.50 g, 4.51 mmol) in i-PrOH (30 mL) was added 4-methylsulfonylanilide (927.31 mg, 5.42 mmol) and HCl / dioxane (6 M, 1.13 mL) at 20 °C, and the mixture was stirred at 90 °C for 12 h. LCMS showed that 24% of the starting material xiv remained, and the desired substance was detected. The mixture was then cooled to 20 °C, and HCl / dioxane (6 M, 376.11 μL) was added to the mixture. The mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered, and the filter cake was washed with i-PrOH (30 mL), then suspended in ethyl acetate (20 mL), cooled to 0 °C, and washed with saturated NaHCO 3 The aqueous solution was adjusted to pH 8, the two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with saturated brine (20 mL) and dried under reduced pressure to obtain a residue. The residue was treated with a mixed solvent of ethanol: water = 1:1 (20 mL), and the solid was collected by filtration. The process was repeated 2 times to obtain 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (1.4 g, 53.31% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6): δ9.60(br s,1H),8.89(s,1H),8.23-8.02(m,3H),7.84(br d,J=8.6Hz,2H),7.45(s,1H),7.28(br d,J=5.6Hz,1H),4.00(s,3H),3.16(s,3H).

[0341] 6-Methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine (16)

[0342] The above compounds were prepared according to Scheme 26 and under the following specific conditions:

[0343] Scheme 26

[0344]

[0345] At 20 °C, intermediate 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (0.8 g, 1.37 mmol) in THF (5 mL) and H 2 Add K into the O (2.5 mL) solution 3 PO 4 (583.72 mg, 2.75 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (254.12 mg, 1.65 mmol), and then Pd(dppf)Cl was added in one portion at 20 °C. 2 (112.29 mg, 137.50 μmol). 2 The resulting mixture was stirred at 80°C for 12 h under a 4% atmosphere. LC-MS showed that the starting material was completely consumed and a main peak with the desired substance was detected. The mixture was diluted with 20 mL of water at 20°C and then filtered, and the filtrate was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 20 mL), anhydrous Na 2 SO 4 Drying, filtration and concentration in vacuo afforded the crude product. The crude product was chromatographed on silica gel (petroleum ether / tetrahydrofuran 80:20-70:30) to afford 6-methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine (16) (0.4 g, 65.67% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6): δ=9.60(s,1H),8.63(s,1H),8.11(d,J=8.9Hz,2H),8.00(d,J=5.8Hz,1H),7.84(d,J=8.9Hz,2H),7.32(s,1H),7.24(d, J=5.8Hz,1H),7.09(dd,J=11.2,17.7Hz,1H),6.12(dd,J=1.5,17.6Hz,1H),5.53-5.38(m,1H),3.97(s,3H),3.17(s,3H).

[0346] 7-Ethyl-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (17)

[0347] The above compounds were prepared according to Scheme 27 under the following specific conditions:

[0348] Solution 27

[0349]

[0350] In N 2 To a solution of 6-methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine 16 (400 mg, 902.88 μmol) in THF (8 mL) was added wet Pd / C (0.1 g, 90.29 μmol) under a THF atmosphere. The suspension was degassed and heated with H 2 The mixture was purged 3 times at 20 °C and under H 2 The mixture was stirred at 40 °C for 1 h at 4 °C (15 Psi). LC-MS showed that the starting material was completely consumed and a main peak with the desired substance was detected. The reaction solution was filtered through celite and the filtrate was concentrated to give a crude product. The crude product was chromatographed on silica gel (petroleum ether / tetrahydrofuran = 77:23) to give 7-ethyl-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine 17 (0.18 g, 50.34% yield) as a light yellow oil. 1 H NMR (400MHz DMSO-d 6 ): δ=9.47(s,1H),8.26(s,1H),8.09(d,J=8.8Hz,2H),7.99(d,J=5.6Hz,1H),7.82(d,J=8.8Hz,2H),7.2 7(s,1H),7.24(d,J=5.8Hz,1H),3.95(s,3H),3.16(s,3H),2.78(q,J=7.4Hz,2H),1.27(t,J=7.4Hz,3H).

[0351] 7-Ethyl-1-(4-methylsulfonylanilino)isoquinolin-6-ol (18)

[0352] The above compounds were prepared according to Scheme 28 under the following specific conditions:

[0353] Scheme 28

[0354]

[0355] To a solution of 7-ethyl-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine 17 (180 mg, 454.50 μmol) in DCM (2 mL) was added BBr dropwise 3 (569.31 mg, 2.27 mmol), and then the mixture was stirred at 20 °C for 4 h. LC-MS showed that the starting material was completely consumed, and a major peak with the desired substance was detected. 3 The mixture was adjusted to pH = 9 with aqueous solution, and then the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with water and brine (2 x 100 mL), and Na 2 SO 4 Drying, filtration and concentration under reduced pressure afforded the crude product. The crude product was purified by preparative HPLC (neutral conditions) and then lyophilized to afford 7-ethyl-1-(4-methylsulfonylanilino)isoquinolin-6-ol (18) (0.023 g, 14.78% yield) as an off-white solid. 1 H NMR (400MHz DMSO-d 6 ): δ=10.31(br d,J=1.1Hz,1H),9.41(s,1H),8.22(s,1H),8.08(br d,J=8.5Hz,2H),7.90(br d, J=5.6Hz, 1H), 7.81 (brd, J=8.4Hz, 2H), 7.15-6.93 (m, 2H), 3.15 (s, 3H), 2.76 (q, J=7.3Hz, 2H), 1.27 (br t, J=7.4Hz, 3H).

[0356] 7-Bromo-1-(4-methylsulfonylanilino)isoquinolin-6-ol (19)

[0357] The above compounds were prepared according to Scheme 29 under the following specific conditions:

[0358] Solution 29

[0359]

[0360] 7-Bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (0.2 g, 441.96 μmol) was added to a 10 mL vertical bottle at 20°C, and then BBr was added dropwise to the mixture at 20°C. 3 (0.2 mL). The mixture was stirred at 70 °C for 6 h. LC-MS showed that 18% of the starting material remained and 53% of the desired compound was detected. The mixture was cooled to 20 °C and saturated NaHCO was added dropwise at 0 °C. 3 The mixture was then extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL) and washed with Na 2 SO 4 The mixture was dried, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under neutral conditions and then lyophilized to afford 7-bromo-1-(4-methylsulfonylanilino)isoquinolin-6-ol (19) (4 mg, 2.01% yield) as an off-white solid. 1 H NMR (400MHz DMSO-d 6 ): δ=11.20(s,1H)9.56(br s,1H)8.84(s,1H)8.11(br d,J=8.63Hz,2H)7.98(br d,J=5.75Hz,1H)7.83(br d,J=8.63Hz,2H)7.23(s,1H)7.16(br d,J=5.75Hz,1H)3.16(s,3H).

[0361] N7-Benzyl-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (20)

[0362] The above compounds were prepared according to Scheme 30 under the following specific conditions:

[0363] Scheme 30

[0364]

[0365] To a solution of 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (50 mg, 122.77 μmol) in 1,4-dioxane (1 mL) was added benzylamine (39.46 mg, 368.30 μmol) and Cs 2 CO 3 (120.00 mg, 368.3 μmol). The flask was filled with N 2 The mixture was vacuumed (3×). Pd 2 (dba) 3The flask was charged with N 2 The mixture was stirred at 100 °C for 12 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly purified by preparative HPLC and lyophilized to give a light yellow solid N7-benzyl-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (20) (16.3 mg, 30.63% yield). 1 H NMR (400MHz DMSO-d 6 ): δ9.11(s,1H),8.04-7.94(m,2H),7.83-7.75(m,3H),7.44(d,J=7.3Hz,2H),7.30(t,J=7.5Hz,2H),7.26 -7.20(m,2H),7.19-7.13(m,2H),6.06(t,J=6.2Hz,1H),4.55(d,J=5.6Hz,2H),3.98(s,3H),3.14(s,3H).

[0366] N7-(Cyclopropylmethyl)-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (21)

[0367] The above compounds were prepared according to Scheme 31 under the following specific conditions:

[0368] Scheme 31

[0369]

[0370] To a solution of 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (50 mg, 122.77 μmol) in 1,4-dioxane (1 mL) at 25 °C were added cyclopropylmethylamine (26.19 mg, 368.30 μmol) and Cs 2 CO 3 (120.00 mg, 368.3 μmol). The flask was filled with N 2 The mixture was vacuumed (3×). Pd 2 (dba) 3 The flask was charged with N 2The mixture was stirred at 100 °C for 12 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly purified by preparative HPLC and lyophilized to give a light yellow solid N7-(cyclopropylmethyl)-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (21) (10.7 mg, 21.93% yield). 1 H NMR (400MHz DMSO-d 6 ): δ9.16(s,1H),8.06-7.98(m,2H),7.84-7.76(m,3H),7.22(s,1H),7.19-7.14(m,2H),5.36(t,J=5.6Hz,1H ), 3.98 (s, 3H), 3.18-3.15 (m, 2H), 3.14 (s, 3H), 1.29-1.15 (m, 1H), 0.58-0.45 (m, 2H), 0.30 (q, J = 4.8Hz, 2H).

[0371] 6-Methoxy-N1-(4-methylsulfonylphenyl)-N7-propyl-isoquinoline-1,7-diamine (22)

[0372] The above compounds were prepared according to Scheme 32 and under the following specific conditions:

[0373] Scheme 32

[0374]

[0375] At 25 °C, Cs 2 CO 3 (120.00 mg, 368.30 μmol). The flask was filled with N 2 The mixture was vacuumed (3×). Pd 2 (dba) 3 The flask was charged with N 2The mixture was stirred at 100 °C for 12 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly purified by preparative HPLC and lyophilized to give 6-methoxy-N1-(4-methylsulfonylphenyl)-N7-propyl-isoquinoline-1,7-diamine (22) (13.4 mg, 26.79% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6 ): δ9.18(s,1H),8.06-7.95(m,2H),7.86-7.73(m,3H),7.21-7.11(m,3H),5.37(br t,J=5.6Hz,1H),3.96(s,3H),3.28-3.21(m,2H),3.14(s,3H),1.76-1.64(m,2H),0.99(t,J=7.4Hz,3H).

[0376] Intermediate 6-bromo-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xix

[0377] Step 1:

[0378] Scheme 33

[0379]

[0380] At 20 °C and N 2 2-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.10 g, 47.61 mmol) and triethylamine (5.26 g, 51.94 mmol) were added to a mixture of 4-bromo-3-methoxy-benzoic acid (10.0 g, 43.28 mmol) in dichloromethane (200 mL) at once. The mixture was stirred at 20 ° C for 30 min, and then 2,2-dimethoxyethylamine (5.23 g, 49.77 mmol) was added to the reaction mixture at 0 ° C. The reaction mixture was stirred at 20 ° C for 2.5 h. LCMS showed that the reaction was complete. The mixture was poured into ice water (100 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (100 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate in petroleum ether from 0% to 20%) to give 4-bromo-N-(2,2-dimethoxyethyl)-3-methoxy-benzamide xvi (12 g, 87.14% yield) as a light yellow solid.

[0381] Step 2:

[0382] Scheme 34

[0383]

[0384] In N 2 4-Bromo-N-(2,2-dimethoxyethyl)-3-methoxybenzamide xvi (12 g, 37.72 mmol) was mixed in sulfuric acid (3.70 g, 37.72 mmol) at once at 20 °C. The reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was then stirred at 60 °C for 2 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was quenched with ice water (100 mL), filtered, the filter cake was washed with water (3 x 100 mL), and concentrated under reduced pressure to give crude 6-bromo-7-methoxy-2H-isoquinolin-1-one xvii (9 g, 89.22% yield) as a yellow solid.

[0385] Step 3:

[0386] Scheme 35

[0387]

[0388] Phosphorus oxychloride (40 mL) was added to a mixture of 6-bromo-7-methoxy-2H-isoquinolin-1-one xvii (9.00 g, 33.65 mmol) in toluene (20 mL) at 20°C. The mixture was stirred at 110°C for 6 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated in ethyl acetate (20 mL) at 25°C for 1 h and then filtered. The filter cake was concentrated under reduced pressure to give 6-bromo-1-chloro-7-methoxy-isoquinoline xviii (5.4 g, 55.94% yield) as a white solid.

[0389] Step 4:

[0390] Scheme 36

[0391]

[0392] To a mixture of 6-bromo-1-chloro-7-methoxy-isoquinoline xviii (2 g, 6.97 mmol) in isopropanol (40 mL) was added 4-methylsulfonylaniline (1.19 g, 6.9 mmol) and HCl / dioxane (6 M, 1.74 mL) at 20 °C. The mixture was then stirred at 90 °C for 16 h. LCMS showed that all the starting material had been consumed and the desired Ms was detected. The reaction mixture was filtered, the filter cake was washed with isopropanol (10 mL), then suspended in ethyl acetate (30 mL), and heated at 0 °C with saturated NaHCO 3 The aqueous solution adjusted pH to 8. The mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL) and water (10 ml), and concentrated under reduced pressure to give 6-bromo-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xix (1.4 g, 46.84% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ9.56(s,1H),8.25(s,1H),8.07(d,J=8.8Hz,2H),8.01(d,J=5.6Hz,1H),7.94 (s,1H),7.86(d,J=8.9Hz,2H),7.27(d,J=5.8Hz,1H),4.07(s,3H),3.17(s,3H).

[0393] N6-(Cyclopropylmethyl)-7-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,6-diamine (23)

[0394] The above compounds were prepared according to Scheme 37 under the following specific conditions:

[0395] Scheme 37

[0396]

[0397] To a solution of 6-bromo-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xix (50 mg, 110.49 μmol) in 1,4-dioxane (1 mL) at 25 °C were added cyclopropylmethylamine (23.57 mg, 331.47 μmol) and Cs 2 CO 3 (108.00 mg, 331.4.7 μmol). The flask was filled with N 2 The mixture was vacuumed (3×). Pd 2 (dba) 3The flask was charged with N 2 The mixture was stirred at 100 °C for 12 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly purified by preparative HPLC and lyophilized to give N6-(cyclopropylmethyl)-7-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,6-diamine (23) (10 mg, 23, 20.83% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6 ): δ9.29-9.15(m,1H),8.02(br d,J=8.0Hz,2H),7.89-7.75(m,3H),7.67-7.59(m,1H),7.07(br d,J=4.8Hz,1H),6.73(s,1H),5.74(br d,J=4.5Hz,1H),4.02(s,3H),3.14(s,3H),3.09(br d,J=5.4Hz,2H),1.26-1.13(m,1H),0.50(br d,J=7.8Hz,2H),0.28(br d,J=3.6Hz,2H).

[0398] 6-(Azetidin-1-yl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (24)

[0399] The above compounds were prepared according to Scheme 38 under the following specific conditions:

[0400] Scheme 38

[0401]

[0402] To a solution of 6-bromo-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xix (50 mg, 110.49 μmol) in 1,4-dioxane (1 mL) at 25 °C were added azetidine (18.92 mg, 331.47 μmol) and Cs 2 CO 3 (108.00 mg, 331.4.7 μmol azetidine. Fill the flask with N 2 The mixture was vacuumed (3×). Pd 2 (dba) 3The flask was charged with N 2 The mixture was stirred at 100 ° C for 12 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was directly purified by preparative HPLC and lyophilized to give 6-(azetidin-1-yl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (24) (9.3 mg, 17.36% yield) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6 ): δ9.25(s,1H),8.06-7.99(m,2H),7.87-7.77(m,3H),7.62(s,1H),7.08(d,J=5.9Hz,1H), 6.55(s,1H),4.09-4.00(m,4H),3.93(s,3H),3.15(s,3H),2.31-2.24(m,2H),2.07(s,1H).

[0403] 6-Ethyl-1-[(4-methylsulfonylphenyl)amino]isoquinolin-7-ol (25)

[0404] The above compounds were prepared according to Schemes 39 to 41 and under the following specific conditions:

[0405] Step 1:

[0406] Scheme 39

[0407]

[0408] To a mixture of 6-bromo-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xix (700 mg, 1.63 mmol) in tetrahydrofuran (12 mL) and water (3 mL) at 20°C were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (276.62 mg, 1.80 mmol) and K 3 PO 4 (693.18 mg, 3.27 mmol). The flask was filled with N 2 The mixture was vacuumed (3×). Di-tert-butyl(cyclopentyl)phosphine, dichloropalladium, and iron (106.42 mg, 163.28 μmol) were added to the mixture, and N 2The mixture was stirred at 80 °C for 4 h. LCMS showed that all starting materials had been consumed and the desired Ms was detected. The reaction mixture was concentrated under reduced pressure and extracted with dichloromethane (3 x 30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC and lyophilized to give 6-vinyl-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xx (380 mg, 59.10% yield) as a yellow solid.

[0409] Step 2:

[0410] Scheme 40

[0411]

[0412] To a mixture of 6-vinyl-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xx (380 mg, 964.95 μmol) in methanol (10 mL) was added Pd / C (102.69 mg, 964.75 μmol) at 20°C. The mixture was then stirred at 20°C for 2 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 6-ethyl-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xxi as a white solid (220 mg, 60.77% yield)

[0413] Step 3:

[0414] Scheme 41

[0415]

[0416] To a solution of 6-ethyl-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xxi (200 mg, 505.00 μmol) in acetic acid (4 mL) was added hydrobromic acid (185.72 mg, 757.50 μmol). The reaction solution was slowly heated to 100 °C and stirred for 12 h. LCMS showed that all the starting materials had been consumed and the desired Ms was detected. The reaction mixture was concentrated under reduced pressure and washed with NaHCO 3 The aqueous solution was adjusted to pH 8. The mixture was filtered and the filter cake was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC and lyophilized to obtain 6-ethyl-7-hydroxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (25) (62.4 mg, yield 35.69%) as a light yellow solid. 1 H NMR (400MHz DMSO-d 6): δ10.09-9.97(m,1H),9.50-9.42(m,1H),7.99-7.92(m,2H),7.90(d,J=5.7Hz,1H),7.79(d,J=8.8H z, 2H), 7.62 (s, 2H), 7.24 (d, J = 5.7Hz, 1H), 3.15 (s, 3H), 2.74 (q, J = 7.5Hz, 2H), 1.24 (t, J = 7.5Hz, 3H).

[0417] N-[4-(Ethylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (26)

[0418] According to Scheme 42, the above compound was prepared under the following specific conditions:

[0419] Scheme 42

[0420]

[0421] Step 1: To a solution of 3,4-diethoxybenzoic acid (25 g, 118.92 mmol) in dichloromethane (250 mL) was added dimethylformamide (434.59 mg, 5.95 mmol) at 20°C. Then, at 0°C and N 2 Oxalyl chloride (18.11 g, 142.70 mmol) was added dropwise to the mixture under reduced pressure. The mixture was stirred at 20°C for 2 h. TLC showed that the starting material had been consumed and a new spot of a small polarity had formed. The mixture was concentrated under reduced pressure to give xxii (28 g, 92.67% yield) as a yellow solid. 1 HNMR (400 MHz, DMSO-d 6 ): δ7.52(dd,J=8.38,1.88Hz,1H)7.41(d,J=2.00Hz,1H)7.01(d,J=8.50Hz,1H)4.06(dq,J=16.63,7.00Hz,4H)1.33(td,J=6.94,3.50Hz,6H).

[0422] Step 2: To a solution of 2,2-dimethoxyethylamine (11.74 g, 111.63 mmol) in tetrahydrofuran (212 mL) was added N,N-diisopropylethylamine (21.64 g, 167.45 mmol) at 20°C. 2To the mixture was added a solution of xxii (31.2 g, 122.80 mmol) in tetrahydrofuran (100 mL). The mixture was stirred at 20 ° C for 16 h. LCMS showed that the starting material had been consumed and the product was detected. The mixture was quenched with ice water (600 mL) and filtered. The filter cake was concentrated under reduced pressure to give xxiii (31.3 g, 84.87% yield) as a white solid. 1 H NMR(400MHz,DMSO-d6):δ8.41(br t,J=5.82Hz,1H)7.38-7.56(m,2H)6.99(d,J=8.25Hz,1H)4.49(t,J=5.50Hz,1H)4.06 (qd,J=6.90,4.69Hz,4H)3.32-3.36(m,2H)3.29(s,6H)1.34(td,J=6.94,1.88Hz,6H).

[0423] Step 3: 2 (15.9 g, 48.13 mmol) was dissolved in H 2 SO 4 (6.41mL). The mixture was stirred at 80 ° C for 16h. LCMS showed that the starting material had been consumed and the product was detected. As mentioned above, a 5g scale bottle was set up again. The mixture was quenched with ice water (30mL) and the pH was adjusted to 7 with 0.5N NaOH (300mL). The mixture was then filtered and the filter cake was concentrated under reduced pressure to obtain the crude product. The crude product was stirred in ethyl acetate (100mL) to form a slurry, and filtered to obtain a gray solid xxiv (8.4g, 38.84% yield). 1 H NMR (400 MHz, DMSO-d 6 ): δ11.04(br s,1H)7.52(s,1H)7.13(s,1H)7.03(br t,J=6.19Hz,1H)6.44(d,J=7.00Hz,1H)3.97-4.35(m,4H)1.30-1.48(m,6H).

[0424] Step 4: xxiv (6.9 g, 20.11 mmol) in POCl 3 The solution (41.4 mL) was heated at 20 °C and stirred at 110 °C for 1 h. LCMS showed that the starting material had been consumed and the product was detected. The reaction mixture was concentrated under reduced pressure to remove POCl. 3 The residue was diluted with water (80 mL) and washed with saturated NaHCO 3 The aqueous solution (90 mL) was used to adjust the pH to 7. The mixture was then filtered and the filter cake was concentrated under reduced pressure to afford 1-chloro-6,7-diethoxyisoquinoline xxv (6.8 g, 94.25% yield) as a grey solid.1 H NMR (400 MHz, DMSO-d 6 ): δ 8.09 (d, J = 5.50 Hz, 1H) 7.68 (d, J = 5.50 Hz, 1H) 7.43 (d, J = 15.76 Hz, 2H) 4.22 (q, J = 6.88 Hz, 4H) 1.43 (td, J = 6.94, 1.13 Hz, 6H).

[0425] Step 5: At 20 °C, to a mixture of 1-chloro-6,7-diethoxyisoquinoline xxv (150 mg, 595.93 μmol) and 4-ethylsulfonyl aniline (110.39 mg, 595.9 μmol) in dioxane (3 mL) was added Cs 2 CO 3 (388.33 mg, 1.19 mmol), the vessel was evacuated and backfilled with N 2 (this process was repeated three times), then (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one was added; under N 2 to the mixture was added palladium (32.74 mg, 35.76 μmol) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (24.46 mg, 59.59 μmol), the vessel was evacuated and backfilled with N 2 (this process was repeated three times), the reaction mixture was heated to 100 °C and stirred for 12 h. LCMS showed that the starting materials had been consumed and the desired product was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC and lyophilized to give N-[4-(ethylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (26) as a yellow solid (138.3 mg, yield 57.02%, purity 98.4%). 1 H NMR (400 MHz, DMSO-d 6 ): δ = 9.34 (s, 1H) 8.05 (d, J = 8.88 Hz, 2H) 7.94 (d, J = 5.63 Hz, 1H) 7.73 - 7.82 (m, 3H) 7.29 (s, 1H) 7.22 (d, J = 5.63 Hz, 1H) 4.22 (dq, J = 18.39, 6.96 Hz, 4H) 3.22 (q, J = 7.30 Hz, 2H) 1.35 - 1.50 (m, 6H) 1.12 (t, J = 7.38 Hz, 3H).

[0426] 6,7-Diethoxy-N-[4-(oxetan-3-yl)phenyl]isoquinolin-1-amine (27)

[0427] The above compound was prepared under the following specific conditions according to Scheme 43:

[0428] Scheme 43

[0429]

[0430] xxv ​​(150 mg, 595.93 μmol), 4-(oxetan-3-yl)aniline (97.80 mg, 655.52 μmol) and Cs 2 CO 3 A mixture of (388.33 mg, 1.19 mmol) in dioxane (3 mL) was degassed and heated to 40 °C with N 2 Purge 3 times, then 2 SPhos (24.46 mg, 59.59 μmol) and Pd 2 (dba) 3 (27.29 mg, 29.80 μmol). 2 The mixture was stirred at 100 ° C for 16 h. LCMS showed that the reaction was complete. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was stirred in a mixture of petroleum ether and ethyl acetate (20 mL, 9: 1) for 15 min, and the solid was collected and then analyzed by preparative TLC (SiO 2 , petroleum ether:tetrahydrofuran = 1:1) to give a crude product. The crude product was stirred in a mixture of petroleum ether and ethyl acetate (15 mL, 4:1) for 15 min, and the solid was collected to give 6,7-diethoxy-N-[4-(oxetan-3-yl)phenyl]isoquinolin-1-amine (27) (111.5 mg, 50.98% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ=8.84(s,1H),7.85-7.74(m,4H),7.34(d,J=8.4Hz,2H),7.22(s,1H),7.03(d,J=5.8Hz,1H) ,4.94(dd,J=5.8,8.3Hz,2H),4.63(t,J=6.3Hz,2H),4.27-4.13(m,5H),1.42(q,J=7.3Hz,6H).

[0431] 6,7-Diethoxy-N-[4-(1,2-oxazol-3-yl)phenyl]isoquinolin-1-amine (28)

[0432] According to Scheme 44, the above compound was prepared under the following specific conditions:

[0433] Scheme 44

[0434]

[0435] To a solution of xxv (150 mg, 595.93 μmol, 1 eq) in dioxane (3 mL) was added 4-(1,2-oxazol-3-yl)aniline (105.00 mg, 655.52 μmol, 1.1 eq) and Cs 2 CO 3 (388.33 mg, 1.19 mmol, 2 eq). The mixture was degassed and heated to 40 ℃ with N 2 SPhos (24.46 mg, 59.59 μmol, 0.1 eq) and Pd 2 (dba) 3 (27.29 mg, 29.80 μmol, 0.05 eq) was added to the reaction mixture. The mixture was degassed and heated with N 2 The reaction mixture was purged 3 times and stirred at 100°C for 12 h. LC-MS showed that the starting material was completely consumed and the desired Ms was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The crude product was purified by preparative HPLC to obtain 6,7-diethoxy-N-[4-(1,2-oxazol-3-yl)phenyl]isoquinolin-1-amine (28) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ):δppm 9.07(s,1H),8.95(d,J=1.63Hz,1H),7.97(d,J=8.76Hz,2H),7.90(d,J=5.63Hz,1H),7.77-7. 86(m,3H),7.26(s,1H),7.02-7.16(m,2H),4.05-4.36(m,4H),1.43(dt,J=9.63,7.00Hz,6H).

[0436] 6,7-Diethoxy-N-[4-(1,2-oxazol-5-yl)phenyl]isoquinolin-1-amine (29)

[0437] According to Scheme 45, the above compound was prepared under the following specific conditions:

[0438] Scheme 45

[0439]

[0440] To a solution of xxv (150 mg, 595.93 μmol, 1 eq) in dioxane (3 mL) was added 4-isoxazol-5-ylaniline (105.00 mg, 655.52 μmol, 1.1 eq) and Cs 2 CO 3 (388.33 mg, 1.19 mmol, 2 eq). The mixture was degassed and heated to 40 ℃ with N2 SPhos (24.46 mg, 59.59 μmol, 0.1 eq) and Pd 2 (dba) 3 (27.29 mg, 29.80 μmol, 0.05 eq) was added to the reaction mixture. The mixture was degassed and heated with N 2 Purge 3 times and stir at 60 ° C for 12 h. LC-MS showed that reactant 1 was completely consumed and the desired Ms was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1). The crude product was purified by preparative HPLC to give 6,7-diethoxy-N-[4-(1,2-oxazol-5-yl)phenyl]isoquinolin-1-amine (29) (27.4 mg, 72.40 μmol, 12.15% yield, 99.2% purity) as a light yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ):δppm 9.13(s,1H),8.59(d,J=1.75Hz,1H),8.00(d,J=8.88Hz,2H),7.91(d,J=5.63Hz,1H),7.72-7.85(m,3H),7.2 7(s,1H),7.14(d,J=5.63Hz,1H),6.86(d,J=1.75Hz,1H),4.04-4.35(m,4H),1.43(dt,J=9.47,7.02Hz,6H).

[0441] 6,7-Diethoxy-N-(3-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine (30)

[0442] According to Scheme 46, the above compound was prepared under the following specific conditions:

[0443] Scheme 46

[0444]

[0445] To a mixture of xxv (150 mg, 595.93 μmol) and 3-fluoro-4-methylsulfonyl-aniline (112.75 mg, 592.93 μmol) in dioxane (3 mL) was added Cs 2 CO 3 (388.33 mg, 1.19 mmol), evacuate the vessel and add N 2 Backfill (the process is repeated three times), and then 2To the mixture were added (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (32.74 mg, 35.76 μmol) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphine (24.46 mg, 59.59 μmol), the container was emptied and the mixture was heated with N 2 After backfilling (this process was repeated three times), the reaction mixture was heated to 100 °C and stirred for 12 h. LCMS showed that the starting material had been consumed and the desired product was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC and lyophilized to give 6,7-diethoxy-N-(3-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine (30) (163.5 mg, 67.16% yield, 99% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ): δ=9.52(s,1H)8.12-8.21(m,1H)7.99(d,J=5.63Hz,1H)7.69-7.81(m,3H)7.32(s,1H)7.27 (d, J=5.63Hz, 1H) 4.22 (dq, J=17.39, 7.00Hz, 4H) 3.26 (s, 3H) 1.43 (dt, J=9.79, 6.99Hz, 6H).

[0446] 6,7-Diethoxy-N-(2-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine (31)

[0447] According to Scheme 47, the above compound was prepared under the following specific conditions:

[0448] Scheme 47

[0449]

[0450] To a solution of xxv (150 mg, 476.74 μmol) and 2-fluoro-4-methylsulfonyl-aniline (90.20 mg, 476.74 μmol) in dioxane (3 mL) was added Cs 2 CO 3 (310.66 mg, 953.49 μmol). Then 2 and 20 °C to the mixture was added Pd 2 (dba) 3(21.83 mg, 23.84 μmol) and sphos (19.57 mg, 47.67 μmol). The mixture was stirred at 100 °C for 16 h. LCMS showed that the starting material had been consumed and the product was detected. The mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC and lyophilized to give 6,7-diethoxy-N-(2-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine (31) (137.7 mg, 70.34% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d 6 ): δ9.09(s,1H)7.89(t,J=8.07Hz,1H)7.84(d,J=5.63Hz,1H)7.78(dd,J=10.51,2.00Hz,1H)7.68 -7.74(m,2H)7.28(s,1H)7.20(d,J=5.75Hz,1H)4.14-4.28(m,4H)3.26(s,3H)1.37-1.48(m,6H).

[0451] N-[4-(Cyclopropylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (32)

[0452] According to Scheme 48, the above compound was prepared under the following specific conditions:

[0453] Scheme 48

[0454]

[0455] To a solution of xxv (130 mg, 413.18 μmol) and 4-cyclopropylsulfonylanilide (81.50 mg, 413.18 μmol) in dioxane (2.6 mL) was added Cs 2 CO 3 (269.24 mg, 826.35 μmol). Then 2 Sphos (16.96 mg, 41.32 μmol) and Pd were added to the mixture at 20°C. 2 (dba) 3 (18.92 mg, 20.66 μmol). The mixture was stirred at 100 °C for 16 h. LCMS showed that the starting material had been consumed and the product was detected. The mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC and lyophilized to give N-[4-(cyclopropylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (32) (103.1 mg, 59.40% yield) as a white solid. 11H NMR (400 MHz, DMSO-d 6 ): δ 9.33 (s, 1H) 8.03 (d, J = 8.88 Hz, 2H) 7.94 (d, J = 5.63 Hz, 1H) 7.74 - 7.83 (m, 3H) 7.29 (s, 1H) 7.21 (d, J = 5.63 Hz, 1H) 4.22 (dq, J = 18.79, 6.95 Hz, 4H) 2.68 - 2.88 (m, 1H) 1.32 - 1.55 (m, 6H) 0.93 - 1.20 (m, 4H).

[0456] 6-Ethoxy-7-(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (33)

[0457] According to Scheme 49, the above compound was prepared under the following specific conditions:

[0458] Scheme 49

[0459]

[0460] At 20 °C, K 2 CO 3 (549.51 mg, 3.98 mmol) and 1-fluoro-2-iodo-ethane (276.66 mg, 1.59 mmol) were added to a solution of 6 (500 mg, 1.33 mmol) in dimethylformamide (5 mL). The mixture was stirred at 60 °C for 3 h. LCMS showed that the starting material had been completely consumed and the desired product was detected. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give 6-ethoxy-7-(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (33) as a white solid (187.0 mg, purity 99.8%). 1 1H NMR (400 MHz, DMSO-d 6 ): δ = 9.34 (s, 1H), 8.04 (d, J = 9.0 Hz, 2H), 7.96 (d, J = 5.6 Hz, 1H), 7.86 - 7.80 (m, 3H), 7.33 (s, 1H), 7.23 (d, J = 5.8 Hz, 1H), 4.95 - 4.78 (m, 2H), 4.51 - 4.39 (m, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.16 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H).

[0461] 6,7-Bis(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine(34)

[0462] According to Scheme 50, the above compound was prepared under the following specific conditions:

[0463] Scheme 50

[0464]

[0465] To a solution of 5 (250 mg, 718.92 μmol) in dimethylformamide (3 mL) was added K 2 CO 3 (298.08 mg, 2.16 mmol) and 1-fluoro-2-iodo-ethane (275.14 mg, 1.58 mmol). The mixture was stirred at 60 ° C for 3 h. LCMS showed that the starting material was completely consumed and the desired product was detected. The reaction mixture was diluted with 10 mL of brine and extracted with ethyl acetate (3 x 5 mL). The combined organic layer was washed with brine (2 x 5 mL) and washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue. The residue was purified by preparative HPLC and lyophilized to give 6,7-bis(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (34) (137.4 mg, purity 99.7%) as a grey solid. 1 H NMR (400MHz DMSO-d 6 ): δ=9.36(s,1H),8.07-8.03(m,2H),7.97(d,J=5.6Hz,1H),7.88(s,1H),7.86-7.82(m,2H),7.39(s,1H),7.22(d,J=5.6Hz,1H),4 .92(dt,J=3.8,7.9Hz,2H), 4.80(dt,J=3.8,7.9Hz,2H), 4.49(td,J=3.8,16.4Hz,2H), 4.41(td,J=3.8,16.4Hz,2H), 3.16(s,3H).

[0466] 1-[(4-Methylsulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline (35)

[0467] According to Scheme 51, the above compound was prepared under the following specific conditions:

[0468] Scheme 51

[0469]

[0470] At argon and 20 °C, to a solution of 6-(propan-2-yloxy)isoquinoline xxvi (1 g, 4.81 mmol) in CH 3 CN (50 mL) was added 2-(4-methylsulfonylphenyl)acetic acid (4.12 g, 19.23 mmol) and [phenyl-(2,2,2-trifluoroacetyl)oxy-iodo]trifluoroacetate (4.13 g, 9.61 mmol). The mixture was stirred for 16 h under irradiation with a 34 W blue LED. LCMS showed 11% of the starting material remaining and 15% of the desired MS detected. Then the reaction mixture was treated with saturated NaHCO 3 aqueous solution (30 mL), extracted with ethyl acetate (20 mL x 3), washed with brine (20 mL), dried over Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC and lyophilized to give 1-[(4-methylsulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline as a white solid (35) (46.6 mg, 2.64% yield, 96.7% purity). 1 H NMR (400 MHz, DMSO-d 6 ): δ = 8.33 (d, J = 5.75 Hz, 1H) 8.23 (d, J = 9.13 Hz, 1H) 7.81 (d, J = 8.38 Hz, 2H) 7.51 - 7.63 (m, 3H) 7.35 (d, J = 2.50 Hz, 1H) 7.21 (dd, J = 9.19, 2.56 Hz, 1H) 4.81 (spt, J = 5.98 Hz, 1H) 4.68 (s, 2H) 3.15 (s, 3H) 1.33 (d, J = 6.00 Hz, 6H).

[0471] 6-[(4-Fluorophenyl)methoxy]-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (36)

[0472] The above compound was prepared under the following specific conditions according to Scheme 52:

[0473] Scheme 52

[0474]

[0475] At 20 °C, to a solution of vi (200 mg, 572.59 μmol) in DMF (2 mL) was added K 2 CO 3(158.28 mg, 1.15 mmol) and 1-(bromomethyl)-2-methyl-benzene (127.16 mg, 687.11 μmol, 92.08 μL). The reaction was stirred at 60 °C for 16 h. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was washed with brine (10 mL) and dried over Na 2 SO 4 filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give 6-[(4-fluorophenyl)methoxy]-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (36) as a gray solid (136 mg, 99.8% purity). 1 1H NMR (400 MHz, DMSO-d 6 6): δ = 9.55 (s, 1H) 8.48 (d, J = 9.25 Hz, 1H) 8.12 (d, J = 8.88 Hz, 2H) 8.03 (d, J = 5.75 Hz, 1H) 7.82 (d, J = 8.88 Hz, 2H) 7.58 (dd, J = 8.63, 5.63 Hz, 2H) 7.42 (d, J = 2.50 Hz, 1H) 7.35 (dd, J = 9.26, 2.50 Hz, 1H) 7.22 - 7.30 (m, 3H) 5.26 (s, 2H) 3.16 (s, 3H).

[0476] 6-Ethoxy-N-(4-methylsulfonylphenyl)-7-propylisoquinolin-1-amine (37)

[0477] The above compound was prepared under the following specific conditions according to Scheme 53:

[0478] Scheme 53

[0479]

[0480] At 0 °C, trimethylamine (1.61 g, 15.90 mmol, 2.21 mL) and a solution of trifluoromethanesulfonic anhydride (1.79 g, 6.36 mmol, 1.05 mL) in dichloromethane (1 mL) were added to a solution of 6 (1.2 g, 3.18 mmol) in dichloromethane (4 mL). The mixture was stirred at 20 °C for 3 h. LCMS showed that the starting material had been completely consumed and the desired product was detected. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL) and dried over Na 2 SO 4Drying, filtering and concentrating under reduced pressure gave a residue. The residue was purified by preparative TLC (petroleum ether:ethyl acetate=1:2) to give xxvii (500 mg, 28.85% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ=9.62(s,1H),8.71(s,1H),8.20-8.01(m,3H),7.91-7.82(m,2H),7.64(s,1H), 7.30(d,J=5.8Hz,1H),4.38-4.28(m,2H),3.19-3.15(m,3H),1.43(t,J=7.0Hz,3H).

[0481] At 20 °C and N 2 xxvii (300 mg, 550.49 μmol) and 4,4,5,5-tetramethyl-2-[(E)-prop-1-enyl]-1,3,2-dioxaborolane (277.51 mg, 1.65 mmol) in tetrahydrofuran (4 mL) and H 2 O (1 mL) solution was added with di-tert-butyl (cyclopentyl) phosphine; dichloropalladium; iron (35.88 mg, 55.05 μmol) and K 3 PO 4 (233.70 mg, 1.10 mmol). The mixture was stirred at 80 °C for 3 h. LCMS showed that the starting material was completely consumed and the desired product was detected. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL) and washed with Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave a residue. The residue was purified by preparative HPLC and lyophilized to give xxviii (90 mg, 41.25% yield) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ=9.53(s,1H),8.52(s,1H),8.10(d,J=8.9Hz,2H),7.96(d,J=5.6Hz,1H),7.83(d,J=8.9Hz,2H),7.25(s,1H),7.20(d,J=5.8Hz,1H), 6.78(dd,J=1.4,15.9Hz,1H),6.68-6.54(m,1H),4.20(q,J=6.9Hz,2H),3.16(s,3H),1.95(dd,J=1.1,6.4Hz,3H),1.44(t,J=6.9Hz,3H).

[0482] In H2 To a mixture of Pd / C (24.17 mg, 22.71 μmol) in methanol (1 mL) was added a solution of xxviii (90 mg, 227.07 μmol) in methanol (1 mL) under a 2% CO atmosphere. The suspension was degassed and heated with H 2 The mixture was purged 3 times at 20 °C and H 2 The reaction mixture was stirred at 40 °C (15 Psi) for 2 h. LCMS showed that the starting material was completely consumed and the desired product was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 6-ethoxy-N-(4-methylsulfonylphenyl)-7-propylisoquinolin-1-amine (37) (64.4 mg, purity 97.2%) as a white solid. 1 H NMR (400MHz DMSO-d 6 ): δ=9.44(s,1H),8.26(s,1H),8.09(d,J=8.9Hz,2H),7.97(d,J=5.8Hz,1H),7.82(d,J=8.9Hz,2H),7.26-7.19(m,2H),4.1 9(q,J=7.0Hz,2H),3.15(s,3H),2.77-2.71(m,2H),1.69(sxt,J=7.5Hz,2H),1.42(t,J=6.9Hz,3H),0.96(t,J=7.4Hz,3H).

[0483] Example 2 In vitro effects of the compounds of the invention in enhancing glucose uptake and secretion of lactate levels

[0484] To evaluate the effects of the compounds described in the present invention, these compounds were tested in primary mouse astrocytes and astrocytes differentiated from human induced pluripotent stem cells (iPSCs). As described below, lactate secretion was indirectly measured by acidification of the extracellular medium using the extracellular pH sensor SNARE-5F-(AND-6)-CAR (SNARF5).

[0485] Table 1 shows the activity of the compounds described in the present invention on the in vitro astrocyte extracellular medium acidification (SNARF5) assay, which indicates their glycolytic activity and ability to produce lactate. "+" indicates the activity of the compound with EC50>1μM, and "++" indicates the activity of the compound with EC50<1μM.

[0486] Table 1

[0487]

[0488]

[0489] Primary mouse cell culture

[0490] Primary cultures of cerebral cortical astrocytes were obtained from OF1 mouse pups aged 1 to 2 days (Charles River Laboratories). In brief, the cortex was separated and cut into small pieces under a dissecting microscope. The cells were incubated for 30 min at 37 ° C and in a solution containing 20 U / ml papain, 1 mM L-cysteine ​​and 10 kU / ml DNase I. After dissociation, papain activity was stopped by adding fetal calf serum (FCS). Single cell suspensions were then obtained by mechanical dissociation, which included grinding cells in DMEM D7777 culture medium supplemented with 44 mm NaHCO 3 , 10 ml / L antibiotic / antimycotic solution and 10% FCS. Depending on the use, cells are plated at approximately 10,000 cells / cm 2 The average density of 100 μg / ml was seeded on poly-D-lysine-coated 96-well or 12-well culture plates and cultured at 37°C in the presence of 5% CO. 2 / 95% air humidified gas and 44 mm NaHCO 3 The cells were grown in DMEM D7777 medium with 10 ml / L antibiotic / antimycotic solution and 10% FCS. The medium was refreshed twice a week. The cells were stimulated and harvested between DIV14 and DIV17, when confluence and cell growth were optimal.

[0491] Primary mouse astrocyte-neuron co-culture

[0492] Primary mouse neuron cultures were obtained from 18-day OF1 mouse embryos (Charles River Laboratories). In brief, the cortex was separated and cut into small pieces under a dissecting microscope. The cells were incubated for 30 min at 37 ° C and in a solution containing 20 U / ml papain, 1 mM L-cysteine ​​and 10 kU / ml DNase I. After dissociation, papain activity was stopped by adding fetal calf serum (FCS). Single cell suspensions were then obtained by mechanical separation, which included grinding cells in Neurobasal + B-27 + GlutaMAX culture medium. The cells were lysed at about 1.5 x 10 5 cells / cm 2 The average density of 100 μg / ml was seeded on a poly-D-lysine-coated 12-well culture plate and incubated at 37°C with 5% CO 2 / 95% air humidified atmosphere and grown in Neurobase medium supplemented with B-27 and GlutaMAX. Neurons were used at DIV10. Primary mouse astrocytes were cultured as previously described, except that they were grown on 15 mm diameter Nunc Thermanox coverslips with two 3 mm paraffin beads per coverslip. On the day of the experiment, co-cultures were initiated by transferring coverslips to each well of a 12-well plate neuronal culture, with astrocytes on the coverslip facing the neurons in the well, separated by 3 mm paraffin beads.

[0493] Extracellular medium acidification (SNARF5)

[0494] The extracellular pH sensor SNARF-5F-(AND-6)-CAR (SNARF5) was used to indirectly measure lactate secretion through acidification of the extracellular medium. The cells were incubated at 37°C with stimulation medium (DMEM (D5030, Sigma), 1 mM NaHCO 2 After washing the cells twice with 5mM glucose, pH 7.4), the cells were stimulated with compounds at a final concentration of 10nM to 30μM, and 50μl of stimulation medium (Life Technologies Corporation) added with 10μM SNARF5 in each well. Each compound was tested in duplicate on two different plates. After stimulation for 30, 60 and 90min, fluorescence was read under excitation 480nm / emission 580nm and excitation 480nm / emission 630nm. The fluorescence ratio between the 630nm and 580nm emission values ​​was calculated, which is directly proportional to the extracellular pH value. In each plate, 8 wells were used for negative control (DMSO 0.1%) and 8 wells were used for positive control (DMSO solution of 2μM CCCP). The results are shown as the percentage of the positive control effect (0% and 100% are the activity of Veh and positive control, respectively).

[0495] The acidification of the culture medium of primary astrocytes treated with the compounds of the present invention is shown in Table 1.

[0496] Extracellular lactate quantification

[0497] After stimulating astrocytes in 96-well plates with vehicle (Vehicle, DMSO), compounds of the invention (100nM to 100μM) or positive controls for 90min (at 37°C, 5% CO2 / 95% air), L-lactate secretion was measured in the extracellular medium. The positive control consisted of carbonyl cyanide m-chlorophenylhydrazone (CCCP, 2μm), which is an inhibitor of mitochondrial oxidative phosphorylation and thus enhances glycolysis and lactate secretion. The stimulation medium consisted of D5030 medium supplemented with 5mM D-glucose and 44mM sodium bicarbonate, pH 7.2. To quantify the lactate concentration in the extracellular medium, 200μl of 0.2M glycine semicarbazide buffer (pH 10) containing 3mMNAD and 14U / ml LDH was added to each well of a 96-well plate containing a 30μl aliquot of the extracellular medium. The samples were incubated at 37°C for 1h. The fluorescence intensity (340 nm excitation / 450 nm emission), which represents the amount of NADH produced, was measured, and the lactate concentration value was determined relative to a standard curve of L-lactic acid concentration.

[0498] 2-Deoxyglucose (2DG) uptake

[0499] Astrocytes grown on 12-well plates and transfected with scramble siRNA or GLUT1-siRNA were used. One day after replacing the transfection medium (DIV13), 2DG uptake was measured after treatment with vehicle (Vehicle, 0.1% DMSO) or compounds (1) to (5) of the present invention (concentrations of 0.1 to 10 μM) for 30 min. During the treatment, 1 mM 2DG was added to the culture medium to evaluate 2DG uptake. At the end of the stimulation, the culture medium was removed, replaced with 150 μl 0.1M NaOH, and stored at -20°C. After thawing, cells were collected using a cell scraper and heated at 85°C for 40 min. Then, 150 μL 0.1M HCl and 200mM TAE buffer were added under each condition. 20 μl was added to a clear 96-well plate, and 2DG was quantified by adding a reaction solution containing 50 mM TAE, 50 mM KCl, 0.02% BSA, 0.1 mM NADP, 0.2 U / ml diaphorase, 2 mM resazurin, and 20 U / ml glucose-6-phosphate dehydrogenase. The concentration of 2DG in the sample was calculated by comparing with a standard curve of deoxyglucose-6-phosphate ranging from 0 to 1 nM.

[0500] After treatment with compounds (1) to (5), the uptake of 2DG by primary astrocytes was analyzed ( Figure 1 A to E), it was observed that these compounds significantly enhanced the uptake of 2DG in astrocytes.

[0501] MTT assay for mitochondrial activity in primary astrocytes

[0502] In order to measure the mitochondrial activity related to the glycolytic metabolic process and lactate production in astrocytes, astrocytes in 96-well plates were stimulated with 10 nM to 10 μM of the compounds of the present invention for 24 h (37° C., 5% CO 2 / 95% air).

[0503] After stimulation, D5030 medium (supplemented with 5 mM D-glucose and 44 mM sodium bicarbonate (pH 7.2)) containing 5 mg / ml thiazolyl blue tetrazolium bromide (MTT) was added to each well, and the cells were incubated at 37°C (5% CO 2 ) for 4 h. The culture medium was then removed, and the amount of reduced MTT (i.e., formazan) dissolved in DMSO (50 μl / well) was measured using a spectrophotometer (absorbance at 570 nm).

[0504] The MTT colorimetric assay was used to measure the activity of compounds (1), (2), (3), (4), (5), (9) and (10) at different concentrations for 1.5 h (as shown in Table 2). Figure 2 A, B, D, E, F, C, H) or 24h (as shown in Figure 2 H, I, K, L, M, J, and N). These data indicate that none of the selected compounds had a direct effect on the mitochondrial activity of astrocytes.

[0505] MTT assay to detect mitochondria in pure cultured neurons and astrocyte-neuron co-cultured neurons

[0506] Pure cultures of neurons or astrocyte-neuron cocultures were treated for 2 h with 10 μM of compound (2) in a solution consisting of Neurobasal supplemented with B-27 and Glutamax and 0.25 mg / ml Thiazolyl Blue Tetrazolium Bromide (MTT). As described above, pure cultures of neurons were treated with empty coverslips, while neurons from cocultures were treated with astrocytes grown on coverslips. After stimulation, empty coverslips (pure cultures of neurons) or astrocytes on coverslips (astrocyte-neuron cocultures) were separated from neurons, the culture medium was removed, and the amount of reduced MTT (i.e., formazan) dissolved in DMSO (50 μl / well) was measured using a spectrophotometer (absorbance at 570 nm).

[0507] The results showed that the therapeutic compound (2) enhanced the mitochondrial activity of neurons in astrocyte-neuron co-cultures (e.g. Figure 3 B), but did not enhance mitochondrial activity in neurons in pure culture ( Figure 3 A), indicating that the compound's effect on neurons requires the presence of astrocytes.

[0508] Human iPSC-derived astrocytes

[0509] Human iPSC-derived astrocytes were purchased from NCardia (NCyte Astrocytes) and cultured at approximately 10,000 cells / cm according to the manufacturer's instructions and using the recommended culture medium. 2 The cells were plated at a density of 1:1 in 96-well or 12-well plates. The experiments were performed in vitro for 7 days. The cells were treated with compound (2) for 1.5 h. 2-DG uptake and lactate release were quantified as described above. Compound (2) increased 2-DG uptake and lactate release by human iPSC-derived astrocytes (respectively Figure 4 A and B).

[0510] Example 3 In vivo effects of the compounds of the present invention

[0511] To evaluate the effects of the compounds of the invention on brain extracellular glucose and lactate levels, they were determined by monitoring glucose and lactate levels in vivo following treatment with the compounds of the invention, as described below.

[0512] animal

[0513] All experiments were performed in strict accordance with the Swiss Federal Guidelines for Animal Experimentation and were approved by the Cantonal Veterinary Office for Animal Experimentation (Canton Geneva, Switzerland). Adult male C57Bl / 6J wild-type mice weighing 18-28 g (8 to 12 weeks old) were used (Charles River Laboratories). Animals were housed in groups of 3-5 in polypropylene cages (30X 40X 15 cm) in a temperature (22±2°C) and humidity (55±15%) controlled environment with a 12 h light cycle (lights on from 07.00 to 19.00 h), except for animals housed individually after surgery. The samples (vehicle or compound of the present invention) were orally administered (gavage) in a solution made of water supplemented with 0.4% hydroxypropyl methylcellulose (HPMC) Methocel 4KM (w / v) and 0.25% Tween-20 (v / v), as previously described (Thackaberry et al., 2010, Toxicol Sci., 117(2): 485-92). The dose of the tested compound was 3-30 mg / kg.

[0514] Lactate and Glucose Biosensors

[0515] According to the manufacturer's instructions, lactate and glucose biosensors (Pinnacle Technology) were used to monitor brain extracellular L-lactate and D-glucose levels in vivo. 5 to 7 days before the experiment, the cannula was surgically implanted into the medial prefrontal cortex of isoflurane-anesthetized mice (coordinates: -1.0mm (to Bregma), lateral + / -1.0mm (to midline), ventral -1.0mm (to dura mater)). After surgery, the mice were closely monitored and received at least 4 days of analgesic treatment. After the mice fully recovered from the surgery, as described above, the vehicle (Vehicle) or the compound of the present invention was orally administered, and the biosensor was used to dynamically record the brain extracellular lactate and glucose levels for 6h. First, the mice were given the vehicle (Vehicle) alone, and the vehicle (Vehicle) or the compound of the present invention was taken 3h later. The concentrations of brain extracellular lactate and glucose were calculated from the biosensor electrical signals using the calibrated values. Each signal of lactate or glucose fluctuation after compound (or vehicle) administration is expressed as the fold change relative to the lactate or blood glucose fluctuation after vehicle (Vehicle) administration alone, so each animal is its own control. The area under the curve (AUC) of the lactate and glucose concentration curves was calculated using Graphad Prism, and the ratio of the AUC after administration to the vehicle (Vehicle) administration was calculated. The extracellular concentrations of lactate and glucose (e.g., 400 mg / kg) were measured in real time in freely moving animals 3 h after administration of vehicle (Vehicle) or 10-30 mg / kg doses of compounds (1) to (4). Figure 5 The results showed that, compared with the vehicle (Vehicle), different doses of compound (1) ( Figure 5 C, D), compound (2) Figure 5 A), compound (3) Figure 5 G, H) and compound (4) ( Figure 5 K) can significantly increase the extracellular glucose level in the mouse brain. The results showed that compared with the vehicle (Vehicle), different doses of compound (1) ( Figure 5 E, F), compound (2) Figure 5 B), compound (3) Figure 5 I, J) and compound (4) ( Figure 5 L) can significantly increase the level of extracellular lactate in the mouse brain.

[0516] 18 F-FDG PET

[0517] use 18 F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) scanning were used to measure glucose uptake in the brain in vivo. Mice were fasted for 12 h before PET / CT scanning. The compounds of the present invention were administered by oral gavage followed by intraperitoneal injection of 5 MBq18 F-FDG was injected into the mouse with 300 μL saline. 20 min after injection, the mouse was anesthetized and placed on the microPET / CT scanner bed. The microPET scan lasted for 40 min, with acquisitions every 5 min, followed by a 5 min CT scan for localization. At the end of the imaging protocol, the animal was returned to the cage and a second measurement was performed seven days later. At the end of the second measurement, the mouse was sacrificed. Blood and brain were collected. Whole brain 18 Quantification of F-FDG (BQML / vol) showed that administration of 30 mg / kg dose of compounds (1) and (2) increased brain glucose uptake by 1.3% and 2.4%, respectively, compared with vehicle. Figure 6 A and B).

[0518] Taken together, these data support that compounds of the invention enhance brain glucose uptake and brain glucose and lactate levels.

[0519] Example 4 In vivo effects of compounds of the invention in preclinical models of hypometabolic diseases including GLUT1-DS.

[0520] To evaluate the in vivo effects of the compounds of the invention, they were tested in the following models.

[0521] animal

[0522] Heterozygous transgenic mice with a 129 / SvJ genetic background in which glucose transporter 1 (GLUT1) has been knocked out (GLUT 1 (+ / -)) (Wang et al., 2016, Human Molecular Genetics, 15(7)) were used. GLUT1 deficiency syndrome (GLUT1-DS) is a typical metabolic disorder caused by GLUT1 mutations and reduced glucose and lactate levels in the brain (Tang et al., 2019, Annals of Clinical and Translational Neurology 6(9)). Mating colonies consisted of wild-type female mice and GLUT1-DS male mice, or GLUT1-DS female mice and wild-type male mice. F1 pups were genotyped using PCR after ear punching at weaning to determine the genotype. Mice aged 2 to 3 months were used.

[0523] Lactate and Glucose Biosensors

[0524] Brain extracellular lactate and glucose levels were monitored in GLUT1-DS transgenic male mice and wild-type (WT) male littermates using lactate and glucose biosensors (Pinnacle Technology) according to the manufacturer's instructions. Cannulas were surgically implanted in the motor cortex M1 / M2 of GLUT1-DS transgenic mice and wild-type littermates (coordinates: +1.94 mm (to bregma), -1.4 mm lateral (to midline), -1.0 mm ventral (to dura mater)). After surgery, mice were closely monitored and received analgesic treatment for at least 4 days. After the mice fully recovered from surgery, the compounds of the present invention or vehicle (Vehicle) were orally administered as described above, and brain extracellular lactate or glucose levels were dynamically recorded for 6 hours using lactate or glucose biosensors, respectively. Mice were first orally administered with vehicle (Vehicle) alone, and 3 hours later, vehicle (Vehicle) or a 10 mg / kg dose of compound (2). During the recording process, mice were exposed to novel objects in the cage, which consisted of colored plastic building blocks to stimulate their activity. The concentration of extracellular lactate or glucose in the brain was calculated from the lactate or glucose probe electrical signal, respectively, using the calibrated values ​​as described by the manufacturer. The area under the curve (AUC) of the lactate or glucose concentration curve was calculated using Graphpad Prism, and the AUC ratio after administration of the compound of the present invention and the vehicle was calculated. After administration of the vehicle or compound (2), the AUC signal of lactate or glucose was expressed as the fold change relative to the lactate or glucose fluctuation AUC after the first administration of the vehicle (Vehicle) (e.g. Figure 7 The results showed that treatment with 10 mg / kg dose of compound (2) significantly increased brain extracellular lactate ( Figure 7 A) levels and glucose levels ( Figure 7 B).

[0525] Rotarod test

[0526] The motor function of wild-type (WT) and GLUT1-DS transgenic mice was measured in the rotarod test after a single administration of Veh or 10 mg / kg of compound (1) or (2) 20 min before the rotarod test. The rotarod test involves placing the mice on an accelerating rotarod (accelerating from 4 to 40 rpm for a maximum of 300 s). The treatment was performed three times in succession, with an interval of 15 min between each. The latency of the mice to fall from the rod was recorded, and the maximum latency of the three trials was used as a criterion for measuring motor function. Mice that did not fall within 300 s were removed and the test was terminated, with a maximum score of 300 s. The data showed that GLUT1-DS transgenic mice performed poorly on the rotarod compared with wild-type mice, and administration of 10 mg / kg dose of compound (1) or (2) was able to improve the rotarod performance of GLUT1-DS-mice (as shown in Table 2, respectively). Figure 8 A and B).

[0527] Grip strength test

[0528] After training in the rotarod test, exercise intensity was measured by the grip strength test (Bioseb). Wild-type (WT) and GLUT1-DS transgenic mice placed all four paws on a grid and the maximum grip strength was recorded in 2 sessions separated by 5 min. The maximum grip strength was recorded for 2 sessions. The data show that Veh or treatment with 10 mg / kg dose of compounds (1) or (2) did not result in any differences in muscle strength, whereas muscle coordination assessed by the rotarod test was affected (respectively). Figure 8 C and D).

[0529] Example 5 In vivo effects of compounds of the invention in preclinical models of hypometabolic diseases including Alzheimer's disease

[0530] The effects of the compounds of the invention were tested in the above-mentioned animal models as described below.

[0531] Adult male C57Bl / 6J wild type (old) (Charles River) aged 3 months (young adults) to 16 months were used. Animals were housed in polypropylene cages (30X 40X 15cm) with wire mesh on the top of the cages in groups of 3-5, in a temperature (22±2°C) and humidity (55±15%) controlled environment with a 12h light cycle (lights on from 07.00 to 19.00h). Samples (vehicle or compound of the present invention) were orally administered (gavage) in a solution made of water supplemented with 0.4% hydroxypropylmethylcellulose (HPMC) Methocel4KM (w / v) and 0.25% Tween-20 (v / v) as previously described (Thackaberry et al., 2010, Toxicol Sci., 117(2):485-92). As described below, memory of young adult mice treated with vehicle or old mice treated with vehicle or 10 mg / kg or 30 mg / kg of compound (1) was tested in the Morris water maze. Treatment was performed during daily training, 30 min before the first training. No treatment was performed during the memory retention test. The data showed that after 1 day of training, the memory of old mice treated with vehicle was significantly lower than that of young mice, and the memory of old mice treated with 10 mg / kg or 30 mg / kg of compound (2) was significantly improved, as measured in the Morris water maze (e.g. Fig. 9 shown).

[0532] APOE4(+) Mouse Model of Alzheimer's Disease

[0533] Compared with models expressing APOE3, mouse models carrying the APOE4 human allele have reduced metabolic gene expression and brain glucose uptake (Williams et al., 2020, neurobiol dis, 136: 104742; Lin et al., 2015, J Cereb Blood Flow Metabl, 37(1): 217-226; Alata et al., 2015, J Cereb Blood Flow Metab, 35(1): 86-94). These physiological perturbations lead to low brain metabolism, which recapitulates the brain metabolic state observed in AD patients carrying the APOE4 allele. Male and female APOE4(+) and APOE3(+) (control) transgenic mice were used at 3 months of age. As described below, memory was tested in the Morris water maze in APOE3(+) mice treated with vehicle (Veh) and APOE4(+) mice treated with vehicle (Veh) or 10 mg / kg and 30 mg / kg doses of compound (2). Treatment was performed during daily training, 30 min before the first training. No treatment was performed during the memory retention test. The data showed that after 7 days of training, the memory of APOE4(+) mice treated with vehicle (Vehicle) was lower than that of APOE3(+) mice, and treatment of APOE4(+) mice with a 30 mg / kg dose of compound (2) significantly improved memory, as measured in the Morris water maze (as Fig.10 shown).

[0534] Intraventricular (ICV) streptozotocin model of Alzheimer's disease

[0535] Isoflurane-anesthetized mice underwent craniectomy for intracerebroventricular injection of vehicle or streptozotocin (coordinates: -0.5 mm (to bregma), + / -1.0 mm lateral (to midline), -2.2 mm ventral (to dura)) ((Kelliny S. et al., Molecular Neurobiology, 2021)). Vehicle (0.9% NaCl) or streptozotocin (5 mg / kg) was injected intraventricularly at a constant rate of 100-200 nl / min using a Hamilton microsyringe. 4.2) was injected into both ventricles. After injection, the skull skin was sutured, and the mice were closely monitored and received analgesic treatment for at least 4 days. After the mice fully recovered from the surgery, memory tests including Morris water maze (MWM), inhibitory avoidance (IA), and novel object recognition (NOR) were performed as described below. Mice injected with vehicle (Veh) and treated with Veh, or injected with streptozotocin and treated with Veh or 10 mg / kg and 30 mg / kg doses were tested in Morris water maze, novel object recognition, and inhibitory avoidance. The memory of mice treated with compound (2) was improved as described below. In the Morris water maze test, treatment was performed 30 min before the first training session in each day's training. In the novel object recognition and inhibitory avoidance tests, treatment was performed once 30 min before the acquisition test. The data showed that in the Morris water maze, novel object recognition and inhibitory avoidance memory tasks, the memory of mice injected with streptozotocin and treated with vehicle (Vehicle) was weaker than that of mice injected with saline and treated with vehicle (Vehicle) (respectively). Fig.11 The data also showed that in the Morris water maze, after 1 day of training, the memory of mice injected with streptozotocin and treated with 30 mg / kg dose of compound (2) was significantly higher than that of mice treated with vehicle (Veh) ( Fig.11 A), mice injected with streptozotocin and treated with 10 mg / kg and 30 mg / kg doses of compound (2) showed novel object recognition after 1 day of training (as shown in Fig.11 B) and inhibitory avoidance after 1 day of training ( Fig.11 C) was significantly higher than that in mice treated with vehicle (Veh).

[0536] Inhibitory avoidance

[0537] The inhibitory avoidance (IA) test is a well-established memory paradigm in rodents that measures contextual memory associated with a mild electric shock in a specific context (the dark compartment of the IA chamber). Each mouse was treated for 5 min per day for at least 4 consecutive days to reduce the stress of the animals caused by the presence / handling of the experimenter during the test. Inhibitory avoidance experiments were performed in an IA chamber (MedAssociates), which consisted of a rectangular plexiglass box divided into a safety chamber and a shock chamber separated by an automatically operated sliding door. The safety chamber was white and illuminated, while the shock chamber was black and dark. Mice were trained in IA 20 min after oral administration of drug or vehicle. During the training, mice were placed in the safety chamber with their heads facing away from the door. After 10 s, the door separating the compartments opened automatically, allowing the mouse to enter the shock chamber (usually completed within 20 s). One s after the mouse entered the dark chamber, the door closed, and a 2-s foot shock of 0.6 mA intensity was delivered to the grid floor of the shock chamber via a constant current scrambler circuit. After the foot shock, the mouse stayed in the dark compartment for 10 seconds and then returned to its cage. After 24 hours of training, memory retention was determined by returning the mouse to the lighted compartment and recording its latency (in seconds) to enter the dark compartment. No foot shock was given during the memory retention test. Once the mouse entered the dark compartment, or after a cutoff limit of 900 seconds, the test was terminated.

[0538] Morris water maze

[0539] The Morris water maze, a well-established test of spatial and contextual memory, will be used. The MWM consists of 4 consecutive training days, each consisting of 4 90-second training sessions in which mice learn to find a hidden platform in a swimming pool. If a mouse does not find the platform within a 90-second training session, it is accompanied by the experimenter to the platform. The mouse is allowed to remain on the platform for 30 seconds. After training, memory is tested in probe trials on days 5 and 12 after the platform is removed. A number of parameters are recorded using automated tracking software (Ethovision), including latency to find the platform, time spent around the platform, path efficiency, percentage of time spent in each quadrant. The type of exploration (direct, random, scanning the area) is also recorded. In case of doubt, motivation to swim and escape and visual acuity are tested by making the platform visible (e.g., flagging). Testing is performed in a circular arena with a diameter of 120 cm, filled with water at a temperature of 23 ± 1 °C (made opaque with white dye) and divided into four quadrants. Visual cues are located outside the swimming pool.

[0540] New object recognition

[0541] Novel object recognition (NOR) is a well-established protocol for assessing recognition memory in rodent models. Each mouse was treated for 5 min per day for at least 4 consecutive days to reduce stress to the animals caused by the presence / handling of the experimenter during the test. Animals were placed in an arena containing two identical plastic objects (plastic blocks, falcon tubes, plastic cups) for 10 min, which the mice could explore, which constituted the acquisition phase. During the acquisition period, the exploration time and the number of contacts with each object were recorded. At the end of the acquisition, the mice were removed from the arena and returned to their cages. 24 h (test 1) and 7 days (test 2) after the end of the acquisition, the mice were returned to the same arena for 10 min and one of the acquisition objects was replaced. The exploration time and the number of contacts with each object were recorded. Activity was automatically recorded using automatic tracking software (Ethovision).

Claims

1. A compound represented by formula (I); in, Y is selected from NH and CH 2 ; R1 is selected from H, halogen, and optionally selected from halogen, OR 12 and NR 13 R 14 The group substituted C 1 -C 6 Alkyl; R2 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, OR 12 NR 13 R 14 , cyano, or an optionally substituted heterocycle; R3 is selected from H, halogen, optionally selected from halogen, OR 12 and NR 13 R 14 The group substituted C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, OR 12 、NHR 13 , optionally substituted heterocycle or cyano; R4 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 alkyl, optionally substituted heterocycle and cyano; R5 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 Alkyl, OR 12 , or NR 13 R 14 ; R6 is selected from H, halogen, optionally selected from halogen, OR 12 and NHR 13 The group substituted C 1 -C 6 Alkyl, OR 12 , or NHR 13 ; R7 and R8 are each independently selected from H and halogen; R9 is selected from SO-C 1 -C 6 Alkyl, SO 2 -C 1 -C 6 Alkyl, SO 2 -C3-C6 cycloalkyl, or an optionally substituted heterocycle selected from optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyrrolidone and optionally substituted oxetane; R10 and R11 are each independently selected from H and halogen; R12, R13 and R14 are each independently selected from H, C(O)-C 1 -C 6 Alkyl and optionally substituted C 1 -C 6 any pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, or polymorph thereof, tautomer thereof, optically active form thereof, mixture of enantiomers thereof, and mixtures thereof, for preventing, inhibiting or treating a nervous system disease or any disease characterized by a hypometabolic state and / or dysfunction of the central or peripheral nervous system, in particular amyotrophic lateral sclerosis (ALS), dementia, in particular Alzheimer's disease at all stages, frontotemporal dementia (FTD), Lewy body dementia (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), movement disorders such as Parkinson's disease at all stages, including levodopa-induced movement disorders, Huntington's disease, spinocerebellar ataxia, essential tremor, dystonia and related neurodegenerative diseases, such as multiple sclerosis, retinopathy, stroke, trauma brain injury, intracerebral and subarachnoid hemorrhage, neuropsychiatric disorders such as depression of any endophenotype, schizophrenia, anxiety disorders, attention deficit syndrome, autism, neurometabolic disorders such as glucose transporter 1 deficiency syndrome (GLUT1-DS), Lafora disease and other glycogen storage disorders, Down syndrome, all types of epilepsy, migraine and cognitive impairment in type 2 diabetes (T2D), brain hypometabolism caused by viral infections such as HIV or COVID-19, prion infections such as Creutzfeldt-Jakob disease, primary and secondary encephalitis, or abnormal protein processing and accumulation such as all types of amyloidosis, synucleinopathies, tauopathies, TD43 diseases and other proteinopathies, brain hypometabolism after anesthesia or postoperative care; or for the treatment or stabilization of neurological diseases with brain hypometabolism or related symptoms, including cognitive impairment, motor function and movement disorders, psychiatric symptoms or epileptic seizures; and for enhancing cognitive and memory function.

2. A compound of formula (I) as claimed in the preceding claims, any pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, or polymorph thereof, tautomer thereof, optically active form thereof, enantiomeric mixture thereof, and mixtures thereof, provided that the compound is not selected from the following compounds: N-[4-[5-ethyl-3-(1-methylethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-63-4; N-[4-[5-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-99-5; N-[4-[5-ethyl-3-(3-pyridyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-04-5; N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251657-94-0; N-[4-[3-(tetrahydro-2-furyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-82-7; N-[4-[3-(3-pyridinyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-03-4; 3-Methyl-N-[4-(4-pyridyl)phenyl]-1-isoquinolinamine, RN: 1368370-93-7; 1-[[4-(4-pyridyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN: 1368269-53-7; 8-Methyl-N 1 -[4-(4-pyridyl)phenyl]-1,5-isoquinolinediamine, RN: 1369288-67-4; 5-Nitro-N-[4-(4-pyridyl)phenyl]-1-isoquinolinamine, RN: 1368370-43-7; N-[4-(4-pyridyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and 4-Bromo-N 1 -[4-(4-pyridyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1.

3. The compound according to claim 2, It is characterized in that Y 2 。 4. The compound according to claim 2, It is characterized in that Y is NH.

5. The compound according to any one of claims 2 to 4, It is characterized in that R1, R5, R4 and R6 are H.

6. The compound according to any one of claims 2 to 5, It is characterized in that R2 is OR 12 .

7. The compound according to any one of claims 2 to 6, It is characterized in that R3 is OR 12 .

8. The compound according to any one of claims 2 to 6, It is characterized in that R3 is NHR 13 .

9. The compound according to any one of claims 2 to 6, It is characterized in that R3 is halogen.

10. The compound according to any one of claims 2 to 6, It is characterized in that R3 is H.

11. The compound according to any one of claims 2 to 6, It is characterized in that R3 is an optionally substituted C 1 -C 6 alkyl.

12. The compound according to any one of claims 1 to 11, It is characterized in that R10 and R11 are H.

13. The compound according to any one of claims 1 to 11, It is characterized in that R10 is halogen.

14. The compound according to any one of claims 1 to 11, It is characterized in that R11 is halogen.

15. The compound according to any one of claims 1 to 12, It is characterized in that R7, R8, R10 and R11 are H.

16. The compound according to any one of claims 1 to 15, It is characterized in that R9 is selected from SO 2 -C 1 -C 6 Alkyl groups, such as SO 2 -CH 3 Or from SO 2 -CH 2 CH 3 .

17. The compound according to any one of claims 1 to 15, It is characterized in that R9 is self-SO 2 -C3-C6 cycloalkyl.

18. The compound according to claim 1, It is characterized in that The compound is as described in any one of claims 2 to 17.

19. The compound of claim 1, wherein the compound is selected from the group consisting of: 1-[4-[(6,7-dimethoxy-1-isoquinolyl)methyl]phenyl]pyrrolidin-2-one; 6,7-Dimethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; 6-methoxy-1-(4-methylsulfonylanilino)isoquinolin-7-ol; 7-methoxy-1-(4-methylsulfonylanilino)isoquinolin-6-ol; 1-(4-Methylsulfonylanilino)isoquinoline-6,7-diol; 6-ethoxy-1-(4-methylsulfonylanilino)isoquinolin-7-ol; 7-ethoxy-1-(4-methylsulfonylanilino)isoquinolin-6-ol; 6,7-diethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; 1-[4-[(6,7-dimethoxy-1-isoquinolyl)amino]phenyl]pyrrolidin-2-one; N-(4-methylsulfonylphenyl)-6-vinyloxy-isoquinolin-1-amine; 6-isopropoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; N-(4-methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine; N-[1-(4-methylsulfonylanilino)-7-isoquinolinyl]acetamide; N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine; 6-methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine; 7-ethyl-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; 7-Bromo-1-(4-methylsulfonylanilino)isoquinolin-6-ol; N7-Benzyl-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine; N7-(cyclopropylmethyl)-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine; 6-Methoxy-N1-(4-methylsulfonylphenyl)-N7-propyl-isoquinoline-1,7-diamine; N6-(cyclopropylmethyl)-7-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,6-diamine; 6-(azetidin-1-yl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; 6-ethyl-1-[(4-methylsulfonylphenyl)amino]isoquinolin-7-ol; N-[4-(ethylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine; 6,7-diethoxy-N-[4-(oxetan-3-yl)phenyl]isoquinolin-1-amine; 6,7-diethoxy-N-[4-(1,2-oxazol-3-yl)phenyl]isoquinolin-1-amine; 6,7-diethoxy-N-[4-(1,2-oxazol-5-yl)phenyl]isoquinolin-1-amine; 6,7-diethoxy-N-(3-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine; 6,7-diethoxy-N-(2-fluoro-4-methylsulfonylphenyl)isoquinolin-1-amine; N-[4-(Cyclopropylsulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine; 6-ethoxy-7-(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; 6,7-Bis(2-fluoroethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; 1-[(4-Methylsulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline; 6-[(4-fluorophenyl)methoxy]-N-(4-methylsulfonylphenyl)isoquinolin-1-amine; and 6-ethoxy-N-(4-methylsulfonylphenyl)-7-propylisoquinolin-1-amine; Any pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, or polymorph thereof, tautomer thereof, optically active form thereof, enantiomeric mixture thereof, and mixture thereof.

20. A pharmaceutical composition comprising a compound of formula (I) as claimed in claim 1 and a pharmaceutically acceptable carrier, diluent or excipient, provided that the compound is not selected from the following table: 3-Methyl-N-[4-(4-pyridyl)phenyl]-1-isoquinolinamine, RN: 1368370-93-7; 1-[[4-(4-pyridyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN: 1368269-53-7; 8-Methyl-N 1 -[4-(4-pyridyl)phenyl]-1,5-isoquinolinediamine, RN: 1369288-67-4; 5-Nitro-N-[4-(4-pyridyl)phenyl]-1-isoquinolinamine, RN: 1368370-43-7; N-[4-(4-pyridyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and 4-Bromo-N 1 -[4-(4-pyridyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1.

21. A compound as claimed in any one of claims 2 to 19 for use as a medicament.

22. A method for preventing or treating diseases or conditions associated with abnormally low energy metabolism or in the central nervous system and / or neurological diseases; or for treating or stabilizing neurological diseases with low brain metabolism or related symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 19, its tautomer, its geometric isomer, its optically active form, its enantiomeric mixture, its pharmaceutically acceptable salt, its pharmaceutically active derivative, or a mixture thereof.

23. A method for increasing the level of glucose and / or lactate in the brain of a subject, the method comprising administering to a subject in need thereof an effective amount of a compound as claimed in any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, a tautomer thereof, an optically active form thereof, a mixture of enantiomers thereof, a pharmaceutically active derivative thereof, and a mixture thereof, to induce an increase in the level of glucose and / or lactate in the brain.

24. A method for enhancing cognitive and memory function in a subject, the method comprising administering an effective amount of a compound as claimed in any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a polymorph thereof, a tautomer thereof, an optically active form thereof, a mixture of enantiomers thereof, a pharmaceutically active derivative thereof, and a mixture thereof.

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