Lactate-enhancing compounds and uses thereof

Abstract

The present invention relates to novel agents useful for stimulating glucose uptake and lactate release by astrocytes. The invention further relates to methods for the preparation, formulations and therapeutic uses of such agents, in particular for the prevention and / or treatment of neurological disorders with cerebral energy hypometabolism, in particular neurodegenerative, neurometabolic and psychiatric disorders, or for the improvement of cognitive and memory function.

Description

[Technical Field]

[0001] The present invention relates generally to the field of lactate-enhancing drugs, and in particular to the use of lactate-enhancing drugs for the treatment of neurological disorders, including neurodegenerative and psychiatric disorders. [Background technology]

[0002] Neurological disorders represent some of the most highly needed yet unaddressed pathologies. They are predicted to become the leading cause of death by 2050. These pathologies 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. The majority of therapeutic strategies have thus far aimed to directly target neurons using a "neuro-centric" approach, largely sidelining the important roles of other cell types in the nervous system, including astrocytes.

[0003] Astrocytes outnumber neurons in the brain and, together with oligodendrocytes and microglia, form a category of cells called glial cells that support neuronal activity and survival. Over the past decade, considerable attention has been focused on understanding the role of astrocytes in physiological processes and their involvement in the development of neurological disorders, including neurodegenerative disorders, age-related cognitive dysfunction, and psychiatric disorders. While glial cells were long thought to be important only for structural support of neural tissue—a kind of brain “glue”—their far more important role in regulating fundamental processes is now being greatly recognized. In particular, astrocytes play a fundamental role by providing neurons with energy, which is required for their function, i.e., electrical information transmission and survival. Thus, astrocytes have been shown to be important for numerous 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).

[0004] Although neurological disorders have historically been thought of as conditions resulting exclusively from neuronal dysfunction and death, it is becoming clear that other cell types, such as astrocytes, contribute to these pathologies. A growing body of evidence has linked astrocyte activation to mild cognitive impairment (MCI), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and depression. For example, in AD patients, activated astrocytes preferentially locate near amyloid plaques, where they exhibit abnormal morphology and mitochondrial function. Early in the disease, activated astrocytes provide neuroprotection by internalizing and degrading amyloid plaques. However, as the disease progresses, amyloid plaque deposition leads to astrocyte death, which in turn leads to further amyloid accumulation (Nagele et al., 2004, Neurobiol. Aging, 25(5):663-74). There are clear indications that age-related changes in astrocytes play a role in the development of age-related neurodegenerative disorders, such as MCI and AD (Cai et al., 2017, J. Neurol. 264(10):2068-74). Astrocytes are a typical morphological feature of the AD brain, representing either astrocyte proliferation in an effort to support dying neurons or a response to degrade increasing amounts of toxic β-amyloid peptides. Of particular interest, exposure of astrocytes to β-amyloid in vitro alters their metabolic activity and thus reduces neuronal protection from oxidative stress (Allaman et al., 2010, J. Neurosci. 30(9):3326-38).

[0005] Dysregulation of cerebral energy metabolism is an important contributor to the development of several neurological disorders and age-related cognitive decline. These disorders have been associated with decreased mitochondrial activity, increased oxidative stress, and decreased cerebral glucose metabolism. For example, cerebral glucose hypometabolism appears early in the development of AD and is in fact a common phenomenon with 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, associated with age-related neurodegeneration, 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 cerebral genes involved in energy regulation (Liang et al., 2008, Proc. Natl. Acad. Sci. USA, March 18;105(11):4441-6). Consequently, a significant correlation between decreased cerebral glucose metabolism and cognitive performance has been demonstrated in AD 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). Taken together, these data indicate that impaired astrocytic activity and metabolic coupling in MCI and AD may lead to the characteristic accumulation of amyloid plaques and neuronal degeneration in specific brain regions.

[0006] In ALS, defects in mitochondrial activity and energy generation have been shown to contribute, at least in part, to the degeneration of motor neurons (Boillee et al., 2006, Neuron, 52:39-59). Astrocytes may also play an important role through the regulation of glutamate uptake, which is dramatically impaired in ALS (Rothstein et al., 1990, Ann. Neurol., 28:18-25; Spreux-Varoquaux et al., 2002, J. Neurol. Sci., 193:73-78).

[0007] Other neurological disorders, including psychiatric disorders such as depression, also exhibit dysfunction of brain energy metabolism (Elsayed and Magistretti, 2015, Front Cell Neurosci, 9:468). Furthermore, increasing evidence indicates that alterations in glial cells also contribute to the pathophysiology and treatment of major depression (Rajkowska and Stockmeier, 2013, Curr Drug Targets 14, 1225-1236; Czeh 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).

[0008] Other neurological disorders exhibit prototypical cerebral energy hypometabolism, such as glucose transporter type 1 deficiency syndrome (GLUT1-DS), also known as De Vivo disease. GLUT1-DS is a genetic disorder caused by mutations in the GLUT1 gene, also known as solute transporter family 2, facilitative glucose transporter member 1 (SLC2A1). Patients who are GLUT1 hemizygous and carry nonsense mutations that result in truncation of the GLUT1 protein have normal circulating blood glucose but low cerebrospinal fluid (CSF) lactate, persistent CSF hypoglycemia (low CSF glucose), and reduced transport of hexoses into isolated red blood cells (De ViVo et al., 1991, N. Engl. J. Med., 325, 703–709). Symptoms of GLUT1-DS can vary in severity depending on the mutation in the SLC2A1 gene. Symptoms include, but are not limited to, mental retardation, cognitive impairment, epilepsy, and motor problems, including ataxia, gait disturbances, dystonia, dysarthria, abnormal gaze saccades, spasticity, and other paroxysmal neurological phenomena (Gras et al., 2014, Revue Neurologoqique 170:91-99).

[0009] Interestingly, a specific metabolic product of glucose, namely lactate, appears to play a particularly important role in astrocyte-neuron metabolic coupling. Indeed, lactate produced by astrocytes is used by neurons as a preferred energy source during neuronal activity through 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 through the process of aerobic glycolysis, i.e., the conversion of glucose to lactate in the presence of oxygen, which is generally well-known to occur in the absence of oxygen to generate energy (e.g., in muscles during physical activity). The source of glucose in the brain can be derived either from the circulation (astrocyte endfeet are in close contact with capillaries) or from internal glycogen stores (cerebral glycogen is present exclusively in astrocytes). During synaptic activity, lactate is produced by astrocytes and translocated to neurons, where it is converted to pyruvate and enters the tricarboxylic acid (TCA) cycle to generate ATP. In this context, lactate has been shown to act as a neuroprotectant against glutamate-mediated excitotoxicity (Jourdain et al., 2016, Sci. Rep., 6:21250) and cerebral ischemia in vivo (Berthet et al., 2012, Cerebrovasc Dis., 34(5-6):329-35). In addition to its neuroprotective effects, ANLS has been shown to be important in regulating long-term memory consolidation (Suzuki et al., 2011, Cell 144(5):810-23) and the expression of genes that modulate 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 an important role in providing energy to neurons, but also acts as a regulator of synaptic plasticity through its signaling activity (Magistretti and Allaman, 2018, Nat Rev Neurosci 19(4):235-249). Furthermore, lactate transport has been found to be impaired in the nervous system of mouse models of ALS and ALS patients (Lee et al., 2012, Nature, 487(7408):443-8), providing further evidence for the role of lactate in neurodegenerative diseases. Furthermore, lactate administration has been found to produce antidepressant-like effects in several animal models of depression (Carrard et al., 2018, Mol Psychiatry, 23(2):488). Based on these recent studies, lactate, previously misunderstood as a waste by-product of glycolysis, has been proposed as a key signaling molecule regulating exercise-induced beneficial brain adaptations, and a central protective mechanism has been proposed that may underlie exercise-induced cognitive benefits. For people who are physically unable to access the benefits of higher-intensity exercise, enhancing lactate levels may partially mimic the benefits of exercise and help more people maintain the physical and brain health benefits of exercise at a low cost (Huang et al., 2021, Front. Physiol., 12:538-962). Furthermore, recent discoveries regarding lactate-related mechanisms promoting brain health and cognitive function during exercise have provided further insights into promoting healthy aging strategies through lactate enhancement (Xue et al., 2022, Nutrition & Metabolism, 19:52).

[0010] WO 99 / 62885 describes the preparation of N-(pyrazolylphenyl)alkanamides as inhibitors of IL-2 production. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] WO 99 / 62885 [Non-patent literature]

[0012] [Non-Patent Document 1] Magistretti et al., 2018, Nat. Rev. Neurosci., 19(4):235~249 [Non-patent document 2] Nagele et al., 2004, Neurobiol. Aging, 25(5):663~74 [Non-patent document 3] Cai et al., 2017, J. Neurol. 264(10):2068~74 [Non-patent document 4] Allaman et al., 2010, J. Neurosci 30(9):3326-38 [Non-patent document 5] Yin et al., 2016, Free Radic.Biol.Med., 100:108~22 [Non-patent document 6] Fu et al., 2014, Biogerontology, 15(6):579-86 [Non-Patent Document 7] Demetrius et al., 2013, Biogerontology, 14(6):641-9 [Non-patent document 8] Demetrius et al., 2014, front Physiol 5:522 [Non-Patent Document 9] Tomi et al., 2013, Brain Res., 1495:61-75 [Non-Patent Document 10] Ferreira et al., 2010, Curr Drug Targets, 11(10):1193~2016 [Non-Patent Document 11] Beal, 2005, Neurobiol Aging, 26(5):585~6 [Non-Patent Document 12] Yaoら, 2011, Curr Pharm Des 17(31):3474~9

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[0013] Given the crucial role of ANLS in neuronal protection and cognition and the observed dysfunction of astrocyte function and brain energy metabolism in several neurological disorders, including MCI, AD, ALS, GLUT1-DS, and depression, there is a need to develop lactate-enhancing drugs. [Means for solving the problem]

[0014] The present invention is based on the unexpected discovery of a new molecule that stimulates lactate release and glucose uptake in primary astrocyte cell cultures in vitro and in mice in vivo, and has therapeutic effects in the GLUT1-DS prototypic mouse model of hypometabolism, as well as in mouse models of aging and AD.

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

[0016] According to another aspect of the present invention there is provided a compound of the present invention for use as a pharmaceutical.

[0017] According to another aspect of the present invention there is provided a pharmaceutical product comprising at least one compound according to the present invention and a pharmaceutically acceptable carrier, diluent or excipient thereof as defined herein.

[0018] According to another aspect, the present invention provides compounds of the invention for use in the prevention and / or treatment of neurological disorders or any medical condition characterized by a hypometabolic state, which is a disease associated with abnormally low energy metabolism or a disease in the central or peripheral nervous system and / or dysfunction of the central or peripheral nervous system, or for the treatment or stabilization of neurological disorders with brain hypometabolism or associated symptoms including cognitive dysfunction, motor function and movement disorders or epileptic seizures.

[0019] According to another aspect, the present invention provides compounds of the present invention for use in the prevention and / or treatment of cognitive dysfunction associated with aging, including, but not limited to, age-related cognitive decline and age-related memory impairment, and for enhancing cognitive and memory function in healthy subjects.

[0020] According to another aspect, the present invention provides the use of the compounds of the present invention and their pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, tautomers, optically active forms, enantiomeric mixtures, and pharmaceutically active derivatives and mixtures thereof for the preparation of a pharmaceutical composition for the prevention and / or treatment of disorders or diseases in the central nervous system and / or neurological disorders associated with abnormally low cerebral energy metabolism or for the treatment or stabilization of neurological disorders with cerebral hypometabolism or related conditions.

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

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

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

[0024] According to another aspect, there is provided a method for preparing a compound according to formula (I), comprising 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, there is provided a method for preparing a compound according to formula (I), comprising reducing an intermediate of formula (IV), wherein the compound of formula (I) is a compound of formula (Ib). [Brief explanation of the drawings]

[0026] [Figure 1] 1 is a graph showing glucose uptake from primary cultures of astrocytes measured 90 minutes after stimulation with compounds (1) to (5) of the present invention at concentrations ranging from 100 nM to 10 μM as described in Example 2. Shown as % of vehicle treatment + SEM. n=6. [Figure 2] 1 is a graph showing in vitro mitochondrial activity of primary astrocytes measured as described in Example 2 1.5 and 24 hours after treatment with compounds (1) to (7) of the present invention at concentrations ranging from 100 nM to 100 μM. Results are shown as % absorbance + SEM of the MTT colorimetric assay of vehicle treatment; n=8. [Figure 3] 1 is a graph showing mitochondrial activity of primary neurons alone or in the presence of astrocytes when treated with compound (2) of the present invention (10 μM) as described in Example 2. Shown as %±SEM of vehicle treatment. n=6. [Figure 4] Figure 1 is a graph showing glucose uptake and lactate release from human induced pluripotent stem cell (iPSC)-derived astrocytes upon treatment with compound (2) of the present invention at concentrations ranging from 10 nM to 10 μM as described in Example 2. Results are shown as % of vehicle treatment + SEM. n=6. [Figure 5]1 is a graph showing extracellular levels of glucose and lactate in the brain of freely moving mice in vivo using a glucose biosensor and a lactate biosensor, respectively, after oral administration of compounds (1) to (4) of the present invention (10-30 mg / kg) or vehicle over a 3-hour duration as described in Example 3. Shown as the mean + SEM of the AUC ratio of compounds (1) to (4) of the present invention to vehicle or vehicle in the same mice. n=4-8. [Figure 6] 1 is a graph showing glucose uptake in the mouse brain in vivo using F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) following oral administration of Compounds (1) or (2) of the present invention (each 30 mg / kg) or vehicle as described in Example 3. FDG accumulation (BQML / volume) is shown as mean ± SEM. n=6. [Figure 7] Figure 1 shows extracellular levels of glucose and lactate in the brain of freely moving GLUT1-DS mice in vivo using glucose and lactate biosensors, respectively, after oral administration of Compound 2 (10 mg / kg) of the present invention or vehicle over a 3-hour duration as described in Example 4. Shown as the mean + SEM of the AUC ratio of Compound 2 to vehicle or vehicle in the same mice. n=4-8. [Figure 8](A-B) are graphs showing the latency of wild-type (WT) or GLUT1-DS mice before falling from a rotarod at a speed accelerating from 4 rpm to 40 rpm over 300 seconds, 20 minutes after oral administration of Compounds (1) or (2) of the present invention (10 mg / kg) or vehicle, as described in Example 4. Data are presented as the mean + SEM for n=16 (n=8 males, n=8 females). (C-D) Data show the four-paw grip strength (Newtons) of WT and GLUT1-DS mice using the grip strength test 20 minutes after oral administration of Compounds (1) or (2) of the present invention (10 mg / kg) or vehicle, as described in Example 4. Data are presented as the mean + SEM for n=16. [Figure 9] 1 is a graph showing the distance traveled by young (3-month-old) and old (16-month-old) wild-type mice to reach the target location in the Morris water maze one day after 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 presented as the mean + SEM of distances (cm) for n=5. [Figure 10] 1 is a graph showing the distance traveled by 3-month-old APOE3(+) and APOE4(+) female and male mice to reach the target location in the Morris water maze 7 days after 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 presented as mean distance (cm) + SEM for n = 20 mice (n = 10 males, n = 10 females). [Figure 11]Graphs depicting memory in mice orally treated with vehicle or compound (2) of the present invention (10 mg / kg and 30 mg / kg) and intracerebroventricularly injected with saline (CT1) or streptozotocin (STZ), as assessed by distance to reach the target location in the Morris water maze 1 day after training (A), by preference index for a novel object versus a familiar object in a novel object recognition task 1 day after training (B), and by latency to enter the dark compartment in an inhibitory avoidance task 1 day after training (C), as described in Example 5. Data are presented as mean + SEM of distance (cm) (A), preference index (%) (B), or latency (seconds) (C) from n=13-16 (n=5-8 males, n=8 females). DETAILED DESCRIPTION OF THE INVENTION

[0027] As used herein, "treatment" and "treating" generally refer to obtaining a desired pharmacological and physiological effect. The effect may be prophylactic, in that the disease, symptom, or condition is prevented or partially prevented, and / or therapeutic, in that the disease, condition, symptom, or adverse effects resulting from the disease are partially or completely cured. The term "treatment," as used herein, covers any treatment of a disease in a mammal, particularly a human, and includes: (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, e.g., preventive early asymptomatic intervention; (b) inhibiting the disease, i.e., preventing its onset; or alleviating the disease, i.e., causing regression of the disease and / or its symptoms or conditions, e.g., reversing or ameliorating damage. In particular, the methods, uses, formulations, and compositions according to the present invention are useful for enhancing lactate, particularly in the treatment of abnormal energy metabolism in the central nervous system.

[0028] 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, etc.

[0029] The term "subject at risk for a disorder associated with defects in brain energy metabolism or the central nervous system (CNS)" refers to a subject who exhibits abnormal CNS energy metabolism, for example, in a neurological disease.

[0030] The term "neurological disorder" according to the present invention includes motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS); dementia, such as Alzheimer's disease, frontotemporal dementia (FTD), dementia with Lewy bodies (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA); movement disorders, such as Parkinson's disease, e.g., L-dopa-induced dyskinesia, Huntington's disease, spinocerebellar ataxia, essential tremor, dystonia and related neurodegenerative conditions; all aspects of multiple sclerosis; all types of retinopathy; stroke, traumatic brain injury, intracerebral and subarachnoid hemorrhage; neuropsychiatric conditions, such as depression, schizophrenia, anxiety. , attention deficit syndrome, any endophenotype of autism; neurometabolic disorders, e.g., glucose transporter type 1 deficiency syndrome (GLUT1-DS), Lafora disease and other glycogen storage disorders; Down syndrome; cognitive dysfunction in all types of epilepsy, migraine and type 2 diabetes (T2D); cerebral hypometabolic states caused by viral infections such as HIV or COVID-19, e.g., prion infection in Creutzfeldt-Jakob disease; primary and secondary encephalitis; neurological diseases or any medical condition characterized by a hypometabolic state and / or dysfunction of the central or peripheral nervous system, such as those found in any cerebral hypometabolic state after anesthesia or post-operative care.

[0031] The term "GLUT1-DS" according to the present invention includes GLUT1 Deficiency Syndrome, Glucose Transporter Type 1 Deficiency Syndrome, GLUT1 Deficiency Disorder, also known as De Vivo Syndrome, De Vivo Disease or De Vivo Syndrome Disorder.

[0032] The term "effective amount," as used herein, refers to an amount of at least one compound of the present invention or a pharmaceutical formulation thereof according to the present invention that elicits the biological or pharmaceutical response being sought in a tissue, system, animal, or human. 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 "prophylactically effective amount" for preventing the symptoms of the disease or condition being prevented. The term, as used herein, also includes an amount of a compound of the present invention (i.e., an "effective amount") that is sufficient to slow the progression of a disease, particularly to slow or inhibit the progression of a neurodegenerative disorder, thereby eliciting the response being sought.

[0033] The term "effectiveness" of a treatment according to the present invention can be measured based on the change in the course of a disease in response to a use or method according to the present invention. For example, the effectiveness of a treatment can be measured by an increase in glucose or lactate levels in the central nervous system and by the use of fluorine-18 ( 18 F) labeled 2-fluoro-2-deoxy-D-glucose or carbon-11, ( 11 C) Pittsburgh compound B (PIB), carbon-13 ( 13 C), phosphorus 31 ( 31 Positron emission tomography (PET) using P, proton magnetic resonance spectroscopy (P) to assess the bioenergetic state of the brain, 1 H) It can be measured by imaging techniques, including MRS.

[0034] Effective treatment is indicated by an increase in cognitive performance (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 related to the specific indication.

[0035] The term "C1-C6 alkyl," when used alone or in combination with other terms, refers to a monovalent alkyl group having from 1 to 6 carbon atoms and includes straight or branched C1-C6 alkyl. 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.

[0036] The term "C2-C6 alkenyl," when used alone or in combination with other terms, includes straight-chain or branched-chain C2-C6 alkenyl. It can have any available number of double bonds in any available position, and the configuration of the double bonds can be either the (E) or (Z) configuration. This term is exemplified 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, and the like.

[0037] The term "C3-C8 heterocycle" includes "C3-C8 heterocycloalkyl" and "heteroaryl".

[0038] The term "C3-C8 heterocycloalkyl" refers to a C3-C8-cycloalkyl in which up to three carbon atoms are replaced by heteroatoms selected from the group consisting of O, S, and NR (where R is defined as hydrogen or methyl). Heterocycloalkyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and the like.

[0039] The term "heteroaryl" refers to a monocyclic heteroaromatic group or a bicyclic or tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, pyrimidinyl, furyl, 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, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isoben Examples include zothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxa-zolyl, quinolidinyl, quinazolinyl, ptalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl, and benzoquinolyl.

[0040] Unless otherwise limited by the definition of the individual substituents, the term "substituted" refers to a group substituted with from 1 to 5 substituents selected from the group consisting of "C1-C6 alkyl," "C3-C8-cycloalkyl," "heterocycloalkyl," "C1-C6 alkylaryl," "C1-C6 alkylheteroaryl," "C1-C6 alkylcycloalkyl," "C1-C6 alkylheterocycloalkyl," "cycloalkylC1-C6 alkyl," "heterocycloalkylC1-C6 alkyl," "amino," "aminosulfonyl," "ammonium," "alkoxy," "acylamino," "aminocarbonyl," "aryl," "arylC1-C6 alkyl," "heteroaryl," "heteroarylC1-C6 alkyl," "sulfinyl," "sulfonyl," "sulfonamido," "alkoxy," "alkoxycarbonyl," "carbamate," "sulfanyl," "halogen," "carboxy," trihalomethyl, cyano, hydroxy, mercapto, nitro, trihalomethyloxy, trihalomethylthio, and the like.

[0041] "Pharmaceutically active derivative" refers to any compound that can directly or indirectly produce the activity disclosed herein upon administration to a recipient. The term "indirectly" also encompasses prodrugs that can be converted to the active form of the drug through endogenous enzymes or metabolism. Prodrugs are derivatives of compounds exhibiting lactate-enhancing activity according to the present invention that have chemically or metabolically degradable groups and can be converted to pharmaceutically active compounds in vivo under physiological conditions.

[0042] The prodrug is converted into the compound according to the present invention by reaction with enzymes, gastric acid, etc. under physiological conditions in the body, for example, by enzymatic oxidation, reduction, hydrolysis, etc., respectively.

[0043] These compounds can be produced from the compounds of the invention according to well-known methods. The term "indirectly" also encompasses metabolic products of the compounds according to the invention.

[0044] The term "metabolite" refers to any molecule derived from any of the compounds according to the invention in a cell or organism, preferably a mammal.

[0045] The present invention encompasses pharmaceutically acceptable salts, hydrates, solvates, or polymorphs, tautomers, optically active forms, enantiomeric mixtures thereof, and mixtures thereof and pharmaceutically active derivatives of the compounds of the present invention. Unless otherwise specified, the present invention includes all such possible diastereomers, as well as their racemic mixtures, their substantially pure separated enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Mixtures of stereoisomers and isolated specific stereoisomers are also included. During the course of synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers. Many organic compounds exist in optically active forms, possessing the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule around its chiral center.

[0046] In the present invention, "a pharmaceutically acceptable salt thereof" refers to a salt formed from an acid addition salt formed with an acid, which may be an inorganic acid (e.g., 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.

[0047] Pharmaceutically acceptable salts for the purposes of the present disclosure can be selected from among salts formed with acids such as hydrochloric acid.

[0048] The term "pharmaceutical formulation" refers to a preparation that is in such a form as to allow the biological activity of the active ingredient to be undoubtedly effective and does not contain additional ingredients that would be toxic to the subject to whom said formulation will be administered.

[0049] Compounds for use according to the invention According to particular aspects of the invention, the present invention is directed to, in particular, motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS), dementia, in particular Alzheimer's disease, frontotemporal dementia (FTD), dementia with Lewy bodies (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), movement disorders, such as Parkinson's disease, e.g., L-dopa-induced dyskinesia, Huntington's disease, spinocerebellar ataxia, essential tremor, dystonia and related neurological disorders. Degenerative conditions, multiple sclerosis, retinopathy, stroke, traumatic brain injury, intracerebral and subarachnoid hemorrhage, neuropsychiatric disorders such as depression, schizophrenia, anxiety, attention deficit syndrome, any endophenotype of autism, neurometabolic disorders such as glucose transporter type 1 deficiency syndrome (GLUT1-DS), Lafora's disease and other glycogen storage disorders, Down's syndrome, all types of epilepsy, migraine and cognitive impairment in type 2 diabetes (T2D), viral infections such as HIV or COVID-19 Thus, there is provided compounds of formula (I), any pharmaceutically acceptable salts, hydrates, solvates thereof, or polymorphs, tautomers, optically active forms, enantiomeric mixtures, and mixtures thereof for the prevention, inhibition, or treatment of neurological diseases or any medical condition characterized by a hypometabolic state and / or dysfunction of the central or peripheral nervous system, e.g., by prion infection, primary and secondary encephalitis in Creutzfeldt-Jakob disease, or in cerebral hypometabolic states caused by abnormal protein processing and accumulation, e.g., all types of amyloidopathies, synucleinopathies, tauopathies, TD43 proteinopathies and other proteinopathies, in cerebral hypometabolic states after anesthesia or racemization or post-operative care known to those skilled in the art, or for the treatment or stabilization of neurological disorders with cerebral hypometabolic or related symptoms, including cognitive dysfunction, motor function, psychiatric and movement disorders or epileptic seizures, and for enhancing cognitive and memory function: [ka] wherein Y is selected from NH and CH; R is H, halogen, and C-C alkyl (halogen, OR 12 and NR 13 R 14 R2 is selected from H, halogen, C1-C6 alkyl (halogen, OR 12 and NHR 13 optionally substituted with a group selected from: or C2-C6 alkenyl, or OR 12 group, NR 13 R 14 or a cyano group or an optionally substituted heterocycle (e.g., optionally substituted 6-pyrimidine, optionally substituted azetidine); R3 is selected from H, halogen (e.g., Br), C1-C6 alkyl (halogen, OR 12 and NR 13 R 14- or C2-C6 alkenyl, or OR 12 group, or NHR 13 or an optionally substituted heterocycle or cyano group; R4 is selected from H, halogen, C1-C6 alkyl (halogen, OR 12 and NHR 13 or an optionally substituted heterocycle and a cyano group; R5 is H, halogen, C1-C6 alkyl (halogen, OR 12 and NHR 13 optionally substituted with a group selected from: OR 12 , or NR 13 R 14 R6 is selected from H, halogen, C1-C6 alkyl (halogen, OR 12 and NHR 13 optionally substituted with a group selected from: OR 12 , or NHR 13groups; R7 and R8 are independently selected from H and halogen; R9 is selected from SO-C1-C6 alkyl, SO2-C1-C6 alkyl, SO2-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 pyrrolinone (e.g., pyrrolidin-2-one), and optionally substituted oxetane; R10 and R11 are independently selected from H and halogen; R12, R13, and R14 are independently selected from H, C(O)-C1-C6 alkyl (e.g., CO-methyl), and optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (e.g., optionally substituted ethyl, e.g., fluoroethyl, ethylphenylethyl, cyclopropylmethyl, optionally substituted propyl).

[0050] According to certain embodiments, there are provided compounds of formula (I) wherein Y is CH2.

[0051] According to certain embodiments, there are provided compounds of formula (I) wherein Y is NH.

[0052] According to certain embodiments, compounds of formula (I) are provided wherein R1, R5, R4 and R6 are H.

[0053] According to a particular embodiment, R2 is OR 12 There is provided a compound of formula (I) wherein:

[0054] According to a particular embodiment, R3 is OR 12 There is provided a compound of formula (I) wherein:

[0055] According to a particular embodiment, R3 is NHR 13 There is provided a compound of formula (I) wherein:

[0056] According to certain embodiments, there are provided compounds of formula (I) wherein R3 is halogen.

[0057] According to certain embodiments, compounds of formula (I) are provided wherein R3 is H.

[0058] According to certain embodiments, compounds of formula (I) are provided wherein R3 is optionally substituted C1-C6 alkyl (eg, optionally substituted propyl).

[0059] According to certain embodiments, there is provided a compound of formula (I) wherein R12 is optionally substituted C1-C6 alkyl (e.g., optionally substituted methyl, ethyl (e.g., ethyl or fluoroethyl), isopropyl, optionally substituted aryl C1-C6 alkyl, such as optionally substituted phenyl C1-C6 alkyl, for example fluorophenylmethyl).

[0060] According to certain embodiments, compounds of formula (I) are provided wherein R12 is H.

[0061] According to certain embodiments, compounds of formula (I) are provided wherein R13 is optionally substituted C1-C6 alkyl (e.g., optionally substituted ethyl, e.g., fluoroethyl, ethylphenylethyl, cyclopropylmethyl, optionally substituted propyl).

[0062] According to certain embodiments, compounds of formula (I) are provided wherein R10 and R11 are H.

[0063] According to certain embodiments, there are provided compounds of formula (I) wherein R10 is halogen, for example fluoro.

[0064] According to certain embodiments, there are provided compounds of formula (I) wherein R11 is halogen, for example fluoro.

[0065] According to certain embodiments, compounds of formula (I) are provided wherein R7, R8, R10 and R11 are H.

[0066] According to certain embodiments, there are provided compounds of formula (I) wherein R9 is selected from SO2-C1-C6 alkyl, for example SO2-CH3 or SO2-CH2CH3.

[0067] According to a particular embodiment, R9 is one of the following groups: [ka] Compounds of formula (I) are provided which are selected from:

[0068] According to certain embodiments, there are provided compounds of formula (I) in which R9 is optionally substituted pyrrolidin-2-one.

[0069] According to certain embodiments, compounds of formula (I) are provided wherein R9 is an optionally substituted oxetane.

[0070] According to certain embodiments, there are provided compounds of formula (I) in which R9 is an optionally substituted isoxazole.

[0071] According to certain embodiments, there are provided compounds of formula (I) in which R9 is optionally substituted SO2-cyclopropyl.

[0072] In a more particular embodiment, the compound for use according to the present invention 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-isoquinolyl]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-methanesulfonylphenyl)amino]isoquinolin-7-ol; N-[4-(ethanesulfonyl)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-methanesulfonylphenyl)isoquinolin-1-amine; 6,7-Diethoxy-N-(2-fluoro-4-methanesulfonylphenyl)isoquinolin-1-amine; N-[4-(cyclopropanesulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine; 6-Ethoxy-7-(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine; 6,7-bis(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine; 1-[(4-methanesulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline; 6-[(4-fluorophenyl)methoxy]-N-(4-methanesulfonylphenyl)isoquinolin-1-amine; and 6-ethoxy-N-(4-methanesulfonylphenyl)-7-propylisoquinolin-1-amine; Any pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, tautomers, optically active forms, enantiomeric mixtures, and mixtures thereof.

[0073] According to a further particular aspect of the present invention, there is provided a compound of formula (I); any pharmaceutically acceptable salt, hydrate, solvate, or polymorph, tautomer, optically active form, enantiomeric mixture, and mixtures thereof, provided that the compound is not a compound selected from the following list: 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-pyridinyl)-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-furanyl)-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-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-93-7; 1-[[4-(4-pyridinyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN:1368269-53-7; 8-Methyl-N 1 -[4-(4-pyridinyl)phenyl]-1,5-isoquinolinediamine, RN:1369288-67-4; 5-nitro-N-[4-(4-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-43-7; N-[4-(4-pyridinyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and 4-Bromo-N 1 -[4-(4-pyridinyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1

[0074] The compounds of the invention were named according to the IUPAC standard used in ChemAxon Marvin Sketch version 20.11.0.

[0075] According to another aspect of the present invention, a method for preparing a compound according to formula (I) comprises reacting an aniline intermediate of formula (III) with an intermediate of formula (II) (Z is a leaving group selected from iodide, bromide, chloride, O-triflate, etc.) in a polar solvent to form a compound of formula (Ia) (Scheme 1): [ka]

[0076] According to another embodiment, a method for preparing a compound according to formula (I) comprises a step of reduction of a carbonyl intermediate of formula (IV) (e.g., by NaBHCN in the presence of ZnCl2 or by catalytic hydrogenation (H2 in the presence of Pd / C and a trace of acid)) to lead to a compound of formula (Ib) (Scheme 2): [ka]

[0077] Compositions according to the present invention The present invention provides pharmaceutical or therapeutic agents as compositions and methods useful for treating a subject, preferably a mammalian subject, most preferably a human patient, suffering from a medical disorder, particularly a disease or disorder defined therein.

[0078] According to a further particular aspect of the present invention, there is provided a medicament comprising at least one compound according to formula (I), with the proviso that the compound is not a compound selected from the list below: 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-pyridinyl)-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-furanyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 1101888-82-7; and N-[4-[3-(3-pyridinyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-1-isoquinolinamine, RN: 251658-03-4

[0079] The agents of the present invention or their formulations can be administered as pharmaceutical preparations containing one or more agents according to the present invention in any of the forms described herein. The compositions according to the present invention, together with conventional adjuvants, carriers, diluents, or excipients, can be incorporated into the form of pharmaceutical compositions and unit dosages thereof. In such forms, they can be used as solids, e.g., tablets or filled capsules, or liquids, e.g., solutions, suspensions, emulsions, elixirs, or filled capsules (all for oral use), or in the form of sterile injectable solutions for parenteral (including subcutaneous) use by injection or continuous infusion. Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. Such pharmaceutical compositions and unit dosage forms thereof can contain the ingredients in conventional proportions, with or without additional active compounds or ingredients. Such unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the prescribed daily dosage range used.

[0080] The compositions of the present invention may be liquid formulations, including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The compositions can also be formulated as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid preparations may contain additives, including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and gum acacia. Preservatives include, but are not limited to, methyl or propyl p-hydroxybenzoate and sorbic acid. Dispersing or wetting agents include, but are not limited to, poly(ethylene glycol), glycerol, bovine serum albumin, Tween®, and Span®.

[0081] Compositions of the present invention may also be formulated as a depot preparation, which may be administered by implantation or by intramuscular injection.

[0082] The solid composition of the present invention may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients, including but not limited to, binders, fillers, lubricants, disintegrants, and wetting agents. Binders include, but are not limited to, syrup, gum arabic, gelatin, sorbitol, tragacanth, mucilage of starch, and polyvinylpyrrolidone. 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 silica. 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 can be coated by methods well known in the art.

[0083] The compounds of this invention can also be administered in sustained release forms or from sustained drug delivery systems.

[0084] According to a particular embodiment, the composition according to the invention is for intravenous use.

[0085] According to a particular embodiment, the formulation of the present invention is an oral formulation.

[0086] In another particular embodiment, the compositions according to the present invention are suitable for delivery by multiple doses.

[0087] According to a particular embodiment, the composition of the present invention is a veterinary composition.

[0088] Further materials and formulation processing techniques, etc. are described in Remington: The Science & Practice of Pharmacy, 23rd Edition, 2020, edited by Adeboye Adejare, which is incorporated herein by reference.

[0089] Mode of administration The compounds of the present invention and their formulations can be administered in any manner, including orally, nasally, parenterally, intravenously, intrathecally, rectally, ophthalmically, etc., or a combination thereof. The compounds of the present invention and their formulations can also be administered by inhalation or intradermally. Parenteral administration includes, but is not limited to, intravenous, intraarterial, intraperitoneal, subcutaneous, and intramuscular. The compositions of the present invention can also be administered in the form of implants that allow for sustained release of the composition, and slow, controlled intravenous infusion.

[0090] According to a particular embodiment, the compounds according to the invention and their formulations will be administered by the oral route.

[0091] combination According to the present invention, the compounds and pharmaceutical formulations thereof can be used alone or in the treatment of neurological disorders or any medical condition characterized by a hypometabolic state and / or dysfunction of the central or peripheral nervous system, such as motor neuron diseases (MND), in particular amyotrophic lateral sclerosis (ALS), dementia, in particular Alzheimer's disease, frontotemporal dementia (FTD), dementia with Lewy bodies (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 conditions, multiple sclerosis, retinopathy, stroke, traumatic brain injury, intracerebral and arachnoid disorders. It can be administered in combination with co-agents useful for treating and / or stabilizing subcutaneous hemorrhage, neuropsychiatric disorders such as depression, schizophrenia, anxiety, attention deficit syndrome, any endophenotype of autism, neurometabolic disorders such as GLUT1-DS, Lafora's disease and other glycogen storage disorders, Down's 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, e.g., prion infection in Creutzfeldt-Jakob disease, primary and secondary encephalitis, cerebral hypometabolic states after anesthesia or post-operative care.

[0092] According to the present invention, the compounds and pharmaceutical formulations thereof can be administered alone or in combination with co-drugs or co-treatments useful for treating and / or stabilizing neurological disorders with cerebral hypometabolism or associated symptoms, including impaired cognitive function, motor function and movement disorders, or epileptic seizures. Such co-drugs or co-treatments would include at least co-drugs useful for treating and / or stabilizing neurological disorders with cerebral hypometabolism or associated symptoms, including, but not limited to, gene therapy to restore expression of genes involved in cerebral energy metabolism, ketogenic diet therapy, or pharmaceutical compounds that modulate the synthesis of ketone bodies, such as triheptanoin.

[0093] The present invention encompasses the administration of a compound of the invention or a formulation thereof to a subject prior to, concurrently with, or sequentially with other therapeutic regimens or co-drugs useful for preventing and / or treating psychiatric disorders or enhancing cognitive and memory function.

[0094] Examples of co-drugs useful in combination with the compounds of the present invention and their pharmaceutical preparations include medications useful for treating cognitive symptoms of Alzheimer's disease (memory loss, confusion, and thinking and reasoning problems), such as cholinesterase inhibitors and memantine, and amyloid targeting agents.Non-limiting examples of cholinesterase inhibitors include donepezil, rivastigmine, and galantamine.Non-limiting examples of amyloid targeting agents include aducanumab.

[0095] Co-drugs according to the present invention can include donepezil and memantine in a single dosage form.

[0096] Examples of co-agents useful in combination with the compounds of the invention and pharmaceutical formulations thereof include medications useful in treating amyotrophic lateral sclerosis, such as riluzole, edaravone, AMX0035 (sodium phenylbutyrate and ursodoxycortaurine) and Nuedexta (dextromethorphan and quinidine).

[0097] Examples of useful co-drugs in combination with the compounds of the present invention include one or more behavioral change drugs, such as antidepressants, antianxiety drugs, or antipsychotic drugs, which act as adjunctive treatment but do not directly treat the symptoms of Alzheimer's disease.Non-limiting examples of suitable antidepressants include citalopram, fluoxetine, paroxetine, sertraline, trazodone, and esketamine.Non-limiting examples of suitable antianxiety drugs include lorazepam and oxazepam.Non-limiting examples of suitable antipsychotic drugs include aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone.

[0098] Compounds of the invention or formulations thereof according to the invention that are administered simultaneously with said co-agents can be administered in the same or different compositions and by the same or different routes of administration.

[0099] According to one embodiment, there is provided a pharmaceutical formulation comprising a compound of the present invention in combination with at least one co-agent and at least one pharmaceutically acceptable carrier useful for treating and / or stabilizing a neurodegenerative disorder.

[0100] Those skilled in the art will readily recognize and appreciate other combinations. In some embodiments, the compounds of the present invention can be used to attenuate or reverse the activity of drugs suitable for treating the neurological disorders described herein and / or to limit the adverse effects of such drugs.

[0101] As one of ordinary skill in the art will readily appreciate, combinations can include pharmaceutical compositions comprising a therapeutic agent according to at least some embodiments of the present invention and / or a therapeutic agent and one other drug, pharmaceutical compositions comprising a therapeutic agent and / or a therapeutic agent described herein and two other drugs, pharmaceutical compositions comprising a therapeutic agent and / or a therapeutic agent described herein and three other drugs, etc. Determination of optimal combinations and dosages can be determined and optimized using methods well known in the art.

[0102] A therapeutic agent according to the present invention and one or more other therapeutic agents may be administered in any order, or simultaneously.

[0103] Use of the compounds according to the invention In another aspect, the present invention provides compounds and methods useful for preventing or treating disorders associated with defective energy metabolism in the central nervous system.

[0104] In another aspect, the present invention provides compounds and methods useful for preventing and / or treating neurodegenerative disorders.

[0105] In another aspect, the present invention provides compounds and methods useful for preventing and / or treating neuropsychiatric disorders.

[0106] In another aspect, the present invention provides compounds and methods useful for increasing lactate secretion by astrocytes.

[0107] The dosage administered to an individual as a single or multiple dose will vary depending on a variety of factors, including pharmacokinetic properties, the condition and characteristics of the patient (sex, age, weight, health, size), the severity of symptoms, concomitant therapy, frequency of treatment, and the desired effect.

[0108] In another embodiment, the present invention provides pharmaceutical compositions comprising at least one compound of the present invention and a pharmaceutically acceptable carrier, diluent, or excipient thereof.

[0109] Synthesis of Compounds of the Invention Novel derivatives according to formula (I) can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvent, etc.) are given, it will be understood that other experimental conditions can also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures. General synthetic approaches to obtain compounds of formula (I) are described in Schemes 1 and 2 above.

[0110] patient In one embodiment, a patient according to the present invention is a subject suffering from a disorder associated with a defect in energy metabolism in the central nervous system.

[0111] In certain embodiments, a patient according to the present invention is suffering from a neurodegenerative disorder.

[0112] In certain embodiments, a patient according to the present invention suffers from a neuropsychiatric disorder.

[0113] In certain embodiments, a patient according to the present invention suffers from a neurometabolic disorder.

[0114] In one embodiment, a patient according to the present invention is a subject suffering from a neurometabolic disorder associated with GLUT1-DS.

[0115] In a particular embodiment, the patient according to the invention suffers from GLUT1-DS.

[0116] In one embodiment, a patient according to the invention is a patient at risk of developing GLUT1-DS.

[0117] In certain embodiments, a patient according to the present invention is a subject who is genetically predisposed to or suffering from a disorder selected from mild cognitive impairment, Parkinson's disease, multiple sclerosis, schizophrenia, stroke, traumatic brain injury, and epilepsy.

[0118] In certain embodiments, the compounds and methods of the present invention are useful for the prevention and / or treatment of neurodegenerative disorders.

[0119] According to a further aspect, the neurodegenerative disorder is Alzheimer's disease.

[0120] According to a further embodiment, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS).

[0121] According to another further aspect, the neuropsychiatric disorder is depression.

[0122] In another particular embodiment, the patient suffers from age-related mild cognitive impairment, such as age-related cognitive decline and age-related memory impairment.

[0123] According to another particular embodiment, the methods of the present invention are useful for enhancing cognitive and memory function in healthy subjects.

[0124] The invention having been described, the following examples are offered by way of illustration and not by way of limitation. [Example]

[0125] The following studies are conducted to support the effectiveness of the compounds of the present invention.

[0126] Example 1 Synthesis of Compounds of the Invention All synthetic reagents and solvents were used as received. If necessary, solvents used in the reactions were previously dried and / or distilled according to the state of the art. Some solvents were commercially available in anhydrous form and were used as received.

[0127] Reaction conditions If anhydrous conditions are required, glassware is first dried in an oven (>100 °C). All reactions were carried out under a nitrogen or argon atmosphere. Room temperature (rt) refers to 20-25 °C. A temperature of -78 °C is obtained by freezing an acetone bath with carboglace 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.

[0128] The progress of the reaction is followed by thin layer chromatography (CCM) using a UV indicator on the plate and enhanced by an oxidizing developer such as phosphomolybdic acid solution.

[0129] Refining techniques Flash chromatography: Silica gel (Kieselgel 60 from MN, 15-40 μm from Macherey-Nagel) is used for the purification of the crude product by flash chromatography. The sample is either deposited directly on the head of the column or applied as a solution in silica gel suspension.

[0130] Automated flash chromatography: The purification system used is a Combiflash Companion™ from Teledyne Isco. The crude sample is dissolved in a small amount of an appropriate solvent and applied to a pre-conditioned RediSep® column. These columns are placed in a Combiflash Companion purification system™, and purification is performed using a solvent gradient program. The system is used with an automated collector. Detection is by UV or by collection of all fractions analyzed by HPLC.

[0131] Nuclear magnetic resonance (NMR) spectroscopy: NMR spectra were obtained at 400 MHz (1H) and 100 MHz ( 13 Spectra are recorded using a Bruker UltraShield spectrometer operating at 1000 K (C). Spectra are calibrated by adding tetramethylsilane (TMS) to the deuterated solvent as an internal reference. Calibration is achieved by setting the TMS signal to 0.

[0132] For fluorine-19, CFCl3 is used as the external reference. Chemical displacements are reported in parts per million (ppm) and coupling constants are given in Hertz (Hz). Abbreviations for the multiplicities of proton and carbon signals are as follows: s singlet, d doublet, dd doublet, dt triplet doublet, ddt triplet doublet, t triplet, tt triplet triplet, q quintet, m multiplet.

[0133] Mass spectrometry (SM): Mass spectra are performed using a Bruker Q-TOF maXis coupled to a Dionex Ultimate 3000 RSLC chain using FIA (flow injection analysis = no column) with a 65 / 35 mixture of ACN / H2O + 0.1% formic acid at up to 200 μL / min as solvent. The injection volume is 0.2 μL. Most analyses are performed in positive mode with an ESI source (electrospray ionization).

[0134] Sample preparation: A sample is taken with the solvent at a concentration of about 1 mg / mL, and then diluted approximately 500-fold (≈2 ng / μL) in methanol (other solvents may be more suitable depending on the structure of the compound being analyzed: water, acetonitrile, etc.). If the signal obtained is insufficient, the sample concentration is increased.

[0135] Melting point determination: Melting points are determined using a STUART SMP3.

[0136] High-performance liquid chromatography (HPLC): HPLC analyses are 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 the appropriate analytical column. Detection is performed with a photodiode strip (Waters 2996) and / or a UV detector with a refractometer.

[0137] 1-[4-[(6,7-dimethoxy-1-isoquinolyl)methyl]phenyl]pyrrolidin-2-one (1) The above compound was prepared according to Scheme 3 under the following specific conditions: [ka] 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, 782.61 μL), 4-bromobenzaldehyde (5.87 g, 31.71 mmol), and 2-hydroperoxy-2-methyl-propane (5 M, 6.34 mL). The mixture was stirred at 110 °C for 16 h. LCMS indicated 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 dried over NaSO, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1). The organics were concentrated under reduced pressure to give (4-bromophenyl)-6,7-dimethoxy-1-isoquinoline-methanone i (800 mg, 19.32% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 8.42 (d, J=5.38 Hz, 1 H) 7.91 (d, J=5.50 Hz, 1 H) 7.73 - 7.82 (m, 4 H) 7.53 (d, J=7.25 Hz, 2 H) 3.97 (s, 3 H) 3.85 (s, 3 H).

[0138] To a solution of i (600 mg, 1.53 mmol) in MeOH (6 mL) was added NaBH4 (63.73 mg, 1.68 mmol) at 0 °C. The mixture was then stirred at 25 °C for 3 h. LCMS showed that the starting material was 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 adjusted to pH = 7 with 1 N HCl. The reaction solution was extracted with ethyl acetate (40 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude ii (460 mg, 76.25% yield) as a gray solid. 1H NMR (400MHz DMSO-d6): δ 8.31 (d, J=5.50 Hz, 1 H) 7.59 - 7.66 (m, 2 H) 7.44 - 7.52 (m, 2 H) 7.39 (d, J=8.50 Hz, 2 H) 7.34 (s, 1 H) 6.42 (d, J=5.50 Hz, 1 H) 6.33 (d, J=5.38 Hz, 1 H) 3.89 (s, 3 H) 3.80 (s, 3 H).

[0139] To a solution of ii (460 mg, 1.17 mmol) in H2SO4 (2 mL) was added triethylsilane (1.36 g, 11.68 mmol, 1.87 mL) at 20 °C. 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 adjusted to pH = 8 with Na2CO3. The mixture was extracted with ethyl acetate (30 mL × 3). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether:ethyl acetate = 1:1). The mixture was filtered and concentrated under reduced pressure to give iii (220 mg, 47.33% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): δ 8.24 (d, J=5.63 Hz, 1 H) 7.55 (d, J=5.63 Hz, 1 H) 7.44 - 7.48 (m, 2 H) 7.42 - 7.44 (m, 1 H) 7.33 (s, 1 H) 7.28 (d, J=8.38 Hz, 2 H) 4.53 (s, 2 H) 3.90 (s, 3 H) 3.87 (s, 3 H).

[0140] To a solution of iii (150 mg, 376.85 μmol) in dioxane (1 mL), pyrrolidin-2-one (38.49 mg, 452.23 μmol, 34.67 μL), Pd(dba) (17.25 mg, 18.84 μmol), CsCO (368.36 mg, 1.13 mmol), and Xantphos (21.81 mg, 37.69 μmol) were added, degassed, and purged with N three times. The reaction mixture was stirred at 110 °C for 12 h. LCMS showed that the starting material was consumed and the desired Ms was detected. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the crude product. The crude product was purified by preparative TLC (SiO, petroleum ether:ethyl acetate = 0:1) to give 1 (70.4 mg, 50.72% yield) as a white solid. 1 H NMR (400MHz CDCl3): δ 8.37 (d, J=5.63 Hz, 1 H) 7.48 - 7.54 (m, 2 H) 7.43 (d, J=5.75 Hz, 1 H) 7.29 (d, J=3.63 Hz, 2 H) 7.25 - 7.27 (m, 1 H) 7.05 (s, 1 H) 4.58 (s, 2 H) 4.01 (s, 3 H) 3.90 (s, 3 H) 3.81 (t, J=7.07 Hz, 2 H) 2.58 (t, J=8.07 Hz, 2 H) 2.13 (m, 2 H).

[0141] 6,7-Dimethoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine(2) The above compounds were prepared according to general Scheme 1 above under the specific conditions of Scheme 4 below: [ka] To a solution of 1-chloro-6,7-dimethoxyisoquinoline (1 g, 4.47 mmol, 1 equiv.) and 4-methylsulfonylaniline (765.54 mg, 4.47 mmol, 1 equiv.) in dioxane (20 mL) was added CsCO (2.91 g, 8.94 mmol, 2 equiv.) and SPhos (183.55 mg, 447.12 μmol, 0.1 equiv.) at 20 °C. N was bubbled through the mixture for 1 min, and then Pd(dba) (204.72 mg, 223.56 μmol, 0.05 equiv.) was added under N. N was bubbled through the mixture for 1 min, and 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 pad of Celite, the cake was washed with methanol (3 × 20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0% to 4% methanol in dichloromethane. The product-containing eluate was 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 give the target compound (2) (1.27 g, 79.46% yield) as a white solid. 1 H NMR 400 MHz (d6-DMSO): δ = 9.36 (s, 1H), 8.04 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 5.6 Hz, 1H), 7.87 - 7.75 (m, 3H), 7.31 (s, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 3H), 3.16 (s, 3H).

[0142] 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). The above compound was prepared according to Scheme 5 under the following specific conditions: [ka] A mixture of compound 2 (1 g, 2.80 mmol) in 47% aqueous HBr (20 mL) was stirred at 100 °C for 7 hours. LCMS showed that the starting material had been consumed, and the desired demethylated MS was detected. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (TFA conditions) and lyophilized to give compounds (3), (4), and (5) (TFA salts). The products were triturated in 4N HCl / MTBE (2 mL), respectively, and the solids were collected by filtration. The cakes were washed with MTBE (2 mL), dissolved in 10 mL of water and 10 mL of acetonitrile, and then lyophilized to give compounds (3) (66.4 mg, 6.02% yield, HCl salt) as a white solid, (4) (36.7 mg, 3.4% yield, HCl salt) as a white solid, and (5) (72.1 mg, 6.8% yield, HCl salt) as a white solid, respectively. (3): 1 H NMR (400MHz DMSO-d6): δ 10.09 - 10.78 (m, 2 H) 7.98 (br d, J=7.88 Hz, 2 H) 7.91 (s, 1 H) 7.81 (br d, J=7.75 Hz, 2 H) 7.60 - 7.71 (m, 1 H) 7.51 (br s, 1 H) 7.38 (br d, J=6.50 Hz, 1 H) 4.02 (s, 3 H) 3.24 (s, 3 H). (4): 1 H NMR (400MHz DMSO-d6): δ 10.75 - 11.27 (m, 1 H) 8.13 (br s, 1 H) 8.03 (br d, J=8.26 Hz, 2 H) 7.83 (br d, J=8.25 Hz, 2 H) 7.59 (br d, J=5.00 Hz, 1 H) 7.32 (br d, J=6.50 Hz, 1 H) 7.29 (s, 1 H) 4.02 (s, 3 H) 3.26 (s, 3 H). (5): 1H NMR (400MHz DMSO-d6): δ 12.71 - 13.50 (m, 1 H) 11.14 - 11.51 (m, 1 H) 10.51 - 10.94 (m, 1 H) 10.02 - 10.44 (m, 1 H) 8.00 (br d, J=8.50 Hz, 2 H) 7.93 (s, 1 H) 7.75 (br d, J=8.50 Hz, 2 H) 7.53 (br d, J=6.50 Hz, 1 H) 7.34 (d, J=6.63 Hz, 1 H) 7.31 (s, 1 H) 3.25 (s, 3 H).

[0143] 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). The above compound was prepared according to Scheme 6 under the following specific conditions: [ka] To a solution of iodoethane (240.78 mg, 1.54 mmol) in DMF (12 mL) was added KCO (640.10 mg, 4.63 mmol) and compound (5) (600 mg, 1.54 mmol) at 0 °C. The mixture was then stirred at 60 °C for 3 h. LCMS showed that all starting material was consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC. The mobile phase was concentrated under high vacuum to give (7) (54.5 mg, 9.33% yield) as a brown solid, (6) (73.6 mg, 13.04% yield) as a brown solid, and (8) (22.1 mg, 3.64% yield) as a brown solid. (6): 1H NMR (400 MHz DMSO-d6): δ 9.52 (s, 1 H) 9.35 (s, 1 H) 8.03 (br d, J=8.76 Hz, 2 H) 7.89 (d, J=5.63 Hz, 1 H) 7.79 (br d, J=9.26 Hz, 3 H) 7.27 (s, 1 H) 7.19 (br d, J=5.63 Hz, 1 H) 4.21 (m, 2 H) 3.14 (s, 3 H) 1.44 (br t, J=6.88 Hz, 3 H). (7): 1 H NMR (400MHz DMSO-d6): δ 10.05 (br s, 1 H) 9.31 (br s, 1 H) 8.04 (br d, J=8.63 Hz, 2 H) 7.74 - 7.92 (m, 4 H) 7.06 - 7.16 (m, 2 H) 4.25 (m, 2 H) 3.16 (s, 3 H) 1.45 (br t, J=6.88 Hz, 3 H). (8): 1 H NMR (400 MHz DMSO-d6): δ 9.32 (s, 1 H) 8.04 (d, J=8.88 Hz, 2 H) 7.94 (d, J=5.63 Hz, 1 H) 7.82 (d, J=8.88 Hz, 2 H) 7.78 (s, 1 H) 7.29 (s, 1 H) 7.21 (d, J=5.63 Hz, 1 H) 4.22 (m, 4 H) 3.16 (s, 3 H) 1.43 (m, 6 H)-

[0144] 1-[4-[(6,7-dimethoxy-1-isoquinolyl)amino]phenyl]pyrrolidin-2-one (9) The above compounds were prepared according to general Scheme 1 under the specific conditions of Scheme 7 below: [ka] To a solution of 1-chloro-6,7-dimethoxyisoquinoline (150 mg, 670.68 μmol, 1 equiv.) and 1-(4-aminophenyl)pyrrolidin-2-one (118.18 mg, 670.68 μmol, 1 equiv.) in dioxane (3 mL), CsCO (437.04 mg, 1.34 mmol, 2 equiv.) and SPhos (27.53 mg, 67.07 μmol, 0.1 equiv.) were added at 20 °C, and N was bubbled through the mixture for 1 min. Pd(dba) (30.71 mg, 33.53 μmol, 0.05 equiv.) was then added under N, and N was bubbled through the mixture 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 pad of Celite, the cake was washed with methanol (3 × 5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under neutral conditions and lyophilized to give 9 (130.7 mg, 52.77% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): 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 = 5.7 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.84 (t, J = 7.0 Hz, 2H), 2.49 - 2.46 (m, 2H), 2.12 - 2.01 (m, 2H).

[0145] N-(4-methylsulfonylphenyl)-6-vinyloxy-isoquinolin-1-amine (10) The above compounds were prepared according to general Scheme 1 under the following specific conditions in Schemes 8-12: Step 1: [ka] To a suspension of 6-bromo-1-chloroisoquinoline (3 g, 12.37 mmol, 1 equiv.) and 4-methylsulfonylaniline (2.12 g, 12.37 mmol, 1 equiv.) in i-PrOH (60 mL) was added HCl / dioxane (6 M, 3.09 mL, 1.5 equiv.) at 20 °C, and the reaction mixture was stirred at 90 °C for 16 h. LCMS indicated that most of the starting material had been consumed, and the product with the desired MS was detected. The reaction mixture was filtered, and the cake was washed with i-PrOH (10 mL). It was then suspended in ethyl acetate (30 mL), cooled to 0 °C, and adjusted to pH 8 with saturated aqueous NaHCO3. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were 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), the solid was collected by filtration, and this process was repeated twice to give the pure product. The 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-d6): δ = 9.72 (s, 1H), 8.52 (d, J = 9.0 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 8.16 - 8.10 (m, 3H), 7.88 - 7.81 (m, 3H), 7.32 (d, J = 5.7 Hz, 1H), 3.17 (s, 3H). Step 2: [ka] To a solution of 6-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine iv (300 mg, 795.22 μmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (242.32 mg, 954.26 μmol, 1.2 equiv) in dioxane (6 mL) was added KOAc (156.09 mg, 1.59 mmol, 2 equiv) at 20 °C, N was bubbled through the mixture for 1 min, then Pd(dppf)Cl (64.94 mg, 79.52 μmol, 0.1 equiv) was added under N, then N was bubbled through the mixture for 1 min, and the reaction mixture was stirred at 80 °C for 12 h. LCMS showed that the desired product (boronic acid) was detected. The reaction mixture was filtered through a pad of Celite, the cake was washed with ethyl acetate (2 × 5 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 0% to 50% ethyl acetate in petroleum ether 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-d6): δ = 9.69 (s, 1H), 8.55 (d, J = 8.5 Hz, 1H), 8.25 (s, 1H), 8.20 - 8.08 (m, 3H), 7.90 - 7.80 (m, 3H), 7.44 (d, J = 5.8 Hz, 1H), 3.17 (s, 3H), 1.35 (s, 12H). Step 3: [ka] 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 equiv) in THF (6 mL) and water (3 mL) was added sodium 3-oxidodioxaborirane tetrahydrate (358.98 mg, 2.33 mmol, 3 equiv) in small 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 and the resulting solid was collected by filtration, the 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-d6): δ = 10.31 (br s, 1H), 9.48 (s, 1H), 8.40 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 8.9 Hz, 2H), 7.95 (d, J = 5.8 Hz, 1H), 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). Step 4: [ka] To a solution of 1-(4-methylsulfonylanilino)isoquinolin-6-ol vi (180 mg, 572.59 μmol, 1 equiv) in DMF (5 mL) was added 1,2-dibromoethane (537.84 mg, 2.86 mmol, 216.00 μL, 5 equiv) and KCO (158.27 mg, 1.15 mmol, 2 equiv) at 20 °C, and 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, and the cake was washed with ethyl acetate (2 × 10 mL). The filtrate was washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated 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 give 6-(2-bromoethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine vii (120 mg, 49.74% yield) as a white solid. 1 H NMR (400MHz CDCL3): δ = 8.14 (d, J = 5.8 Hz, 1H), 7.99 - 7.82 (m, 5H), 7.34 - 7.29 (m, 1H), 7.27 (br d, J = 2.4 Hz, 1H), 7.21 (br d, J = 5.6 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 4.48 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H), 3.07 (s, 3H). Step 5: [ka] To a solution of 6-(2-bromoethoxy)-N-(4-methylsulfonylphenyl)isoquinolin-1-amine vii (110 mg, 261.09 μmol, 1 equiv.) in DMSO (3 mL) was added t-BuOK (1 M, 652.73 μL, 2.5 equiv.) at 20° C., and the reaction mixture was stirred at 20° C. for 1 h. LCMS indicated that the starting material had been consumed and the desired product had been detected. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 5 mL), washed with water (3 mL), dried over anhydrous NaSO, filtered, and concentrated 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 give compound (10) (25 mg, 28.13% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): δ = 9.62 (s, 1H), 8.55 (d, J = 9.3 Hz, 1H), 8.12 (d, J = 9.0 Hz, 2H), 8.06 (d, J = 5.8 Hz, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 2.5 Hz, 1H), 7.41 (dd, J = 2.6, 9.1 Hz, 1H), 7.29 (d, J = 5.8 Hz, 1H), 7.11 (dd, J = 6.0, 13.5 Hz, 1H), 4.94 (dd, J = 1.6, 13.5 Hz, 1H), 4.68 (dd, J = 1.6, 6.0 Hz, 1H), 3.16 (s, 3H).

[0146] 6-Isopropoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (11) The above compound was prepared according to Scheme 13 under the following specific conditions: [ka] To a solution of 1-(4-methylsulfonylanilino)isoquinolin-6-ol vi (170 mg, 540.78 μmol, 1 equiv) in DMF (5 mL) were added 2-iodopropane (459.64 mg, 2.70 mmol, 270.38 μL, 5 equiv) and KCO (149.48 mg, 1.08 mmol, 2 equiv) at 20 °C, and 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 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 under high vacuum to give compound (11) (111.8 mg, 55.39% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): δ = 9.53 (s, 1H), 8.44 (d, J = 9.3 Hz, 1H), 8.11 (d, J = 8.9 Hz, 2H), 8.00 (d, J = 5.8 Hz, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 2.4 Hz, 1H), 7.26 - 7.20 (m, 2H), 4.83 (spt, J = 6.0 Hz, 1H), 3.15 (s, 3H), 1.35 (d, J = 6.0 Hz, 6H).

[0147] N-(4-methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine (12) The above compound was prepared according to Scheme 14 under the following specific conditions: [ka] To a solution of 6-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine iv (200 mg, 530.15 μmol, 1 equiv.) and tributyl(pyrimidin-2-yl)stannane (293.54 mg, 795.22 μmol, 1.5 equiv.) in dioxane (8 mL), CsF (161.06 mg, 1.06 mmol, 39.09 μL, 2 equiv.) was added at 20 °C, and N was bubbled through the mixture for 1 min. Then, CuI (20.19 mg, 106.03 μmol, 0.2 equiv.) and Pd(PPh3)4 (61.26 mg, 53.02 μmol, 0.1 equiv.) were added under N2, and N was bubbled through the mixture for 1 min. 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 pad of Celite, the 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 lyophilized to give compound (12) (75.8 mg, 37.37% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): δ = 9.76 (s, 1H), 9.02 (d, J = 4.9 Hz, 2H), 8.93 (d, J = 1.4 Hz, 1H), 8.71 (d, J = 8.9 Hz, 1H), 8.62 (dd, J = 1.6, 8.9 Hz, 1H), 8.20 - 8.15 (m, 3H), 7.86 (d, J = 8.9 Hz, 2H), 7.58 - 7.53 (m, 2H), 3.18 (s, 3H).

[0148] N-(4-methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine (13) The above compounds were prepared according to Schemes 15-18 under the following specific conditions: Step 1: [ka] To a solution of 7-methoxyisoquinoline (2 g, 12.56 mmol) in dichloromethane (20 mL) was added metachloroperbenzoic acid (3.06 g, 15.08 mmol) at 0° C. The mixture was stirred at 20° C. for 1 hour. LCMS showed that the starting material was consumed and the desired MS was detected. The reaction was quenched with 4 N HCl in methyl tert-butyl ether (5 mL), filtered, and the filter cake was concentrated under reduced pressure to give the crude product. The crude product was triturated with methyl tert-butyl ether (10 mL) at 20° C. for 10 minutes. The mixture was filtered, and then the filter cake was concentrated under reduced pressure to give 7-methoxy-2-oxide-isoquinolin-2-ium viii (1.97 g, 85.03% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.48 (s, 1H), 8.45 (dd, J = 1.6, 7.0 Hz, 1H), 8.25 (d, J = 7.0 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 2.4, 8.9 Hz, 1H), 3.94 (s, 3H) Step 2: [ka] A mixture of 7-methoxy-2-oxide-isoquinolin-2-ium viii (1.9 g, 10.30 mmol) and phosphorus oxychloride (20 mL) was stirred at 80 °C for 2 hours. LCMS showed that the starting material was 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 × 3). The combined organic layer was 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 15% to 50% ethyl acetate in petroleum ether) to give 1-chloro-7-methoxy-isoquinoline ix (1.1 g, 52.38% yield) as a white solid. 1H NMR (400MHz DMSO-d6): δ 8.18 (d, J = 5.5 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.84 (d, J = 5.4 Hz, 1H), 7.54 (dd, J = 2.5, 8.9 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H) Step 3: [ka] To a solution of 1-chloro-7-methoxy-isoquinoline ix (0.5 g, 2.45 mmol) in 1,4-dioxane (10 mL) was added 4-methylsulfonylaniline (420.02 mg, 2.45 mmol) and dicesium carbonate (1.60 g, 4.91 mmol) at 25 °C. The flask was filled with N and evacuated (3x). SPhos (100.71 mg, 245.31 μmol) and Pd(dba) (112.32 mg, 122.66 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 110 °C for 12 h. LCMS indicated that all starting material 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 residue was triturated in ethyl acetate (1 mL) at 25° C. for 30 minutes 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 (400 MHz DMSO-d6): δ 9.73 - 9.35 (m, 1H), 8.07 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 5.5 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.81 (dd, J = 2.9, 9.0 Hz, 3H), 7.40 (dd, J = 2.1, 8.9 Hz, 1H), 7.25 (br d, J = 5.4 Hz, 1H), 3.97 (s, 3H), 3.21 - 3.07 (m, 3H). Step 4: [ka] To a solution of 7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine x (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 starting material was consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure and then adjusted to pH = 8 with aqueous NaHCO3. The mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC and lyophilized to obtain 1-(4-methylsulfonylanilino)isoquinolin-7-ol (13) (112.3 mg, 39.10% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): δ 10.04 (br s, 1H), 9.43 (s, 1H), 8.08 (br d, J = 8.5 Hz, 2H), 7.91 (br d, J = 5.5 Hz, 1H), 7.85 - 7.71 (m, 4H), 7.34 (br d, J = 8.8 Hz, 1H), 7.25 (br d, J = 5.5 Hz, 1H), 3.15 (s, 3H)

[0149] N-[1-(4-methylsulfonylanilino)-7-isoquinolyl]acetamide (14) and N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (15) The above compounds were prepared according to general Scheme 1 under the specific conditions of Schemes 19-20 below: Step 1: [ka] To a mixture of 7-bromo-1-chloro-isoquinoline (2.10 g, 12.27 mmol) in isopropanol (60 mL), 4-methylsulfonylaniline (3 g, 12.27 mmol) and 6 M HCl / dioxane (3.07 mL) were added at 20 °C. The mixture was stirred at 90 °C for 12 hours. LCMS showed that the starting material was consumed and the desired MS was detected. The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 mL). It was then suspended in ethyl acetate (30 mL), cooled to 0 °C, and adjusted to pH 8 with saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate (2 × 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The residue was triturated with ethanol and water (15 mL, 1:1) at 80 °C for 0.5 h, the solid was collected by filtration, and this process was repeated twice to give 7-bromo-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xi (1.4 g, 27.22% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.68 (s, 1H), 8.86 (s, 1H), 8.18 - 8.10 (m, 3H), 7.93 - 7.81 (m, 4H), 7.36 (d, J = 5.6 Hz, 1H), 3.17 (s, 3H).

[0150] N-[1-(4-methylsulfonylanilino)-7-isoquinolyl]acetamide (14) [ka] 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 mmol) and KPO (2.13 g, 10.02 mmol) at 25 °C. The flask was filled with N and evacuated (3x). Pd(dba) (152.92 mg, 167.00 μmol) and Xantphos (193.25 mg, 333.99 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 100 °C for 12 h. LCMS indicated that all starting material 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 (eluted with 0% to 50% ethyl acetate in petroleum ether) to give N-[1-(4-methylsulfonylanilino)-7-isoquinolyl]acetamide (14) (0.75 g, 60.02% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 10.29 (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 = 5.7 Hz, 1H), 3.16 (s, 3H), 2.12 (s, 3H).

[0151] N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (15) The above compound was prepared according to Scheme 21 under the following specific conditions: [ka] To a solution of N-[1-(4-methylsulfonylanilino)-7-isoquinolyl]acetamide (14) (300 mg, 801.89 μmol) in tetrahydrofuran (6 mL) at 25°C. The flask was filled with N2 and evacuated (3x). The reaction mixture was then cooled to 0°C, and BH3-Me2S (10 M, 160.38 μL) was added to the reaction mixture. The mixture was stirred at 0°C for 30 min. The reaction mixture was then warmed to 20°C and stirred for 30 min, then slowly heated to 60°C and stirred for 12 h. LCMS indicated that all starting material had been consumed and the desired Ms was detected. The residue was quenched with methyl alcohol (5 mL) and stirred at 20°C for 30 min. The mixture was then concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC and lyophilized to give N7-ethyl-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (15) (76.2 mg, 27.41% yield) as a yellow solid. 1 H NMR (400 MHz DMSO-d6): δ 10.29 (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 = 5.7 Hz, 1H), 3.16 (s, 3H), 2.12 (s, 3H).

[0152] Intermediate 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xXVII Step 1: [ka] 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) (215.23 mg, 958.68 μmol) at 20 °C. The mixture was stirred at 90 °C under a N atmosphere for 1 h. TLC showed that the starting material was completely consumed and one new spot was formed. The reaction was cooled to 20 °C and poured into an ice-water solution of HCl (50 mL, 1 N). After stirring for 10 min, the mixture was filtered to give the crude product. The crude product was triturated 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 under high vacuum to give (E)-3-(4-bromo-3-methoxy-phenyl)propan-2-enoic acid xii (6 g, 70.11% yield) as a gray solid. Step 2: [ka] To a solution of (E)-3-(4-bromo-3-methoxy-phenyl)propan-2-enoic acid xii (20 g, 71.57 mmol, 92% purity, 1 equiv.) in toluene (160 mL) was added DPPA (19.70 g, 71.57 mmol, 15.51 mL, 1 equiv.) and TEA (10.14 g, 100.20 mmol, 13.95 mL, 1.4 equiv.) at 20 °C. The mixture was stirred at 20 °C for 1 h. TLC showed that the starting material was completely consumed and one new spot was formed. The mixture was filtered through a pad of silica eluting with 1500 mL of toluene, and the filtrate was added to diphenyl ether (150 mL). The mixture was then concentrated under reduced pressure to give the crude product (approximately 20 g) in diphenyl ether (150 mL). A solution of (E)-3-(4-bromo-3-methoxy-phenyl)propan-2-enoyl azide (20.19 g, 71.57 mmol) in diphenyl ether (300 mL) was then stirred at 230 °C for 1 hour. TLC showed that the starting material was completely consumed and one 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 minutes, a solid precipitated and was filtered to obtain the crude product. The crude product was triturated with petroleum ether / ethyl acetate = 5:1 and stirred for 20 minutes. The mixture was then 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, 32.99% yield, 80% purity) as a brown solid. Step 3: [ka] A solution of 7-bromo-6-methoxy-isoquinolin-1-one xiii (6 g, 13.22 mmol) in POCl3 (60 mL) was stirred at 100 °C for 2 h. LC-MS showed complete consumption of the starting material and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate (200 mL), and the mixture was adjusted to pH 9 with saturated aqueous NaHCO3. The mixture was then extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with water and brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the 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. Step 4: [ka] 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-methylsulfonylaniline (927.31 mg, 5.42 mmol) and HCl / dioxane (6 M, 1.13 mL) at 20° C., and the mixture was then stirred at 90° C. for 12 hours. LCMS showed that 24% of the starting material xiv remained, and the desired mass 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 hours. The reaction mixture was filtered, and the filter cake was washed with i-PrOH (30 mL) and then suspended in ethyl acetate (20 mL). The mixture was cooled to 0 °C and adjusted to pH 8 with saturated aqueous NaHCO3. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with saturated brine (20 mL) and dried under reduced pressure to give a residue. The residue was treated with a 1:1 ethanol:water mixture (20 mL), and the solid was collected by filtration. This process was repeated twice to give 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (1.4 g, 53.31% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ9.60 (br s, 1H), 8.89 (s, 1H), 8.23 ​​- 8.02 (m, 3H), 7.84 (br d, J = 8.6 Hz, 2H), 7.45 (s, 1H), 7.28 (br d, J = 5.6 Hz, 1H), 4.00 (s, 3H), 3.16 (s, 3H).

[0153] 6-Methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine (16) The above compound was prepared according to Scheme 26 under the following specific conditions: [ka] To a solution of intermediate 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (0.8 g, 1.37 mmol) in THF (5 mL) and HO (2.5 mL) was added KPO (583.72 mg, 2.75 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (254.12 mg, 1.65 mmol) at 20 °C, followed by Pd(dppf)Cl (112.29 mg, 137.50 μmol) in one portion at 20 °C. The resulting mixture was stirred at 80 °C under a N atmosphere for 12 h. LC-MS showed complete consumption of the starting material and one major peak with the desired mass was detected. The mixture was diluted with 20 mL of water at 20 °C, then filtered, and the filtrate was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the crude product. The crude product was chromatographed on silica gel (petroleum ether / tetrahydrofuran 80:20 to 70:30) to give 6-methoxy-N-(4-methylsulfonylphenyl)-7-vinyl-isoquinolin-1-amine (16) (0.4 g, 65.67% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ = 9.60 (s, 1H), 8.63 (s, 1H), 8.11 (d, J = 8.9 Hz, 2H), 8.00 (d, J = 5.8 Hz, 1H), 7.84 (d, J = 8.9 Hz, 2H), 7.32 (s, 1H), 7.24 (d, J = 5.8 Hz, 1H), 7.09 (dd, J = 11.2, 17.7 Hz, 1H), 6.12 (dd, J = 1.5, 17.6 Hz, 1H), 5.53 - 5.38 (m, 1H), 3.97 (s, 3H), 3.17 (s, 3H).

[0154] 7-Ethyl-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (17) The above compound was prepared according to Scheme 27 under the following specific conditions: [ka] 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 N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under H (15 Psi) at 20 °C for 1 h. LC-MS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The reaction solution was filtered through Celite, and the filtrate was concentrated to give the 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 pale yellow oil. 1 H NMR (400MHz DMSO-d6): δ = 9.47 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 5.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.24 (d, J = 5.8 Hz, 1H), 3.95 (s, 3H), 3.16 (s, 3H), 2.78 (q, J = 7.4 Hz, 2H), 1.27 (t, J = 7.4 Hz, 3H).

[0155] 7-Ethyl-1-(4-methylsulfonylanilino)isoquinolin-6-ol (18)

[0156] The above compound was prepared according to Scheme 28 under the following specific conditions: [ka] 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 BBr3 (569.31 mg, 2.27 mmol) dropwise, and the mixture was stirred at 20 °C for 4 h. LC-MS showed that the starting material was completely consumed and one major peak with the desired mass was detected. The mixture was adjusted to pH = 9 with saturated aqueous NaHCO3, and then the mixture was extracted with ethyl acetate (2 × 100 mL). The combined organic phase was washed with water and brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (neutral conditions) and then lyophilized to give 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-d6): δ = 10.31 (br d, J = 1.1 Hz, 1H), 9.41 (s, 1H), 8.22 (s, 1H), 8.08 (br d, J = 8.5 Hz, 2H), 7.90 (br d, J = 5.6 Hz, 1H), 7.81 (br d, J = 8.4 Hz, 2H), 7.15 - 6.93 (m, 2H), 3.15 (s, 3H), 2.76 (q, J = 7.3 Hz, 2H), 1.27 (br t, J = 7.4 Hz, 3H).

[0157] 7-Bromo-1-(4-methylsulfonylanilino)isoquinolin-6-ol (19) The above compound was prepared according to Scheme 29 under the following specific conditions: [ka] To a 10 mL stand-up bottle, 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv (0.2 g, 441.96 μmol) was added at 20 °C, and then BBr (0.2 mL) was added dropwise to the mixture at 20 °C. The mixture was stirred at 70 °C for 6 hours. 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 added dropwise to saturated aqueous NaHCO (10 mL) at 0 °C, and then the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic phase was washed with brine (2 × 20 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (neutral conditions) and then lyophilized to give 7-bromo-1-(4-methylsulfonylanilino)isoquinolin-6-ol (19) (4 mg, 2.01% yield) as an off-white solid. 1 H NMR (400MHz DMSO-d6): δ = 11.20 (s, 1 H) 9.56 (br s, 1 H) 8.84 (s, 1 H) 8.11 (br d, J=8.63 Hz, 2 H) 7.98 (br d, J=5.75 Hz, 1 H) 7.83 (br d, J=8.63 Hz, 2 H) 7.23 (s, 1 H) 7.16 (br d, J=5.75 Hz, 1 H) 3.16 (s, 3 H).

[0158] N7-benzyl-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (20) The above compound was prepared according to Scheme 30 under the following specific conditions: [ka] 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), phenylmethanamine (39.46 mg, 368.30 μmol) and CsCO (120.00 mg, 368.30 μmol) were added at 25 °C. The flask was filled with N and evacuated (3x). Pd(dba) (5.62 mg, 6.14 μmol) and Xantphos (7.10 mg, 12.28 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 100 °C for 12 h. LCMS indicated that all starting material 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 directly purified by preparative HPLC and lyophilized to give N7-benzyl-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (20) (16.3 mg, 30.63% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.11 (s, 1H), 8.04 - 7.94 (m, 2H), 7.83 - 7.75 (m, 3H), 7.44 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.26 - 7.20 (m, 2H), 7.19 - 7.13 (m, 2H), 6.06 (t, J = 6.2 Hz, 1H), 4.55 (d, J = 5.6 Hz, 2H), 3.98 (s, 3H), 3.14 (s, 3H).

[0159] N7-(cyclopropylmethyl)-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (21) The above compound was prepared according to Scheme 31 under the following specific conditions: [ka] 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 cyclopropylmethanamine (26.19 mg, 368.30 μmol) and CsCO (120.00 mg, 368.30 μmol) at 25 °C. The flask was filled with N and evacuated (3x). Pd(dba) (5.62 mg, 6.14 μmol) and Xantphos (7.10 mg, 12.28 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 100 °C for 12 h. LCMS showed that all starting material 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, which was directly purified by preparative HPLC and lyophilized to give N7-(cyclopropylmethyl)-6-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,7-diamine (21) (10.7 mg, 21.93% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.16 (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 = 5.6 Hz, 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 = 4.8 Hz, 2H).

[0160] 6-Methoxy-N1-(4-methylsulfonylphenyl)-N7-propyl-isoquinoline-1,7-diamine (22) The above compound was prepared according to Scheme 32 under the following specific conditions: [ka] To the solution of 7-bromo-6-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xv, CsCO (120.00 mg, 368.30 μmol) was added at 25 °C. The flask was filled with N and evacuated (3x). Pd(dba) (5.62 mg, 6.14 μmol) and Xantphos (7.10 mg, 12.28 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 100 °C for 12 h. LCMS indicated that all starting material 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 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 pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.18 (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 = 5.6 Hz, 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 = 7.4 Hz, 3H).

[0161] Intermediate 6-bromo-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xix Step 1: [ka] To a mixture of 4-bromo-3-methoxybenzoic acid (10.0 g, 43.28 mmol) in dichloromethane (200 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (18.10 g, 47.61 mmol) and triethylamine (5.26 g, 51.94 mmol) were added in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 30 minutes, and then 2,2-dimethoxyethanamine (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 hours, and LCMS showed that the reaction was complete. The mixture was poured into ice water (100 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 0% to 20% ethyl acetate in petroleum ether) to give 4-bromo-N-(2,2-dimethoxyethyl)-3-methoxy-benzamide xvi (12 g, 87.14% yield) as a pale yellow solid. Step 2: [ka] To a mixture of 4-bromo-N-(2,2-dimethoxyethyl)-3-methoxy-benzamide xvi (12 g, 37.72 mmol) and sulfuric acid (3.70 g, 37.72 mmol) was added in one portion at 20 °C under N. The reaction mixture was stirred at 20 °C for 2 h. Then, the reaction mixture was stirred at 60 °C for 2 h. LCMS showed that all starting material was consumed and the desired MS was detected. The reaction mixture was quenched with ice water (100 mL), filtered, and the filter cake was washed with water (3 × 100 mL) and concentrated under reduced pressure to give crude 6-bromo-7-methoxy-2H-isoquinonil-1-one xvii (9 g, 89.22% yield) as a yellow solid. Step 3: [ka] To a mixture of 6-bromo-7-methoxy-2H-isoquinonyl(-1-one xvii (9.00 g, 33.65 mmol) in toluene (20 mL) was added phosphorus oxychloride (40 mL) at 20° C. The mixture was stirred at 110° C. for 6 hours. LCMS showed that all starting material was 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 hour and 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. Step 4: [ka] 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, 6.97 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 starting material had been consumed and the desired MS was detected. The reaction mixture was filtered, and the filter cake was washed with isopropanol (10 mL). It was then suspended in ethyl acetate (30 mL) and adjusted to pH 8 with saturated aqueous NaHCO3 at 0 °C. 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-d6): δ 9.56 (s, 1H), 8.25 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.27 (d, J = 5.8 Hz, 1H), 4.07 (s, 3H), 3.17 (s, 3H).

[0162] N6-(cyclopropylmethyl)-7-methoxy-N1-(4-methylsulfonylphenyl)isoquinoline-1,6-diamine (23) The above compound was prepared according to Scheme 37 under the following specific conditions: [ka] 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) was added cyclopropylmethanamine (23.57 mg, 331.47 μmol) and CsCO (108.00 mg, 331.47 μmol) at 25 °C. The flask was filled with N and evacuated (3x). Pd(dba) (5.06 mg, 5.52 μmol) and Xantphos (6.39 mg, 11.05 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 100 °C for 12 h. LCMS showed that all starting material 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, which was directly purified by preparative HPLC and lyophilized to give N-(cyclopropylmethyl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinoline-1,6-diamine (23) (10 mg, 23, 20.83% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.29 - 9.15 (m, 1H), 8.02 (br d, J = 8.0 Hz, 2H), 7.89 - 7.75 (m, 3H), 7.67 - 7.59 (m, 1H), 7.07 (br d, J = 4.8 Hz, 1H), 6.73 (s, 1H), 5.74 (br d, J = 4.5 Hz, 1H), 4.02 (s, 3H), 3.14 (s, 3H), 3.09 (br d, J = 5.4 Hz, 2H), 1.26 - 1.13 (m, 1H), 0.50 (br d, J = 7.8 Hz, 2H), 0.28 (br d, J = 3.6 Hz, 2H).

[0163] 6-(Azetidin-l-yl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (24) The above compound was prepared according to Scheme 38 under the following specific conditions: [ka] 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), azetidine (18.92 mg, 331.47 μmol) and CsCO (108.00 mg, 331.47 μmol) were added at 25 °C. The flask was filled with N and evacuated (3x). Pd(dba) (5.06 mg, 5.52 μmol) and Xantphos (6.39 mg, 11.05 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was stirred at 100 °C for 12 h. LCMS indicated that all starting material 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 directly purified by preparative HPLC and lyophilized to give 6-(azetidin-l-yl)-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine (24) (9.3 mg, 17.36% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 9.25 (s, 1H), 8.06 - 7.99 (m, 2H), 7.87 - 7.77 (m, 3H), 7.62 (s, 1H), 7.08 (d, J = 5.9 Hz, 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).

[0164] 6-Ethyl-1-[(4-methanesulfonylphenyl)amino]isoquinolin-7-ol (25) The above compounds were prepared according to Schemes 39-41 under the following specific conditions: Step 1: [ka] 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), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (276.62 mg, 1.80 mmol) and KPO (693.18 mg, 3.27 mmol) were added at 20 °C. The flask was filled with N and evacuated (3x). Di-tert-butyl(cyclopentyl)phosphane, dichloropalladium, and iron (106.42 mg, 163.28 μmol) were added to the mixture, and the flask was filled with N and evacuated (3x). The mixture was then stirred at 80 °C for 4 h. LCMS showed that all starting material 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 phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the 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. Step 2: [ka] To a mixture of 6-vinyl-7-methoxy-N-(4-methylsulfonylphenyl)isoquinolin-1-amine xx (380 mg, 964.95 μmol) in methyl alcohol (10 mL) was added Pd / C (102.69 mg, 964.95 μmol) at 20° C. The mixture was then stirred at 20° C. for 2 hours. LCMS showed that all starting material was 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 (220 mg, 60.77% yield) as a white solid. Step 3: [ka] 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 warmed to 100 °C and stirred for 12 hours. LCMS showed that all starting material was consumed and the desired MS was detected. The reaction mixture was concentrated under reduced pressure and adjusted to pH = 8 with aqueous NaHCO3. The mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain the 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, 35.69% yield) as a pale yellow solid. 1 H NMR (400MHz DMSO-d6): δ 10.09 - 9.97 (m, 1H), 9.50 - 9.42 (m, 1H), 7.99 - 7.92 (m, 2H), 7.90 (d, J = 5.7 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.62 (s, 2H), 7.24 (d, J = 5.7 Hz, 1H), 3.15 (s, 3H), 2.74 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).

[0165] N-[4-(ethanesulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (26) The above compound was prepared according to Scheme 42 under the following specific conditions: [ka] 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, oxalic acid dichloride (18.11 g, 142.70 mmol) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 20 °C for 2 h. TLC showed that the starting material was consumed and one new spot with low polarity was formed. The mixture was concentrated under reduced pressure to give xxii (28 g, 92.67% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) : δ 7.52 (dd, J=8.38, 1.88 Hz, 1 H) 7.41 (d, J=2.00 Hz, 1 H) 7.01 (d, J=8.50 Hz, 1 H) 4.06 (dq, J=16.63, 7.00 Hz, 4 H) 1.33 (td, J=6.94, 3.50 Hz, 6 H). Step 2: To a solution of 2,2-dimethoxyethanamine (11.74 g, 111.63 mmol) in tetrahydrofuran (212 mL) was added N,N-diisopropylethylamine (21.64 g, 167.45 mmol) at 20° C. Then, to the mixture was added a solution of xxii (31.2 g, 122.80 mmol) in tetrahydrofuran (100 mL) dropwise at 0° C. under N2. The mixture was stirred at 20° C. for 16 hours. LCMS showed that the starting material was 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. 1H NMR (400 MHz, DMSO-d6) : δ 8.41 (br t, J=5.82 Hz, 1 H) 7.38 - 7.56 (m, 2 H) 6.99 (d, J=8.25 Hz, 1 H) 4.49 (t, J=5.50 Hz, 1 H) 4.06 (qd, J=6.90, 4.69 Hz, 4 H) 3.32 - 3.36 (m, 2 H) 3.29 (s, 6 H) 1.34 (td, J=6.94, 1.88 Hz, 6 H). Step 3: A solution of 2 (15.9 g, 48.13 mmol) in HSO (6.41 mL) at 20 °C was prepared. The mixture was stirred at 80 °C for 16 h. LCMS showed that the starting material had been consumed and the product was detected. One additional vial on a 5 g scale was set up as above. The mixture was quenched with ice water (30 mL) and adjusted to pH 7 with 0.5 N NaOH (300 mL). The mixture was then filtered, and the filter cake was concentrated under reduced pressure to give the crude product. The crude product was stirred in ethyl acetate (100 mL) to form a slurry, which was filtered to give xxiv (8.4 g, 38.84% yield) as a gray solid. 1 H NMR (400 MHz, DMSO-d6) : δ 11.04 (br s, 1 H) 7.52 (s, 1 H) 7.13 (s, 1 H) 7.03 (br t, J=6.19 Hz, 1 H) 6.44 (d, J=7.00 Hz, 1 H) 3.97 - 4.35 (m, 4 H) 1.30 - 1.48 (m, 6 H). Step 4: A solution of xxiv (6.9 g, 20.11 mmol) in POCl3 (41.4 mL) at 20 °C was heated and stirred at 110 °C for 1 h. LCMS showed that the starting material was consumed and the product was detected. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with water (80 mL) and adjusted to pH 7 with saturated aqueous NaHCO3 (90 mL). The mixture was then filtered, and the filter cake was concentrated under reduced pressure to give 1-chloro-6,7-diethoxyisoquinoline xxv (6.8 g, 94.25% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J=5.50 Hz, 1 H) 7.68 (d, J=5.50 Hz, 1 H) 7.43 (d, J=15.76 Hz, 2 H) 4.22 (q, J=6.88 Hz, 4 H) 1.43 (td, J=6.94, 1.13 Hz, 6 H). Step 5: To a mixture of 1-chloro-6,7-diethoxyisoquinoline xxv (150 mg, 595.93 μmol) and 4-ethylsulfonylaniline (110.39 mg, 595.93 μmol) in dioxane (3 mL) was added Cs2CO3 (388.33 mg, 1.19 mmol) at 20 °C, the vessel was evacuated and refilled with nitrogen (this process was repeated three times), and then (1E,4E)- 1,5-Diphenylpenta-1,4-dien-3-one; palladium (32.74 mg, 35.76 μmol); and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (24.46 mg, 59.59 μmol) were added to the mixture under nitrogen, the vessel was evacuated and refilled with nitrogen (this process was repeated three times), and the reaction mixture was heated to 100 °C and stirred for 12 h. LCMS indicated that the starting material had been consumed and the desired product had been 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 N-[4-(ethanesulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (26) (138.3 mg, 57.02% yield, 98.4% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) : δ= 9.34 (s, 1 H) 8.05 (d, J=8.88 Hz, 2 H) 7.94 (d, J=5.63 Hz, 1 H) 7.73 - 7.82 (m, 3 H) 7.29 (s, 1 H) 7.22 (d, J=5.63 Hz, 1 H) 4.22 (dq, J=18.39, 6.96 Hz, 4 H) 3.22 (q, J=7.30 Hz, 2 H) 1.35 - 1.50 (m, 6 H) 1.12 (t, J=7.38 Hz, 3 H)

[0166] 6,7-Diethoxy-N-[4-(oxetan-3-yl)phenyl]isoquinolin-1-amine (27) The above compound was prepared according to Scheme 43 under the following specific conditions: [ka] A mixture of xxv (150 mg, 595.93 μmol), 4-(oxetan-3-yl)aniline (97.80 mg, 655.52 μmol), and CsCO (388.33 mg, 1.19 mmol) in dioxane (3 mL) was degassed and purged with N three times, then SPhos (24.46 mg, 59.59 μmol) and Pd(dba) (27.29 mg, 29.80 μmol) were added under N. The mixture was stirred at 100 °C under a N atmosphere for 16 h. LCMS indicated the reaction was complete. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a residue. The residue was stirred in a mixture of petroleum ether and ethyl acetate (20 mL, 9:1) for 15 min, the solid was collected, and then purified by preparative TLC (SiO, petroleum ether:tetrahydrofuran = 1:1) to give the 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-d6): δ = 8.84 (s, 1H), 7.85 - 7.74 (m, 4H), 7.34 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H), 7.03 (d, J = 5.8 Hz, 1H), 4.94 (dd, J = 5.8, 8.3 Hz, 2H), 4.63 (t, J = 6.3 Hz, 2H), 4.27 - 4.13 (m, 5H), 1.42 (q, J = 7.3 Hz, 6H).

[0167] 6,7-Diethoxy-N-[4-(1,2-oxazol-3-yl)phenyl]isoquinolin-1-amine (28) The above compound was prepared according to Scheme 44 under the following specific conditions: [ka] To a solution of xxv (150 mg, 595.93 μmol, 1 equiv) in dioxane (3 mL) was added 4-(1,2-oxazol-3-yl)aniline (105.00 mg, 655.52 μmol, 1.1 equiv) and CsCO (388.33 mg, 1.19 mmol, 2 equiv) at 25 °C. The mixture was degassed and purged with N three times. SPhos (24.46 mg, 59.59 μmol, 0.1 equiv) and Pd(dba) (27.29 mg, 29.80 μmol, 0.05 equiv) were added to the reaction mixture at 25 °C. The mixture was degassed and purged with N three times and stirred at 100 °C for 12 h. LC-MS showed complete consumption of the starting material and detection of the desired Ms. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC to give 6,7-diethoxy-N-[4-(1,2-oxazol-3-yl)phenyl]isoquinolin-1-amine (28) (114.6 mg, 305.26 μmol, 51.22% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.07 (s, 1 H), 8.95 (d, J=1.63 Hz, 1 H), 7.97 (d, J=8.76 Hz, 2 H), 7.90 (d, J=5.63 Hz, 1 H), 7.77 - 7.86 (m, 3 H), 7.26 (s, 1 H), 7.02 - 7.16 (m, 2 H), 4.05 - 4.36 (m, 4 H), 1.43 (dt, J=9.63, 7.00 Hz, 6 H)

[0168] 6,7-Diethoxy-N-[4-(1,2-oxazol-5-yl)phenyl]isoquinolin-1-amine (29) The above compound was prepared according to Scheme 45 under the following specific conditions: [ka] To a solution of xxv (150 mg, 595.93 μmol, 1 equiv.) in dioxane (3 mL) was added 4-isoxazol-5-ylaniline (105.00 mg, 655.52 μmol, 1.1 equiv.) and CsCO (388.33 mg, 1.19 mmol, 2 equiv.) at 25 °C. The mixture was degassed and purged with N three times. SPhos (24.46 mg, 59.59 μmol, 0.1 equiv.) and Pd(dba) (27.29 mg, 29.80 μmol, 0.05 equiv.) were added to the reaction mixture at 25 °C. The mixture was degassed and purged with N three times and stirred 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 pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ ppm 9.13 (s, 1 H), 8.59 (d, J=1.75 Hz, 1 H), 8.00 (d, J=8.88 Hz, 2 H), 7.91 (d, J=5.63 Hz, 1 H), 7.72 - 7.85 (m, 3 H), 7.27 (s, 1 H), 7.14 (d, J=5.63 Hz, 1 H), 6.86 (d, J=1.75 Hz, 1 H), 4.04 - 4.35 (m, 4 H), 1.43 (dt, J=9.47, 7.02 Hz, 6 H).

[0169] 6,7-Diethoxy-N-(3-fluoro-4-methanesulfonylphenyl)isoquinolin-1-amine (30) The above compound was prepared according to Scheme 46 under the following specific conditions: [ka] To a mixture of xxv (150 mg, 595.93 μmol) and 3-fluoro-4-methylsulfonyl-aniline (112.75 mg, 595.93 μmol) in dioxane (3 mL) was added CsCO (388.33 mg, 1.19 mmol) at 20 °C, the vessel was evacuated and backfilled with nitrogen (this process was repeated three times), then (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (32.74 mg, 35.76 μmol) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (24.46 mg, 59.59 μmol) were added to the mixture under nitrogen, the vessel was evacuated and backfilled with nitrogen (this process was repeated three times), and 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 had been 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-methanesulfonylphenyl)isoquinolin-1-amine (30) (163.5 mg, 67.16% yield, 99% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) : δ= 9.52 (s, 1 H) 8.12 - 8.21 (m, 1 H) 7.99 (d, J=5.63 Hz, 1 H) 7.69 - 7.81 (m, 3 H) 7.32 (s, 1 H) 7.27 (d, J=5.63 Hz, 1 H) 4.22 (dq, J=17.39, 7.00 Hz, 4 H) 3.26 (s, 3 H) 1.43 (dt, J=9.79, 6.99 Hz, 6 H).

[0170] 6,7-Diethoxy-N-(2-fluoro-4-methanesulfonylphenyl)isoquinolin-1-amine (31) The above compound was prepared according to Scheme 47 under the following specific conditions: [ka] 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 CsCO (310.66 mg, 953.49 μmol) at 20 °C. Then, to the mixture were added pd(dba) (21.83 mg, 23.84 μmol) and SPhos (19.57 mg, 47.67 μmol) under N at 20 °C. The mixture was stirred at 100 °C for 16 h. LCMS showed that the starting material was consumed and the product was detected. The mixture was filtered through a Celite pad, 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-(2-fluoro-4-methanesulfonylphenyl)isoquinolin-1-amine (31) (137.7 mg, 70.34% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) : δ 9.09 (s, 1 H) 7.89 (t, J=8.07 Hz, 1 H) 7.84 (d, J=5.63 Hz, 1 H) 7.78 (dd, J=10.51, 2.00 Hz, 1 H) 7.68 - 7.74 (m, 2 H) 7.28 (s, 1 H) 7.20 (d, J=5.75 Hz, 1 H) 4.14 - 4.28 (m, 4 H) 3.26 (s, 3 H) 1.37 - 1.48 (m, 6 H).

[0171] N-[4-(cyclopropanesulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (32) The above compound was prepared according to Scheme 48 under the following specific conditions: [ka] To a solution of xxv (130 mg, 413.18 μmol) and 4-cyclopropylsulfonylaniline (81.50 mg, 413.18 μmol) in dioxane (2.6 mL) was added CsCO (269.24 mg, 826.35 μmol) at 20 °C. Then, to the mixture was added SPhos (16.96 mg, 41.32 μmol) and pd(dba) (18.92 mg, 20.66 μmol) under N at 20 °C. The mixture was stirred at 100 °C for 16 h. LCMS showed that the starting material was consumed and the product was detected. The mixture was filtered through a Celite pad, 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-(cyclopropanesulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine (32) (103.1 mg, 59.40% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.33 (s, 1 H) 8.03 (d, J=8.88 Hz, 2 H) 7.94 (d, J=5.63 Hz, 1 H) 7.74 - 7.83 (m, 3 H) 7.29 (s, 1 H) 7.21 (d, J=5.63 Hz, 1 H) 4.22 (dq, J=18.79, 6.95 Hz, 4 H) 2.68 - 2.88 (m, 1 H) 1.32 - 1.55 (m, 6 H) 0.93 - 1.20 (m, 4 H).

[0172] 6-Ethoxy-7-(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine (33) The above compound was prepared according to Scheme 49 under the following specific conditions: [ka] To a solution of 6 (500 mg, 1.33 mmol) in dimethylformamide (5 mL) was added K2CO3 (549.51 mg, 3.98 mmol) and 1-fluoro-2-iodo-ethane (276.66 mg, 1.59 mmol) at 20 °C. 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 brine (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was washed with brine (2 × 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give 6-ethoxy-7-(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine (33) (187.0 mg, 99.8% purity) as a white solid. 1 H NMR (400MHz DMSO-d6): 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).

[0173] 6,7-Bis(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine (34) The above compound was prepared according to Scheme 50 under the following specific conditions: [ka] To a solution of 5 (250 mg, 718.92 μmol) in dimethylformamide (3 mL) was added KCO (298.08 mg, 2.16 mmol) and 1-fluoro-2-iodo-ethane (275.14 mg, 1.58 mmol) at 20 °C. 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 × 5 mL). The combined organic layers were washed with brine (2 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized to give 6,7-bis(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine (34) (137.4 mg, 99.7% purity) as a gray solid. 1 H NMR (400MHz DMSO-d6): δ = 9.36 (s, 1H), 8.07 - 8.03 (m, 2H), 7.97 (d, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.86 - 7.82 (m, 2H), 7.39 (s, 1H), 7.22 (d, J = 5.6 Hz, 1H), 4.92 (dt, J = 3.8, 7.9 Hz, 2H), 4.80 (dt, J = 3.8, 7.9 Hz, 2H), 4.49 (td, J = 3.8, 16.4 Hz, 2H), 4.41 (td, J = 3.8, 16.4 Hz, 2H), 3.16 (s, 3H).

[0174] 1-[(4-methanesulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline (35) The above compound was prepared according to Scheme 51 under the following specific conditions: [ka] To a solution of 6-(propan-2-yloxy)isoquinoline xxvi (1 g, 4.81 mmol) in CH3CN (50 mL) was added 2-(4-methylsulfonylphenyl)acetic acid (4.12 g, 19.23 mmol) and [phenyl-(2,2,2-trifluoroacetyl)oxy-iodanyl] 2,2,2-trifluoroacetate (4.13 g, 9.61 mmol) under argon at 20 °C. The mixture was stirred for 16 h under irradiation with a 34 W blue LED. LCMS showed that 11% of the starting material remained and 15% of the desired MS was detected. The reaction mixture was then treated with saturated aqueous NaHCO3 (30 mL), extracted with ethyl acetate (20 mL × 3), washed with brine (20 mL), dried over Na2SO4, 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-methanesulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline (35) (46.6 mg, 2.64% yield, 96.7% purity) as a white solid. 1 H NMR (400MHz, DMSO-d6) : δ = 8.33 (d, J=5.75 Hz, 1 H) 8.23 ​​(d, J=9.13 Hz, 1 H) 7.81 (d, J=8.38 Hz, 2 H) 7.51 - 7.63 (m, 3 H) 7.35 (d, J=2.50 Hz, 1 H) 7.21 (dd, J=9.19, 2.56 Hz, 1 H) 4.81 (spt, J=5.98 Hz, 1 H) 4.68 (s, 2 H) 3.15 (s, 3 H) 1.33 (d, J=6.00 Hz, 6 H).

[0175] 6-[(4-fluorophenyl)methoxy]-N-(4-methanesulfonylphenyl)isoquinolin-1-amine (36) The above compound was prepared according to Scheme 52 under the following specific conditions: [ka] To a solution of vi (200 mg, 572.59 μmol) in DMF (2 mL) was added KCO (158.28 mg, 1.15 mmol) and 1-(bromomethyl)-2-methyl-benzene (127.16 mg, 687.11 μmol, 92.08 μL) at 20 °C. The reaction was stirred at 60 °C for 16 h. LCMS showed the reaction was complete. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC and lyophilized to give 6-[(4-fluorophenyl)methoxy]-N-(4-methanesulfonylphenyl)isoquinolin-1-amine (36) (136 mg, 99.8% purity) as a gray solid. 1 H NMR (400 MHz, DMSO-d6): δ = 9.55 (s, 1 H) 8.48 (d, J=9.25 Hz, 1 H) 8.12 (d, J=8.88 Hz, 2 H) 8.03 (d, J=5.75 Hz, 1 H) 7.82 (d, J=8.88 Hz, 2 H) 7.58 (dd, J=8.63, 5.63 Hz, 2 H) 7.42 (d, J=2.50 Hz, 1 H) 7.35 (dd, J=9.26, 2.50 Hz, 1 H) 7.22 - 7.30 (m, 3 H) 5.26 (s, 2 H) 3.16 (s, 3 H).

[0176] 6-Ethoxy-N-(4-methanesulfonylphenyl)-7-propylisoquinolin-1-amine (37) The above compound was prepared according to Scheme 53 under the following specific conditions: [ka] To a solution of 6 (1.2 g, 3.18 mmol) in dichloromethane (4 mL) was added a solution of trimethylamine (1.61 g, 15.90 mmol, 2.21 mL) and trifluoromethylsulfonyltrifluoromethanesulfonic acid (1.79 g, 6.36 mmol, 1.05 mL) in dichloromethane (1 mL) at 0 °C. The mixture was stirred at 20 °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 × 5 mL). The combined organic layer was washed with brine (2 × 5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the 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-d6): 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 = 5.8 Hz, 1H), 4.38 - 4.28 (m, 2H), 3.19 - 3.15 (m, 3H), 1.43 (t, J = 7.0 Hz, 3H).

[0177] To a solution of xxvii (300 mg, 550.49 μmol) and 4,4,5,5-tetramethyl-2-[(E)-propan-1-enyl]-1,3,2-dioxaborolane (277.51 mg, 1.65 mmol) in tetrahydrofuran (4 mL) and HO (1 mL) was added di-tert-butyl(cyclopentyl)phosphane; dichloropalladium; iron (35.88 mg, 55.05 μmol), and KPO (233.70 mg, 1.10 mmol) under N at 20 °C. The mixture was stirred at 80 °C for 3 h. LCMS showed complete consumption of the starting material and detection of the desired product. The reaction mixture was diluted with brine (10 mL) and extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC and lyophilized to give xxviii (90 mg, 41.25% yield) as a white solid. 1 H NMR (400MHz DMSO-d6): δ = 9.53 (s, 1H), 8.52 (s, 1H), 8.10 (d, J = 8.9 Hz, 2H), 7.96 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 8.9 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J = 5.8 Hz, 1H), 6.78 (dd, J = 1.4, 15.9 Hz, 1H), 6.68 - 6.54 (m, 1H), 4.20 (q, J = 6.9 Hz, 2H), 3.16 (s, 3H), 1.95 (dd, J = 1.1, 6.4 Hz, 3H), 1.44 (t, J = 6.9 Hz, 3H).

[0178] To a mixture of Pd / C (24.17 mg, 22.71 μmol) in methyl alcohol (1 mL) was added a solution of xxviii (90 mg, 227.07 μmol) in methyl alcohol (1 mL) under an H atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred at 20 °C under H (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-methanesulfonylphenyl)-7-propylisoquinolin-1-amine (37) (64.4 mg, 97.2% purity) as a white solid. 1 H NMR (400MHz DMSO-d6): δ = 9.44 (s, 1H), 8.26 (s, 1H), 8.09 (d, J = 8.9 Hz, 2H), 7.97 (d, J = 5.8 Hz, 1H), 7.82 (d, J = 8.9 Hz, 2H), 7.26 - 7.19 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.15 (s, 3H), 2.77 - 2.71 (m, 2H), 1.69 (sxt, J = 7.5 Hz, 2H), 1.42 (t, J = 6.9 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H).

[0179] Example 2 In vitro effects of compounds of the present invention in enhancing glucose uptake and secretion of lactate levels To evaluate the effects of compounds of the present invention, they were tested in primary mouse astrocytes and astrocytes differentiated from human-derived induced pluripotent stem cells (iPSCs). Lactate secretion was measured indirectly via acidification of the extracellular medium using the extracellular pH sensor SNARE-5F-(AND-6)-CAR (SNARF5) as described below.

[0180] Table 1 shows the activity of compounds of the present invention in an in vitro astrocyte extracellular medium acidification (SNARF5) assay, which indicates their glycolytic activity and ability to produce lactate. A "+" indicates activity for compounds with an EC50 > 1 μM, and a "++" indicates activity for compounds with an EC50 < 1 μM.

[0181] [Table 1]

[0182] Primary mouse cell cultures Primary cultures of cerebral cortical astrocytes were obtained from 1-2 day-old OF1 mouse pups (Charles River Laboratories). Briefly, cerebral cortices were isolated and minced into small pieces under a dissecting microscope. Cells were incubated for 30 minutes at 37°C in a solution containing 20 U / ml papain, 1 mM L-cysteine, and 10 kU / ml DNase I. After dissociation, papain activity was quenched by adding fetal calf serum (FCS). Single-cell suspensions were then obtained by mechanical dissociation consisting of cell trituration in DMEM D7777 medium supplemented with 44 mM NaHCO3, 10 mL / L antibacterial / antimycotic solution, and 10% FCS. Cells were plated at approximately 10,000 cells / cm on poly-D-lysine-coated 96- or 12-well culture plates, depending on their use. 2 Cells were seeded at an average density of 1000 μg / ml and grown at 37°C in DMEM D7777 medium supplemented with 44 mm NaHCO3, 10 mL / L antibacterial / antimycotic solution, and 10% FCS in a humidified atmosphere containing 5% CO2 / 95% air. Culture medium was replaced with fresh medium twice weekly. Cells were stimulated and harvested between DIV14 and DIV17, when confluence and cell growth were optimal.

[0183] Co-culture of primary mouse astrocytes and neurons Primary mouse neuron cultures were obtained from 18-day-old OF1 mouse embryos (Charles River Laboratories). Briefly, cerebral cortices were isolated and minced into small pieces under a dissecting microscope. Cells were incubated at 37°C for 30 minutes in a solution containing 20 U / ml papain, 1 mM L-cysteine, and 10 kU / ml DNase I. After dissociation, papain activity was quenched by adding fetal calf serum (FCS). Single-cell suspensions were then obtained by mechanical dissociation, consisting of cell trituration in Neurobasal+B-27+Glutamax medium. Cells were plated at approximately 1.5 × 10 cells onto poly-D-lysine-coated 12-well culture plates. 5 cells / cm 2 Neurons were seeded at an average density of 100 μg / well and grown in Neurobasal medium supplemented with B-27 and Glutamax at 37°C in a humidified environment containing 5% CO2 / 95% air. 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, each with two 3 mm paraffin beads. On the day of the experiment, cocultures were initiated by transferring a coverslip into each well of a 12-well plate containing neuronal cultures, with the astrocytes on the coverslip facing the neurons in the well and separated by 3 mm paraffin beads.

[0184] Acidification of extracellular medium (SNARF5) Lactate secretion was indirectly measured via acidification of the extracellular medium using the extracellular pH sensor SNARF-5F-(AND-6)-CAR (SNARF5). After washing the cells twice with stimulation medium (DMEM (D5030, Sigma), 1 mM NaHCO2, and 5 mM glucose, pH 7.4) at 37 °C, the cells were stimulated with compounds at final concentrations ranging from 10 nM to 30 μM in 50 μL per well of stimulation medium supplemented with 10 μM SNARF5 (Life Technologies). Each compound was tested in duplicate on two different plates. After 30, 60, and 90 min of stimulation, fluorescence was read at exc. (excitation) 480 nm / emm. (emission) 580 nm and exc. 480 nm / emm. 630 nm. The fluorescence ratio between the emission values ​​at 630 nm and 580 nm, which is proportional to extracellular pH, was calculated. In each plate, 8 wells were used for the negative control (DMSO 0.1%) and 8 wells were used for the positive control (CCCP 2 μM in DMSO). Results are shown as % of the effect of the positive control (0% and 100% are the activity of the vehicle and positive control, respectively). The acidification of the medium by primary astrocytes treated with the compounds of the present invention is shown in Table 1.

[0185] Quantification of extracellular lactate L-lactate secretion was measured in the extracellular medium of astrocytes plated in 96-well plates after 90 min of stimulation (at 37°C, 5% CO2 / 95% air) with vehicle (DMSO), compounds of the present invention (100 nM to 100 μM), or a positive control. The positive control consisted of carbonyl cyanide m-chlorophenylhydrazine (CCCP, 2 μM), an inhibitor of mitochondrial oxidative phosphorylation, which led to enhanced glycolysis and lactate secretion. Stimulation medium consisted of D5030 medium supplemented with 5 mM D-glucose and 44 mM sodium bicarbonate, pH 7.2. To quantify lactate concentration in the extracellular medium, 200 μL of 0.2 M glycine-semicarbazide buffer (pH 10) containing 3 mM NAD and 14 U / ml LDH was added to each well of a 96-well plate containing a 30 μL aliquot of extracellular medium. The samples were incubated for 1 hour at 37° C. Fluorescence intensity (340 nm excitation / 450 nm emission), which indicates the amount of NADH produced, was measured and compared with a standard curve of L-lactate concentration to determine lactate concentration values.

[0186] 2-deoxyglucose (2DG) uptake Astrocytes grown in 12-well plates and transfected with scrambled siRNA or GLUT1 siRNA were used. One day after changing the transfection medium (DIV 13), cells were treated with vehicle (0.1% DMSO) or compounds (1) to (5) of the present invention (at concentrations of 0.1 to 10 μM) for 30 minutes, followed by measurement of 2DG uptake. During treatment, 1 mM 2DG was added to the medium for assessment of 2DG uptake. At the end of the stimulation, the medium was removed and replaced with 150 μL of 0.1 M NaOH and stored at -20°C. After thawing, cells were harvested using a cell scraper and heated at 85°C for 40 minutes. Then, 150 μL of 0.1 M HCl and 200 mM TAE buffer were added to each condition. 2DG was quantified by adding 20 μL of 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 to a clear 96-well plate. The concentration of 2DG in the samples was calculated by comparison with a standard curve of deoxy-glucose-6-phosphate ranging from 0 to 1 nmole.

[0187] We analyzed 2DG uptake in primary astrocytes after treatment with compounds (1)–(5) (Figures 1A–E, respectively), and observed that these compounds significantly enhanced 2DG uptake in astrocytes.

[0188] MTT mitochondrial activity assay in primary astrocytes To monitor mitochondrial activity in astrocytes, which is associated with the metabolic processes of glycolysis and production of lactate, astrocytes in 96-well plates were stimulated with compounds of the present invention ranging from 10 nM to 10 μM for 24 h (37°C, 5% CO2 / 95% air).

[0189] After stimulation, 5 mg / ml thiazole blue tetrazolium bromide (MTT) in D5030 medium supplemented with 5 mM D-glucose and 44 mM sodium bicarbonate (pH 7.2) was added to each well, and the cells were incubated for 4 hours at 37°C (5% CO2). The medium was then removed, and the amount of reduced MTT, or formazan, solubilized in DMSO (50 μL / well) was determined using a spectrophotometer (absorbance at 570 nm).

[0190] Mitochondrial activity was monitored by MTT colorimetric assay in primary astrocytes treated with various concentrations of compounds 1, 2, 3, 4, 5, 9, and 10 after 1.5 hours (Figure 2A, B, D, E, F, C, and H, respectively) or 24 hours (Figure 2H, I, K, L, M, J, and N, respectively). These data indicate that none of the selected compounds had a direct effect on mitochondrial activity in astrocytes.

[0191] MTT mitochondria in neurons derived from pure neuronal cultures and neurons derived from astrocyte-neuron cocultures Pure neuron cultures or astrocyte-neuron cocultures were treated with 10 μM compound (2) for 2 hours in a solution consisting of Neurobasal supplemented with B-27 and Glutamax and 0.25 mg / ml thiazole blue tetrazolium bromide (MTT). Pure neuron cultures were treated with the addition of blank coverslips, whereas coculture-derived neurons were treated with the addition of astrocytes grown on coverslips as previously described. After stimulation, blank coverslips (neuron pure cultures) or astrocytes on coverslips (astrocyte-neuron cocultures) were separated from neurons, the medium was removed, and the amount of reduced MTT, or formazan, solubilized in DMSO (50 μL / well) was determined using a spectrophotometer (absorbance at 570 nm).

[0192] The results showed that treatment with compound (2) enhanced mitochondrial activity in neurons in astrocyte-neuron cocultures (Figure 3B), but not in pure cultures (Figure 3A), indicating that the effect of this compound on neurons requires the presence of astrocytes.

[0193] Human iPSC-derived astrocytes Human iPSC-derived astrocytes were purchased from NCardia (NCyte Astrocytes) and cultured at approximately 10,000 cells / cm using the recommended medium according to the manufacturer's instructions. 2 Cells were plated at a density of 1000 μg / ml into 96-well or 12-well plates. Experiments were performed in vitro on day 7. Cells were treated with compound 2 for 1.5 hours. 2-DG uptake and lactate release were quantified as previously described. Compound 2 increased 2-DG uptake and lactate release in human iPSC-derived astrocytes (Figures 4A and 4B, respectively).

[0194] Example 3 In vivo effects of the compounds of the present invention To assess the effect of the compounds of the present invention on brain extracellular levels of glucose and lactate, the compounds of the present invention were tested by in vivo monitoring of glucose and lactate levels after treatment with the compounds of the present invention as follows.

[0195] animal All experiments were performed in strict accordance with the Swiss Federal Guidelines for Animal Experimentation and approved by the Cantonal Veterinary Office for Animal Experimentation (Canton of Geneva, Switzerland). Adult male C57Bl / 6J wild-type mice (8–12 weeks old) weighing 18–28 g were used (Charles River Laboratories). Animals were housed in groups of 3–5 in polypropylene cages (30 × 40 × 15 cm) with wire mesh tops in a controlled environment of temperature (22 ± 2 °C) and humidity (55 ± 15%) under a 12-h light cycle (lights on 07:00–19:00 h), except after surgery, when animals were housed individually. Test samples (vehicle or compounds of the invention) were administered orally (gavage) in a solution consisting of 0.4% hydroxypropylmethylcellulose (HPMC) Methocel 4KM (w / v) and water supplemented with 0.25% Tween-20 (v / v) as previously described (Thackaberry et al., 2010, Toxicol Sci., 117(2):485-92). The concentrations of the tested compounds ranged from 3 to 30 mg / kg.

[0196] Lactate and glucose biosensors Cerebral extracellular levels of L-lactate and D-glucose were monitored in vivo using a lactate biosensor and a glucose biosensor (Pinnacle Technology, Inc.), respectively, according to the manufacturer's instructions. Five to seven days before the experiment, mice were surgically implanted with a cannula into the medial prefrontal cortex (coordinates: -1.0 mm (relative to the bregma), + / -1.0 mm lateral (relative to the midline), -1.0 mm ventral (relative to the dura)) under isoflurane anesthesia. After surgery, mice were closely monitored and provided with analgesia for at least four days. After the mice had fully recovered from surgery, they were orally administered vehicle or a compound of the present invention, as previously described, and cerebral levels of extracellular lactate and glucose were dynamically recorded for six hours using the biosensors. Mice were initially administered vehicle alone, followed three hours later by vehicle or a compound of the present invention. Cerebral extracellular lactate and glucose concentrations were calculated from the biosensor electrical signals using the calibrated values. Each lactate or glucose increase or decrease signal following compound (or vehicle) administration was expressed as a fold change relative to the increase or decrease in lactate or glucose following the first administration of vehicle alone; therefore, each animal served as its own control. The area under the lactate and glucose concentration curves (AUC) were calculated using Graphad Prism, and the ratio of the AUC following drug administration to the AUC following vehicle administration was calculated. Extracellular lactate and glucose concentrations were measured in real time in freely moving animals for 3 hours following administration of vehicle or compounds (1)–(4) ranging from 10 to 30 mg / kg (Figure 5). The results show that treatment with Compound 1 (Figure 5C, D), Compound 2 (Figure 5A), Compound 3 (Figure 5G, H), and Compound 4 (Figure 5K) significantly increased extracellular glucose levels in the brains of mice treated at various doses compared to vehicle. The results show that treatment with Compound 1 (Figure 5E, F), Compound 2 (Figure 5B), Compound 3 (Figure 5I, J), and Compound 4 (Figure 5L) significantly increased extracellular lactate levels in the brains of mice treated at various doses compared to vehicle.

[0197] 18 F-FDG PET Brain glucose uptake was measured in vivo using 18F-fluorodeoxyglucose (FDG) with positron emission tomography (PET) scans. Mice were fasted for 12 hours before PET / CT scans. Compounds of the present invention were administered by gavage, followed by 5MBq of FDG in 300 μL of saline. 18 F-FDG was injected intraperitoneally. 20 minutes after injection, the mice were anesthetized and placed on the microPET / CT scanner bed. The microPET scan continued for 40 minutes, acquired every 5 minutes, followed by a 5-minute CT scan for positioning. At the end of the imaging protocol, the animals were returned to their cages, and a second measurement was performed 7 days later. At the end of the second measurement, the mice were sacrificed. Blood and brain were collected. Whole brain 18 Quantification of F-FDG (BQML / volume) showed that administration of 30 mg / kg of compounds (1) and (2) increased glucose uptake in the brain compared to vehicle (Figures 6A and 6B, respectively).

[0198] Overall, these data support that compounds of the invention enhance glucose uptake and brain glucose and lactate levels in the brain.

[0199] Example 4 In vivo efficacy of compounds of the present invention in preclinical models of hypometabolic disorders, including GLUT1-DS To assess the in vivo efficacy of the compounds of the present invention, the compounds were tested in the following models.

[0200] animal We used heterozygous transgenic mice (GLUT1(+ / -)) on the 129 / SvJ genetic background in which the glucose transporter type 1 (GLUT1) was knocked down (Wang et al., 2016, Human Molecular Genetics, 15(7)). GLUT1 deficiency syndrome (GLUT1-DS) is a prototypical hypometabolic 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-D male mice or GLUT1-DS female mice and wild-type male mice. F1 offspring were ear-punched at weaning and then genotyped using PCR. Mice were used at 2–3 months of age.

[0201] Lactate and glucose biosensors Cerebral extracellular levels of lactate and glucose were monitored in vivo in GLUT1-D transgenic male mice and wild-type (WT) male littermates using lactate and glucose biosensors (Pinnacle Technology) according to the manufacturer's instructions. A cannula was surgically implanted into the motor cortex M1 / M2 (coordinates: +1.94 mm (relative to the bregma), -1.4 mm lateral (relative to the midline), -1.0 mm ventral (relative to the dura)) in GLUT1-DS transgenic mice and wild-type littermates. After surgery, mice were closely monitored and provided with analgesia for at least 4 days. After the mice had fully recovered from surgery, they were orally administered a compound of the present invention or vehicle, as previously described, and cerebral levels of extracellular lactate or glucose were dynamically recorded for 6 hours using a lactate or glucose biosensor, respectively. Mice were first orally administered vehicle alone, followed 3 hours later by vehicle or a 10 mg / kg dose of Compound (2). During recording, mice were exposed to a novel object consisting of colored plastic blocks in their cages to stimulate activity. Cerebral extracellular lactate or glucose concentrations were calculated from the electrical signals of the lactate or glucose probe, respectively, using 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 ratio of the AUC after administration of a compound of the present invention to the AUC after vehicle administration was calculated. The AUC signals of lactate or glucose after administration of vehicle or Compound (2) were expressed as the fold change relative to the AUC of the increase or decrease in lactate or glucose after the first administration of vehicle (Figure 7). The results show that treatment with 10 mg / kg of compound (2) significantly increased extracellular lactate (Figure 7A) and glucose (Figure 7B) levels in the brains of treated GLUT1-DS transgenic mice compared to vehicle.

[0202] rotarod Motor function was measured on the rotarod in wild-type (WT) and GLUT1-DS transgenic mice after a single administration of vehicle or compound (1) or (2) (10 mg / kg) 20 min before the rotarod test. The rotarod test consisted of placing a mouse on an accelerating rotating rod (4-40 rpm) for up to 300 s. Three consecutive sessions were performed with 15 min intervals. The latency until the mouse fell off the rod was recorded, and the maximum latency across the three trials was used as a measure of motor function. Mice that did not fall over the 300 s duration were removed, and the test was terminated with a score of up to 300 s. The data show that GLUT1-DS transgenic mice performed poorly on the rotarod compared to WT mice, but administration of a 10 mg / kg dose of compound (1) or (2) improved rotarod performance in GLUT1-DS mice (Figures 8A and B, respectively).

[0203] Grip strength test After the rotarod session, motor strength was measured using a grip strength test (Bioseb). Wild-type (WT) and GLUT1-DS transgenic mice were placed on a grid with all four paws, and the maximum grip strength was recorded over two sessions separated by a 5-minute interval. The maximum grip strength over the two sessions was recorded. The data show that vehicle or compound (1) or (2) treatment (10 mg / kg) did not result in any difference in muscle strength, but rather in muscle coordination assessed by the rotarod (Figures 8C and 8D, respectively).

[0204] Example 5 In vivo efficacy of compounds of the present invention in preclinical models of hypometabolic diseases, including Alzheimer's disease The efficacy of compounds of the present invention was tested in the above animal models, as described below. Adult male C57Bl / 6J wild-type mice ranging in age from 3 months (young adults) to 16 months (old adults) were used (Charles River). Animals were housed in groups of 3-5 in polypropylene cages (30 x 40 x 15 cm) with wire mesh tops in a controlled environment with a 12-hour light cycle (lights on 07:00-19:00), temperature (22 ± 2°C), and humidity (55 ± 15%). Test substances (vehicle or compounds of the invention) were administered orally (gavage) in a solution consisting of 0.4% hydroxypropylmethylcellulose (HPMC) Methocel 4KM (w / v) and water supplemented with 0.25% Tween-20 (v / v), as previously described (Thackaberry et al., 2010, Toxicol Sci., 117(2):485-92). As described below, memory of vehicle-treated young adults or vehicle-treated or aged adults treated with 10 mg / kg or 30 mg / kg of Compound (1) is tested in the Morris water maze. Treatment is administered 30 minutes before the first training session on each training day. No treatment is administered during memory retention. The data show that, when assessed in the Morris water maze, the memory of vehicle-treated aged mice is significantly lower than that of young mice one day after training, and that treatment of aged mice with 10 mg / kg or 30 mg / kg of Compound (2) results in a significant increase in memory (Figure 9).

[0205] APOE4(+) mouse model of Alzheimer's disease Mouse models carrying the APOE4 human allele exhibit reduced metabolic gene expression and cerebral glucose uptake compared to APOE3-expressing models (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 disturbances induce cerebral hypometabolism, which recapitulates the cerebral metabolic state observed in AD carriers of the APOE4 allele. Male and female APOE4(+) and APOE3(+) (control) transgenic mice are used at 3 months of age. As described below, the memory of vehicle-treated APOE3(+) mice and vehicle-treated or APOE4(+) mice treated with 10 mg / kg and 30 mg / kg of Compound (2) is tested in the Morris water maze. Treatment is administered 30 minutes before the first training session on each training day. No treatment is administered during memory retention. The data show that when assessed in the Morris water maze, the memory of vehicle-treated APOE4(+) mice is lower than that of APOE3(+) mice 7 days after training, and treatment of APOE4(+) mice with 30 mg / kg of Compound (2) results in a significant increase in memory (Figure 10).

[0206] Streptozotocin intracerebroventricular (ICV) injection model of Alzheimer's disease A craniotomy is performed on isoflurane-anesthetized mice for injection of vehicle or streptozotocin into the cerebral ventricles (coordinates: -0.5 mm (relative to the bregma), + / - 1.0 mm lateral (relative to the midline), -2.2 mm ventral (relative to the dura)) (Kelliny S. et al., Molecular Neurobiology, 2021). Using a Hamilton microsyringe at a constant speed of 100-200 nL / min, 1 µL of a solution consisting of vehicle (0.9% NaCl) or streptozotocin (5 mg / kg) prepared in artificial cerebrospinal fluid (aCSF, 20 mM citrate buffer, pH 4.2) is injected into both ventricles. After injection, the cranial skin is sutured, and the mice are closely monitored and analgesic treatment is administered for at least 4 days. After the mice have fully recovered from surgery, memory tests including the Morris water maze (MWM), inhibitory avoidance (IA), and novel object recognition (NOR) are performed as described below. The memory of vehicle-injected and vehicle-treated mice, or streptozotocin-injected and treated with either vehicle or 10 mg / kg and 30 mg / kg of Compound (2) was tested in the Morris water maze, novel object recognition, and inhibitory avoidance tasks as described below. For the Morris water maze, treatment was administered 30 minutes before the first training session on each training day. For the novel object recognition and inhibitory avoidance tests, treatment was administered once 30 minutes before the acquisition test. The data show that the memory of streptozotocin-injected and vehicle-treated mice in the Morris water maze, novel object recognition, and inhibitory avoidance memory tasks was weaker than that of saline-injected and vehicle-treated mice (Figures 11A, B, and C, respectively). The data also show that the memory of streptozotocin-injected mice treated with 30 mg / kg Compound (2) was significantly greater than that of vehicle-treated mice in the Morris water maze (FIG. 11A) one day after training, and that the memory of streptozotocin-injected mice treated with 10 mg / kg and 30 mg / kg Compound (2) was significantly greater than that of vehicle-treated mice in novel object recognition (FIG. 11B) one day after training and in inhibitory avoidance (FIG. 11C) one day after training.

[0207] restraint avoidance The inhibitory avoidance (IA) test is a well-established rodent memory paradigm that measures contextual memory associated with a mild electric foot shock in a specific context (the dark compartment of the IA chamber). Each mouse was handled for 5 min per day for at least 4 consecutive days to reduce stress from the experimenter's presence / manipulation during testing. Inhibitory avoidance was performed in an IA chamber (MedAssociates), which consists of a rectangular Perspex box separated into a safe compartment and a shock compartment by an automatically operated sliding door. The safe compartment is white and illuminated, while the shock compartment is black and dark. Twenty minutes after oral administration of drug or vehicle, mice were trained for IA. During training, mice were placed in the safe compartment with their head facing away from the door. After 10 seconds, the door separating the compartments automatically opened, allowing the mouse access to the shock compartment (this typically occurred within 20 seconds). One second after the mouse entered the dark compartment, the door closed and a 2-second foot shock of 0.6 mA intensity was administered to the grid floor of the shock chamber via a constant-current scrambler circuit. After the foot shock, the mouse remained in the dark compartment for 10 seconds and then returned to its home cage. Memory retention was measured 24 hours after training by returning the mouse to the light compartment and recording the latency (seconds) to enter the dark compartment. No foot shock was administered during the retention test. The test ended once the mouse entered the dark compartment or after a cutoff limit of 900 seconds.

[0208] Morris Water Maze The Morris Water Maze (MWM), a well-established spatial and contextual memory test, is used. The MWM consists of four consecutive training days, each consisting of four 90-second training sessions in which mice learn to locate a hidden platform in a pool. If the mouse does not find the platform within the 90-second training session, the experimenter guides the mouse to the platform. The mouse is allowed to remain on the platform for 30 seconds. Memory is tested on days 5 and 12 after training with a probe trial, in which the platform is removed. Using automated tracking software (Ethovision), several parameters are recorded, including the latency to find the platform, the time spent around the platform, path efficiency, and the percentage of time spent in each quadrant. The type of exploration (direct, random, or scanning the area) is also recorded. Willingness to swim away and visual acuity are tested in case of doubt by making the platform visible (e.g., by placing a flag). Testing takes place in a 120 cm diameter circular arena divided into four essentially quadrants and filled with water (made opaque with white dye) at 23±1° C. Visual cues are located on the outside of the pool.

[0209] Novel object recognition Novel object recognition (NOR) is a well-established protocol for assessing recognition memory in rodent models. Each mouse was handled for 5 min per day for at least 4 consecutive days to reduce stress on the animals due to the presence / handling of the experimenter during the test day. The animal was placed in an area containing two identical plastic objects (plastic building blocks, a Falcon tube, and a plastic cup) for 10 min, during which time it was allowed to explore the objects. This constitutes the acquisition phase. During the acquisition period, the time spent exploring and the number of contacts with each object were recorded. At the end of acquisition, the mouse was removed from the arena and returned to its home cage. 24 h (Test 1) and 7 days (Test 2) after the end of acquisition, one of the acquired objects was replaced, and the mouse was returned to the same arena for 10 min. The time spent exploring and the number of contacts with each object were recorded. Activity was automatically recorded using automated tracking software (Ethovision).

Claims

1. Neurological diseases or any medical condition 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 in all stages, frontotemporal dementia (FTD), dementia with Lewy bodies (LBD), mild cognitive impairment (MCI), vascular dementia, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), movement disorders, for example Parkinson's disease in all stages, for example L-dopa-induced diabetic retinopathy (DLR), Skenesia, Huntington's disease, spinocerebellar ataxia, essential tremor, dystonia and related neurodegenerative conditions, e.g., multiple sclerosis, retinopathy, stroke, traumatic brain injury, intracerebral and subarachnoid hemorrhage, any neuropsychiatric disorder, e.g., depression, schizophrenia, anxiety, attention deficit syndrome, any endophenotype of autism, neurometabolic disorders, e.g., glucose transporter type 1 deficiency syndrome (GLUT1-DS), Lafora's disease and other glycogen storage disorders, Down's syndrome, all types 1. The compound of formula (I), any pharmaceutically acceptable salt, hydrate, solvate thereof, or polymorphs, tautomers, optically active forms, enantiomeric mixtures, and mixtures thereof, for preventing, inhibiting, or treating cerebral hypometabolic states caused by epilepsy, migraine, and cognitive impairment in type 2 diabetes (T2D), by viral infections such as HIV or COVID-19, by prion infections, primary and secondary encephalitis, for example in Creutzfeldt-Jakob disease, or by abnormal protein processing and accumulation, for example all types of amyloidopathies, synucleinopathies, tauopathies, TD43 proteinopathies and other proteinopathies, after anesthesia or post-operative care, or for the treatment or stabilization of neurological disorders with cerebral hypometabolic or related symptoms, including cognitive impairment, motor function and movement disorders, psychiatric symptoms, or epileptic seizures, and for enhancing cognitive and memory function: 【Chemical 1】 In the formula, Y is NH and CH 2 R1 is selected from H, halogen and C 1 ~C 6 Alkyl (halogen, OR 12 and NR 13 R 14 and R2 is selected from H, halogen, C 1 ~C 6 Alkyl (halogen, OR 12 and NHR 13 optionally substituted with a group selected from 2～ C 6 Alkenyl, or OR 12 group, NR 13 R 14 or a cyano group or an optionally substituted heterocycle; R3 is H, halogen, C 1 ~C 6 Alkyl (halogen, OR 12 and NR 13 R 14- or C 2 ~C 6 Alkenyl, or OR 12 group, or NHR 13. or an optionally substituted heterocycle or cyano group; R4 is H, halogen, C 1 ~C 6 Alkyl (halogen, OR 12 and NHR 13 R5 is selected from H, halogen, C 1 ~C 6 Alkyl (halogen, OR 12 and NHR 13 optionally substituted with a group selected from: OR 12 , or NR 13 R 14 R6 is selected from the group consisting of H, halogen, C 1 ~C 6 Alkyl (halogen, OR 12 and NHR 13 optionally substituted with a group selected from: OR 12 , or NHR 13 groups; R7 and R8 are independently selected from H and halogen; and R9 is SO—C 1 ~C 6 Alkyl, SO 2 -C 1 ~C 6 Alkyl, SO 2 -C 3 ~C 6 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 pyrrolinone, and optionally substituted oxetane; R and R are independently selected from H and halogen; R, R, and R are H, C(O)—C 1 ~C 6 Alkyl and optionally substituted C 1 ~C 6 Alkyl or C 3 ~C 6 cycloalkyl.

2. Compounds of formula (I) according to claim 1, any pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, tautomers, optically active forms, enantiomeric mixtures, and mixtures thereof, provided that the compound is not a compound selected from the following list: 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-pyridinyl)-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-furanyl)-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-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-93-7; 1-[[4-(4-pyridinyl)phenyl]amino]-8-isoquinolinecarbonitrile, RN:1368269-53-7; 8-Methyl-N 1 -[4-(4-pyridinyl)phenyl]-1,5-isoquinolinediamine, RN:1369288-67-4; 5-nitro-N-[4-(4-pyridinyl)phenyl]-1-isoquinolinamine, RN:1368370-43-7; N-[4-(4-pyridinyl)phenyl]-5-(trifluoromethyl)-1-isoquinolinamine, RN: 1367803-95-9; and 4-Bromo-N 1 -[4-(4-pyridinyl)phenyl]-1,7-isoquinolinediamine, 1369271-85-1

3. Y is CH 2 3. The compound of claim 2, wherein:

4. 3. The compound of claim 2, wherein Y is NH.

5. The compound of any one of claims 2 to 4, wherein R1, R5, R4 and R6 are H.

6. R2 is OR 12 The compound according to any one of claims 2 to 5, wherein

7. R3 is OR 12 The compound according to any one of claims 2 to 6, wherein

8. R3 is NHR 13 The compound according to any one of claims 2 to 6, wherein

9. The compound of any one of claims 2 to 6, wherein R3 is halogen.

10. The compound of any one of claims 2 to 6, wherein R3 is H.

11. R3 is optionally substituted C 1 ~C 6 The compound of any one of claims 2 to 6, which is alkyl.

12. 12. The compound according to any one of claims 1 to 11, wherein R10 and R11 are H.

13. 12. The compound of any one of claims 1 to 11, wherein R10 is halogen.

14. 12. The compound of claim 1, wherein R11 is halogen.

15. 13. The compound according to any one of claims 1 to 12, wherein R7, R8, R10 and R11 are H.

16. R9 is SO 2 -C to C 6 Alkyl, e.g., SO 2 -CH 3 or SO 2 -CH 2 CH 3 16. The compound according to any one of claims 1 to 15, selected from:

17. R9 is SO 2 -C 3 ~C 6 16. The compound of any one of claims 1 to 15, which is cycloalkyl.

18. A compound according to any one of claims 2 to 17 for the use as defined in claim 1.

19. 10. A compound for use as defined in claim 1, any pharmaceutically acceptable salts, hydrates, solvates, or polymorphs thereof, tautomers, optically active forms, enantiomeric mixtures, and mixtures thereof selected from the list below: 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-(4-methylsulfonylphenyl)-6-pyrimidin-2-yl-isoquinolin-1-amine; N-[1-(4-methylsulfonylanilino)-7-isoquinolyl]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-methanesulfonylphenyl)amino]isoquinolin-7-ol; N-[4-(ethanesulfonyl)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-methanesulfonylphenyl)isoquinolin-1-amine; 6,7-Diethoxy-N-(2-fluoro-4-methanesulfonylphenyl)isoquinolin-1-amine; N-[4-(cyclopropanesulfonyl)phenyl]-6,7-diethoxyisoquinolin-1-amine; 6-Ethoxy-7-(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine; 6,7-bis(2-fluoroethoxy)-N-(4-methanesulfonylphenyl)isoquinolin-1-amine; 1-[(4-methanesulfonylphenyl)methyl]-6-(propan-2-yloxy)isoquinoline; 6-[(4-fluorophenyl)methoxy]-N-(4-methanesulfonylphenyl)isoquinolin-1-amine; and 6-Ethoxy-N-(4-methanesulfonylphenyl)-7-propylisoquinolin-1-amine.

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

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

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

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

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

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