Methods for Treating COVID-Related Disorders

Abstract

The present disclosure relates to methods of treating the long-term sequelae of infection with SARS-CoV-2, also known as long COVID. More specifically, a method of treating long COVID is disclosed, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive regulator.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 313,015, filed February 23, 2022, which is incorporated by reference herein in its entirety for any purpose.

[0002] The present disclosure relates to methods of treating the long-term sequelae of infection with SARS-CoV-2, also known as long COVID or PACS (Post Acute Covid 19 Sequelae). [Background technology]

[0003] The global pandemic caused by SARS-CoV-2 has led to a sharp epidemiological increase in depression and anxiety disorders (Santomauro, 2021). In addition, SARS-CoV-2 infection has led to numerous long-term sequelae after the initial recovery from infection, both in non-specific CNS syndromes (e.g., fatigue) and specific symptoms (e.g., depression, anxiety) (Paul et al., 2021).

[0004] Most psychiatric central nervous system (CNS) disorders have no identified direct neuroanatomical or functional brain correlates. In contrast, the pathophysiology of long Covid CNS symptoms appears to involve the whole brain in a fundamental way, possibly via systemic vasculitis and downstream processes (inflammation, hypoperfusion, hypoxia). In severe cases, SARS-CoV-2 can also result in delirium and psychosis, inflammatory syndromes (such as encephalitis and acute disseminated encephalomyelitis), ischemic and hemorrhagic stroke (Iadecola et al., 2020; Koralnik and Tyler, 2020). “Localized” symptoms such as post-Covid Guillain-Barre syndrome have also been described in long Covid (Raahimi et al., 2021).

[0005] Neurological syndromes that may be part of the prolonged recovery from SARS-CoV2 infection have no rational targeted therapy. All current treatment attempts are off-label, and although these therapies appear to target a common clinical symptom(s), they are not derived from a common pathophysiology and are not causal in their mode of action.

[0006] Hepatocyte growth factor (HGF) is a pleiotropic protein factor involved in numerous biological processes, including embryonic and organ development, regeneration, and inflammation. HGF plays an important role in cortical, motor, sensory, sympathetic, and parasympathetic neurodevelopment and maturation. HGF is translated and secreted as an inactive pro-HGF, but upon cleavage, the resulting α and β subunits are connected by disulfide bonds to form an active heterodimer. HGF expression occurs primarily in mesenchymal cells, such as fibroblasts, chondroblasts, adipocytes, and endothelial cells. It has also been shown to be expressed in the central nervous system (CNS), including neurons, astrocytes, and ependymal cells (Nakamura and Mizuno, 2010). All biological activities of HGF are mediated by MET, a transmembrane receptor tyrosine kinase that serves as the only known receptor for HGF. MET is known to be involved in a variety of biological processes, and roles in development, regeneration, and response to injury have been shown. Binding of HGF to the extracellular domain of MET results in homodimerization of the MET protein and autophosphorylation of the intracellular domain. Phosphorylation of the MET intracellular domain leads to the recruitment and phosphorylation of various effector proteins, including Gab1, GRB2, phospholipase C, and Stat3 (Gherardi et al., 2012; Organ and Tsao, 2011). These effector proteins then interact with downstream signaling pathways, including PI3K / Akt, Ras / Raf / MAPK, RAC1 / CDC42, and RAP / FAK, among others, to affect various cellular components, including gene regulation, cytoskeletal reorganization, cell cycle progression, cell adhesion, survival, and proliferation (Organ and Tsao, 2011). Because HGF has been shown to play roles in development (Nakamura et al., 2011), homeostasis (Funakoshi and Nakamura, 2003), suppression of cell death, and regeneration (Matsumoto et al., 2014), stimulation of the hepatocyte growth factor / MET (HGF / MET) signaling pathway is an ideal target for therapeutic agents in various disease states.Modulation of HGF activity has been proposed as a treatment for diseases and injuries in a wide variety of tissue types, including the liver, kidney, gastrointestinal tract, cardiovascular system, lung, skin, nervous system, and muscular system (Matsumoto et al., 2014).

[0007] Increasing evidence suggests that complex CNS disorders are unlikely to be caused by a single pathological pathway; they are more likely to be the result of multifactorial interactions related to genetics, age, and environment. Pharmacological stimulation of the HGF / MET signaling system may prevent neurodegeneration and promote neuroregeneration. Neurotrophic factor systems are promising therapeutic targets, and drugs that stimulate these systems may address neurodegeneration and improve cognition by protecting existing neurons, promoting connectivity, inducing neuroregenerative mechanisms, reducing inflammation, and improving cerebral blood flow (Funakoshi, 2011). The therapeutic promise of neurotrophic factors in neurological disorders is hindered by the lack of efficient and noninvasive delivery to the brain.

[0008] Therefore, a small molecule approach capable of crossing the blood-brain barrier and entering all regions of the brain represents an excellent therapeutic strategy for targeting neurotrophic factors to treat long COVID. Summary of the Invention

[0009] The present invention, in some embodiments, provides methods of treating long COVID. Embodiment 1. A method of treating long COVID comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 2. A method of treating the long-term sequelae of infection with SARS-CoV-2, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 3. A method of treating post-acute COVID-19 syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 4. A method of treating a post-COVID-19 symptom, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 5. A method of improving event-related potential (ERP) P300 latency in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 6. A method of delaying cognitive decline or improving cognition in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 7. A method of delaying the decline in or improving the ability to perform activities of daily living and verbal fluency in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 8. A method of delaying functional or cognitive decline in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 9. A method of delaying clinical decline in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 10. A method of improving executive memory function in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist. Embodiment 11 The method of any one of the preceding embodiments, wherein the HGF / MET agonist is an antibody, an aptamer, a peptide, and / or a small molecule. Embodiment 12. The method of any one of the preceding embodiments, wherein the HGF / MET agonist is N-hexanoic acid-Tyr-Ile-(6) aminohexanoic acid amide (Dihexa) or a pharma- ceutically acceptable salt or prodrug thereof. Embodiment 13. The HGF / MET agonist is [ka] or a pharma- ceutically acceptable salt thereof. Embodiment 14. The method of any one of the preceding embodiments, comprising administering to the patient between 2 and 90 mg of the HGF / MET agonist per day. Embodiment 15. The HGF / MET agonist is a) a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, L is a direct bond, -C(=O)-, -(CR a R b ) m -C(=O)-, -C(=O)-(CR a R b ) m - or -(CR a R b ) m - and Each R a and R b are independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 1a and R 1b are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, or C6-C 10 is arylalkyl, R 2 is H, oxo, or thioxo, R 3 is C2-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10 arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl; wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R 4 is C6-C 10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl; wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; Each R 5 are independently C1-C6 alkyl, oxo, or halo; R 6 is H, C1-C6 alkyl, or oxo; R 7 is H or oxo, m is 1 or 2; n is an integer from 0 to 3, where each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 The method of any one of embodiments 1-11, wherein the arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclylalkyl are optionally substituted with 1-5 substituents selected from hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl), and -CO2H. Embodiment 16. The compound of formula (I) is a compound of formula (II), (IIa), (IIb), (IIc), (IId), or (IIe): [ka] or a pharma- ceutically acceptable salt thereof, 1a , R 1b , R3 , R 4 , R 5 , R 6 , R 7 and n is as described for formula (I). Embodiment 17. The method of any one of embodiments 1-11 or 15-16, wherein the HGF / MET agonist is a compound set forth in Table 1 or a pharma- ceutically acceptable salt thereof, or a compound set forth in Table 1A or a pharma- ceutically acceptable salt thereof. Embodiment 18. The HGF / MET agonist is [ka] The method according to any one of embodiments 1-11 or 15-17, wherein said compound is a) or a pharma- ceutically acceptable salt thereof. Embodiment 19. The HGF / MET agonist is [ka] or a pharma- ceutically acceptable salt thereof. Embodiment 20. The method of any one of the preceding embodiments, wherein prior to treatment, the patient exhibits one or more symptoms selected from anxiety, lethargy, shortness of breath, chest pain, cognitive impairment, depression, fatigue, impaired pulmonary function, decreased liver function, increased incidence of venous thromboembolism, muscle weakness, idiopathic pulmonary fibrosis, and / or respiratory complications. Embodiment 21 The method of any one of the preceding embodiments, wherein prior to treatment, the patient exhibits cognitive impairment. Embodiment 22. The method of embodiment 21, wherein the cognitive impairment is attention, working memory, processing speed, executive function, phonemic fluency, categorical fluency, memory encoding, memory recall, and / or memory recognition cognitive impairment. Embodiment 23 The method of embodiment 21 or 22, wherein the cognitive impairment is indicative of an executive pattern. Embodiment 24. The method of any one of embodiments 21 to 23, wherein the cognitive impairment is indicative of a dysexecutive syndrome. Embodiment 25. The method of any one of the preceding embodiments, wherein the patient has previously been diagnosed with an airway disease, asthma, such as moderate to severe asthma, bronchiectasis, bronchopulmonary dysplasia, cancer, chronic lung disease, chronic obstructive pulmonary disease (COPD), diabetes, hypertension, interstitial lung disease, pulmonary embolism, and / or pulmonary hypertension. Embodiment 26. The method of any one of the preceding embodiments, wherein the decline in functional or cognitive ability of the patient is delayed. Embodiment 27. The method of any one of the preceding embodiments, wherein the patient's cognitive decline is delayed. Embodiment 28. The method of any one of the preceding embodiments, wherein the method improves cognition in the patient. Embodiment 29. The method of any one of the preceding embodiments, wherein the decline in practical activities of daily living, ability to perform basic activities of daily living, ability to manage finances, and / or language fluency in said patient is delayed. Embodiment 30. The method of any one of the preceding embodiments, wherein the method improves the patient's ability to perform activities of daily living, ability to manage finances, and / or language fluency. Embodiment 31. The method of any one of the preceding embodiments, wherein the delay or amelioration of the decline is determined after administration of the treatment for at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks. Embodiment 32. The method of any one of the preceding embodiments, wherein the rate of decline in practical (23-item) Activities of Daily Living (ADL) scores is reduced, stabilized, or improved. Embodiment 33. The method of embodiment 32, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 34. The method of embodiment 32 or 33, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 35. The method of any one of the preceding embodiments, wherein the rate of decline in basic (19-item) Activities of Daily Living (ADL) score is reduced, stabilized, or improved. Embodiment 36. The method of embodiment 35, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 37. The method of embodiment 35 or 36, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 38. The method of any one of the preceding embodiments, wherein the rate of decline in Financial Competence Index (FCI) scores is reduced, stabilized, or improved. Embodiment 39. The method of embodiment 38, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 40. The method of embodiment 38 or 39, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 41 The method of any one of the preceding embodiments, wherein the patient has a Mini-Mental State Examination (MMSE) score of 27 or less prior to initiating the treatment. Embodiment 42 The method of any one of the preceding embodiments, wherein the rate of decline in MMSE score is reduced, stabilized, or improved. Embodiment 43. The method of embodiment 42, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 44. The method of embodiment 42 or 43, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 45. The method of any one of the preceding embodiments, wherein cognitive performance is assessed using the Alzheimer's Disease (AD) Assessment Scale-Cognitive Subscale (ADAS-Cog) by determining the patient's score before and after administration of the treatment. Embodiment 46. The method of embodiment 45, wherein cognitive performance is assessed before initiation of said treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of said treatment. Embodiment 47. The method of embodiment 45 or 46, wherein the rate of decline in ADAS-Cog is reduced, stabilized, or improved. Embodiment 48. The method of any one of the preceding embodiments, wherein the rate of decline in Montreal Cognitive Assessment (MoCA) scores is reduced, stabilized, or ameliorated. Embodiment 49. The method of embodiment 48, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 50. The method of embodiment 48 or 49, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 51. The method of any one of the preceding embodiments, wherein the rate of decline in Digit Symbol Substitution Test (DSST) scores is reduced, stabilized, or improved. Embodiment 52. The method of embodiment 51, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 53. The method of embodiment 51 or 52, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 54. The method of any one of the preceding embodiments, wherein the rate of decline in Disability Assessment of Dementia (DAD) score is reduced, stabilized, or improved. Embodiment 55. The method of embodiment 54, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 56. The method of embodiment 54 or 55, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 57. The method of any one of the preceding embodiments, wherein the rate of decline in a Neuropsychiatric Inventory (NPI) score is reduced, stabilized, or improved. Embodiment 58. The method of embodiment 57, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 59. The method of embodiment 57 or 58, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 60. The method of any one of the preceding embodiments, wherein the rate of decline in a Controlled Word Association Test (COWAT) score is reduced, stabilized, or improved. Embodiment 61. The method of embodiment 60, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 62. The method of embodiment 60 or 61, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 63. The method of any one of the preceding embodiments, wherein the rate of decline of numerical span forward and / or backward scores is reduced, stabilized, or improved. Embodiment 64. The method of embodiment 63, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 65. The method of embodiment 63 or 64, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 66. The method of any one of the preceding embodiments, wherein the rate of decline in Trail Making Test Part A and / or Part B is reduced, stabilized, or improved. Embodiment 67. The method of embodiment 66, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 68. The method of embodiment 66 or 67, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 69. The method of any one of the preceding embodiments, wherein the rate of decline in phoneme and category fluency scores is reduced, stabilized, or improved. Embodiment 70. The method of embodiment 69, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 71. The method of embodiment 69 or 70, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 72. The method of any one of the preceding embodiments, wherein the rate of decline in Hopkins Verbal Learning Test-Revised scores is reduced, stabilized, or improved. Embodiment 73. The method of embodiment 72, wherein the reduction, stabilization, or improvement in the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 74. The method of embodiment 72 or 73, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's score before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment. Embodiment 75. A method according to any one of the preceding embodiments, resulting in rapid improvement or normalization of P300 amplitude values. Embodiment 76. The method of any one of the preceding embodiments, which results in a rapid improvement or normalization of event-related potential (ERP) P300 latency values. Embodiment 77. The method of any one of the preceding embodiments, which results in rapid improvement or normalization of ERP P300 latency values, with some maintenance of efficacy 4 weeks after cessation of treatment. Embodiment 78. The method of any one of the preceding embodiments, which provides a rapid improvement or normalization of ERP P300 latency values ​​that is maintained 4 weeks after cessation of treatment. Embodiment 79. The method of any one of the preceding embodiments, wherein the method improves event-related potential (ERP) P300 latency. Embodiment 80. The method of any one of embodiments 75-79, wherein said improvement or normalization of P300 value occurs at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of said treatment. Embodiment 81. The method of any one of the preceding embodiments, wherein the HGF / MET agonist has an acceptable safety and tolerability profile. Embodiment 82. The method of any one of the preceding embodiments, wherein said HGF / MET agonist is generally safe and well tolerated. Embodiment 83 The method of any one of the preceding embodiments, wherein the HGF / MET agonist is administered by oral dosing, such as by subcutaneous injection or by a solid oral dosage form. Embodiment 84 The method of any one of the preceding embodiments, wherein the HGF / MET agonist is administered by subcutaneous injection. Embodiment 85. The method of any one of the preceding embodiments, comprising administering the HGF / MET agonist for 26 weeks or more. Embodiment 86 The method of any one of the preceding embodiments, wherein the HGF / MET agonist is a sodium salt of a compound of formula A19. Embodiment 87. The method of any one of the preceding embodiments, wherein the HGF / MET agonist is the monosodium salt of a compound of formula A19. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Definitions and General Parameters As used herein, the following words and phrases generally are intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0011] As used herein, reference to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. In certain embodiments, the term "about" includes the stated amount ±10%. In other embodiments, the term "about" includes the stated amount ±5%. In certain other embodiments, the term "about" includes the stated amount ±1%. Additionally, the term "about X" includes the description of "X." Additionally, the singular forms "a" and "the" include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those of skill in the art.

[0012] The disclosure illustratively described herein may suitably be practiced in the absence of any element(s), limitation(s) not specifically disclosed herein. Thus, for example, terms such as "comprising," "including," "containing," and the like, are to be interpreted expansively and without limitation. Furthermore, the terms and expressions used herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions to exclude the features shown and described or any equivalents thereof, but it is recognized that various modifications are possible within the scope of the disclosure as claimed.

[0013] In some embodiments, the compounds of the present disclosure may be in the form of a "prodrug". The term "prodrug" is defined in the pharmaceutical arts as a biologically inactive derivative of a drug that, when administered to the human body, is converted into the biologically active parent drug via some chemical or enzymatic pathway. Examples of prodrugs include esterified carboxylic acids.

[0014] The compounds of the present disclosure may take the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, such as inorganic bases or acids and organic bases or acids. When the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically available salts. Thus, compounds of the present disclosure that contain acidic groups may exist on these groups and may be used according to the present disclosure, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to those skilled in the art. Compounds of the present disclosure that contain one or more basic groups, i.e., groups that can be protonated, may exist and may be used according to the present disclosure in the form of their addition salts with inorganic or organic acids.

[0015] The present disclosure provides pharmaceutical compositions comprising as an active ingredient a compound of the present disclosure or a pharma- ceutically acceptable salt or solvate thereof, in association with a pharma- ceutically acceptable carrier.

[0016] "Pharmaceutical composition" refers to one or more active ingredients and one or more inactive ingredients that make up the carrier, as well as any product that results directly or indirectly from the combination, complex formation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Thus, the pharmaceutical composition of the present disclosure can include any composition made by mixing at least one compound of the present disclosure and a pharma- ceutical acceptable carrier.

[0017] As used herein, a "pharmaceutically acceptable carrier" includes excipients or agents that are not deleterious to the disclosed compounds or their use, such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. The use of such carriers and agents to prepare compositions of pharma- ceutically active substances is well known in the art (see, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0018] The terms "therapeutically effective amount" and "effective amount" are used interchangeably and refer to an amount of a compound sufficient to effect treatment as defined herein when administered in one or more doses to a patient (e.g., a human) in need of such treatment. The therapeutically effective amount will vary depending on the patient, the disease being treated, the patient's weight and / or age, the severity of the disease, or the method of administration as determined by a qualified formulator or caregiver.

[0019] The term "treatment" or "treating" means the administration of a compound or a pharma- ceutically acceptable salt thereof in order to: (i) delay the onset of the disease, i.e., to prevent or delay the onset of clinical symptoms of the disease; (ii) inhibit the disease, i.e., to prevent the onset of clinical symptoms; and / or (iii) ameliorate the disease, i.e., to cause regression of the clinical symptoms or their severity.

[0020] "Amino" refers to the -NH2 radical.

[0021] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0022] "Cyano" refers to the -CN radical.

[0023] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0024] "Nitro" refers to the -NO2 radical.

[0025] "Oxo" refers to the =O substituent.

[0026] "Thioxo" refers to the =S substituent.

[0027] "Thiol" refers to a -SH substituent.

[0028] "Alkyl" means an unbranched or branched saturated hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having one to twelve carbon atoms (C1-C 12alkyl), preferably having 1 to 8 carbon atoms (C1-C8 alkyl), 1 to 6 carbon atoms (C1-C6 alkyl), or 1 to 3 carbon atoms (C1-C3 alkyl) and attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise in the specification, alkyl groups are optionally substituted.

[0029] "Alkenyl" means an unbranched or branched unsaturated hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds and having from 2 to 12 carbon atoms (C2-C 12 alkenyl), preferably having 2 to 8 carbon atoms (C2-C8 alkenyl) or 2 to 6 carbon atoms (C2-C6 alkenyl) and attached to the remainder of the molecule by a single bond, such as ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless stated otherwise in the specification, alkenyl groups are optionally substituted.

[0030] "Alkynyl" means an unbranched or branched unsaturated hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds and having 2 to 12 carbon atoms (C2-C 12 Alkynyl), preferably having 2 to 8 carbon atoms (C2-C8 alkynyl) or 2 to 6 carbon atoms (C2-C6 alkynyl) and attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise in the specification, alkynyl groups are optionally substituted.

[0031] "Alkoxy" means a group of the formula -OR a where R ais an alkyl radical, as defined above, containing 1 to 12 carbon atoms. Preferred alkoxy groups have 1 to 6 carbon atoms (i.e., C1-C6 alkoxy) or 1 to 3 carbon atoms (i.e., C1-C3 alkoxy) in the alkyl radical. Unless stated otherwise in the specification, an alkoxy group is optionally substituted.

[0032] "Aromatic ring" refers to a cyclic planar portion of a molecule (i.e., a radical) that has a ring of resonance bonds that exhibit increased stability compared to other connection arrangements of the same atomic group. In general, aromatic rings contain covalently bonded coplanar atoms and contain an even number of pi electrons (e.g., alternating double and single bonds) that is not a multiple of four (i.e., 4n+2 pi electrons, where n=0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridonyl, pyridazinyl, and pyrimidonyl. Unless otherwise specified herein, aromatic rings include all radicals that are optionally substituted.

[0033] "Aryl" refers to an alkyl group having 6 to 18 carbon atoms and at least one aromatic ring (i.e., C6-C 18 aryl), preferably containing 6 to 10 carbon atoms (i.e., C6-C 10 For purposes of the present disclosure, aryl radicals are monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, phenyl, pleiadene, pyrene, and triphenylene. Unless otherwise stated in the specification, aryl groups are optionally substituted.

[0034] An "arylalkyl" is a group of the formula -Rb -R c where R b is an alkylene chain, and R c is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. An arylalkyl group is a C6-C 10 C1-C connected to aryl radical 10 Alkylene chain (i.e., C6-C 10 Unless stated otherwise in the specification, an arylalkyl group may be optionally substituted.

[0035] "Cycloalkyl" means a stable non-aromatic monocyclic or polycyclic carbocyclic radical, consisting solely of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from 3 to 15 carbon atoms (i.e., C3-C 15 cycloalkyl), preferably having 3 to 10 carbon atoms (i.e., C3-C 10 Cycloalkyl refers to a group having from 3 to 6 carbon atoms (i.e., C3-C6 cycloalkyl), saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated in the specification, cycloalkyl groups are optionally substituted.

[0036] "Cycloalkylalkyl" refers to a group of the formula -R b -R c where R b is an alkylene chain, and R cis one or more cycloalkyl radicals as defined above, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkylalkyl groups are C3-C 12 C1-C connected to cycloalkyl radical 10 Alkylene chain (i.e., C3-C 12 C1-C connected to a cycloalkyl alkyl or C3-C6 cycloalkyl radical 10 It may contain an alkylene chain (i.e., C3-C6 cycloalkylalkyl). Unless stated otherwise in the specification, a cycloalkylalkyl group is optionally substituted.

[0037] "Fused" refers to any ring structure described herein that is fused to an existing ring structure in a compound of the present disclosure. When the fused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclyl ring or fused heteroaryl ring is replaced with a nitrogen atom.

[0038] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0039] "Haloalkyl" refers to an alkyl radical as defined above substituted with one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Preferred haloalkyl groups include alkyl groups having 1 to 6 carbon atoms and substituted with one or more halo radicals (i.e., C1-C6 haloalkyl). The halo radicals may all be the same or the halo radicals may be different. Unless otherwise stated in the specification, haloalkyl groups are optionally substituted.

[0040] "Haloalkoxy" refers to a group of the formula -OR a where R ais a haloalkyl radical, as defined herein, containing 1 to 12 carbon atoms. Preferred haloalkoxy groups include alkoxy groups having 1 to 6 carbon atoms (i.e., C1-C6 haloalkoxy) or 1 to 3 carbon atoms (C1-C3 haloalkoxy) and substituted with one or more halo radicals. The halo radicals can all be the same or all different. Unless stated otherwise in the specification, a haloalkoxy group is optionally substituted.

[0041] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or multiple fused rings (e.g., a 5-14 membered ring system) containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 1-10 ring carbon atoms and 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur in the ring. Preferred heteroaryl groups have 5-10 membered ring systems containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., 5-10 membered heteroaryl) and 5-6 membered ring systems containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., 5-6 membered heteroaryl). For purposes of embodiments of the present disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Heteroaryl can include one or more N-oxide (NO-) moieties, such as pyridine-N-oxide. Unless otherwise stated herein, heteroaryl groups are optionally substituted.

[0042] "Heteroarylalkyl" refers to a group of the formula -R b -R c where R b is an alkylene chain, and Rc is one or more heteroaryl radicals as defined above. A heteroarylalkyl group is a C1-C6 alkyl group connected to a 5- to 10-membered heteroaryl group. 10 C1-C connected to an alkylene chain (i.e., 5-10 membered heteroarylalkyl) or a 5-6 membered heteroaryl group 10 It may contain an alkylene chain (i.e., a 5-6 membered heteroarylalkyl).Unless stated otherwise in the specification, a heteroarylalkyl group is optionally substituted.

[0043] "Heterocyclyl" refers to a saturated or unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls can be monocyclic or polycyclic, where the polycyclic rings can be fused, bridged, or spiro, and can contain one or more oxo (C=O) or N-oxide (NO-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the bond (i.e., it can be bonded through a carbon atom or a heteroatom). Additionally, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom that can be fused to an aryl or heteroaryl ring, regardless of the bond to the rest of the molecule. As used herein, a heterocyclyl has 1 to 10 ring carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms and 1 to 5 ring heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Preferred heterocyclyls have 5 to 10 members in a ring system containing 1 to 4 heteroatoms selected from nitrogen and oxygen (i.e., 5-10 membered heterocyclyl) or 5 to 8 members in a ring system containing 1 to 4 heteroatoms selected from nitrogen and oxygen (i.e., 5-8 membered heterocyclyl). Examples of heterocyclyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Unless stated otherwise in the specification, a heterocyclyl group is optionally substituted.

[0044] "Heterocyclylalkyl" refers to a group of the formula -R b -R c where R b is an alkylene chain, and R c is one or more heterocyclyl radicals as defined above. A heterocyclylalkyl group is a C-C alkyl group connected to a 5- to 10-membered heterocyclyl radical. 10 C1-C attached to an alkylene chain (i.e., 5- to 10-membered heterocyclylalkyl) or a 5- to 8-membered heterocyclyl radical 10 It may contain an alkylene chain (i.e., a 5- to 8-membered heterocyclylalkyl).Unless stated otherwise in the specification, a heterocyclylalkyl group is optionally substituted.

[0045] In some embodiments, the term "substituted" as used herein refers to any of the above groups or other substituents (e.g., C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 12 Cycloalkyl, C3-C 12 In any of the following groups (cycloalkyl, alkyl, aryl, and heteroaryl), it is meant that at least one hydrogen atom (e.g., 1, 2, 3, or all hydrogen atoms) is replaced by a bond to a non-hydrogen atom, including, but not limited to, a halogen atom (i.e., "halo") such as F, Cl, Br, and I; an oxygen atom in a group such as a hydroxyl group or an alkoxy group (e.g., alkoxy or haloalkoxy); a nitrogen atom in a group such as an amine (e.g., -NH), amide (e.g., -(C=O)NH), and nitro; an alkyl group that contains one or more halogens such as F, Cl, Br, and I (e.g., haloalkyl); and cyano.

[0046] L, R 1a , R 1b , R 2 , R 3 , R 4 , R 5, R 6 , and R 7 It is understood that each selection for is optionally substituted as above, unless otherwise specified, provided that all valences are satisfied by substitution. In particular, L, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Each of the options for is optionally substituted, unless otherwise specified, provided that such substitution results in a stable molecule (e.g., groups such as H and halo are not optionally substituted).

[0047] HGF / MET Positive Modulator Positive modulators (i.e., agonists) of HGF / MET are small, brain-permeable molecules that specifically enhance HGF / MET signaling in the presence of HGF. In damaged tissues, for example, during inflammation, local tissue HGF concentrations are elevated. This localizing effect leads to targeting HGF / MET positive modulators, such as ATH-1017, towards desired brain regions requiring increased neurotrophic activity. Phosphorylation of intracellular MET receptor sites results in a cascade of intracellular effects that in turn combat inflammation, promote perfusion and metabolic homeostasis, and result in increased axonal branching and synaptic connections. Impaired synaptic connections or structurally compromised synaptic connections are known to result in impaired cognitive abilities, including, but not limited to, the ability to focus, orientation in time and space, and executive memory function. In addition, this functional or structural synapse disconnection syndrome may contribute to behavioral and psychological manifestations of dementia (e.g., BPSD, including depression and anxiety) and thus may also contribute to clinical CNS syndromes in long COVID.

[0048] HGF / MET positive modulators have been shown preclinically to saturate targets at clinically relevant exposures. In healthy volunteers and Alzheimer's disease (AD) subjects, ATH-1017 has been shown to increase gamma power and reduce prolonged ERP P300 latency (Hua, 2022). These results support blood-brain barrier crossing and target engagement in humans.

[0049] ATH-1017 and related compounds ATH-1017 is an experimental treatment, formulated as a sterile solution for subcutaneous (SC) injection. ATH-1017 is a prodrug that is rapidly converted to the active metabolite ATH-1001 (Dihexa; see US2014 / 0094413) in plasma following SC injection. ATH-1017 was developed as a water-soluble prodrug of ATH-1001, allowing for SC administration in an aqueous vehicle. The active drug ATH-1001 acts as a positive modulator of the hepatocyte growth factor (HGF) receptor and its tyrosine kinase MET receptor system. Central nervous system (CNS) MET expression is essential for maintaining a healthy adult brain (Hawrylycz, 2015) and is reduced in AD, particularly in the hippocampus and prefrontal cortex (Hamasaki, 2014). The HGF / MET system presents a therapeutic target for treating neurodegeneration and restoring cognitive function following infection with SARS-CoV-2.

[0050] ATH-1017 is a pharma- ceutically acceptable salt of a compound having the formula of A19: [ka]

[0051] As used herein, and in the absence of specific reference to a particular pharma- ceutically acceptable salt and / or solvate of ATH-1017, any dosage amount, whether expressed in milligrams or by weight, should be construed as referring to an amount of ATH-1017, i.e., the following amount: [ka]

[0052] Thus, for example, reference to "40 mg of ATH-1017, or a pharma- ceutically acceptable salt and / or solvate thereof" means the amount of ATH-1017, or a pharma- ceutically acceptable salt and / or solvate thereof, that provides the same amount of ATH-1017 as 40 mg of A19 free acid.

[0053] Non-limiting examples of pharma- ceutically acceptable salts of A19 include: [ka]

[0054] Unless otherwise indicated, ATH-1017 refers to the monosodium salt of A19, shown below: [ka]

[0055] Compounds of A19 and their pharma- ceutically acceptable salts (including ATH-1017) can be synthesized and characterized using methods known to those of skill in the art, such as those described in PCT Publication No. WO2017 / 210489 A1.

[0056] In some embodiments, ATH-1017 is formulated for subcutaneous administration.In some such embodiments, ATH-1017 is provided in a pre-filled syringe containing 1 mL of 40 mg / mL ATH-1017 or 70 mg / mL ATH-1017.In some embodiments, ATH-1017 is in a solution containing 10 mM sodium phosphate.

[0057] Compounds of formula (I) Some embodiments provide for the use of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, L is a direct bond, -C(=O)-, -(CR a R b ) m -C(=O)-, -C(=O)-(CR a R b ) m - or -(CR a R b ) m - and Each R a and R b are independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 1a and R 1b are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, or C6-C 10 is arylalkyl, R 2 is H, oxo, or thioxo, R 3 is C2-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10 arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl; wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R 4 is C6-C 10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl; wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; Each R 5 are independently C1-C6 alkyl, oxo, or halo; R 6 is H, C1-C6 alkyl, or oxo; R 7 is H or oxo, m is 1 or 2; n is an integer from 0 to 3, where each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 The arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclylalkyl are optionally substituted with 1 to 5 substituents selected from hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl), and -CO2H.

[0058] In some embodiments, L is a direct bond. In some embodiments, L is -C(=O)- or -(CR a R b ) m In some embodiments, L is -C(=O)-. In some embodiments, L is -(CR a R b ) m In some embodiments, L is -(CR a R b ) m -C(=O)- or -C(=O)-(CR a R b ) m In some embodiments, L is -(CR a R b ) m In some embodiments, L is -C(=O)-(CR a R b ) m -It is.

[0059] In some embodiments, each R aand R b is independently H, C-C alkyl, C-C alkenyl, or C-C alkynyl. a and R b is independently H, C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl. In some embodiments, R a and R b are each H. In some embodiments, R a is H. In some embodiments, R a is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R a is a C2-C6 alkenyl, such as vinyl or propenyl. In some embodiments, R a is a C2-C6 alkynyl, such as ethynyl or propynyl. In some embodiments, R b is H. In some embodiments, R b is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R b is a C2-C6 alkenyl, such as vinyl or propenyl. In some embodiments, R b is a C2-C6 alkynyl, such as ethynyl or propynyl.

[0060] In some embodiments, R 1a and R 1b are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, or C6-C 10 In some embodiments, R 1a is H. In some embodiments, R 1a is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 1a is a C2-C6 alkenyl, such as vinyl or propenyl. In some embodiments, R 1ais a C2-C6 alkynyl, such as ethynyl or propynyl. In some embodiments, R 1a is C1-C6 alkoxy, such as methoxy, ethoxy, or propoxy. In some embodiments, R 1a is halo, such as fluoro, chloro, or bromo. In some embodiments, R 1a C6-C such as benzyl 10 In some embodiments, R 1b is H. In some embodiments, R 1b is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 1b is a C2-C6 alkenyl, such as vinyl or propenyl. In some embodiments, R 1b is a C2-C6 alkynyl, such as ethynyl or propynyl. In some embodiments, R 1b is C1-C6 alkoxy, such as methoxy, ethoxy, or propoxy. In some embodiments, R 1b is halo, such as fluoro, chloro, or bromo. In some embodiments, R 1b C6-C such as benzyl 10 It is arylalkyl.

[0061] In some embodiments, R 1a and R 1b are each independently selected from H; C1-C6 alkyl optionally substituted with 1-3 substituents selected from halo, -CO2H, and -C(=O)NH2; C1-C6 alkoxy; halo; or C6-C optionally substituted with 1-3 substituents selected from halo and amino. 10 In some embodiments, R 1a is C1-C6 alkyl substituted with 1 to 3 halo, such as fluoro or chloro. 1a is a C1-C6 alkyl substituted with 1 to 3 -CO2H groups.1a is a C1-C3 alkyl substituted with 1 to 2 CO2H groups, e.g., -CH2CO2H or -CH2CH2CO2H. In some embodiments, R 1a is a C1-C6 alkyl substituted with 1 to 3 -C(=O)NH2 groups. 1a is a C1-C3 alkyl substituted with 1 to 2 -C(=O)NH2 groups, e.g., -CH2C(=O)NH2 or -CH2CH2C(=O)NH2. In some embodiments, R 1a is a C6-C substituted with 1 to 3 substituents selected from halo and amino 10 In some embodiments, R 1a is a C6-C substituted with 1-3 halo, such as fluoro, chloro, or bromo. 10 In some embodiments, R 1a is a C6-C substituted with 1 to 3 amino groups. 10 In some embodiments, R 1b is C1-C6 alkyl substituted with 1 to 3 halo, such as fluoro or chloro. 1b is a C1-C6 alkyl substituted with 1 to 3 -CO2H groups. 1b is a C1-C3 alkyl substituted with 1 to 2 CO2H groups, e.g., -CH2CO2H or -CH2CH2CO2H. In some embodiments, R 1b is a C1-C6 alkyl substituted with 1 to 3 -C(=O)NH2 groups. 1b is a C1-C3 alkyl substituted with 1 to 2 -C(=O)NH2 groups, e.g., -CH2C(=O)NH2 or -CH2CH2C(=O)NH2. In some embodiments, R 1b is a C6-C substituted with 1 to 3 substituents selected from halo and amino 10 In some embodiments, R 1bis a C6-C substituted with 1-3 halo, such as fluoro, chloro, or bromo. 10 In some embodiments, R 1b is a C6-C substituted with 1 to 3 amino groups. 10 In some embodiments, R 1a and R 1b are each independently H, methyl, fluoro, 2-methylbutyl, -CHF, methoxy, -CHCOH, -CHC(=O)NH, benzyl, or 4-aminobenzyl. 1a and R 1b are each independently H or C1-C3 alkyl. 1a is methyl, R 1b is H. In some embodiments, R 1a and R 1b are each H. In some embodiments, R 1a and R 1b One of these is H and the other is a C1-C3 alkyl, such as methyl.

[0062] In some embodiments, R 2 is H, oxo, or thioxo. In some embodiments, R 2 is H. In some embodiments, R 2 In some embodiments, R 2 is thioxo.

[0063] In some embodiments, R 3 is C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10arylalkyl, 5-10 membered heteroarylalkyl, or 5-10 membered heterocyclylalkyl, where the 5-10 membered heteroarylalkyl or 5-10 membered heterocyclylalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen. 3 is C3-C6 alkyl, such as propyl, butyl, pentyl, or hexyl. In some embodiments, R 3 is C4-C6 alkyl. In some embodiments, R 3 is C-C alkenyl. In some embodiments, R 3 is C-C alkenyl. In some embodiments, R 3 is C-C alkynyl. In some embodiments, R 3 is C-C alkynyl. In some embodiments, R 3 is a C3-C aryl such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 12 In some embodiments, R 3 is C-C cycloalkyl. In some embodiments, R 3 is -(CH2) 1-3 (C-C cycloalkyl). In some embodiments, R 3 C6-C such as benzyl 10 In some embodiments, R 3 is -(CH2) 1-3 (5-10 membered heteroaryl) or -(CH2) 1-3 (5-6 membered heteroaryl). In some embodiments, the 5-10 membered heteroaryl alkyl contains 1-2 nitrogen atoms. In some embodiments, R 3 is -(CH2) 1-3 (5-10 membered heterocyclyl) or -(CH2) 1-2(5- to 6-membered heterocyclyl). In some embodiments, the 5- to 10-membered heterocyclylalkyl contains 1 to 2 nitrogen atoms.

[0064] In some embodiments, R 3 is C-C alkyl, C-C alkenyl, or C-C cycloalkyl alkyl optionally substituted with 1-3 substituents selected from halo and -C(=O)NH. In some embodiments, R 3 is a C2-C6 alkyl optionally substituted with 1-3 substituents selected from halo, C1-C3 alkoxy, hydroxy, -NH2, -SO2(C1-C3 alkyl), and -C(=O)NH2; a C2-C6 alkenyl; a C3-C6 cycloalkylalkyl; a 5-6 membered heteroarylalkyl; a 5-6 membered heterocyclylalkyl; or a C6 arylalkyl. In some embodiments, R 3 is a C2 alkyl substituted with 1 to 3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(C1-C3 alkyl). 3 is: [ka]

[0065] In some embodiments, R 3 is: [ka]

[0066] In some embodiments, R 3 is 2-methylbutyl.

[0067] In some embodiments, R 4 is C6-C 10aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl, where the 5-10 membered heteroaryl or 5-10 membered heterocyclyl contains 1-3 heteroatoms selected from nitrogen and oxygen. 4 C6-C such as phenyl 10 In some embodiments, R 4 is a 5-10 membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, R 4 is 5-10 membered heterocyclyl. In some embodiments, R 4 is a 5-9 membered heterocyclyl containing 1-2 nitrogen atoms. 4 is a 5-9 membered heterocyclyl containing 1-2 oxygen atoms. 4 is a 5-9 membered heterocyclyl containing one nitrogen atom and one oxygen atom.

[0068] In some embodiments, R 4 is a C6-C optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy; 10 In some embodiments, R 4 is phenyl substituted with 1 to 3 substituents selected from -CF, -OCHF, -OH, fluoro, and chloro. 4 is: [ka] In some embodiments, R 4 is: [ka]

[0069] In some embodiments, R 4is a 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 is pyridyl or indolyl optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 teeth, [ka] In some embodiments, R 4 is pyridyl substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 teeth, [ka] In some embodiments, R 4 is a 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 is indolinyl. [ka]

[0070] In some embodiments, -LR 4 is -CH2(phenyl) or -C(O)(phenyl), where phenyl is substituted with 1 to 3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. 4is -CH2(pyridyl) or -C(O)(pyridyl), where the pyridyl is substituted by 1 to 3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. 4 is as follows: [ka]

[0071] In some embodiments, each R 5 is independently C-C alkyl, oxo, or halo. In some embodiments, R 5 is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 5 In some embodiments, R 5 is halo, such as fluoro, chloro, or bromo. 5 is oxo or halo. In some embodiments, R 5 is oxo or fluoro.

[0072] In some embodiments, R 6 is H, C1-C6 alkyl, or oxo. In some embodiments, R 6 is H. In some embodiments, R 6 is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 6 is oxo.

[0073] In some embodiments, R 7 is H or oxo. In some embodiments, R 7 is H. In some embodiments, R 7 is oxo.

[0074] In some embodiments, m is 1. In other embodiments, m is 2.

[0075] In some embodiments, n is 0. In other embodiments, n is an integer from 1 to 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0076] In any embodiment of formula (I) or variations thereof, each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 The arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclylalkyl are optionally substituted with 1 to 3 substituents selected from hydroxyl, halo (such as fluoro, chloro, or bromo), amino, C1-C6 haloalkyl (such as -CF3 or -CHF2), C1-C6 alkoxy (such as methoxy or ethoxy), C1-C6 haloalkoxy (such as -OCHF2 or -OCF3), and -(C=O)NH2.

[0077] In some embodiments, the compound of formula (I) is a compound of formula (II), (IIa), (IIb), (IIc), (IId), or (IIe): [ka] or a pharma- ceutically acceptable salt thereof, 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7and n are as described for Formula (I). In some embodiments, the compound is represented by Formula (II) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IIa) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IIb) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IIc) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IId) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IIe) or a pharma- ceutically acceptable salt thereof.

[0078] In some embodiments, the compound of Formula (I) is a compound of Formula (IIIa), (IIIb), (IIIc), or (IIId): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1a , R 1b , R 3 , R 5 , R 6 and n are as described for formula (I), and R represents one or more optional substituents, such as hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, as described for formula (I). In some embodiments, the compound is represented by formula (IIIa) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IIIb) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IIIc) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IIId) or a pharma- ceutically acceptable salt thereof.

[0079] In some embodiments, the compound of formula (I) is a compound of formula (IVa), (IVb), (IVc), or (IVd): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 5 and n are as described for formula (I), and R represents one or more optional substituents, such as hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, as described for formula (I). In some embodiments, the compound is represented by formula (IVa) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IVb) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IVc) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IVd) or a pharma- ceutically acceptable salt thereof.

[0080] In some embodiments, the compound of formula (I) has the formula (V): [ka] or a pharma- ceutically acceptable salt thereof, 1a , R 1b , R 3 , and R 4 is as described for formula (I). In some embodiments, L is -C(=O)- or -CH-, and R 1a and R 1b is independently H, or C-C alkyl optionally substituted with -COH, R 3 is C1-C3 alkyl substituted with C4-C5 alkyl, C4-C5 alkenyl, or C3-C5 cycloalkyl; R 4 is phenyl or pyridyl substituted with 1-3 substituents selected from -CF, -OCHF, -OH, fluoro, and chloro. 1a and R 1b One of is H and the other is a C1-C3 alkyl such as methyl.

[0081] In the description herein, it is understood that any description, variation, embodiment, or aspect of a moiety can be combined with any description, variation, embodiment, or aspect of any other moiety, just as if each and every combination of descriptions were specifically and individually recited. For example, any description, variation, embodiment, or aspect provided herein with respect to L in formula (I) can be combined with R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n may be combined with any description, variation, embodiment, or aspect thereof as if each and every combination were specifically and individually listed. It is understood that all descriptions, variations, embodiments, or aspects of formula (I), where applicable, also apply and are similarly described to other formulas detailed herein as if each and every description, variation, embodiment, or aspect of all formulas were individually and independently listed. For example, any statement, variation, embodiment, or aspect with respect to formula (I) equally applies and is equally described, where applicable, to any of the formulas detailed herein, such as formulas (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd), and (V), as if each and every statement, variation, embodiment, or aspect with respect to all formulas was individually and independently listed.

[0082] In some embodiments, provided is a compound selected from the compounds of Table 1, or a pharma- ceutically acceptable salt thereof. Certain compounds described in this disclosure, including those in Table 1, are depicted as particular stereoisomeric and / or non-stereochemical forms, but it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any of the compounds of this disclosure, including those in Table 1, are also described herein. TIFF2025508768000023.tif234170TIFF2025508768000024.tif226170TIFF2025508768000025.tif243170TIFF2025508768000026.tif237170TIFF2025508768000027.tif248170TIFF2025508768000028.tif221170TIFF2025508768000029.tif248170TIFF2025508768000030.tif98170, or a pharmacy acceptable salt thereof.

[0083] In some embodiments, the compound of Formula (I) is not compound 3a, 3b, 9, 10, 13, 15, 16, 18, 21, 23-29, 31-41, 43-48, 50, 52, or 54.

[0084] In some embodiments, provided is a compound selected from the compounds of Table 1A, or a pharma- ceutically acceptable salt thereof. Certain compounds described in this disclosure, including those in Table 1A, are depicted as specific stereoisomeric and / or non-stereochemical forms, but it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any of the compounds of this disclosure, including those in Table 1A, are also described herein. TIFF2025508768000031.tif239170TIFF2025508768000032.tif248170TIFF2025508768000033.tif98170, or a pharma- ceutically acceptable salt thereof.

[0085] In describing the present invention, it is understood that combinations of substituents and / or variables of the depicted formulae are permissible only if such combinations result in stable compounds.

[0086] Additionally, all compounds of formula (I) that exist in free base or free acid form can be converted to their pharma- ceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid by methods known to those skilled in the art. Salts of compounds of formula (I) can be converted to their free base or free acid forms by standard techniques.

[0087] Synthesis method The compound of formula (I), or its pharma-ceutically acceptable salt, isotopic form, or stereoisomer, can be prepared by using organic chemical synthesis methods known in the art.In general, starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)), or can be prepared as described herein.

[0088] General reaction scheme 1. [ka] General Reaction Scheme 1 provides an exemplary method for preparing compounds of formula (I). 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7, L, and n are as defined herein. X is a reactive moiety selected to facilitate the desired reaction (e.g., halo). P1 and P2 are suitable protecting groups. L' is a group selected from the group consisting of L'-R 4 and a secondary amine. Compounds of structure A1 are purchased or prepared according to methods known in the art. A1 and A2 are reacted under suitable coupling conditions (e.g., T3P and base) to give the product A3 of the coupling reaction between A1 and A2. A3 and A4 are then reacted under suitable coupling conditions (e.g., T3P and base) to give compound A5. Compound A5 is then cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to give compound A6. Compound A6 is then reacted with compound A7 to give the final compound of formula (I) shown.

[0089] General reaction scheme 2. [ka] An alternative method for the synthesis of compounds of formula (I) is shown in General Reaction Scheme 2. 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, and n are as defined herein. P2 is a suitable protecting group. Each X is a reactive moiety selected to facilitate the desired reaction (e.g., halo). L' is selected from L'-R 4 Intermediate A5 is selected to yield the desired L moiety from the reaction between R 3 A removable protecting group P 3(e.g., para-methoxybenzyl) to give intermediate A8. A8 is then cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to give compound A9. Compound A9 is then reacted with A7 to give compound A10. Compound A10 is then deprotected (e.g., with ceric ammonium nitrate) to give compound A11. Compound A11 is then reacted with A12 to give the final compound of formula (I).

[0090] General reaction scheme 3. [ka] A method related to that shown in General Reaction Scheme 2 is shown in General Reaction Scheme 3. In this method, the two amine nitrogen atoms of the bicyclic core are deprotected to provide compound A10, which is then reacted with A7 to give compound A11. Subsequent reaction with A12 gives the final compound of formula (I).

[0091] It should be noted that various alternative strategies for preparing compounds of formula (I) are available to one skilled in the art. For example, other compounds of formula (I) can be prepared according to similar methods using appropriate starting materials.

[0092] It will be understood by those skilled in the art that in the process of preparing the compounds described herein, it may be necessary to protect the functional groups of intermediate compounds by suitable protecting groups. Such functional groups may include hydroxy, amino, and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino and amidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or arylalkyl esters. Protecting groups are optionally added or removed according to standard techniques known to those skilled in the art or described herein. The use of protecting groups is described in detail in Green, TW and PGM Hutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As will be appreciated by those skilled in the art, the protecting group may be a polymer resin such as a Wang resin, a Rink resin or a 2-chlorotrityl-chloride resin.

[0093] Method of Treatment / Use Provided herein are methods for treating SARS-CoV-2 infection, also known as long COVID.

[0094] In some embodiments, a method of treating long COVID is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

[0095] In some embodiments, a method of treating the long-term sequelae of infection with SARS-CoV-2 is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0096] In some embodiments, a method of treating post-acute COVID-19 syndrome is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0097] In some embodiments, a method of treating a post-COVID-19 symptom is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0098] In some embodiments, a method of improving event-related potential (ERP) P300 latency in a patient diagnosed with long COVID is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0099] In some embodiments, a method of slowing cognitive decline or improving cognition in patients diagnosed with long COVID is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0100] In some embodiments, provided is a method of delaying the decline in or improving the ability to perform activities of daily living and verbal fluency in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0101] In some embodiments, a method of slowing functional or cognitive decline in a patient diagnosed with long COVID is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0102] In some embodiments, a method of delaying clinical decline in a patient diagnosed with long COVID is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0103] In some embodiments, a method of improving executive memory function in a patient diagnosed with long COVID is provided, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET positive modulator.

[0104] In some embodiments, the HGF / MET positive modulator is an antibody, an aptamer, a peptide, and / or a small molecule.

[0105] In some embodiments, the HGF / MET positive modulator is N-hexanoic acid-Tyr-Ile-(6) aminohexanoic acid amide (Dihexa) or a pharma- ceutically acceptable salt or prodrug thereof.

[0106] In some embodiments, the HGF / MET positive modulator comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the methods comprise administering to the patient between 2 and 90 mg of an HGF / MET positive modulator per day.

[0108] In some embodiments, the HGF / MET positive modulator comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0109] In some embodiments, the HGF / MET positive modulator comprises: [ka] or a pharma- ceutically acceptable salt thereof.

[0110] In some embodiments, the HGF / MET positive modulator is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof, L is a direct bond, -C(=O)-, -(CR a R b ) m -C(=O)-, -C(=O)-(CR a R b ) m - or -(CR a R b ) m - and Each R a and R b are independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 1a and R 1b are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, or C6-C 10 is arylalkyl, R 2 is H, oxo, or thioxo, R 3 is C2-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10 arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl; wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R 4 is C6-C10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl; wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; Each R 5 are independently C1-C6 alkyl, oxo, or halo; R 6 is H, C1-C6 alkyl, or oxo; R 7 is H or oxo, m is 1 or 2; n is an integer from 0 to 3, where each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 The arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclylalkyl are optionally substituted with 1 to 5 substituents selected from hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl), and -CO2H.

[0111] In some embodiments, the compound of Formula (I) is represented by Formula (II), (IIa), (IIb), (IIc), (IId), or (IIe): [ka] or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound set forth in Table 1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound is a compound set forth in Table 1A, or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, prior to treatment, the patient exhibits one or more symptoms selected from anxiety, lethargy, shortness of breath, chest pain, cognitive impairment, depression, fatigue, impaired pulmonary function, decreased liver function, increased incidence of venous thromboembolism, muscle weakness, idiopathic pulmonary fibrosis, and / or respiratory complications.

[0113] In some embodiments, prior to treatment, the patient exhibits cognitive impairment, such as impaired attention, working memory, processing speed, executive function, phonemic fluency, categorical fluency, memory encoding, memory recall, and / or memory recognition. In some embodiments, the cognitive impairment is indicative of an executive pattern or executive dysfunction syndrome.

[0114] In some embodiments, the patient has been previously diagnosed with airway disease, asthma, such as moderate to severe asthma, bronchiectasis, bronchopulmonary dysplasia, cancer, chronic lung disease, chronic obstructive pulmonary disease (COPD), diabetes, hypertension, interstitial lung disease, pulmonary embolism, and / or pulmonary hypertension.

[0115] In some embodiments, the treatment slows the decline in functional or cognitive ability in the patient. In some embodiments, the treatment improves cognitive ability in the patient.

[0116] In some embodiments, the treatment slows cognitive decline in the patient. In some embodiments, the treatment improves cognition in the patient.

[0117] In some embodiments, treatment slows the decline in practical activities of daily living, ability to perform basic activities of daily living, ability to manage finances, and / or speech fluency in the patient.

[0118] In some embodiments, treatment improves a patient's ability to perform activities of daily living, ability to manage finances, and / or speech fluency.

[0119] In some embodiments, the delayed or ameliorated decline is determined after at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks of treatment.

[0120] A variety of methods are available to assess a patient's cognitive abilities.

[0121] In some embodiments, cognitive performance is assessed by determining a patient's scores before and after administering a treatment.

[0122] In some embodiments, patients are assessed by a practical (23-item) Activities of Daily Living (ADL) score. In some embodiments, the practical (23-item) ADL score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the practical (23-item) ADL score.

[0123] In some embodiments, patients are assessed by a basic (19-item) Activities of Daily Living (ADL) score. In some embodiments, the basic (19-item) ADL score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the basic (19-item) ADL score.

[0124] In some embodiments, the patient is assessed by the Financial Care Index (FCI) score. In some embodiments, the FCI score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the FCI score.

[0125] In some embodiments, the patient has, prior to the start of treatment, a Mini-Mental State Examination (MMSE) score of less than or equal to 27. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in MMSE scores.

[0126] In some embodiments, patients are assessed by the Alzheimer's Disease (AD) Assessment Scale-Cognitive Subscale (ADAS-Cog) score. In some embodiments, the ADAS-Cog score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the ADAS-Cog score.

[0127] In some embodiments, the patient is evaluated by Montreal Cognitive Assessment (MoCA) score. In some embodiments, the MoCA score is evaluated before treatment starts and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment starts. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline of MoCA score.

[0128] In some embodiments, patients are evaluated by Digit Symbol Substitution Test (DSST) scores. In some embodiments, DSST scores are evaluated before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, treatment methods reduce, stabilize, or improve the rate of decline in DSST scores.

[0129] In some embodiments, the patient is evaluated by Dementia Assessment (DAD) score. In some embodiments, the DAD score is evaluated before treatment starts and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment starts. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline of DAD score.

[0130] In some embodiments, the patient is evaluated by Neuropsychiatric Inventory (NPI) score. In some embodiments, the NPI score is evaluated before the start of treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after the start of treatment. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline of the NPI score.

[0131] In some embodiments, patients are assessed by the Controlled Word Association Test (COWAT) score. In some embodiments, the COWAT score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the COWAT score.

[0132] In some embodiments, patients are assessed by a Numeric Span Forward and / or Backward score. In some embodiments, the Numeric Span Forward and / or Backward score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the Numeric Span Forward and / or Backward score.

[0133] In some embodiments, patients are assessed by Trail Making Test Part A and / or Part B scores. In some embodiments, Trail Making Test Part A and / or Part B scores are assessed prior to initiation of treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of treatment. In some embodiments, treatment methods reduce, stabilize, or ameliorate the rate of decline in Trail Making Test Part A and / or Part B scores.

[0134] In some embodiments, patients are assessed by phoneme and category fluency scores. In some embodiments, phoneme and category fluency scores are assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in phoneme and category fluency scores.

[0135] In some embodiments, the patient is assessed by the Hopkins Language Learning Test-Revised score. In some embodiments, the Hopkins Language Learning Test-Revised score is assessed before treatment begins and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment begins. In some embodiments, the treatment method reduces, stabilizes, or improves the rate of decline in the Hopkins Language Learning Test-Revised score.

[0136] In some embodiments, the treatment results in a rapid improvement or normalization of P300 amplitude values ​​and / or a rapid improvement or normalization of event-related potential (ERP) P300 latency values. In some embodiments, the treatment results in a rapid improvement or normalization of ERP P300 latency values, with some effect maintained 4 weeks after treatment is discontinued. In some embodiments, the treatment provides a rapid improvement or normalization of ERP P300 latency values ​​that is maintained 4 weeks after treatment is discontinued. In some embodiments, the treatment improves event-related potential (ERP) P300 latency. In some embodiments, the treatment results in an improvement or normalization of P300 values ​​by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after treatment initiation.

[0137] In some embodiments, the treatment comprises administering a compound of formula A19 or a pharma- ceutically acceptable salt thereof, e.g., a sodium salt of a compound of formula A19, e.g., a monosodium salt of a compound of formula A19, e.g., ATH-1017, by subcutaneous injection.

[0138] In some embodiments, the treatment includes administering a compound of formula A19 or a pharma- ceutically acceptable salt thereof, e.g., a sodium salt of the compound of formula A19, e.g., a monosodium salt of the compound of formula A19, e.g., ATH-1017, for 26 weeks or more.

[0139] In some embodiments, treatment comprises administering a compound of formula 2a or a pharma- ceutically acceptable salt thereof by subcutaneous injection or by oral dosing, such as, for example, by solid oral dosage form.

[0140] In some embodiments, treatment comprises administering a compound of formula 1a or a pharma- ceutically acceptable salt thereof by subcutaneous injection or by oral dosing, such as, for example, by solid oral dosage form.

[0141] In some embodiments, the treatment comprises administering a compound of formula 2a or a pharma- ceutically acceptable salt thereof for 26 weeks or more.

[0142] In some embodiments, the treatment comprises administering a compound of formula 1a or a pharma- ceutically acceptable salt thereof for 26 weeks or more.

[0143] In some embodiments, the treatment methods have an acceptable safety and tolerability profile, hi some embodiments, the treatment methods are generally safe and well tolerated.

[0144] Pharmaceutical Compositions In some embodiments, the methods comprise administering the HGF / MET agonist by subcutaneous injection.

[0145] In some embodiments, the methods include administering ATH-1017 by subcutaneous injection.

[0146] The pharmaceutical compositions of the drugs provided herein may be in a form suitable for the route of administration. The formulations may be conveniently provided in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).

[0147] The pharmaceutical composition of the present disclosure may take the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as, for example, oleic acid may also be used in the preparation of injectable drugs.

[0148] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0149] The formulations can be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit-dose formulations are those containing a daily dose or unit daily sub-dose, or an appropriate fraction thereof, of the active ingredient, as recited hereinabove.

[0150] The amount of active ingredient that can be combined with carrier material to produce a single dosage form will vary depending on the host treated and the specific mode of administration, such as subcutaneous injection. Pharmaceutical compositions can be prepared to provide an easily measurable amount for administration. For example, in some embodiments, ATH-1017 is formulated for subcutaneous administration and provided in a pre-filled syringe containing 1 mL of 40 mg / mL ATH-1017 or 70 mg / mL ATH-1017. In some embodiments, ATH-1017 is in a solution containing 10 mM sodium phosphate.

[0151] In some embodiments, the methods comprise administering an HGF / MET positive modulator via an oral dosage form.

[0152] In some embodiments, the methods include administering compound 2a, or a pharma- ceutically acceptable salt thereof, via an oral dosage form.

[0153] In some embodiments, the methods include administering compound 1a, or a pharma- ceutically acceptable salt thereof, via an oral dosage form.

[0154] Pharmaceutical Compositions and Formulations In a further aspect, provided herein is a pharmaceutical composition. The pharmaceutical composition comprises any one (or more) of the aforementioned compounds and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In still other embodiments, the pharmaceutical composition comprises an HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described herein below.

[0155] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, and intramedullary injections, as well as intrathecal, intravenous, intraperitoneal, intralymphatic, and intranasal injections.

[0156] In certain embodiments, the HGF / MET positive modulator, such as the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered locally rather than systemically, for example, by injecting the compound directly into an organ, often in a depot preparation or sustained release formulation. In certain embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, a liposome coated with an organ-specific antibody. In such embodiments, the liposome is targeted to the organ and selectively taken up by the organ. In still other embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is provided in the form of a fast release formulation, a sustained release formulation, or an intermediate release formulation. In still other embodiments, the compounds described herein are administered locally.

[0157] The HGF / MET positive modulators, such as the compounds of formula (I) or their pharma- ceutically acceptable salts, isotopic forms, or stereoisomers, are effective over a wide dosage range. The exact dosage may depend on the route of administration, the form in which the compound is administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0158] In some embodiments, the HGF / MET positive modulator, such as the compound of formula (I), or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is administered in a single dose.Typically, such administration is by injection, for example, intravenous injection, to rapidly introduce the drug.However, other routes are also used as appropriate.A single dose of the compound of the present disclosure can also be used to treat acute conditions (e.g., traumatic brain injury).

[0159] In some embodiments, the HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered in multiple doses. In some embodiments, the dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, the dosing is about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and another therapeutic agent are administered together about once per day to about six times per day. In another embodiment, the administration of the HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and another therapeutic agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration can be provided and maintained for as long as necessary.

[0160] Administration of the HGF / MET positive modulator, such as the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, can be continued as long as necessary. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered continuously, for example, chronically, for the treatment of chronic effects (e.g., dementia).

[0161] In some embodiments, the HGF / MET positive modulator, such as the compound of formula (I), or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is administered in multiple doses.It is known in the art that due to subject-to-subject variability in the pharmacokinetics of the compound, optimal treatment requires individualized dosing regimen.The dosage of the compound can be found by routine experimentation in light of the present disclosure.

[0162] In some embodiments, the HGF / MET positive modulator, such as compound formula (I), or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is formulated into a pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the active compound into a pharma- ceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any pharma- ceutically acceptable technique, carrier, and excipient may be used as suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

[0163] Provided herein is a pharmaceutical composition comprising an HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharma- ceutically acceptable diluent(s), excipient(s), or carrier(s).Also provided herein is a method for administering a pharmaceutical composition comprising an HGF / MET agonist, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharma- ceutically acceptable diluent(s), excipient(s), or carrier(s).

[0164] In certain embodiments, the compound is administered as a pharmaceutical composition in which the HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is mixed with other therapeutic agents as a combination therapy. All combinations of active ingredients described in the methods section below and throughout this disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises one or more compounds of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0165] Pharmaceutical composition, as used herein, refers to a mixture of an HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the compound to an organism. In some embodiments, to practice the methods of treatment or use provided herein, a therapeutically effective amount of an HGF / MET positive modulator, such as a compound of formula (I), provided herein, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered in a pharmaceutical composition to a mammal having a disease, disorder, or medical condition to be treated. In a specific embodiment, the mammal is a human. In certain embodiments, the therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compounds described herein are used alone or as components of a mixture in combination with one or more therapeutic agents.

[0166] In one embodiment, one or more HGF / MET positive modulators, such as one or more compounds of formula (I), or pharma- ceutically acceptable salts, isotopic forms, or stereoisomers thereof, are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected from physiologically compatible buffers, such as, by way of example only, Hank's solution, Ringer's solution, or saline buffer. In another embodiment, one or more compounds of formula (I), or pharma-ceutically acceptable salts, isotopic forms, or stereoisomers thereof, are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation comprises a penetrant appropriate for the barrier to be permeated (e.g., the blood-brain barrier). In yet another embodiment, in which the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions comprise physiologically compatible buffers and / or excipients.

[0167] Suitable HGF / MET positive modulators, such as compounds of formula (I), can be formulated for oral administration. Compounds are formulated by combining active compounds, for example, with pharma-ceutically acceptable carriers or excipients. In various embodiments, HGF / MET agonists, such as compounds of formula (I), or their pharma-ceutically acceptable salts, isotopic forms, or stereoisomers, are formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0168] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing with one or more HGF / MET positive modulators, such as one or more compounds of formula (I), or one or more of its pharma- ceutically acceptable salts, isotopic forms, or stereoisomers, optionally grinding the mixture obtained, processing the mixture of granules, and obtaining tablets or dragee cores after adding suitable auxiliaries if necessary.Suitable excipients are in particular sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.; or other fillers, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.In a specific embodiment, disintegrants are optionally added. Disintegrants include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0169] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In a specific embodiment, concentrated sugar solutions are used to coat the dosage forms. The sugar solutions optionally contain additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. Furthermore, dyes and / or pigments are optionally used to characterize different combinations of active compound doses.

[0170] In certain embodiments, a therapeutically effective amount of an HGF / MET positive modulator, such as at least one of the compounds of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In a specific embodiment, the push-fit capsules contain the active ingredient mixed with one or more fillers. The fillers include, by way of example only, binders, such as lactose, starch, and / or lubricants, such as talc or magnesium stearate, and optionally, stabilizers. In other embodiments, the soft capsules contain one or more active compounds dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added.

[0171] In other embodiments, a therapeutically effective amount of an HGF / MET positive modulator, such as at least one of the compounds of formula (I) described herein, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, an HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In a specific embodiment, the injectable formulation is provided in a unit dosage form (e.g., ampoules) or in a multi-dose container. Preservatives are optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection, such as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection preparations optionally contain formulations such as suspending agents, stabilizing agents and / or dispersing agents. In a specific embodiment, pharmaceutical preparations for parenteral administration include aqueous solutions of active compounds in water-soluble form. In additional embodiments, suspensions of one or more active compounds (e.g., HGF / MET positive modulators such as compounds of formula (I), or pharma-ceutically acceptable salts, isotopic forms, or stereoisomers thereof) are prepared as suitable oily injection suspensions. Lipophilic solvents or vehicles suitable for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents that increase the solubility of the compounds, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0172] In yet another embodiment, the HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered topically. The compound is formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0173] In yet other embodiments, the HGF / MET positive modulator, such as the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches, which may be lipophilic emulsions or buffered aqueous solutions dissolved and / or dispersed in a polymer or adhesive. In various embodiments, such patches may be configured for continuous pulsed or on-demand delivery of the drug. In additional embodiments, transdermal delivery of the HGF / MET positive modulator, such as the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is accomplished by means of an iontophoretic patch or the like. In certain embodiments, the transdermal patch provides controlled delivery of the HGF / MET positive modulator, such as the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In specific embodiments, the rate of absorption is slowed by using a rate-controlling membrane or by trapping the compound within a polymer matrix or gel. In an alternative embodiment, an absorption enhancer is used to enhance absorption. The absorption enhancer or carrier comprises a pharma- ceutically acceptable absorbent solvent that aids in passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a support member, a reservoir that contains the compound, optionally with a carrier, an optional rate-controlling barrier that delivers the compound to the host's skin at a controlled, predetermined rate over an extended period of time, and a means for fixing the device to the skin.

[0174] In other embodiments, the HGF / MET positive modulator, such as the compound of formula (I), or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosol, mist, or powder. The pharmaceutical composition of the HGF / MET positive modulator, such as the compound of formula (I), or any of its pharma- ceutically acceptable salts, isotopic forms, or stereoisomers, is conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer by using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In a specific embodiment, the dosage unit of the pressurized aerosol is determined by providing a valve that delivers a metered amount. In certain embodiments, by way of example only, gelatin capsules and cartridges for use in an inhaler or insufflator are formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0175] In yet other embodiments, an HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated into a rectal composition, such as an enema, rectal gel, rectal foam, rectal aerosol, suppository, jelly suppository, or retention enema, containing a conventional suppository base, such as cocoa butter or other glycerides, and a synthetic polymer, such as polyvinylpyrrolidone, PEG, or the like. In a suppository form of the composition, a low melting wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

[0176] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compounds into medicament-usable preparations.The appropriate formulation depends on the route of administration selected.Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used suitably.The pharmaceutical compositions containing HGF / MET positive modulators, such as the compound of formula (I), or its pharmaceutically acceptable salts, isotopic forms, or stereoisomers, are prepared in conventional manner, such as, for example, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or compressing processes.

[0177] A pharmaceutical composition comprises at least one pharma- ceutically acceptable carrier, diluent, or excipient, and at least one HGF / MET positive modulator, such as at least one compound of formula (I) described herein, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, as an active ingredient. The active ingredient is in the form of a free acid or free base, or in the form of a pharma- ceutically acceptable salt. In addition, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, the HGF / MET positive modulator, such as the compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, include unsolvated as well as solvated forms with pharma- ceutically acceptable solvents such as water, ethanol, and the like. Solvates of the compounds presented herein are also considered to be disclosed herein. In addition, pharmaceutical compositions optionally contain other medicinal or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizing agents, wetting agents or emulsifying agents, solution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0178] Methods for preparing compositions containing an HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, include formulating the compound with one or more pharma- ceutically acceptable inert excipients or carriers to form a solid, semi-solid, or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing an HGF / MET positive modulator, such as a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0179] In some embodiments, the pharmaceutical composition comprising at least one HGF / MET positive modulator, such as a compound of formula (I), or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is illustratively in the form of a liquid, in which the agent is in solution, in suspension, or both.Typically, when the composition is administered as a solution or suspension, a first portion of the agent is in solution, and a second portion of the agent is in particulate form that is in suspension in a liquid matrix.In some embodiments, the liquid composition comprises a gel formulation.In other embodiments, the liquid composition is aqueous.

[0180] In certain embodiments, useful aqueous suspensions contain one or more polymers, such as suspending agents. Useful polymers include water-soluble polymers, such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers, such as water-crosslinkable carboxyl-containing polymers. Certain pharmaceutical compositions described herein include mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0181] Useful pharmaceutical compositions also optionally include a solubilizer that aids in the dissolution of the HGF / MET positive modulator, such as the compound of formula (I), or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer. The term "solubilizer" generally includes agents that provide a micellar or true solution form of the drug. Certain acceptable non-ionic surfactants, such as polysorbate 80, are useful as solubilizers, as are ophthalmologically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0182] In addition, useful pharmaceutical compositions optionally include one or more pH adjusting or buffering agents, for example, acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and trishydroxymethylaminomethane; and buffers such as citric acid / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition in an acceptable range.

[0183] Additionally, useful compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions, with suitable salts including sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0184] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merphen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0185] Still other useful compositions contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, such as octoxynol 10, octoxynol 40.

[0186] Still other useful compositions optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium disulfite.

[0187] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case it is typical to include a preservative in the composition.

[0188] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, HGF / MET positive modulators, such as the compound of formula (I), or pharma-ceutically acceptable salts, isotopic forms, or stereoisomers thereof, are delivered using sustained release systems, such as semipermeable matrices of hydrophobic solid polymers containing therapeutic agents. A variety of sustained release materials are useful herein. In some embodiments, sustained release capsules release the compound for several weeks up to 100 days or more. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stability are employed.

[0189] In certain embodiments, the formulations described herein include one or more antioxidants, metal chelators, thiol-containing compounds, and / or other general stabilizing agents. Examples of such stabilizers include, but are not limited to, (a) about 0.5% to about 2% w / v glycerol, (b) about 0.1% to about 1% w / v methionine, (c) about 0.1% to about 2% w / v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w / v ascorbic acid, (f) 0.003% to about 0.02% w / v polysorbate 80, (g) 0.001% to about 0.05% w / v polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0190] In some embodiments, the concentration of an HGF / MET positive modulator such as a compound of Formula (I) provided in a pharmaceutical composition of the present disclosure is 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0. 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0191] In some embodiments, the concentration of an HGF / MET positive modulator, such as a compound of Formula (I), provided in a pharmaceutical composition of the present disclosure is 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%. ,16%,15.75%,15.50%,15.25%,15%,14.75%,14.50%,14.25%,14%,13.75%,13.50%,13.25%,13%,12.75%,12.50%,12.25%,12%,11.75%,11.50%,11.25%,11%,10.75%,10.50%,10.25%,10%,9.75%,9.50%,9.25%,9%,8.75%,8.50%,8.25%, ,8%,7.75%,7.50%,7.25%,7%,6.75%,6.50%,6.25%,6%,5.75%,5.50%,5.25%,5%,4.75%,4.50%,4.25%,4%,3.75%,3.50%,3.25%,3%,2.75%,2.50%,2.25%,2%,1.75%,1.50%,125%,1%,0.5%,0.4%,0.3%,0.2%,0.1%,0.09%,0.08%,0.07%, , 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or greater than 0.0001% w / w, w / v, or v / v.

[0192] In some embodiments, the concentration of the HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical composition is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 28%, from about 0.08% to about 29%, from about 0.09% to about 30%, from about 0.10% to about 10%, from about 0.15% to about 15%, from about 0.16% to about 16%, from about 0.17% to about 17%, from about 0.18% to about 18%, from about 0.19% to about 20%, from about 0.20% to about 20%, from about 0.21% to about 20%, from about 0.22% to about 20%, from about 0.23% to about 20%, from about 0.24% to about 20%, from about 0.25% to about 20%, from about 0.26% to about 20%, from about 0.27% to about 20%, from about 0.28% to about 20%, from about 0.29% to about 20%, from about 0.30% to about 30%, from about 0.30% to about 30%, from about 0.31% to about 30%, from about 0.32% to about 30%, from about 0.33% to about 30%, from about 0.34% to about 30%, from about 0.3 5%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10% w / w, w / v, or v / v.

[0193] In some embodiments, the concentration of the HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical composition is in the range of about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, or about 0.1% to about 0.9% w / w, w / v, or v / v.

[0194] In some embodiments, the amount of an HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical composition is 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g.

[0195] In some embodiments, the amount of an HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in a pharmaceutical composition of the present disclosure is 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0009 g, 0.0008 g, 0.0009 g, 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.0001 g, 0.0002 g, 0.0003 g g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.004 5g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095 g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0. 065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35 g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g , 2g, 2.5g, 3g, 3.5g, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or more than 10g.

[0196] In some embodiments, the amount of an HGF / MET positive modulator, such as a compound of Formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in a pharmaceutical composition is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g. EXAMPLES

[0197] The following examples are included to illustrate certain embodiments of the present disclosure. Those skilled in the art should understand that the methods disclosed in the following examples represent methods that work well in implementing the present disclosure, and therefore can be considered to constitute certain modes for its implementation. However, in light of the present disclosure, those skilled in the art should understand that these examples are illustrative and not exhaustive. Many changes can be made in the specific embodiments disclosed and still obtain the same or similar results without departing from the spirit and scope of the present disclosure.

[0198] The chemical reactions of the described synthetic examples can be easily adapted to prepare some other compounds disclosed herein, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure.For example, the synthesis of compounds according to the present disclosure that are not exemplified can be carried out by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than the reagents described, or by routinely modifying reaction conditions, reagents, and starting materials.Alternatively, it will be recognized that other reactions disclosed herein or known in the art can be applied to the preparation of the compounds of the present disclosure.

[0199] Unless otherwise indicated in the examples below, the compounds are isolated as racemic mixtures.

[0200] In this application the following abbreviations may be relevant:

[0201] Abbreviation AcOH: acetic acid CAN: Cerium ammonium nitrate DAST: Diethylaminosulfur trifluoride DCM: dichloromethane DIPEA: N,N-diisopropylethylamine DMEM: Dulbecco's modified Eagle's medium DMF: Dimethylformamide DMSO: Dimethyl sulfoxide EMEM: Eagle's minimum essential medium EtOAc: ethyl acetate EtOH: Ethanol FBS: Fetal bovine serum Fmoc: fluorenylmethoxycarbonyl HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate LC / MS: Liquid chromatography mass spectrometry Me: Methyl MeOH: Methanol PBS: Phosphate-buffered saline Pic-BH3: picoline borane PMB: para-methoxybenzyl ether Prep HPLC: Preparative High Performance Liquid Chromatography rt or RT: room temperature TFA: Trifluoroacetic acid TLC: Thin Layer Chromatography T3P: Propane phosphonic anhydride

[0202] Synthesis Example Example S1. Synthesis of (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this starting compound is shown in Scheme 1. Scheme 1. [ka] Step 1. Synthesis of (9H-fluoren-9-yl)methyl (2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylcarbamate. To a stirred solution of compound (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (5.0 g, 16.07) in dichloromethane (100 mL), T3P (15.2 mL, 24.1) and DIPEA (5.6 mL, 32.1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 15 min, N-(2,2-dimethoxyethyl)-2-methylbutan-1-amine (2.81 g, 32.1 mmol.) was added and stirring was continued at room temperature for 8 h. The reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash column chromatography (100-200 mesh silica gel, eluted with 40% ethyl acetate / petroleum ether) to obtain the pure compound (9H-fluoren-9-yl)methyl (2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylcarbamate (5.2 g, 69.1%) as a gummy compound.

[0203] Step 2. Synthesis of (2S)-2-amino-N-(2,2-dimethoxyethyl)-N-(2-methylbutyl)propenamide. To a stirred solution of (9H-fluoren-9-yl)methyl (2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylcarbamate (34.0 g, 72.6 mmol) in DMF (230 mL) was added 20% piperidine in DMF (70 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion of the reaction, excess DMF (100 mL) was added and then washed with excess n-hexane (3×200 mL). The DMF layer was collected, poured into ice-cold water (1000 mL) and extracted with 10% methanol-dichloromethane (3×500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give (2S)-2-amino-N-(2,2-dimethoxyethyl)-N-(2-methylbutyl)propanamide (20.4 g, 68.4%) as a gummy solid.

[0204] Step 3. Synthesis of (9H-fluoren-9-yl)methyl 3-((2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylamino)-3-oxopropylcarbamate. To a stirred solution of 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (20.2 g, 81.2 mmol) in dichloromethane (500 mL) at room temperature was added T3P (80 mL, 121.8 mmol) and DIPEA (28.6 mL, 160.4 mmol) and the mixture was stirred for 10 min. To this was added (2S)-2-amino-N-(2,2-dimethoxyethyl)-N-(2-methylbutyl)propanamide (25.53 81.2 mmol) and stirring was continued at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (500 mL) and the mixture was extracted with dichloromethane (2 x 500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by flash column chromatography (100-200 mesh silica gel, eluted with 70% ethyl acetate / petroleum ether) to obtain the pure compound (9H-fluoren-9-yl)methyl 3-((2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylamino)-3-oxopropylcarbamate (21.2 g, 78.6%) as a gummy compound.

[0205] Step 4. Synthesis of (6S)-(9H-fluoren-9-yl)methyl 6-methyl-8-(2-methylbutyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate. To a stirred solution of (9H-fluoren-9-yl)methyl 3-((2S)-1-((2,2-dimethoxyethyl)(2-methylbutyl)amino)-1-oxopropan-2-ylamino)-3-oxopropylcarbamate (21.0 g, 38.9 mmol) was added formic acid (105 mL). The reaction mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was taken up in saturated aqueous NaHCO3 (200 mL) and then extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine solution (500 mL), then the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100-200 mesh silica gel, eluted with 50% ethyl acetate / petroleum ether) to obtain the pure compound (6S)-(9H-fluoren-9-yl)methyl 6-methyl-8-(2-methylbutyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate (25 g, 69.0%) as a gum.

[0206] Step 5. Synthesis of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione. To a stirred solution of (6S)-(9H-fluoren-9-yl)methyl 6-methyl-8-(2-methylbutyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate (14.0 g, 29.4 mmol) in DMF (70 mL) at 0° C. was added 20% piperidine in DMF (30 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was monitored by TLC. Upon complete consumption of the starting material, additional DMF was added (50 mL) and the mixture was then washed with excess n-hexane (3×200 mL). The DMF layer was poured into ice-cold water (1000 mL) and extracted with 10% methanol-dichloromethane (3×500 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude desired compound (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (6.25 g, 83.8%) as a solid.

[0207] Example S2. Synthesis of Compound 1a The synthetic route for preparing compound 1a is shown in Scheme 2. Scheme 2. [ka] To a stirred solution of 4-(trifluoromethyl)benzoic acid (0.232 g, 0.91 mmol) in dichloromethane (20 mL) at room temperature, T3P (1.2 mL, 1.37 mmol) and DIPEA (0.42 mL, 1.82 mmol) were added and the mixture was stirred for 15 min. To this was added (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.310 g, 0.91 mmol) and stirring was continued for 8 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC. Pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give 1a (0.340 g, 65.3%) as a solid. Prep HPLC method: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: X-Select Phenylhexyl (150×19 mm 5μ); Flow rate: 16 mL / min. MS(ESI) m / z[M+H] + :426.05.

[0208] Example S3. Synthesis of Compound 2a The synthetic route for preparing compound 2a is shown in Scheme 3. Scheme 3. [ka] To a solution of 4-(difluoromethoxy)benzoic acid (0.37 g, 1.968 mmol) in dichloromethane (15 mL) at room temperature was added DIPEA (0.8 ml, 5.904 mmol) and T3P (2.0 mL, 3.936 mmol). The mixture was stirred for 30 min, then (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.4 g, 1.578 mmol) was added and stirring was continued for 16 h. The progress of the reaction was monitored by TLC and LC / MS. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (50 mL) and saturated sodium chloride solution (50 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Pure fractions were collected and lyophilized to give 2a (380 mg 46%) as a solid. Prep HPLC conditions: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: Chromosyl Phenyl (150×25 mm 10μ); Flow rate: 25 mL / min. MS(ESI) m / z[M+H] + :424.11.

[0209] Example S4. Synthesis of Compound 3a The synthetic route for preparing compound 3a is shown in Scheme 4. Scheme 4. [ka] To a stirred solution of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.500 g, 1.97 mmol) in methanol (20 mL) at room temperature was added 4-hydroxybenzaldehyde (0.289 g, 1.97 mmol) and acetic acid (0.23 mL, 3.95 mmol). The reaction mixture was stirred at room temperature for 5 minutes. To this was added picoline borane (0.253 g, 2.37 mmol) and stirring was continued for 48 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the mixture was extracted with 10% methanol-dichloromethane (3×40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC. Pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give 3a (0.180 g, 46.09%) as a solid. Prep HPLC method: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: chromosyl phenyl (150×25 mm 10μ); Flow rate: 25 mL / min. MS(ESI) m / z[M+H] + :360.11.

[0210] Example S5. Synthesis of Compound 4a. The synthetic route for preparing compound 4a is shown in Scheme 5. Scheme 5. [ka] To a solution of 6-hydroxynicotinic acid (0.340 g 2.446 mmol) in DMF (15 mL) at room temperature was added DIPEA (1.30 mL, 7.338 mmol) and HATU (1.39 g, 3.669 mmol). The resulting reaction mixture was stirred for 30 min, then (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.495 g, 1.956 mmol.) was added and the mixture was stirred for 16 h. The progress of the reaction was monitored by TLC and LC / MS (TLC system: 10% methanol / dichloromethane, Rf: 0.15, detection: UV). The reaction mixture was quenched with cold water (100 mL) and extracted with 10% methanol / dichloromethane (3 x 100 mL). The combined organic layers were washed with cold water (50 mL) and cold brine solution (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC. Pure fractions were collected and lyophilized to give 4a (160 mg, 21.8%) as a solid. Preparative HPLC method: Mobile phase A: 0.01 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: X-Select Phenylhexyl (150×19 mm, 5μ); Flow rate: 15 mL / min. MS(ESI) m / z[M+H] + :375.05.

[0211] Example S6. Synthesis of Compound 5a. The synthetic route for preparing compound 5a is shown in Scheme 6. Scheme 6. [ka] To a stirred solution of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.5 g, 1.97 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.470 g, 1.97 mmol) in DMF (20 mL) at room temperature was added K2CO3 (0.546 g, 3.95 mmol) and the mixture was stirred for 8 h. The reaction progress was monitored by TLC. After completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC. Pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give 5a (0.270 g, 63.8%) as a gum. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: Chromosil C 18 (150×25mm 10μ);Flow rate: 25mL / min. MS(ESI)m / z[M+H] + :412.2.

[0212] Example S7. Synthesis of Compound 6a. The synthetic route for preparing compound 6a is shown in Scheme 7. Scheme 7. [ka] To a stirred solution of (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.500 g, 1.97 mmol) and 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.466 g, 1.97 mmol) in DMF (20 mL) at room temperature was added K2CO3 (0.546 g, 9.95 mmol). The reaction mixture was stirred at room temperature for 18 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC. The pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give 6a (0.178 g, 41.5%) as a semi-solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: X-Select C 18 (250×19mm, 5μ); Flow rate: 18mL / min. MS(ESI)m / z[M+H] + :410.11.

[0213] Example S8. Synthesis of Compound 7a. The synthetic route for preparing compound 7a is shown in Scheme 8. Scheme 8. [ka] To a stirred solution of compound (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.500 g, 1.97 mmol) in methanol (20 mL) at room temperature, 6-hydroxynicotinaldehyde (0.243 g, 1.97 mmol) and acetic acid (0.25 mL, 3.95 mmol) were added and the mixture was stirred for 5 minutes. To this was added picoline borane (0.318 g, 2.96 mmol) and stirring was continued for 96 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and extracted with 10% methanol-dichloromethane (3×40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC. Pure fractions were collected, concentrated under reduced pressure, and then lyophilized to give 7a (0.164 g, 42%) as a solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: X-BRIDGE C 18 (250×19mm, 5μ); Flow rate: 18mL / min. MS(ESI)m / z[M+H] + :361.11.

[0214] Example S9. Synthesis of Compound 8a. The synthetic route for preparing compound 8a is shown in Scheme 9. Scheme 9. [ka] Step 1. Synthesis of (6S)-1-(4-(benzyloxy)benzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a stirred solution of 4-(benzyloxy)benzoic acid (0.360 g, 1.42 mmol) in dichloromethane (20 mL) at room temperature was added T3P (1.2 mL, 1.7 mmol) and DIPEA (0.55 mL, 2.84 mmol) and the mixture was stirred for 15 min. To this was added (6S)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.400 g, 1.42 mmol) and stirring was continued at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (2 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 0.9 g of crude material. Analysis of the crude material by LC / MS showed 54.59% of the desired product. The crude material was used in the next step without purification.

[0215] Step 2. Synthesis of compound 8a. To a stirred solution of (6S)-1-(4-(benzyloxy)benzoyl)-6-methyl-8-(2-methylbutyl)tetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (0.900 g) in methanol (20 mL) at room temperature, 10% Pd-C (0.200 g) was added under N2 atmosphere. The reaction mixture was stirred at room temperature under H2 balloon for 8 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through Celite and evaporated under reduced pressure to obtain the crude compound. The crude compound was dissolved in dichloromethane (50 mL) and washed with aqueous NaHCO3 (20 mL) and brine solution (20 mL). The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was triturated with diethyl ether to give 8a (0.330 g, 82%) as a solid. MS (ESI) m / z [M+H] + :374.11.

[0216] Example S10. Synthesis of Compound 9. The synthetic route for preparing compound 9 is shown in Scheme 10. Scheme 10. [ka] Step 1. Synthesis of (9H-fluoren-9-yl)methyl 2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylcarbamate. To a stirred solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)acetic acid (10 g, 33.6 mmol) in dichloromethane (100 mL) cooled to 0 °C, DIPEA (11.88 mL, 67.3 mmol), N-(2,2-dimethoxyethyl)butan-2-amine (10.84 g, 67.3 mmol) and T3P (53.0 mL, 84.1 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, ice-cold water (100 mL) was added and extracted with ethyl acetate (2 x 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired crude product. The crude compound was purified by flash column chromatography (100-200 mesh silica gel) and eluted with 20-25% ethyl acetate / petroleum ether to give (9H-fluoren-9-yl)methyl 2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylcarbamate (10.8 g, 72.9%) as a solid.

[0217] Step 2. Synthesis of 2-amino-N-sec-butyl-N-(2,2-dimethoxyethyl)acetamide. To a solution of (9H-fluoren-9-yl)methyl 2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylcarbamate (10.8 g, 24.5 mmol) in DMF (20 mL) cooled to 0° C., piperidine (2.4 mL) was added and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. When TLC showed complete consumption of the starting material, the reaction mixture was diluted with petroleum ether (2×100 mL), then water was added and the mixture was separated. The aqueous layer was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the desired pure product 2-amino-N-sec-butyl-N-(2,2-dimethoxyethyl)acetamide (3.6 g, 67.2%) as a solid.

[0218] Step 3. Synthesis of (9H-fluoren-9-yl)methyl-3-(2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylamino)-3-oxopropylcarbamate. To a stirred solution of 2-amino-N-sec-butyl-N-(2,2-dimethoxyethyl)acetamide (3.6 g, 16.5 mmol) in dichloromethane (40 mL) was added DIPEA (31.91 mL, 49.5 mmol), 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)propanoic acid (5.14 g, 16.5 mmol) and T3P (39.13 g, 33 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction water (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography using silica (230-400 mesh; 23-25% ethyl acetate / petroleum ether as eluent). The collected pure fractions were concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl-3-(2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylamino)-3-oxopropylcarbamate (4.1 g, 48.6%) as a gum.

[0219] Step 4. Synthesis of (9H-fluoren-9-yl)methyl 8-sec-butyl-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate. A solution of (9H-fluoren-9-yl)methyl-3-(2-(sec-butyl(2,2-dimethoxyethyl)amino)-2-oxoethylamino)-3-oxopropylcarbamate (4.1 g, 8.01 mmol) in acetic acid (2 mL) was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. Once TLC showed complete consumption of starting material, the reaction mixture was concentrated and the resulting mass was diluted with water and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (9H-fluoren-9-yl)methyl 8-sec-butyl-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate (3.2 g, 89.3%) as a gum.

[0220] Step 5. Synthesis of 8-sec-butyltetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione. To a solution of (9H-fluoren-9-yl)methyl 8-sec-butyl-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxylate (3.2 g, 7.1 mmol) in DMF (20 mL) cooled to 0 °C, piperidine (0.7 mL, 1.0 equiv.) was added and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. When TLC showed complete consumption of starting material, the reaction mixture was washed with petroleum ether (2 x 50 mL) to remove non-polar impurities. Cold water was added and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the pure product 8-sec-butyltetrahydro-1H-pyrazino[1,2-a]pyrimidine-4,7(6H,8H)-dione (900 mg, 55.9%) as a solid.

[0221] Step 6. Synthesis of compound 9. To a stirred solution of (8-(sec-butyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.500 g, 2.2 mmol) and 4-hydroxybenzaldehyde (0.271 g, 2.2 mmol) in methanol (10 mL) was added acetic acid (0.27 mL, 2.0 equiv.) and picoline borane (0.285 g, 2.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 48 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude The compound was analyzed by LC / MS. Crude LC / MS data showed 8.28% of the desired mass. The crude compound was purified by column chromatography on silica gel (100-200) and the desired compound was eluted with 50-70% ethyl acetate / petroleum ether. LC / MS of the eluted fraction showed 72.16% of the desired mass, which was further purified by preparative HPLC. After preparative HPLC purification, the fractions were collected, concentrated under reduced pressure, and then lyophilized to give 9 (0.168 g, 22.8%) as a solid. Preparative HPLC Method: Mobile Phase A: 10 mM ammonium bicarbonate in water; Mobile Phase B: acetonitrile; Column: X-BRIDGE C 18 (150×19mm 5μ);Flow rate: 18mL / min. MS(ESI)m / z[M+H] + :332.2.

[0222] Example S11. Synthesis of Compound 10. The synthetic route for preparing compound 10 is shown in Scheme 11. Scheme 11. [ka] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 0.98 mmol) and 4-chlorobenzoic acid (170 mg, 1.09 mmol) in DMF (4 mL) at 0° C., HATU (413 mg, 1.08 mmol) was added followed by DIPEA (0.35 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with cold H2O (30 mL) followed by saturated brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / hexanes) to give 1-(4-chlorobenzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione 10 (150 mg, 0.383 mmol, 39.2% yield) as a solid. MS (ESI) m / z [M+H] + :392.05. 1 H NMR(400 MHz, DMSO-d6) δ 0.66 - 0.89 (m,6 H)0.91 -1.42 (m,4 H)1.57 -1.78 (m,1 H)2.16 -2.35 (m,2 H)2.55-2.65 (m,2 H)3.08-3.23 (m,2 H)3.28-3.40 (m,1 H)3.51-3.64 (m,2 H)4.76-4.89 (m,1 H)5.88-6.02 (m,1 H)7.46-7.56 (m,4 H).

[0223] Example S12. Synthesis of Compound 11. The synthetic route for preparing compound 11 is shown in Scheme 12. Scheme 12. [ka] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 0.98 mmol) and 4-fluorobenzoic acid (153 mg, 1.09 mmol) in DMF (4 mL) at 0° C., HATU (413 mg, 1.08 mmol) was added followed by DIPEA (0.35 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with cold H2O (30 mL) followed by saturated brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / hexanes) to give 1-(4-fluorobenzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione 11 (140 mg, 0.37 mmol, 38.0% yield) as a solid. MS (ESI) m / z [M+H] + :376.05. 1 H NMR (400 MHz, DMSO-d6) δ0.69 -0.81 (m,3 H)0.86 (t,J=7.23 Hz,3 H)0.95 -1.14 (m,2 H)1.20 -1.43 (m,4 H)1.59 -1.80 (m,2 H)2.26 (d,J=16.95 Hz,1 H)2.55 -2.72 (m,1 H)3.20 -3.31 (m,2 H)3.35 -3.39 (m,1 H)3.52 -3.70 (m,2 H)4.73 -4.89 (m,1 H)7.33 (t,J=8.73 Hz,2 H)7.61 (dd, J=8.23, 5.73 Hz,2H).

[0224] Example S13. Synthesis of Compound 12. The synthetic route for preparing compound 12 is shown in Scheme 13. Scheme 13. [ka] To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 0.98 mmol) and 3-chloro-4-(trifluoromethyl)benzoic acid (242 mg, 1.09 mmol) in DMF (4 mL) at 0° C., HATU (413 mg, 1.08 mmol) was added followed by DIPEA (0.35 mL, 1.97 mmol). The reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with cold H2O (30 mL) followed by saturated brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / hexanes) to give 1-(3-chloro-4-(trifluoromethyl)benzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione 12 (250 mg, 0.55 mmol, 55.2% yield) as a solid. MS (ESI) m / z [M+H] + :460.0. 1 H NMR (400 MHz, DMSO-d6) δ0.74 -0.93 (m,6 H)0.98 -1.19 (m,2 H)1.28 -1.46 (m,3 H)1.64 -1.81 (m,1 H)2.22 (d,J=17.45 Hz,1 H)2.57 -2.70 (m,1 H)3.14 (dd, J=13.21, 6.23 Hz,1 H)3.25 -3.31 (m,2 H)3.44 -3.57 (m,1 H)3.61 -3.87 (m,2 H)4.78 -4.90 (m,1 H)5.89 -6.05 (m,1 H)7.72 (d,J=7.98 Hz,1H)7.90 -8.02 (m,2 H).

[0225] Example S14. Synthesis of intermediate compound 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this intermediate compound is shown in Scheme 14. Scheme 14. [ka] Step 1. Synthesis of 2,2-diethoxy-N-(4-methoxybenzyl)ethan-1-amine. A 500 mL round bottom flask was charged with anisaldehyde (12 mL, 90.22 mmol) and 2,2-diethoxyethanamine (10 g, 75.18 mmol). The reaction mixture was heated at 100° C. for 1 h. The reaction mixture was allowed to cool at room temperature and EtOH (100 mL) was added followed by NaBH4 (4.28 g, 112.7 mmol). The resulting reaction mixture was stirred at room temperature for 16 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced vacuum. The resulting crude was dissolved in EtOAc (300 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to give the crude product. The resulting crude product was purified by column chromatography (silica 100-200 mesh; 70% EtOAc / hexanes) to give 2,2-diethoxy-N-(4-methoxybenzyl)ethan-1-amine (15 g, 59.28 mmol, 78% yield) as a liquid. MS (ESI) m / z [M+H] + :254.3.

[0226] Step 2. (9H-Fluoren-9-yl)methyl = (1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate. To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)alanine (32 g, 102.76 mmol) in anhydrous DMF (140 mL) maintained at 0 °C was added HATU (42 g, 110.67 mmol), DIPEA (21.06 mL, 118.57 mmol) followed by 2,2-diethoxy-N-(4-methoxybenzyl)ethan-1-amine (20 g, 79.05 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon complete consumption of the starting material, the reaction mixture was quenched with ice-cold water (300 mL) and the aqueous layer was extracted with EtOAc (200 mL x 2). The organic layer was washed with cold HO (200 mL), followed by brine (100 mL), dried over NaSO and concentrated under reduced pressure to give the crude product. The resulting crude was purified by column chromatography (silica 100-200 mesh; 50% EtOAc / hexanes) to give (9H-fluoren-9-yl)methyl(1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate (28 g, 51.22 mmol, 64.8% yield) as a gummy liquid. MS (ESI) m / z [M+H-EtOH] + :501.2.

[0227] Step 3. Synthesis of 2-amino-N-(2,2-diethoxyethyl)-N-(4-methoxybenzyl)propanamide. To a solution of (9H-fluoren-9-yl)methyl(1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)carbamate (28 g, 51.22 mmol) in CHCl (30 mL) was added diethylamine (200 mL). The reaction mixture was stirred at room temperature for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the resulting crude was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 2-amino-N-(2,2-diethoxyethyl)-N-(4-methoxybenzyl)propanamide (14.5 g, 44.75 mmol, 87% yield) as a viscous liquid. MS(ESI)m / z[M+H-EtOH] + :279.05.

[0228] Step 4. Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (14.78 g, 47.53 mmol) in anhydrous DMF (120 mL) maintained at 0 °C was added HATU (18.06 g, 47.53 mmol), DIPEA (9.21 mL, 51.85 mmol) followed by 2-amino-N-(2,2-diethoxyethyl)-N-(4-methoxybenzyl)propanamide (14 g, 43.20 mmol). The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL x 2). The organic layer was washed with cold H2O (500 mL) followed by saturated brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / Hexanes) to give (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (18 g, 29.14 mmol, 67.44% yield) as a viscous liquid. MS (ESI) m / z [M+H-EtOH] + :572.

[0229] Step 5. Synthesis of (9H-fluoren-9-yl)methyl 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. A solution of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(4-methoxybenzyl)amino)-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (18 g, 29.14 mmol) in formic acid (120 mL) was stirred at room temperature for 12 h. Upon completion, the reaction mixture was concentrated and the resulting crude material was purified by column chromatography (silica 100-200 mesh, 30% EtOAc in hexanes) to give (9H-fluoren-9-yl)methyl 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (14.5 g, 27.58 mmol, 94% yield) as a solid. MS (ESI) m / z [M+H] + :526.

[0230] Step 6. Synthesis of 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of (9H-fluoren-9-yl)methyl 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (14 g, 26.63 mmol) in CHCl (150 mL), diethylamine (100 mL) was added and the reaction mixture was stirred at room temperature for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the resulting crude was purified by column chromatography (silica 100-200 mesh, 5% MeOH / DCM) to give 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (7 g, 23.07 mmol, 87% yield) as a sticky solid. MS (ESI) m / z [M+H] + :304.

[0231] Example S15. Synthesis of intermediate compound 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this intermediate compound is shown in Scheme 15. Scheme 15. [ka] Step 1. Synthesis of 8-(4-methoxybenzyl)-6-methyl-1-(4-trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 4-(trifluoromethyl)benzoic acid (5.26 g, 27.69 mmol) in DMF (100 mL) maintained at 0 °C, HATU (10.52 g, 27.69 mmol), DIPEA (12.30 mL, 69.23 mmol) followed by 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (7 g, 23.07 mmol) were added and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL x 2). The organic layer was washed with cold HO (200 mL) followed by saturated brine (150 mL), dried over NaSO and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / hexane) to give 8-(4-methoxybenzyl)-6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (9 g, 18.92 mmol, 82.04% yield) as a solid. MS (ESI) m / z [M+H] + : 476.15 and MS (ESI) m / z [M + Na] + :498.05.

[0232] Step 2. Synthesis of 6-methyl-1-(4-trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 8-(4-methoxybenzyl)-6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (9 g, 18.92 mmol) in CH3CN:H2O (2:1, 150 mL) maintained at 0 °C, CAN (31.15 g, 56.82 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with HO (200 mL), followed by saturated brine solution (150 mL), dried over NaSO, and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 10% MeOH / DCM) to give 6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.5 g, 9.85 mmol, 52.8% yield) as a solid. MS (ESI) m / z [M+H+CHCN] + :397.0. 1 H NMR (400 MHz, DMSO-d6) δ1.25 -1.46 (m,3 H)2.15-2.30 (m,1 H)2.56 -2.69 (m,1 H)3.16 (d,J=4.99 Hz,1 H)3.22-3.30 (m,1 H)3.42 -3.72 (m,2 H)4.70 -4.87 (m,1 H)5.85-5.95 (m,1 H)7.75 (d,J=7.98 Hz,2 H)7.86 (d,J=7.98 Hz,2 H)8.11 (brs, 1 H).

[0233] Example S16. General Procedure A for the synthesis of final compounds. To a solution of 6-methyl-1-(4-(trifluoromethyl)benzoyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (200 mg, 0.56 mmol) in DMF (2 mL), KO t Bu (1M in THF, 1.69 mmol, 1.69 mL) was added followed by alkyl halide (1.12 mmol) and the reaction mixture was exposed to microwave irradiation at 120° C. for 1 h. The reaction mixture was cooled to room temperature and quenched with H2O (25 mL). The aqueous layer was extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine and concentrated. The crude product was purified by CombiFlash.

[0234] Example S17. Synthesis of compound 15. Compound 15 was synthesized by general procedure A using (bromomethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :438.65. 1 H NMR (400 MHz, DMSO-d6) δ1.02 -1.26 (m,3 H)1.28 -1.42 (m,2 H)1.44 -1.76 (m,6 H)1.80 -2.08 -2.33 (m,2 H)2.55 -2.71 (m,1 H)3.22 (dd, J=12.96, 7.48 Hz,1 H)3.26 -3.32 (m,1 H)3.39 (d,J=6.98 Hz,1 H)3.49-3.57 (m,1 H)3.59-3.74 (m,1 H)3.76-3.91 (m,1 H)4.80-4.90 (m,1 H)5.95-6.05 (m,1 H)7.72 -7.79 (m,2 H)7.84 -7.91 (m,2 H).

[0235] Example S18. Synthesis of compound 16. Compound 16 was synthesized by general procedure A using bromomethylcyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :424.15. 1H NMR (400 MHz, DMSO-d6) δ1.29 -1.44 (m,2 H)1.58 -1.89 (m,4 H)1.90 -2.08 (m,2 H)2.16-2.31 (m,1 H)2.55 -2.70 (m,2 H)3.18 -3.31 (m,1 H)3.25 -3.26 (m,1 H)3.34 -3.42 (m,1 H)3.36 -3.57 (m,2 H)3.60-3.69 (n,1 H)3.71-3.83 (m,1 H)4.75-4.89 (m,1 H)5.90-6.05 (m,1 H)7.70 -7.79 (m,2 H)7.87 (d,J=8.31 ​​Hz,2 H).

[0236] Example S19. Synthesis of compound 19. Compound 19 was synthesized by general procedure A using (2-bromoethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :452.35. 1 H NMR (400 MHz, DMSO-d6) δ0.94 -1.18 (m,3 H)1.26 -1.61 (m,9 H)1.66-1.83 (m,2 H)2.16-2.31 (m,1 H)2.56 -2.70 (m,1 H)3.16 -3.28 (m,1 H)3.35 -3.56 (m,3 H)3.60-3.73 (m,1 H)3.77-3.90 (m,1 H)4.72 -4.92 (m,1 H)5.94-6.06 (m,1 H)7.77 (d,J=7.98 Hz,2 H)7.87 (d,J=7.98 Hz,2 H).

[0237] Example S20. Synthesis of compound 20. Compound 20 was synthesized by general procedure A using (2-bromoethyl)cyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :438.25. 1H NMR (400 MHz, DMSO-d6) δ1.27 -1.44 (m,3 H)1.50-1.71 (m,4 H)1.71-1.88 (m,2 H)1.93 -2.09 (m,2 H)2.13 -2.34 (m,2 H)2.56 -2.70 (m,2 H)3.25 -3.32 (m,1 H)3.35 -3.42 (m,1 H)3.45-3.55 (m,1 H)3.59 -3.72 (m,1 H)3.74-3.90 (m,1 H)4.75-4.89 (m,1 H)5.94-6.05 (m,1 H)7.71 -7.79 (m,2 H)7.87 (d,J=8.31 ​​Hz,2 H).

[0238] Example S21. Synthesis of compound 21. Compound 21 was synthesized by general procedure A using 1-bromobutane as the alkyl halide. MS (ESI) m / z [M+H] + :412.20. 1 H NMR (400 MHz, DMSO-d6) δ0.81-0.97 (m,3 H)1.15 -1.57 (m,7 H)2.15-2.31 (m,1 H)2.57 -2.69 (m,1 H)3.14 -3.28 (m,1 H)3.35 -3.60 (m,3 H)3.62-3.73 (m,1 H)3.74 -3.92 (m,1 H)4.75 -4.91 (m,1 H)5.94-6.06 (m,1 H)7.76 (d,J=7.34 Hz,2 H)7.87 (d,J=7.83 Hz,2 H).

[0239] Example S22. Synthesis of compound 22. Compound 22 was synthesized by general procedure A using 4-bromobut-1-ene as the alkyl halide. MS (ESI) m / z [M+H] + :410.20. 1H NMR (400 MHz, DMSO-d6) δ1.28-1.45 (m,3 H)2.14-2.38 (m,3 H)2.55 -2.69 (m,1 H)3.36 -3.57 (m,4 H)3.58-3.72 (m,1 H)3.75-3.89 (m,1 H)4.75 -4.90 (m,1 H)4.98 -5.19 (m,2 H)5.69-5.84 (m,1 H)5.93-6.05 (m,1 H)7.76 (d,J=7.98 Hz,2 H)7.88 (d,J=7.98 Hz,2 H).

[0240] Example S23. Synthesis of compound 23. Compound 23 was synthesized by general procedure A using 1-bromo-2-methylpropane as the alkyl halide. MS (ESI) m / z [M+H] + :412.25. 1 H NMR (400 MHz, DMSO-d6) δ0.80-0.96 (m,6 H)1.30 -1.48 (m,3 H)1.85-2.03 (m,1 H)2.15-2.31 (m,1 H)2.57 -2.70 (m,1 H)3.06-3.16 (m,1 H)3.18-3.28 (m,1 H)3.36-3.45 (m,1 H)3.44 -3.57 (m,1 H)3.60-3.74 (m,1 H)3.73 -3.87 (m,1 H)4.77-4.92 (m,1 H)5.93-6.07 (m,1 H)7.76 (d,J=7.48 Hz,2 H)7.87 (d,J=7.48 Hz,2 H).

[0241] Example S24. Synthesis of compound 24. Compound 24 was synthesized by general procedure A using 2-bromopropane as the alkyl halide. MS (ESI) m / z [M+H] + :398.55. 1H NMR (400 MHz, DMSO-d6) δ1.10 (d,J=5.49 Hz,6 H)1.28-1.45 (m,3 H)2.16-2.24 (m,1 H)2.56 -2.71 (m,1 H)3.34-3.40 (m,1 H)3.44 -3.79 (m,3 H)4.59-4.72 (m,1 H)4.75-4.90 (m,1 H)5.86-6.00 (m,1 H)7.79 (d,J=7.98 Hz,2 H)7.83 -7.92 (m,2 H).

[0242] Example S25. Synthesis of intermediate compound 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. The synthetic route for preparing this intermediate compound is shown in Scheme 16. Scheme 16. [ka] Step 1. Synthesis of 1-(4-(difluoromethoxy)benzoyl)-8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 4-(difluoromethoxy)benzoic acid (1.71 g, 9.08 mmol) in DMF (25 mL) maintained at 0 °C, HATU (3.45 g, 9.08 mmol), DIPEA (4.34 mL, 24.8 mmol) followed by 8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (2.5 g, 8.25 mmol) were added and the reaction mixture was stirred at room temperature for 12 h. After completion, the reaction mixture was quenched with ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (100 mL x 2). The organic layer was washed with cold HO (100 mL), followed by saturated brine (100 mL), dried over NaSO and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / hexanes) to give 1-(4-(difluoromethoxy)benzoyl)-8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.5 g, 7.38 mmol, 89.5% yield) as a solid. MS (ESI) m / z [M+H] + :474.12.

[0243] Step 2. Synthesis of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 1-(4-(difluoromethoxy)benzoyl)-8-(4-methoxybenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.0 g, 6.34 mmol) in CH3CN:H2O (2:1, 45 mL) maintained at 0 °C, CAN (12.0 g, 21.90 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (100 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with HO (250 mL), followed by saturated brine solution (250 mL), dried over NaSO, and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 10% MeOH / DCM) to give 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (2.0 g, 5.66 mmol, 89.6% yield) as a solid. MS (ESI) m / z [M+H] + :353.95. 1 H NMR (400 MHz, DMSO-d6) δ1.10 -1.39 (m,3 H)2.17-2.18 (m,1 H)2.52 -2.68 (m,1 H)3.18 -3.27 (m,2 H)3.44 -3.71 (m,2 H)4.69 -4.83 (m,1 H)5.75 -5.92 (m,1 H)7.24 (d,J=7.83 Hz,2 H)7.32 (t,J=72.0 Hz,1 H)7.57 (d,J=8.31 ​​Hz,2 H)8.04 (brs, 1 H).

[0244] Example S26. General procedure B for the synthesis of final compounds. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (200 mg, 0.56 mmol) in DMF (4 mL) maintained at 0° C., NaH (122 mg, 2.8 mmol, 55% mineral oil dispersion) was added and the reaction mixture was stirred at the same temperature for 15 min. To this reaction mixture, alkyl halide (1.6 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 3 h. After completion, the reaction mixture was quenched with ice-cold H2O (15 mL) and the aqueous layer was extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine and concentrated. The crude product was purified by CombiFlash.

[0245] Example S27. Synthesis of compound 13. Compound 13 was synthesized by general procedure B using (bromomethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :436.05. 1 H NMR (400 MHz, DMSO-d6) δ1.07-1.16 (m,3 H)1.32 (d,J=6.48 Hz,3 H)1.41 -1.73 (m,7 H)2.06 -2.21 (m,1 H)2.21 -2.34 (m,1 H)2.54 -2.70 (m,1 H)3.14 -3.29 (m,1 H)3.35 -3.45 (m,1 H)3.52 -3.69 (m,1 H)3.75 -3.93 (m,1 H)4.75 -4.91 (m,1 H)5.88-5.99 (m,1 H)7.27 (d,J=8.48 Hz,2 H)7.35 (t,J=72.0 Hz,1H)7.61 (d, J = 8.98 Hz, 2 H).

[0246] Example S28. Synthesis of compound 14. Compound 14 was synthesized by general procedure B using (bromomethyl)cyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :421.14. 1H NMR (400 MHz, DMSO-d6) δ1.16-1.25 (m,1 H)1.27-1.43 (m,3 H)1.54 -1.73 (m,2 H)1.73 -1.86 (m,2 H)1.89-2.03 (m,2 H)2.24 (d,J=17.12 Hz,1 H)2.53 -2.69 (m,2 H)3.20-3.28 (m,1 H)3.29-3.40 (m,1 H)3.40 -3.66 (m,2 H)3.69 -3.87 (m,1 H)4.75-4.86 (m,1 H)5.74 -6.02 (m,1 H)7.26 (d,J=8.31Hz,2H)) 7.33 (t, J=72.0 Hz,1 H)7.59 (d, J=8.31 ​​Hz,2 H).

[0247] Example S29. Synthesis of compound 17. Compound 20 was synthesized by general procedure B using 1-bromobutane as the alkyl halide. MS (ESI) m / z [M+H] + :410.0. 1 H NMR (400 MHz, DMSO-d6) δ0.81 -0.96 (m,3 H)1.15 -1.39 (m,4 H)1.40-1.55 (m,2 H)2.26 (d,J=16.95 Hz,1 H)2.53 -2.70 (m,2 H)3.12 -3.30 (m,2 H)3.38 -3.46 (m,1 H)3.56-3.74 (m,2 H)3.75-3.92 (m,1 H)4.84 (q,J=6.81 Hz,1 H)5.86-6.06 (m,1 H)7.28 (d,J=7.98 Hz,2 H)7.36 (t,J=72.0 Hz,1 H)7.62 (d,J=8.48 Hz,2 H).

[0248] Example S30. Synthesis of compound 18. Compound 18 was synthesized by general procedure B using 4-bromobut-1-ene as the alkyl halide. MS (ESI) m / z [M+H] + :408.06. 1H NMR (400 MHz, DMSO-d6) δ1.16 -1.45 (m,3 H)2.18 -2.33 (m,3 H)2.53 -2.70 (m,1 H)3.36 -3.46 (m,3 H)3.51 -3.72 (m,2 H)3.74-3.90 (m,1 H)4.84 (q,J=6.65 Hz,1 H)4.91-5.15 (m,2 H)5.67-5.84 (m,1 H)5.86 -6.03 (m,1 H)7.29 (d,J=8.48 Hz,2 H)7.36 (t,J=72.0 Hz,1 H)7.61 (d,J=8.48 Hz,2 H).

[0249] Example S31. Synthesis of compound 27. Compound 27 was synthesized by general procedure B using 2-(bromomethyl)tetrahydrofuran as the alkyl halide. MS (ESI) m / z [M+H] + :438.1. 1 H NMR (400 MHz, CDCl3) δ7.48 -7.55 (m,2 H),7.20 -7.30 (m,2 H),6.40 -6.76 (m,1 H),5.90 -6.20 (m,1 H),5.16 -5.26 (m,1 H),4.06 -4.17 (m,2H), 3.82 - 3.92 (m,4 H),3.61 -3.77 (m,2 H),2.83 -2.99 (m,1 H),2.47 -2.59 (m,2 H),2.01 -2.12 (m,4 H),1.49 (s,3 H).

[0250] Example S32. Synthesis of compound 28. Compound 28 was synthesized by general procedure B using (2-bromoethyl)benzene as the alkyl halide. MS (ESI) m / z [M+H] + :458.10. 1H NMR (400 MHz, CDCl3) δ7.40-7.50 (m,2 H),7.20 -7.28 (m,2 H),7.33 -7.43 (m,5 H),6.40 -6.76 (m,1 H),5.90 -6.20 (m,1 H),5.16 -5.26 (m,1 H),3.72 -3.96 (m,2H), 3.44 - 3.52 (m,1 H),3.25 -3.35 (m,2 H),2.83 -2.99 (m,2 H),2.47 -2.59 (m,1 H),2.42 -2.60 (m,1 H),2.30 -2.57 (m,1H), 1.49 (s, 3 H).

[0251] Example S33. Synthesis of compound 29. Compound 29 was synthesized by general procedure B using 4-(2-bromoethyl)pyridine as the alkyl halide. MS (ESI) m / z [M+H] + :459.10. 1 H NMR (400 MHz, CDCl3) δ8.50 -8.58 (m,2 H),7.24 -7.46 (m,4 H),7.18 (d,J =7.99Hz, 2H), 6.40 - 6.76 (m,1 H),5.90 -6.20 (m,1 H),5.16 -5.26 (m,1 H),3.72 -3.96 (m,2H), 3.44 - 3.52 (m,1 H),3.25 -3.35 (m,2 H),2.83 -2.99 (m,2 H),2.47 -2.59 (m,1 H),2.42 -2.60 (m,1 H),2.30 -2.57 (m,1H), 1.49 (s, 3 H).

[0252] Example S34. Synthesis of compound 30. Compound 30 was synthesized by general procedure B using (3-bromopropyl)cyclopropane as the alkyl halide. MS (ESI) m / z [M+H] + :459.10. 1H NMR (400 MHz, CDCl3) δ8.50 -8.58 (m,2 H),7.24 -7.46 (m,4 H),7.18 (d,J =7.99Hz, 2H), 6.40 - 6.76 (m,1 H),5.90 -6.20 (m,1 H),5.16 -5.26 (m,1 H),3.72 -3.96 (m,2H), 3.44 - 3.52 (m,1 H),3.25 -3.35 (m,2 H),2.83 -2.99 (m,2 H),2.47 -2.59 (m,1 H),2.42 -2.60 (m,1 H),2.30 -2.57 (m,1H), 1.49 (s, 3 H).

[0253] Example S35. Synthesis of compound 31. Compound 31 was synthesized by general procedure B using (2-bromoethyl)cyclopropane as the alkyl halide. MS (ESI) m / z [M+H] + :422.2. 1 H NMR (400 MHz, CDCl3) δ7.48 (d,J =8.01 Hz,2H), 7.20 - 7.28 (m,2 H),6.40 -6.76 (m,1 H),5.90 -6.20 (m,1 H),5.16 -5.26 (m,1 H),3.72 -3.96 (m,1H), 3.46 - 3.64 (m,5 H),2.46 -2.64 (m,2 H),1.43 -1.56 (m,5 H),0.43-0.65 (m,2H), 0.75-0.85 (m, 2 H).

[0254] Example S36. Synthesis of compound 32. Compound 32 was synthesized by general procedure B using 1-bromo-2-methoxyethane as the alkyl halide. MS (ESI) m / z [M+H] + :412.1. 1H NMR (400 MHz, DMSO-d6) δ7.52-7.62 (m,2 H),7.16 -7.34 (m,3 H),5.85 -5.95 (m,1 H),4.80 -4.90 (m,1 H),3.85 -3.95 (m,1 H),3.70 -3.80 (m,2 H),3.25 -3.46 (m,5H), 3.22 (s, 3 H),2.62 -2.72 (m,1 H),2.20 -2.30 (m,1 H),1.49 (s,3 H).

[0255] Example S37. Synthesis of compound 33. Compound 33 was synthesized by general procedure B using 1-bromo-3-methoxypropane as the alkyl halide. MS (ESI) m / z [M+H] + :426.20. 1 H NMR (400 MHz, DMSO-d6) δ7.52-7.62 (m,2 H),7.16 -7.34 (m,3 H),5.85 -5.95 (m,1 H),4.80 -4.90 (m,1 H),3.85 -3.95 (m,1 H),3.70 -3.80 (m,2 H),3.58 -3.68 (m,2H), 3.45 - 3.55 (m,4H), 3.22 (s, 3 H),2.62 -2.72 (m,1 H),2.20 -2.30 (m,2 H),1.49 (s,3 H).

[0256] Example S38. Synthesis of compound 36. Compound 36 was synthesized by general procedure B using (2-bromoethyl)methylsulfone as the alkyl halide. MS (ESI) m / z [M+H] + :459.95. 1H NMR (400 MHz, CHLOROFORM) δ7.49 (d,J =8.01 Hz,2 H),7.15 -7.26 (m,2 H),6.40 -6.76 (m,1 H),5.90 -6.20 (m,1 H),5.15 -5.25 (m,1 H),3.86 -3.97 (m,3 H),3.66 -3.77 (m,2 H),3.38 -3.49 (m,3 H),2.97 (s,3 H),2.59 -2.69 (m,2 H),1.49 (s,3 H).

[0257] Example S39. Synthesis of compound 34. Step 1. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.300 g, 0.849 mmol) in DMF (6 mL) was added Cs2CO3 (0.827 g, 2.547 mmol) followed by (2-bromoethoxy)(tert-butyl)dimethylsilane (0.243 g, 1.018 mmol) at 0 °C and the reaction mixture was heated at 120 °C for 1 h in a sealed tube. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (30 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with ice-cold brine solution (3×30 mL), dried over Na2SO4, and concentrated under reduced pressure to give 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.250 g, crude). The crude compound was used directly in the next reaction without further purification. MS (ESI) m / z [M+H] + :512.10.

[0258] Step 2. To a solution of 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.250 g, 0.4886 mmol) in THF (5 mL) was added TBAF (3 mL) at a temperature of 0° C. The reaction mixture was allowed to reach room temperature and stirred for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched slowly with ice-cold water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with ice-cold brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound obtained was purified by column chromatography (silica gel 60-120 mesh; 10% MeOH / DCM) to give 1-(4-(difluoromethoxy)benzoyl)-8-(2-hydroxyethyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.102 g, 52% yield) as a white solid. MS (ESI) m / z [M+H] + :398.2. 1 H NMR (400 MHz, DMSO-d6) δ7.52-7.62 (m,2 H),7.16 -7.34 (m,3 H),5.92 -6.02 (m,1 H),6.78 -6.88 (m,2 H),3.86 -3.92 (m,1 H),3.47 -3.62 (m,6 H),3.21 -3.31 (m,1H), 2.57 - 2.67 (m,1 H),2.25 -3.35 (m,1 H),1.49 (s,3 H).

[0259] Example S40. Synthesis of compound 35. Step 1. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.300 g, 0.849 mmol) in DMF (6 mL) was added NaH (0.050 g, 1.274 mmol) followed by 2-bromoacetonitrile (0.112 g, 0.933 mmol) at 0° C. and the reaction mixture was allowed to stand at room temperature for 1 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (70 mL) and extracted with EtOAc (100 mL). The combined organic layers were washed with ice-cold brine solution (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by column chromatography (silica gel 60-120 mesh; 10% MeOH / DCM) to give 2-(1-(4-(difluoromethoxy)benzoyl)-6-methyl-4,7-dioxooctahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)acetonitrile (0.120 g, 36% yield) as a white solid. MS(ESI) m / z[M+H] + :393.05.

[0260] Step 2. To a solution of 2-(1-(4-(difluoromethoxy)benzoyl)-6-methyl-4,7-dioxooctahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)acetonitrile (0.120 g, 0.305 mmol) in ethanol (5 mL), concentrated HCl (0.100 mL) was added followed by platinum oxide (0.012 g, 0.030 mmol) at room temperature and the reaction mixture was heated under hydrogen gas atmosphere for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a Celite pad. The Celite pad was washed with ethanol (20 mL) and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with n-pentane to give 8-(2-aminoethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.110 g, 90% yield) as a white solid. MS (ESI) m / z [M+H] +:397.05. 1 H NMR (400 MHz, DMSO d6) δ7.96 (s,2 H),7.55 -7.65 (m,2 H),7.20 -7.35 (m,3 H),5.90 -6.20 (m,1 H),4.85 -4.95 (m,1 H),3.82 -3.92 (m,1H), 3.55. - 3.85 (m,2 H),3.35 -3.45 (m,3 H),2.95 -3.05 (m,2 H),2.60 -2.70 (m,1H), 2.20 - 2.30 (m,1 H),1.35 (s,3 H).

[0261] Example S41. General procedure C for the synthesis of final compounds. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.200 g, 0.566 mmol) in DMF (5 mL) was added Cs2CO3 (0.735 g, 2.264 mmol, 4 equiv.) followed by alkyl halide (0.679 mmol, 1.2 equiv.) at 0° C. and the reaction mixture was heated at 50° C. for 1 h under microwave irradiation. The reaction progress was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (6 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with saturated brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by column chromatography to give the final compound.

[0262] Example S42. Synthesis of compound 25. Compound 25 was synthesized by general procedure C using 2-(2-iodoethyl)furan as the alkyl halide. MS (ESI) m / z [M+H] + :448.10. 1H NMR: δ7.40 -7.50 (m,2 H),7.28 -7.38 (m,1 H),7.15-7.25 (m,2 H),6.39 -6.78 (m,1 H),6.25-6.35 (m,1 H),5.90 -6.12 (m,2 H),5.25 -5.35 (m,1 H),5.10 -5.20 (m,1 H),3.70 -3.80 (m,1 H),3.50 -3.60 (m,1 H),3.20 -3.40 (m,2 H),2.95 -3.05 (m,3 H),2.45 -2.60 (m,2 H),1.59 (s,3 H).

[0263] Example S43. Synthesis of compound 26. Compound 26 was synthesized by general procedure C using 2-(2-bromoethyl)thiophene as the alkyl halide. MS (ESI) m / z [M+H] + :464.1. 1 H NMR (400 MHz, CDCl3) δ7.40 -7.48 (m,2 H),7.15-7.26 (m,3 H),6.85 -6.95 (m,2 H),6.39 -6.95 (m,2 H),5.90 -6.20 (m,1 H),5.15 -5.25 (m,1 H),3.72 -3.96 (m,2 H),3.47 -3.54 (m,1 H),3.32 -3.42 (m,3 H),3.10 -3.20 (m,2 H),2.42 -2.56 (m,2 H),1.49 (s,3 H).

[0264] Example S44. Synthesis of intermediate compound 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. [ka] Step 1. Synthesis of (9H-fluoren-9-yl)methyl 6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. A solution of (9H-fluoren-9-yl)methyl 8-(4-methoxybenzyl)-6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (1.0 g, 26.63 mmol) in TFA (10 mL) was stirred in a microwave at 130° C. for 2 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under vacuum and the crude product was extracted with ethyl acetate (100 ml) and a saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous Na2SO4, concentrated under vacuum and purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give (9H-fluoren-9-yl)methyl 6-methyl-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (300 mg, 42% yield) as a sticky solid. MS (ESI) m / z [M+H] + :406.

[0265] Step 2. Synthesis of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of (9H-fluoren-9-yl)methyl 6-methyl-4.7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (300 mg, 0.74 mmol) in CHCl (5 mL) was added diethylamine (6 mL). The reaction mixture was stirred at room temperature for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the crude product was purified by column chromatography (silica 100-200 mesh; 10% MeOH / DCM) to give 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (120 mg, 92% yield) as a white solid. MS(ESI)m / z[M+H] + :184.

[0266] Step 3. Synthesis of 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.700 g, 3.820 mmol) in DMF (8.0 mL), K2CO3 (1.58 g, 11.46 mmol) was added at room temperature and stirred for 10 min. To the resulting reaction mixture, 1-(bromomethyl)-4-(difluoromethoxy)benzene (1.086 g, 4.584 mmol) was added and the reaction mixture was heated at 80 °C for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature, quenched with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with saturated brine solution (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.550 g, 43.0% yield) as an off-white solid. MS (ESI) m / z [M+H] + :340.34.

[0267] Example S45. General procedure D for the synthesis of final compounds. To a solution of 1-(4-(difluoromethoxy)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.100 g, 0.2949 mmol) in DMF (2 mL) was added NaH (0.021 g, 0.8847 mmol) at 0° C., followed by the appropriate alkyl halide (2 eq.), and the reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was slowly quenched with a saturated aqueous solution of NaHCO3 (2 mL) and extracted with EtOAc (10 mL×2). The combined organic layers were washed with H2O (5 mL), followed by a saturated brine solution (5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by combiflash column chromatography (5% MeOH / DCM) to give the final product.

[0268] Example S46. Synthesis of compound 37. Compound 37 was synthesized by general procedure D using 4-bromo-1,1,1-trifluorobutane as the alkyl halide. MS (ESI) m / z [M+H] + :354.2. 1 H NMR (400 MHz, CDCl3): δ1.41 (d,J =7.13 Hz,3 H),1.71 -1.86 (m,2 H),2.01 -2.15 (m,2 H),2.26 -2.35 (m,1 H),2.60 -2.67 (m,1 H),2.89 -3.01 (m,1 H),3.07 -3.15 (m,1 H),3.21 -3.34 (m,2 H),3.46 -3.65 (m,2 H),3.81 -3.95 (m,2 H),4.35 -4.41 (m,1 H),5.20 -5.29 (m,1 H),6.53 (t,J =72.0 Hz,1 H),7.08 -7.16 (m,2 H),7.30 -7.36 (m,2 H).

[0269] Example S47. Synthesis of compound 38. Compound 38 was synthesized by general procedure D using (2-bromoethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :436.2. 1 H NMR (400 MHz, CDCl3) δ1.01 -1.15 (m,2 H),1.41 (d,J =7.13 Hz,3 H),1.45 -1.62 (m,8 H),1.66 -1.80 (m,2 H),2.23 -2.34 (m,1 H),2.58 -2.72 (m,1 H),2.89 -2.98 (m,1 H),3.04 -3.18 (m,2 H),3.23 -3.33 (m,1 H),3.43 -3.54 (m,1 H),3.55 -3.65 (m,1 H),3.78 -3.93 (m,1 H),4.31 -4.39 (m,1 H),5.15 -5.26 (m,1 H),6.53 (t,J =72.0 Hz,1 H),7.13 (d,J =8.50 Hz,2 H),7.34 (d,J =8.50 Hz,2 H).

[0270] Example S48. Synthesis of compound 39. Compound 39 was synthesized by general procedure D using 4-bromobut-1-ene as the alkyl halide. MS (ESI) m / z [M+H] + :394.2. 1 H NMR (400 MHz, CDCl3) δ1.41 (d,J =7.13 Hz,3 H),2.23 -2.35 (m,3 H),2.60 -2.71 (m,1 H),2.92 -3.01 (m,1 H),3.06 -3.14 (m,1 H),3.22 -3.46 (m,3 H),3.53 -3.64 (m,1 H),3.79 -3.93 (m,2 H),4.28 -4.38 (m,1 H),4.91 -5.00 (m,2 H),5.16 -5.26 (m,1 H),5.64 -5.76 (m,1 H),6.52 (t,J =72.0 Hz,1 H),7.10 -7.16 (m,2 H),7.30 -7.36 (m,2 H).

[0271] Example S49. Synthesis of compound 40. Compound 40 was synthesized by general procedure D using (2-bromoethyl)cyclobutene as the alkyl halide. MS (ESI) m / z [M+H] + :422.25 1 H NMR (400 MHz, CDCl3) δ1.41 (d,J =7.13 Hz,3 H),1.56 -1.65 (m,4 H),1.73 -1.92 (m,2 H),1.95 -2.07 (m,2 H),2.14 -2.25 (m,1 H),2.26 -2.35 (m,1 H),2.59 -2.72 (m,1 H),2.91 -2.99 (m,1 H),3.04 -3.14 (m,2 H),3.23 -3.43 (m,2 H),3.53 -3.63 (m,1 H),3.87 (q,J =13.38 Hz,2 H),4.29 -4.39 (m,1 H),5.17 -5.24 (m,1 H),6.53 (t,J =72.0 Hz,1 H),7.13 (d,J =8.63 Hz,2 H),7.30 -7.37 (m,2 H).

[0272] Example S50. Synthesis of compound 41. Compound 41 was synthesized by general procedure D using 1-bromobutane as the alkyl halide. MS (ESI) m / z [M+H] + :396.05. 1H NMR (400 MHz, DMSO-d6) δ0.86 (t,J =7.34 Hz,3 H),1.14 -1.24 (m,2 H),1.24 -1.30 (m,2 H),1.38 -1.50 (m,2 H),1.98 -2.10 (m,1 H),2.53 -2.61 (m,2 H),2.64 -2.77 (m,2 H),3.07 -3.25 (m,3 H),3.32 -3.41 (m,1 H),3.62 -3.73 (m,1 H),3.87 -3.93 (m,2 H),4.49 -4.58 (m,1 H),4.84 -4.94 (m,1 H),7.15 (d,J =8.56 Hz,2 H),7.22 (t,J =72.0 Hz,1 H),7.43 (d,J =8.56 Hz,1 H).

[0273] Example S51. Synthesis of compound 52. Compound 52 was synthesized by general procedure D using 2-trifluoromethyl-1-bromoethane as the alkyl halide. MS (ESI) m / z [M+H] + :420.16. 1 H NMR (400 MHz, CDCl3) δppm 7.31 - 7.38 (m,2 H),7.11 -7.16 (m,2 H),6.31 -6.73 (m,1 H),5.26 (q,J =7.21 Hz,1 H),4.23 -4.44 (m,2 H),3.98 -4.13 (m,1 H),3.80 -3.93 (m,3 H),3.59 (t,J =11.07 Hz,1 H),3.10 (dd, J = 11.51, 3.75 Hz, 1H), 2.90 - 2.99 (m,1 H),2.62 -2.72 (m,1 H),2.32 (dd, J = 4.38, 2.38 Hz, 1H), 2.28 (dd, J =4.31, 2.31 Hz, 1 H),1.48 (d,J =7.25 Hz,1 H),1.41 (d,J =7.13 Hz,3 H).

[0274] Example S52. General procedure E for the synthesis of final compounds. To a stirred solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.300 g, 1.184 mmol) in DMF (6 mL) in a flask immersed in an ice / water bath, cesium carbonate (0.771 g, 2.368 mmol, 2 equiv.) was added followed by the appropriate alkyl halide (1.1 equiv.). The flask was removed from the bath and stirred until TLC indicated complete consumption of the starting material. The reaction mixture was poured into ice-cold water (70 mL) and the aqueous layer was extracted with EtOAc (100 mL). The organic layer was washed with ice-cold brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the final compound.

[0275] Example S53. Synthesis of compound 42. Compound 42 was synthesized by general procedure E using 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene as the alkyl halide. MS (ESI) m / z [M+H] + :362.2. 1 H NMR (400 MHz, DMSO-d6) δ0.75 -0.89 (m,3 H),0.82 -0.87 (m,3 H),0.96 -1.13 (m,1 H),1.23 -1.31 (m,4 H),1.64 -1.75 (m,1 H),2.06 -2.09 (m,1 H),2.55 -2.62 (m,1 H),2.65 -2.76 (m,1 H),3.05 -3.15 (m,1 H),3.15 -3.26 (m,3 H),3.64 -3.74 (m,1 H),3.84 -3.95 (m,2 H),4.52-4.60 (m,1 H),4.86 -4.94 (m,1 H),7.17 (t,J =8.76 Hz,2 H),7.41 (dd, J = 8.19, 5.82 Hz, 2H).

[0276] Example S54. Synthesis of compound 43. Compound 43 was synthesized by general procedure E using 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene as the alkyl halide. MS (ESI) m / z [M+H] + :446.2. 1 H NMR (400 MHz, DMSO-d6) 0.72-0.80 (m, 3 H),0.80 -0.87 (m,3 H),0.96 -1.10 (m,1 H),1.21 - 1.27 (m,1 H),1.28 -1.34 (m,3 H),1.62 -1.79 (m,1 H),2.00 -2.13 (m,1 H),2.53 -2.65 (m,1 H),2.66 -2.76 (m,1 H),3.00 -3.10 (m,1 H),3.17 -3.29 (m,3 H),3.62 -3.72 (m,1 H),4.00 -4.08 (m,2 H),4.55 -4.65 (m,1 H),4.85 -4.95 (m,1 H),7.52 -7.60 (m,1 H),7.73 (s,1 H),7.80 -7.88 (m,1 H).

[0277] Example S55. Synthesis of compound 44. To a solution of 6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.420 g, 1.657 mmol) and 1H-indole-3-carbaldehyde (0.264 g, 1.823 mmol) in DCE (15 mL) was added acetic acid (1 mL, 1.657 mmol) and the reaction mixture was heated at 80° C. for 1 h. To the resulting reaction mixture was added NaBH4 (0.188 g, 4.973 mmol) in small portions and the reaction mixture was heated at 80° C. and stirred for 4 h. When TLC analysis (5% MeOH / DCM) showed complete consumption of starting material, the reaction mixture was diluted with water (40 mL) and the aqueous layer was extracted with DCM (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM), followed by washing with water (30 mL) and drying under reduced pressure to give compound 44 (0.250 g, 39% yield) as an off-white solid. MS (ESI) m / z [M+H] + :383.4. 1 H NMR (400 MHz, DMSO-d6) δ0.70 (t,J =7.09 Hz,3 H),0.75 -0.82 (m,3 H),0.91 -1.11 (m,1 H),1.22 -1.31 (m,3 H),1.57 -1.72 (m,1 H),1.97 -2.07 (m,1 H),2.55 -2.70 (m,2 H),2.83 (dt, J = 10.91, 2.74 Hz, 1H), 2.95 - 3.07 (m,1 H),3.10 -3.26 (m,3 H),3.54 -3.69 (m,1 H),3.96 -4.04 (m,1 H),4.06 -4.15 (m,1 H),4.54 -4.64 (m,1 H),4.84 -4.95 (m,1 H),6.94 -7.02 (m,1 H),7.04 -7.13 (m,1 H),7.29 -7.40 (m,2 H),7.65 (d,J =7.95 Hz,1 H),10.95 (s,1 H).

[0278] Example S56. Synthesis of intermediate compound 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione. To a solution of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (250 mg, 1.40 mmol) in DMF (3 mL), potassium carbonate (580 mg, 4.20 mmol) was added followed by 4-fluorobenzyl bromide (0.320 g, 1.70 mmol) and stirred at a temperature of 80° C. for 3 h. After completion, the reaction mixture was monitored by TLC (5% MeOH / DCM). The reaction mixture was poured into ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (160 mg, 70% yield) as a white solid. MS(ESI) m / z[M+H] + :292.

[0279] Example S57. Synthesis of compound 45. To a solution of 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (80 mg, 0.2739 mmol) in DMF (3 mL) at 0° C. under ice-cooled bath, NaH (20 mg, 0.2739 mmol) was added and stirred for 20 min, then after 3 h, (2-bromoethyl)cyclopentane (67 mg, 0.41 mmol) was added. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 8-(2-cyclobutylethyl)-1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (13 mg, 16% yield) as a gummy liquid. MS (ESI) m / z [M+H] + :374. 1 H NMR (400 MHz, CD3Cl3): δ7.30 -7.40 (m,2H), 7.00 - 7.10 (m,2H), 5.15 - 5.25 (m,1H), 4.25 - 4.35 (m,1H), 3.80 - 3.95 (m,2H), 3.55 - 3.65 (m,1H), 3.25 - 3.45 (m,2H), 3.05 - 3.20 (m,2H), 2.90 - 3.0 (m,1H), 2.60 - 2.70 (m,1H), 2.15 - 2.40 (m,2H), 1.75 - 2.10 (m,4H), 1.55 - 1.65 (m,4H), 1.20 - 1.30 (m,3H).

[0280] Example S58. Synthesis of compound 46. To a solution of 1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)dione (80 mg, 0.2739 mmol) in DMF (3 mL) at 0° C. under ice-cooled bath, NaH (20 mg, 0.2739 mmol) was added and stirred for 20 min, then after 3 h, (2-bromoethyl)cyclopentane (72 mg, 0.41 mmol) was added, the completion of starting material was monitored by TLC, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 8-(2-cyclopentylethyl)-1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione as a gummy liquid.

[0281] Example S59. Synthesis of intermediate compound 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride. Step 1. Synthesis of N-(2,2-diethoxyethyl)-2-methylbutan-1-amine. To stirring pure 2,2-diethoxyethan-1-amine (20.0 g, 0.137 mmol), 2-methylbutanal (11.60 g, 0.137 mmol) was added at room temperature and the reaction mixture was heated to 100 °C for 3 h. To the resulting reaction mixture, ethanol (200 mL) was slowly added at room temperature followed by NaBH4 (15.40 g, 0.413 mmol) and the reaction mixture was stirred for 16 h. After complete consumption of the starting material (monitored by TLC). The reaction mixture was cooled to room temperature and slowly quenched with a saturated solution of NH4Cl (100 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude compound. The resulting crude material was purified by column chromatography (silica 100-200 mesh; 10% MeOH / DCM) to give N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (25.8 g, 88% yield) as a colorless liquid. MS (ESI) m / z [M+H] + :204.3. 1 H NMR (400 MHz, DMSO-d6) δ0.80 -0.89 (m,6 H)1.11 (t,J=6.98 Hz,6H) 1.35 - 1.48 (m,2 H)2.28-2.32 (m,1 H)2.41-2.45 (m,1 H)2.55 (d,J=5.49 Hz,2 H)3.42 -3.52 (m,2 H)3.57 -3.65 (m,2 H)4.49 (t,J=5.49 Hz,1 H).

[0282] Step 2. (9H-Fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate. To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)serine (15.0 g, 45.81 mmol) in anhydrous DMF (150 mL) maintained at 0 °C was added HATU (26.0 g, 68.80 mmol), DIPEA (23.92 mL, 137.61 mmol) followed by N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (12.10 g, 59.63 mmol). The reaction mixture was stirred at room temperature for 4 h. Upon complete consumption of the starting material, the reaction mixture was quenched with ice-cold water (500 mL) and the aqueous layer was extracted with EtOAc (250 mL x 2). The combined organic layers were washed with cold H2O (200 mL) followed by brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by column chromatography (silica 100-200 mesh; 80% EtOAc / hexanes) to give (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (21.0 g, 89.43% yield) as a yellow sticky solid. MS (ESI) m / z [M+Na] + :535.35.

[0283] Step 3. Synthesis of 2-amino-N-(2,2-diethoxyethyl)-3-hydroxy-N-(2-methylbutyl)propenamide. To a stirred solution of (9H-fluoren-9-yl)methyl(1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate (21.0 g, 41.01 mmol) in anhydrous DCM (110 mL) maintained at 0° C., diethylamine (58 mL, 2.80 vol) was added and the reaction mixture was stirred at room temperature for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude product. The resulting crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 2-amino-N-(2,2-diethoxyethyl)-3-hydroxy-N-(2-methylbutyl)propenamide (9.50 g, 80% yield) as a yellow sticky solid. MS (ESI) m / z [M+H] + :291.4.

[0284] Step 4. Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (9.50 g, 30.54 mmol) in anhydrous DMF (95 mL) maintained at 0 °C, HATU (17.40 g, 45.81 mmol), DIPEA (16.0 mL, 91.62 mmol) followed by 2-amino-N-(2,2-diethoxyethyl)-3-hydroxy-N-(2-methylbutyl)propanamide (13.20 g, 45.81 mmol) were added at room temperature and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL x 2). The organic layer was washed with cold H2O (500 mL) followed by saturated brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica 100-200 mesh; 80% EtOAc / hexanes) to give (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (8.0 g, 31.0% yield) as a yellow viscous oil. MS (ESI) m / z [MH] - :582.2.

[0285] Step 5. Synthesis of (9H-fluoren-9-yl)methyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. A stirred solution of (9H-fluoren-9-yl)methyl(3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-3-hydroxy-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate (8.0 g, 13.77 mmol) in formic acid solution (48.0 mL, 6.0 vol) at room temperature and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (6.0 g, crude) as a brown semi-solid. The crude compound was used directly in the next reaction without further purification. MS (ESI) m / z [M+H] + :492.2.

[0286] Step 6. Synthesis of (6-(hydroxymethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of (9H-fluoren-9-yl)methyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (6.0 g, 12.20 mmol) in CHCl (36.0 mL) was added diethylamine (18.0 mL) at 0 °C to the reaction mixture. The mixture was stirred at room temperature for 3 hours. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 6-(hydroxymethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.0 g, 93.75% yield) as a colorless viscous oil. MS (ESI) m / z [M+H] + :270.20.

[0287] Step 7. Synthesis of tert-butyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. To a solution of 6-(hydroxymethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (3.0 g, 11.15 mmol) in CHCl (60 mL) was added triethylamine (4.5 mL, 33.45 mmol) followed by Boc anhydride (3.78 mL, 16.72 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was slowly quenched with ice-cold water (30 mL) and extracted with DCM (40 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica 100-200 mesh; 10% MeOH / DCM) to give tert-butyl 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (8.0 g, 31.0% yield) as a yellow viscous oil. MS (ESI) m / z [M+H] + :370.25.

[0288] Step 8. Synthesis of tert-butyl 6-(fluoromethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. To a solution of 6-(hydroxymethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (1.50 g, 4.065 mmol) in DCM (30 mL) was added DAST (1.97 g, 12.19 mmol) at -78 °C and stirred for 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and the aqueous layer was extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give tert-butyl 6-(fluoromethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (0.800 g, 72.0% yield) as a colorless viscous oil. MS (ESI) m / z [M+H] + :372.2.

[0289] Step 9. Synthesis of 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride. To a stirred solution of tert-butyl 6-(fluoromethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (1.0 g, 2.695 mmol) in 1,4-dioxane (5 mL), 4 M HCl in dioxane (5 mL) was added at 0 °C and the reaction mixture was stirred at room temperature for 3 h. Once the starting material was completely consumed (monitored by TLC), the reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure to give 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride (0.630 g, crude) as a brown sticky oil. MS (ESI) m / z [M+H] + Free base: 271.00.

[0290] Example S60. Synthesis of compound 47. To a solution of 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride (0.150 g, 0.550 mmol) in DMF (1.5 mL), K2CO3 (0.381 g, 2.760 mmol) was added followed by 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.261 g, 1.100 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was slowly quenched with ice-cold water (6 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give 1-(4-(difluoromethoxy)benzyl)-6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.040 g, 17.0% yield) as a white solid. MS (ESI) m / z [M+H] + :428.10. 1 H NMR (400 MHz, CDCl3) δ7.34 (d,J =8.01, 2 H), 7.11 (d, J =8.01, 2 H), 6.32 - 6.69 (m,1 H),5.14-5.25 (m,2 H),4.60 -4.76 (m,2 H),3.84 -3.97 (m,2 H),3.35 -3.45 (m,2 H),3.12 -3.40 (m,4 H),2.85 -3.05 (m,1 H),2.65 -2.75 (m,1 H),2.29 -2.34 (m,1 H),1.65 -1.75 (m,1H), 1.30 - 1.40 (m,1 H),1.05 -1.18 (m, 1 H),0.80 -0.90 (m,6 H).

[0291] Example S61. Synthesis of compound 48. To a solution of 6-(fluoromethyl)-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione hydrochloride (0.340 g, 1.253 mmol) in DMF (3.4 mL), Cs2CO3 (0.814 g, 2.506 mmol) was added followed by 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.598 g, 2.506 mmol) and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was quenched slowly with ice-cold water (6 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give 6-(fluoromethyl)-8-(2-methylbutyl)-1-(4-(trifluoromethyl)benzyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.045 g, 8.0% yield) as a white solid. MS (ESI) m / z [M+H] + :430.10. 1 H NMR (400 MHz, CDCl3) δ7.34 (d,J =8.01, 2 H), 7.11 (d, J =8.01, 2 H), 5.14-5.25 (m, 2 H),4.60 -4.76 (m,2 H),3.84 -3.97 (m,2 H),3.35 -3.45 (m,2 H),3.12 -3.40 (m,4 H),2.85 -3.05 (m,1 H),2.65 -2.75 (m,1 H),2.29 -2.34 (m,1 H),1.65 -1.75 (m,1H), 1.30 - 1.40 (m,1 H),1.05 -1.18 (m, 1 H),0.80 -0.90 (m,6 H).

[0292] Example S62. Synthesis of intermediate compound methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate. Step 1. Synthesis of methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. To a stirred solution of 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-methoxy-4-oxobutanoic acid (1.90 g, 9.475 mmol) in anhydrous DMF (30 mL) at 0 °C, HATU (3.60 g, 1.137 mmol) was added followed by DIPEA (2.70 mL, 1.895 mmol) and the reaction mixture was stirred at the same temperature for 10 min. To the resulting reaction mixture, N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (3.50 g, 9.475 mmol) was added and then the mixture was allowed to warm to room temperature and stirred for 6 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and the aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with cold H2O (50 mL) followed by brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude material was purified by CombiFlash column chromatography using 50% EtOAc / n-hexane to give methyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (4.30 g, 83.0% yield) as a white solid. MS (ESI) m / z [M+H-EtOH] + :509.2.

[0293] Step 2. Synthesis of methyl 3-amino-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. To a solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (1.36 g, 2.451 mmol) in CHCl (27.0 mL), diethylamine (1.53 mL, 14.71 mmol) was added at room temperature and the reaction mixture was stirred for 3 h. Once the starting material was completely consumed (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by CombiFlash column chromatography using 5% MeOH / DCM to give methyl 3-amino-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.700 g, 86% yield) as a yellow viscous liquid. MS (ESI) m / z [M+H-EtOH] + :287.68.

[0294] Step 3. Synthesis of methyl 3-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (0.490 g, 1.594 mmol) in anhydrous DMF (10 mL) maintained at 0 °C was added HATU (0.720 g, 1.913 mmol), DIPEA (0.555 mL, 3.188 mmol), followed by methyl 3-amino-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.530 g, 1.594 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 6 h. Upon completion, the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EtOAc (20 mL x 2). The organic layer was washed with cold H2O (10 mL) followed by saturated brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography using 5% MeOH / DCM to give methyl 3-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.630 g, 70% yield) as an off-white solid. MS (ESI) m / z [M+H-EtOH] + :580.20.

[0295] Step 4. Synthesis of (9H-fluoren-9-yl)methyl 6-(2-methoxy-2-oxoethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. To a stirred solution of methyl 3-(3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanamido)-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate (0.300 g, 0.4794 mmol), formic acid (1.5 mL) was added at room temperature and the reaction mixture was stirred for 16 h. Upon completion, the reaction mixture was concentrated and the resulting crude was purified by column chromatography (silica 100-200 mesh; 0-5% MeOH / DCM) to give (9H-fluoren-9-yl)methyl 6-(2-methoxy-2-oxoethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (0.200 g, 80% yield) as a yellow solid. MS (ESI) m / z [M+H] + :534.67

[0296] Step 5. Synthesis of methyl 2-(8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate. To a solution of methyl (9H-fluoren-9-yl)methyl 6-(2-methoxy-2-oxoethyl)-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (0.240 g, 0.4499 mmol) in CHCl (0.5 mL), diethylamine (0.280 mL) was added and the reaction mixture was stirred at room temperature for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the crude material was purified by Combiflash column chromatography using 0-5% MeOH / DCM to give 2-(8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (0.130 g, 93% yield) as a white solid. MS(ESI) m / z [MH] + :310.4.

[0297] Step 6. Synthesis of methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate. To a solution of methyl 2-(8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (3.08 g, 9.890 mmol) in DMF (30 mL) was added K2CO3 (4.10 g, 29.66 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 15 min. To the resulting reaction mixture was added 1-(bromomethyl)-4-(difluoromethoxy)benzene (3.48 g, 14.36 mmol) and the stirred mixture was heated to 80 °C for 2 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (200 mL x 2). The organic layer was washed with cold H2O (200 mL) followed by saturated brine (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography (5% MeOH / DCM) to give methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (2.20 g, 48% yield) as a yellow solid. MS (ESI) m / z [M-CH3] + :454.10.

[0298] Example S63. Synthesis of compound 49. To a solution of methyl 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetate (2.20 g, 4.705 mmol) in THF (22.0 mL) was added NaOH (0.560 g, 14.11 mmol) followed by water (4 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in water (10 mL) and slowly acidified with 6N HCl (10 mL) and stirred for 5 min. The resulting solid precipitate was filtered through a Buchner funnel and dried under reduced pressure to give 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetic acid (0.85 g, 40% yield) as a white solid. MS (ESI) m / z [M+H] + :454.10. 1 H NMR (400 MHz, CDCl3) δ7.28 -7.38 (m,2 H),7.11 (d,J =7.99 Hz,2 H),6.33 -6.71 (m,1 H),5.36 -5.40 (m,1 H),4.70 -4.80 (m,1 H),4.65 -4.75 (m,1 H),3.80 -4.00 (m,2 H),3.55 -3.65 (m,1 H),3.35 -3.45 (m,1 H),2.85 -3.30 (m,6 H),2.70 -2.80 (m,1 H),2.25 -2.35 (m,1 H),1.65 -1.76 (m,1 H),1.25 -1.35 (m,1H), 1.10 - 1.20 (m,1H), 0.8- 0.9(m,6H).

[0299] Example S64. Synthesis of compound 50. To a solution of 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetic acid (0.470 g, 1.036 mmol) in THF (5 mL) was added 1,1'-carbonyldiimidazole (0.500 g, 3.109 mmol) at room temperature and the reaction mixture was stirred for 15 min. To the resulting reaction mixture was added an aqueous solution of NH3 (10 mL) and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched slowly with ice-cold water (6 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The resulting crude compound was purified by Combiflash column chromatography using 5% MeOH / DCM followed by preparative HPLC to give 2-(1-(4-(difluoromethoxy)benzyl)-8-(2-methylbutyl)-4,7-dioxooctahydro-2H-pyrazino[1,2-a]pyrimidin-6-yl)acetamide (0.070 g, 15% yield) as a white solid. MS (ESI) m / z [M+H] + :453.20. 1 H NMR (400 MHz, CDCl3) δ7.30 -7.40 (m,2 H),7.05-7.15 (m,2 H),6.39 -6.70 (m,1 H),5.20 -5.40 (m,2 H),4.75 -4.85 (m,1 H),3.95 -4.05 (m,1 H),3.75 -3.85 (m,1 H),3.50 -3.60 (m,1 H),3.30 -3.40 (m,1 H),3.05 -3.25 (m,2 H),2.85 -2.95 (m,2 H),2.55 -2.70 (m,1 H),2.25 -2.35 (m,1H), 1.70 - 1.80 (m,2H), 1.30 - 1.40 (m,2H), 1.05 - 1.20 (m,2H), 0.75 - 0.90 (m,6H).

[0300] Example S65. Synthesis of intermediate compound 1-(3-chloro-4-(trifluoromethyl)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (500 mg, 2.732 mmol) in DMF (7 mL) was added potassium carbonate (1.13 g, 8.196 mmol) followed by 4-(bromomethyl)-2-chloro-1-(trifluoromethyl)benzene (0.894 g, 3.278 mmol) and stirred at a temperature of 80° C. for 12 h. After completion of the reaction was monitored by TLC (5% MeOH / DCM). The reaction mixture was poured into ice-cold water (50 mL) and the aqueous layer was extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give 1-(3-chloro-4-(trifluoromethyl)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (320 mg, 42% yield) as a white solid. MS(ESI) m / z[M+H] + :376.34.

[0301] Example S66. General procedure F for the synthesis of final compounds. To a solution of 1-(3-chloro-4-(trifluoromethyl)benzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (150 mg, 0.400 mmol) in DMF (2 mL) at 0 °C, Cs2CO3 (4 equiv.) was added and stirred for 20 min, after which the appropriate alkyl halide (1.2 equiv.) was added at room temperature and the reaction mixture was heated at 80 °C and stirred for 12 h. Once the starting material was consumed (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography (silica 100-200 mesh; 5% MeOH / DCM) to give the final compound.

[0302] Example S67. Synthesis of compound 51. Compound 51 was synthesized by general procedure F using (2-bromoethyl)cyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :458.2. 1 H NMR (400 MHz, CDCl3) δppm 7.70 (d, J =8.07 Hz,1 H),7.54 (s,1 H),7.33 (d,J =8.68 Hz,1 H),4.34 (dd, J = 10.64, 3.55 Hz, 1H), 3.87 - 3.99 (m,2 H),3.61 (t,J =11.13 Hz,1 H),3.25 -3.42 (m,2 H),3.08 -3.19 (m,2 H),2.89 -2.98 (m,1 H),2.64 -2.74 (m,1 H)2.29 -2.38 (m,1 H)2.17 -2.27 (m,1 H)1.97 -2.09 (m,2 H)1.72 -1.92 (m,3 H)1.58 -1.66 (m,4 H)1.55 (br. s, 3 H).

[0303] Example S68. Synthesis of compound 54. Compound 54 was synthesized by general procedure F using (2-bromoethyl)cyclopentane as the alkyl halide. MS (ESI) m / z [M+H] + :472.15. 1H NMR (400 MHz, CDCl3) δppm 7.69 (d, J =8.11 Hz,1 H)7.52 -7.56 (m,1 H)7.33 (d,J =7.89 Hz,1 H),5.23 (q,J =7.23 Hz,1 H),4.36 (dd, J = 10.52, 3.29 Hz, 1H), 3.87 - 3.98 (m,2 H),3.63 (t,J =11.07 Hz,1 H),3.46 -3.56 (m,1 H),3.25 -3.35 (m,1 H),3.12 -3.23 (m,2 H),2.87 -2.97 (m,1 H),2.60 -2.70 (m,1 H),2.29 -2.37 (m,1 H),1.66 -1.82 (m,2 H),1.54 -1.63 (m,1 H),1.51 (d,J =,2.63 Hz, 2 H),1.42 (d,J =7.23 Hz,3 H),1.26 (br. s, 2 H)1.04 -1.16 (m,2 H)0.80 -0.92 (m,2 H).

[0304] Example S69. Synthesis of compound 53. Step 1. Synthesis of (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate. To a stirred solution of (((9H-fluoren-9-yl)methoxy)carbonyl)leucine (20.0 g, 56.58 mmol) in anhydrous DMF (200 mL), HATU (21.50 g, 56.58 mmol) was added followed by DIPEA (10.62 mL, 61.10 mmol) at 0 °C and the reaction mixture was stirred at the same temperature for 10 min. To the resulting reaction mixture, N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (11.48 g, 56.58 mmol) was added at room temperature and the reaction mixture was stirred for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice-cold water (100 mL) and the aqueous layer was extracted with EtOAc (50 mL×4). The combined organic layers were washed with cold H2O (50 mL×2), followed by brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by CombiFlash column chromatography using 5% MeOH / DCM to give (9H-fluoren-9-yl)methyl (1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (14.5 g, 47.57% yield) as a white solid. MS(ESI)m / z[M+H] + :539.04.

[0305] Step 2. Synthesis of 2-amino-N-(2,2-diethoxyethyl)-4-methyl-N-(2-methylbutyl)pentanamide. To a solution of (9H-fluoren-9-yl)methyl(1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (8.50 g, 15.77 mmol) in CHCl (50 mL) was added diethylamine (16 mL, 157.7 mmol) at room temperature and the reaction mixture was stirred for 3 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by CombiFlash column chromatography using 5% MeOH / DCM to give 2-amino-N-(2,2-diethoxyethyl)-4-methyl-N-(2-methylbutyl)pentanamide (3.60 g, 72% yield) as a yellow viscous liquid. MS (ESI) m / z [M+H-EtOH] + :272.10.

[0306] Step 3. Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopropan-2-yl)amino)-3-oxopropyl)carbamate. To a stirred solution of 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)propanoic acid (3.80 g, 12.28 mmol) in anhydrous DMF (35 mL) maintained at 0° C. was added HATU (6.48 g, 17.05 mmol) and DIPEA (4.90 mL, 28.42 mmol), followed by 2-amino-N-(2,2-diethoxyethyl)-4-methyl-N-(2-methylbutyl)pentanamide (3.60 g, 11.37 mmol). The reaction mixture was allowed to reach room temperature and stirred for 3 h. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EtOAc (30 mL×2). The organic layer was washed with cold H2O (10 mL) followed by saturated brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combiflash column chromatography using 5% MeOH / DCM to give (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)amino)-3-oxopropyl)carbamate (3.8 g, 55% yield) as an off-white solid. MS (ESI) m / z [M+H-EtOH] + :565.30.

[0307] Step 4. Synthesis of (9H-fluoren-9-yl)methyl 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate. To a stirred solution of (9H-fluoren-9-yl)methyl 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (3.80 g, 6.231 mmol) was added formic acid (20 mL) at room temperature and the reaction mixture was stirred for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica 100-200 mesh; 0-5% MeOH / DCM) to give (9H-fluoren-9-yl)methyl 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (3.60 g, 94% yield) as a yellow solid. MS (ESI) m / z [M+H] + :518.23.

[0308] Step 5. Synthesis of 6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of (9H-fluoren-9-yl)methyl 6-isobutyl-8-(2-methylbutyl)-4,7-dioxohexahydro-2H-pyrazino[1,2-a]pyrimidine-1(6H)-carboxylate (3.60 g, 6.954 mmol) in CHCl (36 mL), diethylamine (6.8 mL, 69.54 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Upon complete consumption of the starting material (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the crude product was purified by Combiflash column chromatography using 10-50% ethyl acetate in n-hexane to give 6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (1.20 g, 60% yield) as a white solid. MS(ESI) m / z[M+H] + :296.10.

[0309] Step 6. Synthesis of 1-(4-(difluoromethoxy)benzyl)-6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. To a solution of 6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.170 g, 0.576 mmol) in DMF (5 mL), K2CO3 (0.159 g, 1.152 mmol) was added at 0 °C and the reaction mixture was stirred for 10 min. To the resulting reaction mixture, 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.150 g, 0.632 mmol) was added at room temperature and stirred for 3 h. After completion, the reaction mixture was quenched with ice-cold water (200 mL) and the aqueous layer was extracted with EtOAc (20 mL×2). The organic layer was washed with cold HO (20 mL) followed by saturated brine (15 mL), dried over NaSO and concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give 1-(4-(difluoromethoxy)benzyl)-6-isobutyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (0.103 g, 40% yield) as a white solid. MS (ESI) m / z [M+H] + :452.3. 1 H NMR (400 MHz, DMSO d6) δ7.42 (d,J =8.8 Hz,2 H),7.14 -7.24 (m,3 H),5.0 -5.10 (m,1 H),4.50 -4.60 (m,1H), 3.90 - 4.00 (m,2 H),3.60 -3.70 (m,1 H),3.02 -3.40 (m,4 H),2.70 -2.85 (m,2 H),2.0 -2.10 (m,1 H),1.50 -1.70 (m,4H), 1.20 - 1.35 (m,1H), 1.0- 1.10 (m, 1H), 0.70 - 0.98 (m,12H).

[0310] Example 1 Treating Long COVID A. Overview ATH-1017 ATH-1017 will be administered to patients requiring treatment for long COVID by subcutaneous (SC) injection, preferably once daily (OD) during the day. The first SC injection of ATH-1017 will be administered on-site under supervision.

[0311] Exemplarily, a 40 mg prefilled syringe of ATH-1017 contains 1.0 mL of 40 mg / mL ATH-1017 in a solution of 10 mM sodium phosphate and 0.5% NaCl. A 70 mg prefilled syringe of ATH-1017 contains 1.0 mL of 70 mg / mL ATH-1017 in a solution of 10 mM sodium phosphate. A placebo prefilled syringe contains 1.0 mL of a solution of 10 mM sodium phosphate and 1.1% NaCl, respectively. All solutions are adjusted to a pH of about 7.0 to about 7.6.

[0312] ATH-1017 and placebo will be administered subcutaneously.

[0313] A compound of formula (I) or a pharma- ceutically acceptable salt thereof A compound of formula (I), such as Compound 2a or Compound 1a, or a pharma- ceutically acceptable salt thereof, is orally administered to a patient in need of treatment for long COVID.

[0314] B. Screening Assessment Alzheimer's Disease Cooperative Study-Activities of Daily Living, 23-item version (ADCS-ADL23)

[0315] In some embodiments, patients requiring long COVID treatment are assessed with the ADCS-ADL23. The ADCS-ADL23 (Galasko, 1997) is a 23-item assessment of impairment in activities of daily living administered to a support person / caregiver. It includes 23 questions regarding the subject's level of engagement and performance across items representing daily living. Questions range from basic to practical activities of daily living. Each item is rated from the highest level of independent performance to complete loss. Total scores range from 0 to 78, with lower scores indicating greater impairment.

[0316] Alzheimer's Disease Cooperative Study-Activities of Daily Living, 19-Item Version (ADCS-ADL19) In some embodiments, patients requiring long COVID treatment are assessed with the ADCS-ADL19. The ADCS-ADL19 (Galasko, 1997) is a 19-item assessment of impairment in activities of daily living administered to a supporter / caregiver. It includes 19 questions regarding the subject's level of engagement and performance across items representing daily living. Questions range from basic to practical activities of daily living. Each item is rated from the highest level of independent performance to complete loss. Total scores range from 0 to 54, with lower scores indicating greater impairment.

[0317] Financial Competence Inventory (FCI) In some embodiments, patients requiring long COVID treatment are evaluated with the FCI. The Financial Competence Scale (FCI) (Marson, 2000) is a prototype psychometric tool that tests financial competency using 14 financial competency tasks consisting of six clinically relevant domains: bank statement management, basic financial skills, cash transactions, checkbook management, financial concept knowledge, and financial judgment. Its usefulness is its sensitivity to the very early stages of cognitive impairment.

[0318] Mini-Mental State Examination (MMSE) In some embodiments, patients requiring treatment for long COVID are evaluated with the MMSE. The Mini-Mental State Examination (MMSE) (Folstein, 1975) is a short battery of tests and a widely used test of global cognitive function that evaluates memory, orientation, and performance. Scores range from 0 to 30, with 30 being the highest possible score and 0 being the lowest possible score. The MMSE is used as a screening tool to determine the severity of cognitive impairment, and a score of 26 or less is conventionally considered pathological.

[0319] Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cognitive 11 ) In some embodiments, patients requiring treatment for long COVID are assessed using the ADAS-Cog 11 The original ADAS-Cog 11 was designed to measure incremental changes in cognitive impairment in subjects with AD (Rosen, 1984), but has also been used in other conditions of cognitive impairment. The cognitive domains covered can be summarized as memory as well as new learning, language, and practice. The standard 11 items are word recall, commands, construction practice, object and finger naming, idea practice, orientation, word recognition, spoken language ability, spoken language comprehension, word-finding difficulties, and recall of test instructions. The test includes seven performance items and four clinician-rated items, with total scores ranging from 0 (no impairment) to 70 (severe impairment). Thus, higher scores indicate more severe cognitive impairment. Later versions (ADAS-Cog13, 14) added test items to increase sensitivity in less impaired cases.

[0320] Due to known diurnal variations in cognitive performance ( Hilt, 2015 ), the ADAS-Cog 11 will be assessed at approximately the same time (morning) as the baseline assessment to reduce variance in all subsequent tests.

[0321] Montreal Cognitive Assessment (MoCA) In some embodiments, patients requiring long COVID treatment are evaluated with MoCA. MOCA was designed as a rapid screening tool for mild cognitive impairment. It evaluates various cognitive domains: attention and concentration, executive function, memory, language, visuo-constructive skills, conceptual thinking, calculation, and orientation. See Nasreddine ZS, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr; 53(4): 695-9. Erratum in: J Am Geriatr Soc. 2019 Sep; 67(9): 1991. The possible total score is 30 points; a final total score of 26 or more is considered normal.

[0322] Digit Sign Substitution Test (DSST) In some embodiments, patients who require treatment for long COVID are evaluated with the DSST. The DSST is a timed neuropsychological test that is sensitive to brain injury, dementia, age, and depression. See Jaeger, JJ Clin Psychopharmacol. 2018 Oct;38(5):513-519. The test is not sensitive to the location of brain injury (except for injuries that constitute part of the visual field). It consists of a list of (e.g., nine) digit-sign pairs (e.g., 1 / -, 2 / ┴...7 / Λ, 8 / X, 9 / =), followed by a number. Under each number, the subject must write down the corresponding symbol as quickly as possible. The number of correct signs within the allowed time (e.g., 90 or 120 seconds) is measured. The test procedure is non-verbal, and the patient's results indicate nonspecific cognitive impairment with high sensitivity.

[0323] Disability Assessment for Dementia (DAD) In some embodiments, patients requiring treatment for long COVID are assessed by the DAD. The purpose of the DAD scale is to quantitatively measure the functional capacity in activities of daily living (ADL) of individuals with cognitive impairment such as dementia and to help delineate areas of cognitive impairment that may impair ADL performance. See Gelinas I, et al. Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther. 1999 Sep-Oct; 53(5): 471-81. Basic and practical activities of daily living are examined in relation to executive skills to identify problem areas and to make it possible to inform treatment decisions. Thus, activities of daily living are subdivided and assessed according to executive functions that have shown a pattern of regression in dementia. These are initiation, planning and organization, and effective performance.

[0324] Neuropsychiatric Inventory (NPI) In some embodiments, patients requiring treatment for long COVID are assessed with the NPI. The NPI is an interview-based rating scale of mental and behavioral disorders associated with dementia (Cummings, 1994). The support person / caregiver is interviewed by a qualified NPI assessor for the presence or absence of 12 symptoms, such as delusions, hallucinations, agitation / aggression, depression / dysphoria, anxiety, elation / euphoria, lethargy / apathy, disinhibition, irritability / lability, abnormal motor behavior, sleep and nighttime behavior disorders, and appetite and eating disorders. For symptoms present, the support person / caregiver rates the frequency, severity, and distress of each symptom. A total score and a caregiver distress score are calculated. Higher scores indicate more severe psychopathology.

[0325] Controlled Word Association Test (COWAT) In some embodiments, patients who require long COVID treatment are evaluated with the COWAT, which is applied to evaluate executive memory function. The Controlled Word Association Test (COWAT) is a timed oral language fluency test in which subjects are required to verbally associate various letters of the alphabet by saying all possible words that begin with a given letter. Individuals are given one minute to name as many words as possible that begin with each of the letters. The procedure is then repeated for the remaining two letters (Benton, 1994; Strauss, 2006). The test score is the total number of different words generated for all three letters.

[0326] ERP P300 Patients in need of long COVID treatment are assessed with ERP P300. ERP P300 is a quantitative, unbiased, non-invasive method to record task-related brain processing speed triggered by external stimuli, e.g., strange auditory stimuli, and is a well-established functional biomarker of working memory access in particular (Ally, 2006). ERP P300 is characterized by a stereotyped series of voltage deflections occurring after each unnatural tone to be counted, with early features (<100 ms) corresponding to unconscious sensory transmission (auditory cortex, N100) and later features resulting from cognitive processing in the ventral attention network, i.e., P300 refers to a large positive deflection of about 300 ms in healthy adults (young or elderly). P300 latency is sensitive to detect reduced synaptic transmission associated with cognitive decline in AD patients and other dementias (Olichney, 2011).

[0327] To assess the P300 wave (latency and amplitude), the subject must perform a task involving auditory stimuli. The stimuli can consist, for example, of an odd-o'-the-odds paradigm with two sound stimuli. The stimuli are presented through headphones and the auditory stimulation of the P300 is assessed with repeated recordings for a total of up to 10 minutes.

[0328] C. Results Treatment with ATH-1017, Compound 2a or a pharma- ceutically acceptable salt thereof, or Compound 1a or a pharma- ceutically acceptable salt thereof reduces the rate of decline, stabilizes, or improves patient outcomes as measured by one or more of the above screening assessments, with acceptable safety and tolerability.

[0329] Example B2: Neuroprotection against LPS toxic inflammatory challenge To evaluate the neuroprotective effects of compound treatment against inflammatory damage such as that associated with long COVID, primary cultured cortical neurons were subjected to lipopolysaccharide (LPS) treatment for 24 hours with various compound doses of the compound of formula (I) or compound A19. LPS is a potent activator of toll-like receptor 4 (TLR4), expressed on both neurons and microglia, and can initiate the release of several proinflammatory mediators. For example, LPS induced a strong release of tumor necrosis factor-α (TNFα) and IL-6 in primary mouse neuronal cultures, both of which are characteristic proinflammatory mediators associated with neurodegeneration and cytotoxicity. To demonstrate the neuroprotective potential of test compounds against inflammation-induced cytotoxicity, the Cell Titer-Glo Luminescent Cell Viability Assay (Promega, Cat. No. G7571) was utilized. Rat primary cortical neuronal cultures were grown to maturity at 37°C, 5% CO2 in complete neurobasal medium supplemented with B27 / GDNF / BDNF containing 10% FBS. 25 μl of culture volume was seeded at 5,000 cells / well in 384-well plates and treated with 1 μM, 100 nM, 10 nM, 1 nM, or 0.1 nM of test compound for 15 min. Cells were then subjected to 1 μM LPS challenge for 24 h. Luminescence measurements to assess relative levels of ATP were performed on an Envision plate reader (Perkin Elmer). Data for DMSO control were set to 100% cell viability and averaged for each group (n=4) and presented as mean ± SEM.

[0330] The results are shown in Table 2. Compounds 1a, 2a, 5a, 6a, and A19 active metabolite all protected primary neurons from LPS-stimulated inflammatory toxicity at at least one dose tested. Statistical analysis was performed using one-way ANOVA with Tukey's multiple comparison test. ++ indicates p<0.01 and +++ indicates p<0.001 relative to DMSO+LPS. TIFF2025508768000059.tif203170

[0331] Example B3: Neurotrophic effects on neurite outgrowth and synaptogenesis. The progression of neurological diseases is associated with loss of neural network connectivity, which can have various causes, including infection with SARS-CoV-2. Loss of intact brain circuits is a major cause of cognitive impairment, regardless of the cause of degeneration. Neural connectivity is driven by the outgrowth of axons or dendrites, collectively called dendrites, as well as the formation of functional chemical connections between neurons, collectively called synapses. Test compounds were tested for their ability to stimulate neurons to extend neurites and form synapses in culture.

[0332] Neonatal rat hippocampal neurons were isolated and cultured in brain neuron culture medium (Neurobasal medium supplemented with 5% FBS, 2% B-27 supplement, and 0.003% gentamicin) at 37°C under 5% CO2. On day 1 in vitro (DIV1), cells were transferred to poly-D-lysine coated 24-well plates at approximately 10,000 cells / well. Cells were then grown in 3 mL serum-free medium and treated with 0.1% dimethyl sulfoxide (DMSO; vehicle), 10 nM dihydrotestosterone (positive control), or compound A19 active metabolite at the following concentrations: 0, 1, 1, or 10 nM. Because compound A19 is a prodrug, it is more appropriate to administer the active metabolite form when testing this compound in vitro. All treatments contained a final concentration of 0.1% DMSO. For neurite outgrowth assays, treatment medium was refreshed on DIV3 and cells were processed for analysis on DIV4. For synaptogenesis assays, treatment medium was renewed on DIV3 and DIV6, and cells were processed for analysis on DIV8. Processing for both neurite outgrowth and synaptogenesis assays was performed as follows: medium was removed, cells were fixed with 100% methanol for 20 min at room temperature (RT), then methanol was aspirated and each well was washed twice with Dulbecco's phosphate-buffered saline (DPBS). Cells were permeabilized with 0.02% Triton X-1000 (ThermoFisher, Waltham, Massachusetts) in DPBS for 2 min at RT without shaking, and plates were blocked with 5% bovine serum albumin (BSA) in DPBS for 1 h at RT. Plates were then incubated with beta-III tubulin antibody (ab201740; Abcam, Boston, Massachusetts) with gentle shaking to assess neurite outgrowth, or with 1:500 rabbit anti-synaptobrevin-II antibody (Synaptic Systems, cat# 104 202, Göttingen, Germany) overnight at 4°C to assess synaptogenesis.After overnight incubation, plates were washed three times with DPBS and incubated for 1 h at RT with anti-rabbit immunoglobulin G secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, Carlsbad, California, 1:500).

[0333] Imaging was performed using a BX43 Olympus microscope driven by Olympus' standard "CellSens" software. Images were taken under a 60x water immersion objective using a DP74 camera (Olympus, Center Valley, Pennsylvania). Ten images of single cells from a total of two assays were analyzed using the NeuroJ plugin in ImageJ to assess neurite length. For synaptogenesis assays, synapse counts (number of synapses) were quantified for each cell. Data were assessed for normality (Shapiro-Wilk) and homoscedasticity (Brown-Forsythe). For data analysis, the mean of each treatment group was compared to the mean of the vehicle (0.1% DMSO) group and analyzed using one-way ANOVA / Dunnett's post-hoc test. A value of p<0.05 was considered to represent a statistically significant difference.

[0334] The results are shown in Table 3. In this study, treatment with the active metabolite of Compound A19 promoted neurite outgrowth. TIFF2025508768000060.tif78170

[0335] An identical study was performed to test the ability of additional test compounds to stimulate neurite growth and synaptogenesis. Compounds 1a, 2a, and 5a also demonstrated the ability to increase neurite length and synapse number in cultured primary neurons. In this study, compound 1a was found to increase both measures at all doses tested. Compound 2a was found to increase neurite length at a concentration of 10 nM and synapse number at all concentrations tested. Compound 5a was found to increase neurite length at 1 nM and synapse number at doses of 1 nM and 100 nM (Table 4). HGF at a dose of 5 ng / ml was also used as a positive control and was found to increase both neurite length and synapse number. The results are shown in Table 4. TIFF2025508768000061.tif120170

[0336] Example B4: Rodent Lipopolysaccharide Model of Brain Inflammation Brain inflammation (encephalitis) that can lead to brain swelling, headache, confusion, and seizures. The causes of neuroinflammation can be wide and diverse, including due to viral, bacterial, parasitic, or fungal infections, or due to autoimmune diseases. Neuroinflammation has been reported in cases of long COVID. Lipopolysaccharide (LPS) is a bacterial endotoxin that induces a potent neuroinflammatory response and is associated with cognitive decline. Using a T-maze assay, we studied the ability of compound A19 to reverse cognitive decline induced by LPS in a mouse model of encephalitis. In a separate identical assay, compounds 1a and 5a were also evaluated.

[0337] Spontaneous and sequential alternation is the innate tendency of rodents to alternate free choices in a T-maze (T-CAT) over a series of consecutive runs. This sequential procedure depends on working memory and is sensitive to a variety of pharmacological manipulations that affect memory processes. The present study was conducted to evaluate the ability of compound A19, compound 1a, and compound 5a to reverse LPS-induced cognitive impairment in the T-maze assay.

[0338] Compound A19 was dissolved in 0.9% NaCl (physiological saline), vortexed periodically until completely dissolved, and the pH was adjusted between 7.4-7.8. Compound A19 was used at concentrations of 0.125, 0.1, 0.05, 0.025, and 0.0125 mg / ml, resulting in doses of 1.25, 1, 0.5, 0.25, and 0.125 mg / kg, respectively, when given in a volume of 10 ml / kg. Compound 1a was dissolved in 100% DMSO at 160 mg / ml, and vortexed until completely dissolved. The above stock solution was then diluted with 20% PEG-400 and 78% 0.9% NaCl, such that the stock solution constituted 2% of the final solution. Compound 1a was used at concentrations of 0.05, 0.2, 0.8, 1.6, and 3.2 mg / ml, which resulted in doses of 0.5, 2, 8, 16, and 32 mg / kg, respectively, when administered in a volume of 10 ml / kg. Compound 5a was dissolved in 100% DMSO at 100 mg / ml and vortexed until completely dissolved. The above stock solution was then diluted with 20% PEG-400 and 78% 0.9% NaCl, so that the stock solution constituted 2% of the final solution. Compound 5a was used at concentrations of 0.125, 0.25, 0.5, 1, and 2 mg / ml, which resulted in doses of 1.25, 2.5, 5, 10, and 20 mg / kg, respectively, when administered in a volume of 10 ml / kg.

[0339] Memantine was dissolved in saline. Memantine was used at concentrations of 0.1 mg / ml and 0.01 mg / ml, which when given in a volume of 10 ml / kg, would result in doses of 1 and 0.1 mg / kg, respectively. Memantine is approved for the symptomatic treatment of Alzheimer's disease and was tested as a reference compound.

[0340] LPS was dissolved in saline, prepared at a concentration of 0.0125 mg / ml and given intraperitoneally in a dose volume of 20 ml / kg to give a dose of 0.25 mg / kg (250 μg / kg).

[0341] Male CD-1 mice (Janvier; Le Genest St Isle-France), 4- to 5-week-old, were used in the study.

[0342] Compound A19 was administered subcutaneously (sc) at doses of 1.25, 1, 0.5, 0.25, and 0.125 mg / kg for 14 days, with the last treatment administered 60 minutes before the T-maze test. Compound 1a was administered orally (po) at doses of 0.5, 2, 8, 16, and 32 mg / kg for 14 days, with the last treatment administered 60 minutes before the T-maze test. Compound 5a was administered orally (po) at doses of 1.25, 2.5, 5, 10, and 20 mg / kg for 14 days, with the last treatment administered 60 minutes before the T-maze test. LPS was injected intraperitoneally 2 weeks before the T-maze test. Table 5 shows the administration route and treatment schedule for each treatment group. TIFF2025508768000062.tif140170

[0343] The T-maze apparatus was made of gray plexiglass with a main stem (55 cm long x 10 cm wide x 20 cm high), and two arms (30 cm long x 10 cm wide x 20 cm high) positioned at a 90 degree angle to the main stem. A start box (15 cm long x 10 cm wide) was separated from the main stem by a guillotine door. A horizontal door was also provided to close off a specific arm during the force-choice alternation task.

[0344] The experimental protocol consisted of one session, beginning with one "forced choice" trial followed by 14 "free choice" trials. In the "forced choice" trial, the animal was restrained in the start arm for 5 s and then released while either the left or right goal arm was blocked by a horizontal door. It exited the maze but eventually entered the open goal arm and returned to the start position. Immediately after the animal returned to the start position, the left and right gold doors were opened and the animal was allowed to freely choose between the left and right goal arms ("free choice trial"). An arm was considered to have been entered when the animal placed all four forepaws into the arm. The session was terminated and the animal was removed from the maze after 14 free choice trials had been performed or after 10 min had elapsed, whichever occurred first.

[0345] The percentage of alternations across 14 free-choice trials (number of alternations / 14*100) was determined for each mouse and used as an index of working memory performance, defined as entries into different arms of the T-maze across consecutive trials (i.e., left-right-left-right, etc.).

[0346] Analysis of variance (ANOVA) was performed on the outcome data. Fisher's PLSD test was used for pairwise comparisons, and a p-value of <0.05 was considered significant. Drug-induced reversal of LPS-induced memory impairment was calculated by setting the respective response of saline / vehicle as 100% and the respective response of group LPS / vehicle as 0% reversal.

[0347] A single injection of 250 μg / kg LPS resulted in a significant decrease in spontaneous alternation in mice (approximately 24% decrease in the study evaluating A19 and 44% decrease in the studies evaluating compounds 1a and 5a) compared to the performance of saline-injected mice (no LPS) when evaluated 2 weeks after injection. Indeed, in the study evaluating A19, the substitution rates for the LPS / vehicle and saline / vehicle groups were 45 and 69%, respectively. In the studies evaluating compounds 1a and 5a, the substitution rates were 44% and 70% for the LPS / vehicle and saline / vehicle groups, respectively. The reduced alternation rate in LPS mice suggests cognitive impairment. Table 6 shows the spontaneous alternation and recovery rates for each treatment group.

[0348] As shown in Table 6, compound A19 produced dose-dependent recovery of LPS-induced deficits in mouse T-maze alternation test. Indeed, the alternation rates for compound A19 doses of 1.25, 1, 0.5, 0.25 and 0.125 mg / kg were 61, 61, 64, 60 and 42%, respectively. These alternation rates correspond to 65, 65, 79, 62 and -12% recovery in cognitive performance of LPS mice for compound A19 doses of 1.25, 1, 0.5, 0.25 and 0.125 mg / kg, respectively. The effect of compound A19 was significant at all doses except 0.125 mg / kg. Furthermore, compound 1a produced dose-dependent recovery of LPS-induced deficits in mouse T-maze alternation test. The alternation rates were 49, 59, 56, 51, and 56% at 0.5, 2, 8, 16, and 32 mg / kg, respectively. The antagonism rates were 17, 56, 47, 28, and 44% at 0.5, 2, 8, 16, and 32 mg / kg, respectively. Compound 5a was also evaluated for reversal of LPS-induced deficits in the mouse T-maze alternation test. The alternation rates were 59, 58, 61, 58, and 60% at 1.25, 2.5, 5, 10, and 20 mg / kg, respectively. The antagonism rates were 58, 53, 64, 53, and 61% at 1.25, 2.5, 5, 10, and 20 mg / kg, respectively.

[0349] LPS mice treated with memantine (1 and 0.1 mg / kg) showed alternation rates of 54 and 64%, respectively (see Table 6). These rates correspond to a 38 and 76% recovery in cognitive performance in LPS-treated mice. The effect of memantine was significant at both doses.

[0350] In line with literature findings, memantine produced a significant increase in spontaneous alternation in LPS-treated mice, suggesting improved cognitive performance in the T-maze assay. Compound A19 at 0.125 mg / kg (the lowest tested dose) was ineffective in reversing LPS-induced cognitive impairment, but higher dose levels (up to 1.25 mg / kg) significantly improved cognitive performance in LPS mice.

[0351] The results for compounds 1a and 5a are shown in Table 7. Compound 1a showed significant reversal of LPS-induced cognitive impairment at 2 mg / kg and showed a trend at 8 and 32 mg / kg. Compound 5a produced significant reversal of LPS-induced cognitive impairment at all doses.

[0352] The results show that Compound A19, Compound 1a, and Compound 5a reversed LPS-induced cognitive impairment in the mouse T-maze assay. TIFF2025508768000063.tif78170TIFF2025508768000064.tif107170

[0353] Example B5: Reduction of pro-inflammatory cytokine expression in macrophage-like cell cultures. Neuroinflammation plays a key role in disease progression such as long COVID and is a complex phenomenon involving various cells that affect many extracellular and intracellular signaling pathways as well as cytokine production. Brain macrophages (microglia) are the main agents of innate immunity in the CNS and perform various functions, including neuroprotection, in response to inflammatory signals. Activated microglia are involved in the development of neuroinflammation and respond to toxic exogenous substances (such as LPS) or endogenous substances (such as amyloid beta). Here, we use THP1 cells as an in vitro cell model to evaluate mechanisms related to CNS inflammation. Upon differentiation with PMA, THP1 monocytic cells acquire functional and morphological similarities to macrophages. LPS interacts with THP-1 differentiated macrophages via toll-like receptor 4, inducing an inflammatory response, stimulating proinflammatory cytokine release, and ultimately resulting in cell death. Here, we investigated whether test compounds have anti-inflammatory effects on LPS-challenged macrophage cultures. THP1-differentiated macrophages were treated with test compounds for 20 min followed by a 24-h LPS challenge, and culture supernatants were then collected and analyzed for the presence of proinflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α).

[0354] Cytokine quantification in cell culture supernatants was achieved by HTRF kits to assess the levels of IL-1β (Human IL-1β Kit, #62HIL1BPEG, Cisbio) and IL-6 (Human IL-6 Kit, 62HIL06PET, Cisbio), and ELISA to determine the levels of TNF-α (Human TNF-α ELISA Kit, KHC3011, ThermoFisher).

[0355] Data analysis was performed using Prism statistical software (GraphPad) via one-way ANOVA with Tukey post-hoc test compared to LPS-treated cultures. Tabulated data show the significance of reduction in culture supernatants of the indicated analytes at the indicated doses.

[0356] The results are summarized in Table 8. Treatment with compounds 1a, 5a, 6a, and the active metabolite of compound A19 (dihexa) all significantly reduced the expression of IL-1β and TNF-α at at least one dose tested. Treatment with compounds 1a, 5a, and the active metabolite of A19 all significantly reduced the expression of IL-6 at at least one dose tested, with "NS" indicating a non-significant reduction in the indicated cytokine. "+" indicates a p-value of <0.05 in the Tukey post-hoc test. "++" indicates a p-value of <0.01 in the Tukey post-hoc test. TIFF2025508768000065.tif104170

[0357] Example B6: Treatment of bleomycin-induced pulmonary fibrosis with compound 1a. The ability of compound 1a to reduce pulmonary fibrosis was tested in a model of bleomycin-induced pulmonary fibrosis, with some long COVID patients developing pulmonary fibrosis.

[0358] Briefly, tail-deprived male C57BL / 6 mice (Envigo) were used. Mice were 3.5-4 months old and approximately 24-30 g (weight). On day -1, animals were randomized based on body weight and assigned permanent numbers by ear notch. Cages were identified by cage cards detailing study code, group number, sex, dose, cage number, animal number, and animal number.

[0359] On day 0, all animals (except sham control animals) received bleomycin (0.03 U in 50 μl saline) intratracheally (it) under ketamine + xylazine anesthesia. Sham control animals received 50 μl saline intratracheally. Pirfenidone was used as a positive control; this compound is known to downregulate growth factors and procollagen to reduce fibrosis and is an approved drug for the treatment of idiopathic pulmonary fibrosis.

[0360] Vehicle, pirfenidone, and test compound 1a were administered from day 3 to day 21, as described in Table 9 below. On day 21, whole blood was collected 1 hour after administration into EDTA and then processed into plasma. Right lung was then collected, weighed, flash frozen, and then homogenized for biochemical analysis. Hydroxyproline, collagen, and TGF-beta levels were measured in right lung homogenate.

[0361] The study groups were as follows: TIFF2025508768000066.tif113170

[0362] Induction of disease in this mouse model with bleomycin caused significant weight loss, as determined by daily weight monitoring.Treatment with compound 1a or pirfenidone did not prevent weight loss.Weight loss was similar in bleomycin alone, bleomycin + pirfenidone and bleomycin + compound 1a groups during the study period.Mice treated with compound 1a at 0.8mg / k showed slightly greater weight loss compared to other treatment groups.

[0363] At termination (day 21), total right lung weights were lower in the highest dose of Compound 1a, 8 mg / kg, and 2 mg / kg treatment groups than in the positive control pirfenidone-treated animals. Because fibrosis increases lung weight, this result indicated that Compound 1a was active in reducing fibrosis in this model.

[0364] Collagen is deposited at the site of injury and fibrosis in this model. Hydroxyproline concentration, which is the main component of protein collagen and a biomarker of fibrosis, was measured in right lung homogenate at termination. The treatment groups using the highest dose of compound 1a, 8 mg / kg and 2 mg / kg, had lower concentrations of hydroxyproline, and the hydroxyproline concentration in these groups was lower than that of the positive control pirfenidone-treated animals. Similarly, the collagen concentration in right lung homogenate at 8 mg / kg compound 1a was reduced compared to the pirfenidone positive control. Treatment with 2 mg / kg compound 1a and pirfenidone resulted in approximately the same level of collagen in right lung homogenate.

[0365] TGF-β promotes fibrosis in this model by increasing macrophage density at the injury site. On day 21, all doses of compound 1a and pirfenidone significantly prevented the bleomycin-induced increase in TGF-β in right lung homogenates. Table 10 summarizes the changes in bleomycin-induced (BLM-induced) changes in this model. TIFF2025508768000067.tif63170

[0366] These data indicate that compound 1a was active in treating pulmonary fibrosis in a model.

[0367] Example B7: Treatment of acute pneumonia as a precursor to pulmonary fibrosis. Acute pulmonary inflammation can be effectively modeled in rats by intratracheal administration of bacterial lipopolysaccharide (LPS). Lung inflammation that is left unresolved can lead to pulmonary fibrosis, which has been reported in long Covid patients. The normal process of inflammation is regulated and promoted by the expression, secretion, and distribution of inflammatory signaling proteins. Therapeutics intended to reduce inflammation are generally identified by their ability to alter the expression levels of inflammatory signaling molecules, either by direct disruption of inflammatory pathways or by degradation of inflammatory signaling cascades. The severity of the inflammatory response can be measured by quantifying the amount of immune cell infiltration and secretion of cytokine signaling proteins in the bronchoalveolar lavage fluid (BALF). Activation of the HGF / MET signaling system by HGF / MET positive modulators is expected to reduce the inflammatory response. Two test compounds, compound 1a and compound 5a, were evaluated for their ability to reduce acute lung inflammation in the LPS model.

[0368] In this study, acute pneumonia was induced in healthy male Sprague-Dawley rats (7-9 weeks old at the start of the study) by intratracheal instillation of 20 μg LPS in saline. Test animals were treated twice with test compounds by intravenous (IV) injection, 24 h and 0.5 h prior to LPS treatment. The anti-inflammatory corticosteroid, dexamethasone (Dex), was used as a positive control and was administered 1 h prior to LPS treatment by intraperitoneal (IP) injection of 3 mg / kg. Four hours after LPS administration, animals were euthanized by intraperitoneal injection of thiopentone, and 20 mL of cold Hank's balanced salt solution (pH 7.2) was instilled into the lungs through the tracheal cannula. BALF was then collected.

[0369] Immune cell infiltration in BALF was quantified as an assessment of the inflammatory response, and the results are shown in Table 11. Immune cell infiltration was performed by counting total white blood cells using a MUSE® miniature flow cytometer and by manually counting neutrophil cells in cytospin smears stained with Leishman's staining reagent. Treatment with Compound 1a and Compound 5a reduced both total white blood cell and neutrophil counts compared to the LPS-only control. TIFF2025508768000068.tif57170

[0370] Cytokine expression in BALF supernatants was quantified by multiplex immunoassay using a MAGPIX multiplex unit with a cytokine multiplex kit (Merck-Millipore, Cat. No. RECYMAG65K27PMX). The panel of cytokines tested included growth factors (G-CSF, GM-CSF, EGF, VEGF, TNF-α), chemokines (CCL2, CCL3, CCL5, CCL11, CXCL1, CXCL2, CXCL5, CXCL10, CX3CL1), interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A), and interferon gamma (IFNγ). The results of this analysis are shown in Table 12. Statistically significant changes from LPS-only animals were determined by Student's T-test, with p<0.05 indicating a statistically significant change in cytokine expression levels. Treatment with compound 1a results in significant changes in the expression of G-CSF, CXCL2, CXCL10, IFN-γ, and IL-1β. Treatment with compound 5a results in significant changes in the expression of CCL3, CXCL1, IFN-γ, IL-1α, IL-1β, IL-10, IL-12p70, and IL-17A. These results indicate that treatment with the test compound significantly affected the acute pulmonary inflammatory response to LPS by reducing the levels of pro-inflammatory molecules. The normal process of inflammation is regulated and promoted by the expression, secretion, and distribution of inflammatory signaling proteins. TIFF2025508768000069.tif193170

[0371] Example B8: In vivo efficacy: Scopolamine-induced spatial memory impairment in the Morris water maze. Compounds 2a and 6a were evaluated in the Morris water maze for their ability to reverse scopolamine-induced spatial memory deficits in rats. Scopolamine impairs cognition through inhibition of neurotransmitter systems, acetylcholine, and muscarinic acetylcholine receptors. It has been suggested that the SARS-CoV-2 viral spike protein may produce cognitive deficits by binding to and inhibiting the nicotinic acetylcholine receptor. It is proposed that compound A19 and the compound of formula 1 can overcome the inhibition of the nicotinic acetylcholine receptor, thereby compensating for cognitive deficits. The activity of compounds 2a and 6a was tested in this scopolamine-induced spatial memory deficit model to determine whether compound A19 and the compound of formula 1 can compensate for cognitive deficits, such as spatial memory deficits, through the relevant neurotransmitter systems.

[0372] The water maze consisted of a large circular tank (2.1 m diameter) filled with 26–28°C water to a depth of approximately 30 cm, and the water was made cloudy with white paint. A circular platform (13 cm diameter) was fixed 2–3 cm below the water surface. High-contrast visual cues were placed around the tank to aid the spatial orientation of the test animals. Testing consisted of placing the animal in the water facing the tank wall at one of three randomly assigned starting points and allowing the animal to swim for up to 120 s to search for the hidden platform. The time it took the animal to locate the platform was recorded as escape latency. Animals were tested five times per day with a 30-s break between trials. Testing took place over a total of eight consecutive days.

[0373] Animals were divided into groups (N=8 / group) according to treatment. Control animals received only empty vehicle. Scopolamine group received 3 mg / kg scopolamine dissolved in sterile saline by intraperitoneal (IP) injection 30 min before testing. Test compound group received various concentrations of test compound dissolved in 48% sterile saline, 50% polyethylene glycol (PEG-400), and 2% DMSO by oral gavage (PO) 40 min before testing. For each animal, escape latency was recorded for 8 consecutive days with 5 trials per day. Curve changes in escape latency were statistically analyzed by two-way ANOVA and Bonferroni post-hoc test. The results are shown in Table 13.

[0374] Exemplary compound 1a was evaluated in the Morris water maze for its ability to reverse chemically induced spatial memory impairment in rats. The water maze consisted of a large circular tank (1.5 m diameter) filled with 23-26°C water to a depth of approximately 30 cm, and the water was made opaque with white paint. A circular platform was fixed 2-3 cm below the water surface. High contrast visual cues were placed around the tank to aid in spatial orientation of the test animals. Testing consisted of placing the animal in the water facing the tank wall at one of three randomly assigned starting points and allowing the animal to swim for up to 90 seconds to search for the hidden platform. The time it took the animal to locate the platform was recorded as escape latency. Animals were tested five times per day with a 30 second break between trials. Testing was performed for a total of five consecutive days.

[0375] Animals were divided into groups (N=12 / group) according to treatment. Control animals received only empty vehicle. Scopolamine group received 2 mg / kg scopolamine dissolved in sterile saline by intraperitoneal (IP) injection 30 min before testing. Test compound group received various concentrations of test compound dissolved in 78% sterile saline, 20% polyethylene glycol (PEG-400), and 2% DMSO by oral gavage (PO) 40 min before testing. For each animal, escape latency was recorded for 5 consecutive days with 5 trials per day. Curve changes in escape latency were statistically analyzed by two-way ANOVA and Bonferroni post-hoc test. The results are shown in Table 13. TIFF2025508768000070.tif94170

[0376] Example B9: Treatment with compound ATH-1017 reduces GST and levels of biomarkers of neuroinflammation. Patients with mild to moderate Alzheimer's disease (AD) were treated with the compound ATH-1017 or placebo as part of the randomized, double-blind, placebo-controlled Phase 2 ACT-AD study (NCT04491006). As part of this study, changes from baseline using the Global Statistical Test (GST), a composite score informed by both the ADAS-Cog11 and Activities of Daily Living (ADCS-ADL23), were measured in participants with mild to moderate Alzheimer's disease (AD) treated with the compound ATH-1017 or placebo. Changes from baseline in plasma biomarkers were also measured in these participants. The study enrolled 77 patients (ages 55-85 years) from the United States and Australia. Patients were allowed to continue their standard of care (AChEI), with 60% continuing on a stable dose of AChEI during the study and 40% not receiving AChEI. Patients were randomized 1:1:1 to receive placebo or the compound ATH-1017 at either 40 mg / day or 70 mg / day.

[0377] The compound ATH-1017 was generally well tolerated and had a favorable safety profile. No treatment-related serious adverse events or deaths were observed in this study. Participants treated with 40 mg or 70 mg of the compound ATH-1017 for 26 weeks showed a higher incidence of treatment-emergent adverse events compared to placebo. The most frequent adverse event was injection site reaction (occasionally accompanied by a transient and asymptomatic increase in absolute eosinophil counts). The study had a 14% early termination rate.

[0378] The primary endpoint, ERP P300 latency, was not met by protocolized analysis. A post-hoc analysis comparing participants receiving the compound ATH-1017 without background therapy to those receiving placebo showed that 79% of patients showed improved cognition over 6 months versus placebo as measured by ADAS-Cog11. 51% showed improvement over 6 months versus placebo as measured by ADCS-ADL23 in the full study population (including patients receiving background therapy). Overall, patients receiving the compound ATH-1017 showed improvement in GST.

[0379] Blood samples were collected at baseline (N=77) and at week 26 of treatment. Biomarkers evaluated included neurofilament light chain (NfL, indicative of ongoing neurodegeneration), GFAP (indicative of microglial activation), and YKL-40 (indicative of neuroinflammation). Results are presented as pooled active arms versus placebo, without background therapy.

[0380] Baseline biomarker levels were similar between treatment groups. Participants receiving compound ATH-1017 demonstrated a statistically significant change from baseline versus placebo in NfL (-7.9 pg / mL, SE 2.7, p=0.0059) and directionally favorable improvements in GFAP (-29.3 pg / mL, SE 28.6, p=0.312), YKL-40 (-34.9 ng / mL, SE 26.5, p=0.195). Participants' ApoE4 genotype, baseline Mini-Mental State Examination score, sex, or age did not affect these results. In analyses to confirm correlations between biomarkers and clinical endpoints, the composite endpoint GST proved to be highly correlated with changes in NfL (r=0.46, P=0.0011) and GFAP (r=0.30, P=0.0394).

[0381] Statistically significant improvements in NfL, as well as descriptive and consistent improvements in GFAP and YKL-40 plasma concentrations, were observed, which would be consistent with ATH-1017's neuroprotective effects and multimodal mechanism of action. The significant correlation of NfL and GFAP reductions with composite clinical endpoints further supports clinical relevance, suggesting that the compound ATH-1017 reduces inflammation and improves cognition in patients with long COVID.

[0382] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0383] Thus, although the present disclosure has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications, improvements, and variations of the present disclosure embodied therein disclosed herein may be employed by those skilled in the art, and that such modifications, improvements, and variations are considered to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments and are illustrative, and are not intended to limit the scope of the present disclosure.

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Claims

1. A method of treating long COVID comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

2. A method of treating the long-term sequelae of infection with SARS-CoV-2, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

3. 1. A method of treating acute post-COVID-19 syndrome, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

4. 1. A method of treating a post-COVID-19 symptom, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

5. 1. A method of improving event-related potential (ERP) P300 latency in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

6. 1. A method of slowing cognitive decline or improving cognition in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

7. 1. A method of delaying the decline in or improving the ability to perform activities of daily living and verbal fluency in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

8. 1. A method of slowing functional or cognitive decline in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

9. 1. A method of delaying clinical decline in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

10. 1. A method of improving executive memory function in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

2. The method of any one of the preceding claims, wherein the HGF / MET agonist is an antibody, an aptamer, a peptide, and / or a small molecule.

11. 1. A method of treating fibrosis in a patient diagnosed with long COVID, comprising administering to a patient in need thereof a therapeutically effective amount of an HGF / MET agonist.

12. The method of claim 11, wherein the fibrosis is pulmonary fibrosis or peripheral nerve fibrosis.

13. 10. The method of any one of the preceding claims, comprising administering to said patient 2-90 mg of said HGF / MET agonist per day.

14. 13. The method of any one of the preceding claims, wherein the HGF / MET agonist is N-hexanoic acid-Tyr-Ile-(6) aminohexanoic acid amide (Dihexa) or a pharma- ceutically acceptable salt or prodrug thereof.

15. The HGF / MET agonist is 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof.

16. The HGF / MET agonist is Compounds of formula (I): 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, L is a direct bond, -C(=O)-, -(CR ａ R ｂ ) ｍ -C(=O)-, -C(=O)-(CR ａ R ｂ ) ｍ - or - (CR ａ R ｂ ) ｍ - and Each R ａ and R ｂ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ is alkynyl, R １ａ and R １ｂ are independently H, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Alkoxy, halo, or C ６ -C １０ is arylalkyl, R ２ is H, oxo, or thioxo; R ３ is C ２ -C ６ Alkyl, C ３ -C ６ Alkenyl, C ３ -C ６ Alkynyl, C ３ -C １２ Cycloalkyl, C ３ -C ６ Cycloalkylalkyl, C ６ -C １０ arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl; wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R ４ is C ６ -C １０ aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl; wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; Each R ５ is independently １ -C ６ alkyl, oxo, or halo; R ６ is H, C １ -C ６ alkyl, or oxo; R ７ is H or oxo, m is 1 or 2; n is an integer from 0 to 3, Here, each C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １２ Cycloalkyl, C ３ -C １２ Cycloalkylalkyl, C ６ -C １０ Aryl, C ６ -C １０ Arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl are hydroxyl, halo, amino, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, cyano, -(C=O)NH ２ , nitro, -SO ２ (C １ -C ６ alkyl), and -CO ２ The method of any one of claims 1 to 13, optionally substituted with 1 to 5 substituents selected from H.

17. The compound of formula (I) is a compound of formula (II), (IIa), (IIb), (IIc), (IId), or (IIe): 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, １ａ , R １ｂ , R ３ , R ４ , R ５ , R ６ , R ７ 17. The method of claim 16, wherein and n are as described for formula (I).

18. The method of any one of claims 1-13 or 16-17, wherein the HGF / MET agonist is a compound listed in Table 1 or a pharma- ceutically acceptable salt thereof, or a compound listed in Table 1A or a pharma- ceutically acceptable salt thereof.

19. The HGF / MET agonist is 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof.

20. The HGF / MET agonist is 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof.

21. 10. The method of any one of the preceding claims, wherein prior to treatment, the patient exhibits one or more symptoms selected from anxiety, lethargy, shortness of breath, chest pain, cognitive impairment, depression, fatigue, impaired lung function, decreased liver function, increased incidence of venous thromboembolism, muscle weakness, fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, peripheral nerve fibrosis, and / or respiratory complications.

22. 10. The method of any one of the preceding claims, wherein prior to treatment, the patient exhibits cognitive impairment.

23. 23. The method of claim 22, wherein the cognitive impairment is attention, working memory, processing speed, executive function, phonemic fluency, categorical fluency, memory encoding, memory recall, and / or memory recognition cognitive impairment.

24. 24. The method of claim 22 or 23, wherein the cognitive impairment is indicative of an executive pattern.

25. The method of any one of claims 22 to 24, wherein the cognitive impairment is indicative of a dysexecutive syndrome.

26. 10. The method of any one of the preceding claims, wherein prior to treatment, the patient exhibits fibrosis.

27. 27. The method of claim 26, wherein the fibrosis is pulmonary fibrosis and / or peripheral nerve fibrosis.

28. 10. The method of any one of the preceding claims, wherein the patient has previously been diagnosed with airway disease, asthma, such as moderate to severe asthma, bronchiectasis, bronchopulmonary dysplasia, cancer, chronic lung disease, chronic obstructive pulmonary disease (COPD), diabetes, hypertension, interstitial lung disease, pulmonary embolism, and / or pulmonary hypertension.

29. 10. The method of any one of the preceding claims, which slows the decline in functional or cognitive ability of the patient.

30. 10. A method according to any one of the preceding claims, wherein the method slows cognitive decline in the patient.

31. 2. A method according to any one of the preceding claims, which improves cognition in the patient.

32. 13. A method according to any one of the preceding claims, which delays the decline in practical activities of daily living, ability to perform basic activities of daily living, ability to manage finances, and / or language fluency in said patient.

33. 13. A method according to any one of the preceding claims, which improves the patient's ability to carry out activities of daily living, ability to manage finances, and / or language fluency.

34. 2. The method of any one of the preceding claims, wherein the delay or amelioration of the decline is determined after at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks of administration of the treatment.

35. 13. The method of any one of the preceding claims, which reduces, stabilises or improves the rate of decline in practical (23-item) Activities of Daily Living (ADL) scores.

36. 36. The method of claim 35, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

37. 37. The method of claim 35 or 36, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

38. 13. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline in basic (19-item) Activities of Daily Living (ADL) scores.

39. 39. The method of claim 38, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

40. 40. The method of claim 38 or 39, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

41. 13. The method of any one of the preceding claims, which reduces, stabilises or improves the rate of decline in Financial Capability Index (FCI) scores.

42. 42. The method of claim 41, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

43. 43. The method of claim 41 or 42, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

44. 10. The method of any one of the preceding claims, wherein the patient has a Mini-Mental State Examination (MMSE) score of 27 or less prior to initiating the treatment.

45. 13. The method of any one of the preceding claims, wherein the rate of decline in MMSE score is reduced, stabilized, or improved.

46. 46. ​​The method of claim 45, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

47. 47. The method of claim 45 or 46, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

48. 13. The method of any one of the preceding claims, wherein cognitive performance is assessed using the Alzheimer's Disease (AD) Assessment Scale-Cognitive Subscale (ADAS-Cog) by determining the patient's score before and after administration of the treatment.

49. 49. The method of claim 48, wherein cognitive performance is assessed prior to initiation of said treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of said treatment.

50. 50. The method of claim 48 or 49, wherein the rate of decline in ADAS-Cog is reduced, stabilized, or ameliorated.

51. 10. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline in Montreal Cognitive Assessment (MoCA) scores.

52. 52. The method of claim 51, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

53. 53. The method of claim 51 or 52, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

54. 13. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline in Digit Symbol Substitution Test (DSST) scores.

55. 55. The method of claim 54, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

56. 56. The method of claim 54 or 55, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

57. 10. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline in Disability Assessment of Dementia (DAD) scores.

58. 58. The method of claim 57, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

59. 59. The method of claim 57 or 58, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

60. 10. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline in Neuropsychiatric Inventory (NPI) scores.

61. 61. The method of claim 60, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

62. 62. The method of claim 60 or 61, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

63. 13. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline in Controlled Word Association Test (COWAT) scores.

64. 64. The method of claim 63, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

65. 65. The method of claim 63 or 64, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

66. 13. A method according to any one of the preceding claims, which reduces, stabilises or improves the rate of decline of numerical span forward and / or backward scores.

67. 67. The method of claim 66, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

68. 68. The method of claim 66 or 67, wherein the reduction, stabilization, or improvement in the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

69. 13. The method of any one of the preceding claims, which reduces, stabilizes or improves the rate of decline of the Trail Making Test Part A and / or Part B.

70. 70. The method of claim 69, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

71. 71. The method of claim 69 or 70, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

72. 10. A method according to any one of the preceding claims, which reduces, stabilises or improves the rate of decline in phoneme and category fluency scores.

73. 73. The method of claim 72, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

74. 74. The method of claim 72 or 73, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

75. 13. A method according to any one of the preceding claims, which reduces, stabilises or improves the rate of decline in Hopkins Verbal Learning Test-Revised scores.

76. 76. The method of claim 75, wherein the reduction, stabilization, or amelioration of the rate of decline occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

77. 77. The method of claim 75 or 76, wherein the reduction, stabilization, or amelioration of the rate of decline is assessed by determining the patient's scores before initiation of the treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

78. 10. A method according to any one of the preceding claims, which reduces, stabilises or delays the onset of fibrosis.

79. 79. The method of claim 78, wherein the fibrosis is pulmonary fibrosis and / or peripheral nerve fibrosis.

80. 80. The method of claim 78 or 79, wherein the reduction, stabilization, or delay in onset occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of the treatment.

81. 81. The method of any one of claims 78-80, wherein the reduction, stabilization, or delay in onset is assessed by determining the patient's scores before initiation of treatment and at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of treatment.

82. 10. A method according to any one of the preceding claims, resulting in a rapid improvement or normalisation of P300 amplitude values.

83. 13. A method according to any one of the preceding claims, resulting in a rapid improvement or normalisation of event-related potential (ERP) P300 latency values.

84. 10. The method of any one of the preceding claims, which results in rapid improvement or normalization of ERP P300 latency values, with some maintenance of efficacy 4 weeks after cessation of treatment.

85. 13. The method of any one of the preceding claims, which results in a rapid improvement or normalization of ERP P300 latency values ​​that is maintained 4 weeks after cessation of treatment.

86. 13. A method according to any one of the preceding claims, which improves event-related potential (ERP) P300 latency.

87. 87. The method of any one of claims 82-86, wherein said improvement or said normalization of P300 value occurs by at least 2 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 18 weeks, at least 20 weeks, at least 22 weeks, at least 24 weeks, or at least 26 weeks after initiation of said treatment.

88. 2. The method of any one of the preceding claims, wherein the HGF / MET agonist has an acceptable safety and tolerability profile.

89. 10. The method of any one of the preceding claims, wherein the HGF / MET agonist is generally safe and well tolerated.

90. 13. The method of any one of the preceding claims, wherein the HGF / MET agonist is administered by oral dosing, such as by subcutaneous injection or by a solid oral dosage form.

91. 2. The method of any one of the preceding claims, wherein the HGF / MET agonist is administered by subcutaneous injection.

92. 2. The method of any one of the preceding claims, comprising administering the HGF / MET agonist for 26 weeks or more.

93. 4. The method of any one of the preceding claims, wherein the HGF / MET agonist is the sodium salt of a compound of formula A19.

94. 4. The method of any one of the preceding claims, wherein the HGF / MET agonist is the monosodium salt of the compound of formula A19.

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