Treatment methods for neuropathy

Abstract

Provided herein are compounds and compositions thereof for modulating hepatocyte growth factor. In some embodiments, the compounds and compositions are provided for the treatment of diseases, including neurological disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 338,199, filed May 4, 2022, U.S. Provisional Application No. 63 / 424,350, filed November 10, 2022, and U.S. Provisional Application No. 63 / 445,864, filed February 15, 2023, each of which is incorporated by reference in its entirety and for all purposes.

[0002] The present disclosure relates generally to compounds, compositions, and methods for treating diseases such as neuropathies, e.g., polyneuropathies and mononeuropathies. [Background technology]

[0003] Hepatocyte growth factor (HGF) is a pleiotropic protein factor involved in numerous biological processes, including embryonic and organ development, regeneration, and inflammation. HGF plays a key role in the development and maturation of cortical, motor, sensory, sympathetic, and parasympathetic neurons. 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).

[0004] HGF has shown roles in development (Nakamura et al., 2011), homeostasis (Funakoshi and Nakamura, 2003), inhibition of cell death, and regeneration (Matsumoto et al., 2014). The HGF / MET signaling pathway has also been implicated in several chronic pain disorders. Thus, stimulation of the HGF / MET signaling system is an ideal target for the treatment of 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). However, highly effective compounds useful for modulating HGF / MET signaling activity have yet to be explored or discovered.

[0005] Despite advances in the field, there remains a need for improved compounds and methods for the treatment of HGF-regulated disorders. Summary of the Invention

[0006] Provided herein are compounds that modulate HGF for use in treating neuropathies, including mononeuropathies and polyneuropathies. Non-limiting exemplary embodiments include the following:

[0007] Embodiment 1. A method of treating a neurological disorder in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein 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 cycloalkyl alkyl, 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, Here, each of C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C 12 Cycloalkyl, C3~C 12 Cycloalkylalkyl, C6-C10 Aryl, C6-C 10 Arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclylalkyl are hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, The process, wherein the alkyl group is optionally substituted with 1 to 5 substituents selected from -SO2(C1-C6 alkyl), and -CO2H.

[0008] Embodiment 2. L is -C(=O)- or -(CR a R b ) m 2. The method of embodiment 1, wherein

[0009] Embodiment 3. The method of embodiment 1 or 2, wherein L is -C(=O)-.

[0010] Embodiment 4. L is -(CR a R b ) m 3. The method of embodiment 1 or 2, wherein

[0011] Embodiment 5.R a and R b 5. The method of embodiment 4, wherein each is H and m is 1.

[0012] Embodiment 6.R 1a and R 1b each independently represents 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 The method of any one of the preceding embodiments, wherein the is arylalkyl.

[0013] Embodiment 7.R 1a and R 1bare each independently H, methyl, fluoro, 2-methylbutyl, -CH2F, methoxy, -CH2CO2H, The method of embodiment 6, wherein the is -CH2C(=O)NH2, benzyl, or 4-aminobenzyl.

[0014] Embodiment 8.R 1a and R 1b is each independently H or C1-C3 alkyl.

[0015] Embodiment 9.R 1a is methyl and R 1b 9. The method of embodiment 8, wherein

[0016] Embodiment 10.R 1a and R 1b 9. The method of embodiment 8, wherein each is H.

[0017] Embodiment 11.R 2 The method of any one of the preceding embodiments, wherein

[0018] Embodiment 12.R 2 The method of any one of the preceding embodiments, wherein is thioxo.

[0019] Embodiment 13.R 2 The method of any one of embodiments 1-10, wherein is oxo.

[0020] Embodiment 14.R 3 is C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkyl alkyl, C6-C 10The method of any one of embodiments 1-13, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl is 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.

[0021] Embodiment 15.R 3 The method of any one of embodiments 1-13, wherein 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 cycloalkyl alkyl; a 5-6 membered heteroaryl alkyl; a 5-6 membered heterocyclyl alkyl; or a C6 aryl alkyl.

[0022] Embodiment 16.R 3 is a C2 alkyl substituted with 1 to 3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(C1-C3 alkyl).

[0023] Embodiment 17.R 3 The method according to any one of embodiments 14 to 16, wherein [ka]

[0024] Embodiment 18.R 3 18. The method of embodiment 17, wherein: [ka]

[0025] Embodiment 19.R 4 is optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1 to C6 haloalkyl, and C1 to C6 haloalkoxy; 10 The method of any one of the preceding embodiments, wherein the is aryl.

[0026] Embodiment 20.R 4 is phenyl substituted with 1 to 3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.

[0027] Embodiment 21.R 4 21. The method of embodiment 20, wherein: [ka]

[0028] Embodiment 22.R 4 22. The method of embodiment 21, wherein: [ka]

[0029] Embodiment 23.R 4 The method of any one of embodiments 1-18, wherein is a 5-10 membered heteroaryl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0030] Embodiment 24.R 4 is pyridyl or indolyl optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0031] Embodiment 25.R 4 but, [ka] 25. The method of embodiment 24, wherein

[0032] Embodiment 26.R 4 but, [ka] 26. The method of embodiment 25, wherein

[0033] Embodiment 27.R 4 The method of any one of embodiments 1-18, wherein is a 5-10 membered heterocyclyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0034] Embodiment 28.R 4 28. The method of embodiment 27, wherein is indolinyl.

[0035] Embodiment 29.R 4 but, [ka] 29. The method of embodiment 28, wherein

[0036] Embodiment 30.-LR 4 The method of any one of embodiments 1 to 26, wherein: [ka]

[0037] Embodiment 31. The method of any one of embodiments 1 to 30, wherein n is 0.

[0038] Embodiment 32. The method of any one of embodiments 1 to 30, wherein n is 1.

[0039] Embodiment 33.R 5 is oxo or halo.

[0040] Embodiment 34.R 5 is oxo or fluoro.

[0041] Embodiment 35.R 6 The method of any one of the preceding embodiments, wherein

[0042] Embodiment 36.R 7 The method of any one of embodiments 1-35, wherein is oxo.

[0043] Embodiment 37. The compound has the formula (V): [ka] (V), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0044] Embodiment 38. L is -C(=O)- or -CH2-; R 1a and R 1b is independently H, or C1-C3 alkyl optionally substituted with -CO2H; R 3 is C1-C3 alkyl substituted with C4-C5 alkyl, C4-C5 alkenyl, or C3-C5 cycloalkyl; R 4 38. The method of embodiment 37, wherein is phenyl or pyridyl substituted with 1 to 3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.

[0045] Embodiment 39. A method of treating a neurological disorder in a subject in need thereof, comprising administering to a subject an effective amount of compound A19: [ka] or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0046] Embodiment 40. A method of treating a neurological disorder in a subject in need thereof, comprising administering to a subject an effective amount of a compound of Table 1A and compound A19: [ka] and pharma- ceutically acceptable salts, isotopic forms, and stereoisomers thereof.

[0047] Embodiment 41 The method of any one of the preceding embodiments, wherein the neuropathy is a mononeuropathy or a polyneuropathy.

[0048] Embodiment 42 The method of any one of the preceding embodiments, wherein the neuropathy is a polyneuropathy.

[0049] Embodiment 43 The method of any one of the preceding embodiments, wherein the neuropathy is a sensory neuropathy.

[0050] Embodiment 44. The method of embodiment 43, wherein the subject is experiencing numbness, tingling, and / or pain associated with the neuropathy prior to administration of the compound.

[0051] Embodiment 45 The method of embodiment 44, wherein the subject is experiencing neuropathic pain prior to administration of the compound.

[0052] Embodiment 46. The method of any one of embodiments 43-45, wherein the sensory neuropathy is peripheral, autonomic, proximal, or focal.

[0053] Embodiment 47. The method of any one of the preceding embodiments, wherein the neuropathy is associated with nerve damage or dysfunction, such as nerve compression or trigeminal neuralgia, excessive alcohol consumption, stroke, shingles (e.g., postherpetic neuralgia (PHN)), HIV, leprosy, Guillain-Barré syndrome, vascular disease, vascular malformation, diabetes (e.g., painful diabetic neuropathy), chemotherapy, radiation therapy, or an autoimmune disease.

[0054] Embodiment 48 The method of any one of the preceding embodiments, wherein the neuropathy is painful diabetic neuropathy.

[0055] Embodiment 49. The method of any one of embodiments 1 to 46, wherein the neuropathy is idiopathic.

[0056] Embodiment 50. The method of any one of the preceding embodiments, wherein the neuropathy is not associated with cancer or chemotherapy.

[0057] Embodiment 51. The method of any one of embodiments 1 to 49, wherein the neuropathy is associated with chemotherapy or radiation therapy.

[0058] Embodiment 52. The method of any one of the preceding embodiments, wherein the treating comprises relieving neuropathic numbness, tingling, and / or pain.

[0059] Embodiment 53 The method of any one of the preceding embodiments, wherein the compound is formulated as a pharmaceutical composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] definition 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. In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. It should be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not intended to limit any of the subject matter claimed. In the event that any material incorporated herein by reference contradicts the express content of the present disclosure, the express content shall prevail. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless otherwise stated. Additionally, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0061] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are intended to be interpreted in their open and inclusive sense, i.e., "including, but not limited to."

[0062] In the present description, any concentration range, percentage range, ratio range, or integer range is understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as 1 / 10 and 1 / 100 of an integer), unless otherwise specified. Also, any numerical range recited herein for any physical characteristic, such as polymer subunits, size, or thickness, is understood to include any integer within the recited range, unless otherwise specified. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure, unless otherwise specified.

[0063] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrase "one embodiment" or "embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0064] "Amino" refers to the -NH2 radical.

[0065] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0066] "Cyano" refers to the -CN radical.

[0067] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0068] "Nitro" refers to the -NO2 radical.

[0069] "Oxo" refers to the =O substituent.

[0070] "Thioxo" refers to the =S substituent.

[0071] "Thiol" refers to a -SH substituent.

[0072] "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 12 alkyl), 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.

[0073] "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 2 to 12 carbon atoms (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.

[0074] "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 (C 12Alkynyl), 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.

[0075] "Alkoxy" means a group of the formula -OR a where R a is 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.

[0076] "Aromatic ring" refers to a cyclic planar portion (i.e., radical) of a molecule having a resonance-bonded ring that exhibits enhanced 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.

[0077] "Aryl" refers to an aryl group containing 6 to 18 carbon atoms and at least one aromatic ring (i.e., C6-C18 aryl), preferably 6 to 10 carbon atoms (i.e., C6-C 10For 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.

[0078] "Arylalkyl" 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 aryl radicals as defined above, for example benzyl, diphenylmethyl, etc. Arylalkyl groups are 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.

[0079] "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 to C4). 15 cycloalkyl), preferably having 3 to 10 carbon atoms (i.e., C 10Cycloalkyl refers to a group having from 3 to 6 carbon atoms (i.e., C3-C6 cycloalkyl), which may be saturated or unsaturated, and which is 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 stated otherwise in the specification, cycloalkyl groups are optionally substituted.

[0080] "Cycloalkylalkyl" 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 cycloalkyl radicals as defined above, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkylalkyl groups are C3-C 12 C1-C attached to cycloalkyl radical 10 Alkylene chain (i.e., C3-C 12 C1-C connected to cycloalkyl (alkyl) or C3-C6 cycloalkyl radicals 10 It may contain an alkylene chain (i.e., a C3-C6 cycloalkylalkyl). Unless stated otherwise in the specification, a cycloalkylalkyl group is optionally substituted.

[0081] "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.

[0082] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0083] "Haloalkyl" refers to an alkyl radical as defined above substituted by one or more halo radicals as defined above, e.g., 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 by 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 this specification, haloalkyl groups are optionally substituted.

[0084] "Haloalkoxy" refers to a group of the formula -OR a where R a is 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.

[0085] "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.

[0086] "Heteroarylalkyl" 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 heteroaryl radicals as defined above. A heteroarylalkyl group is a C1-C6 alkyl group attached 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.

[0087] "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 ring or a 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, heterocyclyl groups are optionally substituted.

[0088] "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 C1-C alkyl group attached to a 5- to 10-membered heterocyclyl radical. 10 C1-C connected 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.

[0089] 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 alkyl, C4-C6 alkynyl, C5-C6 alkyl, C6-C6 alkynyl, C7-C8 alkyl, C8-C9 alkyl, C9-C10 alkyl, C10-C11 alkyl, C10-C12 12 Cycloalkyl, C3-C 12In 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.

[0090] 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. Specifically, 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).

[0091] An "effective amount" or "therapeutically effective amount" of a compound or composition refers to the amount of the compound or composition that produces the intended result desired based on the disclosure herein. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, ED 50 (the dose therapeutically effective in 50% of the population) and LD 50(the dose that is lethal to 50% of the population). In some embodiments, an effective amount of a compound results in a reduction or inhibition of symptoms or a prolongation of survival in a subject (i.e., a human patient). Multiple administrations of a compound may be required for results.

[0092] "Treating" or "treatment" of a disease of interest refers to 1) preventing the occurrence of the disease in a patient who is predisposed to or does not yet exhibit symptoms of the disease, 2) inhibiting or arresting the development of the disease, or 3) alleviating or causing remission of the disease. As used herein, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: relieving one or more symptoms caused by a disease or disorder of a subject, reducing the extent of a disease or disorder, stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder), delaying the onset or recurrence of a disease or disorder, delaying or slowing the progression of a disease or disorder, improving the condition of a disease or disorder, providing remission (whether partial or total) of a disease or disorder, reducing the dosage of one or more other drugs required to treat a disease or disorder, enhancing the effect of another drug used to treat a disease or disorder, delaying the progression of a disease or disorder, improving quality of life, and / or prolonging survival. Relief of the pathological consequences of a disease or disorder is also encompassed by "treatment". The method of the present invention contemplates any one or more of these modes of treatment.

[0093] As used herein, the terms "individual(s)," "subject(s)," and "patient(s)" refer to any mammal. Examples include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, the mammal is a human.

[0094] The term "therapeutic benefit" as used herein encompasses therapeutic and / or prophylactic benefits as described herein. A therapeutic benefit includes delaying or eliminating the appearance of a disease or condition; delaying or eliminating the onset of symptoms of a disease or condition; slowing, halting, or reversing the progression of a disease or condition; causing partial or complete remission of a disease or condition; or any combination thereof.

[0095] The terms "co-administration," "administered in combination with," and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including a human, such that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in one composition in which both agents are present.

[0096] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in the preparation of pharmaceutical compositions suitable for animal or human pharmaceutical use.

[0097] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0098] "Pharmaceutically acceptable acid addition salts" refers to salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable, for example, but not limited to, those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, geranilic acid, glycerin, glycerol ... It is formed with organic acids such as antiseptic, glucoheptonic, gluconic, glucuronic, glutamic, glutaric, 2-oxo-glutaric, glycerophosphoric, glycolic, hippuric, isobutyric, lactic, lactobionic, lauric, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthalene-1,5-disulfonic, naphthalene-2-sulfonic, 1-hydroxy-2-naphthoic, nicotinic, oleic, orotic, oxalic, palmitic, pamoic, propionic, pyroglutamic, pyruvic, salicylic, 4-aminosalicylic, sebacic, stearic, succinic, tartaric, thiocyanic, p-toluenesulfonic, trifluoroacetic, and undecylenic acids.

[0099] "Pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of its free acid and is not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0100] In some embodiments, pharma- ceutically acceptable salts include quaternary ammonium, such as a quaternary amine alkyl halide salt (eg, methyl bromide).

[0101] As used herein, a "therapeutic agent" refers to a biological, pharmaceutical, or chemical compound or other moiety. Non-limiting examples include simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, toxins, or chemotherapeutic compounds. A variety of compounds can be synthesized, including small molecules and oligomers (e.g., oligopeptides and oligonucleotides), as well as synthetic organic compounds based on a variety of core structures. In addition, compounds for screening can be obtained from a variety of natural sources, such as plant or animal extracts.

[0102] The term "in vivo" refers to events that take place inside a subject's body.

[0103] Embodiments of the present disclosure are also intended to encompass all pharma- ceutically acceptable compounds of formula (I) that are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number (i.e., "isotopic forms" of compounds of formula (I). Examples of isotopes that can be introduced into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125I. These radiolabeled compounds may be useful to aid in determining or measuring the effectiveness of a compound, for example, by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of formula (I), for example those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose because of its ease of incorporation and ready means of detection.

[0104] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may be preferable in some circumstances as they may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced required dosage.

[0105] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples set forth below, using appropriate isotopically labeled reagents in place of previously employed non-labeled reagents.

[0106] In certain embodiments, it is also intended to encompass in vivo metabolic products of the compounds of the present disclosure. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. Thus, embodiments include compounds produced by a process comprising administering a compound of the present disclosure to a mammal for a period of time sufficient to produce its metabolic products. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present disclosure to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0107] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0108] In many cases, crystallization produces a solvate of the disclosed compound. As used herein, the term "solvate" refers to an aggregate that includes one or more molecules of the compound of formula (I) together with one or more solvent molecules. In some embodiments, the solvent is water, in which case the solvate is a hydrate. Alternatively, in other embodiments, the solvent is an organic solvent. Thus, the compound of formula (I) can exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as the corresponding solvates. In some aspects, the compound of formula (I) is a true solvate, and in other cases, the compound of the disclosed compound simply retains adventitious water or is a mixture of water and some adventitious solvent.

[0109] "Optional" or "optionally" means that the subsequently described circumstance event may or may not occur, and the description includes both cases where the event or circumstance occurs and does not occur. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and the description includes both substituted and unsubstituted aryl radicals. Polymers or similar infinite structures that are reached by defining a substituent with unlimited addition of further substituents (e.g., a substituted aryl with a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.) are not intended to be included herein. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with five fluorines, or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art.

[0110] A "pharmaceutical composition" or "pharmaceutical acceptable composition" refers to a formulation of a compound of the present disclosure with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, e.g., a human. Such a vehicle includes any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0111] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, flow agent, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0112] The compounds of formula (I), or pharma- ceutically acceptable salts or isotopic forms thereof, may contain one or more centers resulting in geometric asymmetry and thus may give rise to enantiomers, diastereomers, and other stereoisomers, defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids, (D)- or (L)-. Accordingly, the embodiments include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using conventional techniques, e.g., chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives), e.g., using chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomers.

[0113] "Stereoisomers" refer to compounds consisting of the same atoms joined by the same bonds, but with different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0114] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0115] "Tautomer" refers to the migration of a proton from one atom of a molecule to another atom of the same molecule. Thus, embodiments include tautomers of the compounds of the present disclosure.

[0116] The chemical naming protocol and structural diagrams used herein are modified IUPAC nomenclature using ACD / Name Version 9.07 software program and / or ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft). In complex chemical names used herein, a substituent is typically named before the group to which it is attached. For example, cyclopropylethyl contains an ethyl skeleton with a cyclopropyl substituent. Except as noted below, in the chemical structural diagrams herein, all bonds are specified, except for all bonds on some carbon atoms, and it is assumed that the bonds on carbon atoms are attached to enough hydrogen atoms to satisfy the valence.

[0117] Although various features of the invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the invention may be described herein for clarity in the context of separate embodiments, the invention may also be implemented in a single embodiment.

[0118] compound In one aspect, provided herein is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein: 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; R1a 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 cycloalkyl alkyl, 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, Here, each of C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, C3 to C 12 Cycloalkyl, C3~C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10Arylalkyl, 5-10 membered heteroaryl, 5-10 membered heteroarylalkyl, 5-10 membered heterocyclyl, and 5-10 membered heterocyclylalkyl are hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, Optionally substituted with 1 to 5 substituents selected from -SO2(C1-C6 alkyl), and -CO2H.

[0119] 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.

[0120] In some embodiments, each R a and R b is independently H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. a and R b is independently H, C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl. a and R bare each H. In some embodiments, R a is H. In some embodiments, R a is a C1-C6 alkyl, such as methyl, ethyl, or propyl. a is a C2-C6 alkenyl, such as vinyl or propenyl. a is a C2-C6 alkynyl, such as ethynyl or propynyl. b is H. In some embodiments, R b is a C1-C6 alkyl, such as methyl, ethyl, or propyl. b is a C2-C6 alkenyl, such as vinyl or propenyl. b is a C2-C6 alkynyl such as ethynyl or propynyl.

[0121] 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 a C1-C6 alkyl, such as methyl, ethyl, or propyl. 1a is a C2-C6 alkenyl, such as vinyl or propenyl. 1a is a C2-C6 alkynyl, such as ethynyl or propynyl. 1a is a C1-C6 alkoxy, such as methoxy, ethoxy, or propoxy. 1a is halo, such as fluoro, chloro, or bromo. In some embodiments, R 1a C6-C such as benzyl 10In some embodiments, R 1b is H. In some embodiments, R 1b is a C1-C6 alkyl, such as methyl, ethyl, or propyl. 1b is a C2-C6 alkenyl, such as vinyl or propenyl. 1b is a C2-C6 alkynyl, such as ethynyl or propynyl. 1b is a C1-C6 alkoxy, such as methoxy, ethoxy, or propoxy. 1b is halo, such as fluoro, chloro, or bromo. In some embodiments, R 1b C6-C such as benzyl 10 It is arylalkyl.

[0122] 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 1-3 halo, such as fluoro or chloro. 1a is a C1-C6 alkyl substituted with 1-3 -CO2H groups. 1a is a C1-C3 alkyl substituted with 1-2 CO2H groups, e.g., -CH2CO2H or -CH2CH2CO2H. In some embodiments, R 1a is a C1-C6 alkyl substituted with 1-3 -C(=O)NH2 groups. 1ais a C1-C3 alkyl substituted with 1-2 -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 1-3 amino groups 10 In some embodiments, R 1b is C1-C6 alkyl substituted with 1-3 halo, such as fluoro or chloro. 1b is a C1-C6 alkyl substituted with 1-3 -CO2H groups. 1b is a C1-C3 alkyl substituted with 1-2 CO2H groups, e.g., -CH2CO2H or -CH2CH2CO2H. In some embodiments, R 1b is a C1-C6 alkyl substituted with 1-3 -C(=O)NH2 groups. 1b is a C1-C3 alkyl substituted with 1-2 -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 1b is 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 1-3 amino groups 10 In some embodiments, R 1a and R1b 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.

[0123] 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.

[0124] In some embodiments, R 3 is C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkyl alkyl, C6-C 10 arylalkyl, 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 a C3-C6 alkyl, such as propyl, butyl, pentyl, or hexyl. 3 is C4-C6 alkyl. In some embodiments, R 3 is C-C alkenyl. In some embodiments, R3 is C4-C6 alkenyl. In some embodiments, R 3 is C-C alkynyl. In some embodiments, R 3 is C4-C6 alkynyl. In some embodiments, R 3 is a C3-C alkyl group 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.

[0125] In some embodiments, R 3 is a C-C alkyl, C-C alkenyl, or C-C cycloalkyl alkyl optionally substituted with 1-3 substituents selected from halo and -C(=O)NH. 3is 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 cycloalkyl alkyl; a 5-6 membered heteroaryl alkyl; a 5-6 membered heterocyclyl alkyl; or a C6 aryl alkyl. In some embodiments, R 3 is a C2 alkyl substituted with 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(C1-C3 alkyl). 3 is: [ka]

[0126] In some embodiments, R 3 is: [ka]

[0127] In some embodiments, R 3 is 2-methylbutyl.

[0128] In some embodiments, R 4 is C6~C 10 aryl, 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 4is 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.

[0129] In some embodiments, R 4 is a C6-C alkyl group 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]

[0130] In some embodiments, R 4 is: [ka]

[0131] 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 pyridyl or indolyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 teeth, [ka] In some embodiments, R 4 is pyridyl substituted with 1-3 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 heterocyclyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 is indolinyl. [ka]

[0132] In some embodiments, -LR 4 is -CH2(phenyl) or -C(O)(phenyl), where phenyl is substituted by 1-3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. 4 is -CH2(pyridyl) or -C(O)(pyridyl), where the pyridyl is substituted by 1-3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. 4 is: [ka]

[0133] In some embodiments, each R 5 is independently C1-C6 alkyl, oxo, or halo. In some embodiments, R 5 is a C1-C6 alkyl, such as methyl, ethyl, or propyl.5 In some embodiments, R 5 is halo, such as fluoro, chloro, or bromo. In some embodiments, R 5 is oxo or halo. In some embodiments, R 5 is oxo or fluoro.

[0134] 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 a C1-C6 alkyl, such as methyl, ethyl, or propyl. 6 is oxo.

[0135] In some embodiments, R 7 is H or oxo. In some embodiments, R 7 is H. In some embodiments, R 7 is oxo.

[0136] In some embodiments, m is 1. In other embodiments, m is 2.

[0137] 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.

[0138] 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 10The 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.

[0139] 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, isotopic form, or stereoisomer thereof, wherein L, R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7 and n are as described for formula (I). In some embodiments, the compound is of formula (II), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIa), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIb), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIc), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IId), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIe), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0140] 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, isotopic form, or stereoisomer 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 as described for formula (I), such as hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, etc. In some embodiments, the compound is of formula (IIIa), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIIb), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIIc), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IIId), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0141] 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, isotopic form, or stereoisomer thereof, wherein R 5and n are as described for formula (I), and R represents one or more optional substituents as described for formula (I), such as hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, etc. In some embodiments, the compound is of formula (IVa), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IVb), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IVc), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of formula (IVd), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0142] In some embodiments, the compound of formula (I) is a compound of formula (V): [ka] or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein L, R 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 C1-C3 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 these is H, and the other is a C1-C3 alkyl such as methyl.

[0143] 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.

[0144] In some embodiments, provided is a compound selected from the compounds of Table 1, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. Although some compounds described in this disclosure, including those in Table 1, are depicted as specific stereoisomeric and / or non-stereochemical forms, 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. TIFF2025515044000026.tif224170TIFF2025515044000027.tif242170TIFF2025515044000028.tif242170TIFF2025515044000029.tif242170TIFF2025515044000030.tif220170TIFF2025515044000031.tif242170TIFF2025515044000032.tif242170TIFF2025515044000033.tif51170 or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0145] 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.

[0146] In some embodiments, provided is a compound selected from the compounds of Table 1A, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. Although some compounds described in this disclosure, including those in Table 1A, are depicted as specific stereoisomeric and / or non-stereochemical forms, 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. TIFF2025515044000034.tif228170TIFF2025515044000035.tif242170TIFF2025515044000036.tif102170 or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0147] 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.

[0148] 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.

[0149] Phosgonimeton and related compounds Phosgonimeton is a prodrug that is rapidly converted to the active drug ATH-1001 (Dihexa; see US2014 / 0094413) in plasma after subcutaneous injection, which acts as a positive modulator of the hepatocyte growth factor (HGF) receptor and its tyrosine kinase MET, a receptor system.

[0150] Phosgonimeton is a pharma- ceutically acceptable salt of compound A19: [ka]

[0151] Non-limiting examples of pharma- ceutically acceptable salts of Compound A19 include the following: [ka]

[0152] Unless otherwise indicated, phosgonimeton refers to the monosodium salt of compound A19, shown below: [ka]

[0153] Compound A19 and its pharma- ceutically acceptable salts, isotopic forms, or stereoisomers, such as phosgonimetone, can be synthesized and characterized using methods known to those of skill in the art, such as those described in PCT Publication No. WO2017 / 210489A1.

[0154] In some embodiments, phosgonimeton is formulated for subcutaneous administration.

[0155] Method of synthesis 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, the starting components can be obtained from commercial sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or can be synthesized according to materials 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.

[0156] General reaction scheme 1. [ka]

[0157] 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 either 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.

[0158] General reaction scheme 2. [ka]

[0159] An alternative 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 the group consisting of 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).

[0160] General reaction scheme 3. [ka]

[0161] 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 give compound A10, which is then reacted with A7 to give compound A11, which is then reacted with A12 to give the final compound of formula (I).

[0162] It should be noted that various alternative strategies for the preparation of 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.

[0163] It will be appreciated 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.

[0164] 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 a compound of formula (I) or compound A19, 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.

[0165] 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.

[0166] In certain embodiments, the compound of formula (I) or compound A19, 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 compound A19, 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.

[0167] The compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, is effective over a wide dosage range. For example, in the treatment of an adult, dosages of 0.01-1000 mg per day, 0.5-100 mg per day, 1-50 mg per day, and 5-40 mg per day are examples of dosages used in some embodiments. An exemplary dosage is 10-30 mg per day. 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.

[0168] In some embodiments, the compound of formula (I) or compound A19, 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 agent.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.

[0169] In some embodiments, the compound of formula (I) or compound A19, 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 compound of formula (I) or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof and another therapeutic agent are administered together about once a day to about six times a day. In another embodiment, the administration of the compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and the therapeutic agent continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is possible and is maintained for as long as necessary.

[0170] Administration of the compound of formula (I) or compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer can be continued as long as necessary. In some embodiments, the compound of formula (I) or compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer 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 compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer 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 compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer is administered continuously, for example, chronically for the treatment of chronic effects (e.g., neurological disorders).

[0171] In some embodiments, compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer is administered in multiple doses.It is known in the art that due to the subject-to-subject variability in the pharmacokinetics of compound, optimal treatment requires individualized administration regimen.The dosage of compound can be found by routine experimentation in light of the present disclosure.

[0172] In some embodiments, the compound of formula (I) or compound A19, 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 active compounds into pharma- ceutically usable preparations.The appropriate formulation depends on the route of administration selected. Any pharma- ceutically acceptable technology, carrier, and excipient may be suitably used to formulate 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).

[0173] Provided herein is a pharmaceutical composition comprising a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). Also provided herein is a method for administering a pharmaceutical composition comprising a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s).

[0174] In certain embodiments, the compound is administered as a pharmaceutical composition in which the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer is mixed with other therapeutic agents as a combination therapy.All combinations of active ingredients described in the method section below and throughout this disclosure are encompassed herein.In specific embodiments, the pharmaceutical composition comprises one or more compounds of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer.

[0175] Pharmaceutical composition, as used herein, refers to a mixture of a compound of formula (I) or Compound A19, 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 a compound of formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided herein 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.

[0176] In one embodiment, one or more compounds of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer 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 compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer 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.

[0177] In another embodiment, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer is formulated for oral administration.The compound is formulated by combining the active compound with, for example, a pharmaceutically acceptable carrier or excipient.In various embodiments, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer is formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0178] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipients with the compound of formula (I) or compound A19, or one or more of its pharma- ceutically acceptable salts, isotopic forms, or stereoisomers, optionally grinding the resulting mixture, processing the mixture of granules, and optionally adding suitable auxiliaries to obtain tablets or dragee cores.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.

[0179] 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 dosage forms. 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.

[0180] In certain embodiments, a therapeutically effective amount of at least one of the compounds of formula (I) or compound A19, 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.

[0181] In other embodiments, a therapeutically effective amount of at least one of the compounds of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, described herein, 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, the compounds of formula (I) or compound A19, 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 multi-dose containers. Preservatives are optionally added to the injectable formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection, as a sterile suspension, solution, or emulsion in an oily or aqueous vehicle. Parenteral injection formulations optionally contain formulations such as suspending agents, stabilizing agents, and / or dispersing agents. In a specific embodiment, pharmaceutical formulations 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., compound of formula (I) or compound A19, or its pharma- ceutically acceptable salts, isotopic forms, or stereoisomers) are prepared as appropriate 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 to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0182] In yet another embodiment, the compound of formula (I) or compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is administered topically. The compound is formulated into various 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.

[0183] In yet other embodiments, the compound of formula (I) or Compound A19, 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 further embodiments, transdermal delivery of the compound of formula (I) or Compound A19, 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 compound of formula (I) or Compound A19, 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 alternative embodiments, absorption enhancers are used to enhance absorption. Absorption enhancers or carriers include pharma- ceutically acceptable absorbent solvents that aid in passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage comprising a support member, a reservoir containing the compound, optionally with a carrier, an optional rate-controlling barrier that delivers the compound to the host's skin at a controlled, pre-determined rate over an extended period of time, and a means for securing the device to the skin.

[0184] In other embodiments, the compound of formula (I) or compound A19, 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 compound of formula (I) or compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, 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 inhalers or insufflators are formulated to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0185] In yet another embodiment, the compound of formula (I) or compound A19, 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.

[0186] 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 technology, carrier, and excipient are optionally used suitably.The pharmaceutical composition containing the compound of formula (I), or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, is prepared in a conventional manner, such as, for example, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or compressing processes.

[0187] A pharmaceutical composition comprises at least one pharma- ceutically acceptable carrier, diluent or excipient and at least one compound of formula (I) or compound A19 as 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 compounds of formula (I) or compound A19, 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.

[0188] The method of preparing a composition comprising a compound of formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, includes 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 a compound of formula (I) or Compound A19, 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 non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffers, and the like.

[0189] In some embodiments, the pharmaceutical composition comprising at least one compound of formula (I) or compound A19, 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.

[0190] 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.

[0191] Useful pharmaceutical compositions also optionally contain a solubilizer that aids in the dissolution of the compound of formula (I) or compound A19, or its pharma-ceutically acceptable salt, isotopic form, or stereoisomer. "Solubilizer" generally includes agents that provide a micellar or true solution form of the agent. 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.

[0192] 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.

[0193] In addition, 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.

[0194] 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.

[0195] 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 alkylphenyl ethers, such as octoxynol 10 and octoxynol 40.

[0196] 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.

[0197] 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.

[0198] 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, the compound of formula (I) or compound A19, or a pharma-ceutically acceptable salt, isotopic form, or stereoisomer thereof, is delivered using a sustained release system, such as a semipermeable matrix of hydrophobic solid polymers containing a therapeutic agent. 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.

[0199] 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.

[0200] In some embodiments, the concentration of compound of formula (I) or Compound A19 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%, 0.08%, 0. 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.

[0201] In some embodiments, the concentration of the compound of formula (I) or Compound A19 provided in the 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%, 15.7 5%, 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. 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.

[0202] In some embodiments, the concentration of the compound of Formula (I) or Compound A19, 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 25%, from about In some embodiments, the range is from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% w / w, w / v or v / v.

[0203] In some embodiments, the concentration of the compound of Formula (I) or Compound A19, 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.

[0204] In some embodiments, the amount of the compound of Formula (I) or Compound A19, 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, 0.45 g, 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.

[0205] In some embodiments, the amount of the compound of formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof provided in the 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, 0.0008 g, or 0.0009 g. , 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005 g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01 g, 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, 0.35g, 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 greater than 10g.

[0206] In some embodiments, the amount of the compound of Formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the 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.

[0207] In some embodiments, the method includes administering compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, by subcutaneous injection.

[0208] In some embodiments, the methods comprise administering the HGF / MET positive modulator via an oral dosage form.

[0209] In some embodiments, the method comprises administering compound 2a, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0210] In some embodiments, the methods include administering compound 1a, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0211] In some embodiments, the method comprises administering compound 5a, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0212] In some embodiments, the methods include administering compound 6a, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0213] In some embodiments, the method comprises administering compound 7a, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0214] Kits / Products Kits and articles of manufacture are also provided for use in the therapeutic applications described herein. In some embodiments, such kits include a case, package, or container that is partitioned to receive one or more containers, such as vials, tubes, etc., each of the container(s) containing one of the individual elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials, such as glass or plastic.

[0215] The products provided herein contain packaging materials. Packaging materials used for packaging pharmaceutical products include, for example, those found in U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. For example, the container(s) contain one or more compounds described herein, optionally in a composition or in combination with another agent disclosed herein. The container(s) optionally have a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic needle). Such kits optionally contain the compound with identification information or labels or instructions for use in the methods described herein.

[0216] For example, the kit typically includes one or more additional containers each containing one or more of various materials (such as reagents (optionally in concentrated form) and / or devices) that are desirable from a commercial and user standpoint for use of the compound of formula (I), or a pharma-ceutically acceptable salt, isotopic form, or stereoisomer thereof. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packages, containers, vials, and / or tube labels with contents and / or instructions for use, as well as package inserts with instructions for use. A set of instructions is also typically included. The label is optionally on or associated with the container. For example, the label is on the container when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, or in a receptacle or carrier that holds the container, e.g., as a package insert. In addition, the label is used to indicate that the contents are to be used for a particular therapeutic application. Additionally, the label indicates instructions for use of the contents, such as the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a pack or dispenser device containing one or more unit dosage forms containing the compound provided herein. The pack contains, for example, metal or plastic foil, such as a blister pack. Alternatively, the pack or dispenser device is accompanied by instructions for administration. Alternatively, the pack or dispenser is accompanied by a label attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which reflects the agency's approval of the drug form for human or veterinary administration. Such a label is, for example, a label for prescription drugs approved by the U.S. Food and Drug Administration, or an approved product insert. In some embodiments, a composition containing a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, formulated in a compatible pharmaceutical carrier, is prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0217] Method of Use / Treatment An embodiment of the present disclosure provides a method for modulating hepatocyte growth factor in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein (e.g., a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof). In some embodiments, the compounds described herein activate hepatocyte growth factor. In some embodiments, the compounds described herein positively modulate hepatocyte growth factor activity. Modulation (e.g., inhibition or activation) of hepatocyte growth factor can be assessed and demonstrated in a wide variety of ways known in the art. Kits and commercially available assays can be utilized to determine whether and to what extent hepatocyte growth factor is modulated (e.g., inhibited or activated).

[0218] In some embodiments, provided herein is a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, for use in a subject in need thereof to regulate hepatocyte growth factor. In some embodiments, provided herein is a compound of formula (I) or compound A19, or a pharma-ceutically acceptable salt, isotopic form, or stereoisomer thereof, for use in the manufacture of a medicament for regulating hepatocyte growth factor in a subject in need thereof.

[0219] Applicant has discovered that the compound of formula (I) or compound A19 shows promising activity in relation to certain diseases of interest. Thus, in one aspect, provided herein is a method for regulating hepatocyte growth factor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, provided herein is a method for activating hepatocyte growth factor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, provided herein is a method for activating hepatocyte growth factor in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0220] In more specific embodiments, modulating includes treating or alleviating a disease, condition, or injury. In some embodiments, the disease, condition, or injury is neuropathy. As used herein, neuropathy refers to a type of nerve damage that is often associated with other health problems. In some embodiments, the neuropathy is peripheral neuropathy. The neuropathy can be mononeuropathy or polyneuropathy. In some embodiments, the neuropathy is sensory neuropathy. The sensory neuropathy can cause numbness, tingling, and / or pain in some embodiments. In some such embodiments, the numbness, tingling, and / or pain occurs in one or more extremities, such as the hands and / or feet. In some embodiments, the subject experiences numbness, tingling, and / or pain associated with neuropathy prior to administration of the compound. In some embodiments, the sensory neuropathy is peripheral, autonomic, proximal, or local. In various embodiments, the neuropathy is associated with nerve damage or dysfunction, such as nerve compression or trigeminal neuralgia, excessive alcohol consumption, stroke, shingles (e.g., postherpetic neuralgia (PHN)), HIV, leprosy, Guillain-Barre syndrome, vascular disease, vascular malformation, diabetes (e.g., painful diabetic neuropathy), chemotherapy, radiation therapy, or autoimmune disease. In some embodiments, the neuropathy is neuropathic pain. In some embodiments, neuropathic pain results from mononeuropathy (damage to one nerve) or polyneuropathy (damage to multiple nerves).

[0221] In some embodiments, the neuropathic pain is painful diabetic neuropathy. For example, in some embodiments, the painful diabetic neuropathy is peripheral, autonomic, proximal, or focal. In some embodiments, the painful diabetic neuropathy is peripheral painful diabetic neuropathy.

[0222] In some embodiments, the neuropathy is idiopathic.

[0223] In some embodiments, the neuropathy is not cancer or chemotherapy associated. In some embodiments, the neuropathy is chemotherapy associated. In some embodiments, the neuropathy is not radiation therapy associated.

[0224] Also provided herein is a method for reducing numbness, tingling, and / or pain in a subject with neuropathy, comprising administering to the subject an effective amount of a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In various embodiments, the neuropathy is associated with nerve damage or dysfunction, such as nerve compression or trigeminal neuralgia, excessive alcohol consumption, stroke, shingles (e.g., postherpetic neuralgia (PHN)), HIV, leprosy, Guillain-Barre syndrome, vascular disease, vascular malformation, diabetes (e.g., painful diabetic neuropathy), chemotherapy, radiation therapy, or autoimmune disease. In some embodiments, the numbness, tingling, and / or pain is due to mononeuropathy (damage to one nerve) or polyneuropathy (damage to multiple nerves). In some embodiments, the subject has painful diabetic neuropathy.

[0225] In some embodiments, the present disclosure provides a method for modulating protein activity (e.g., hepatocyte growth factor activity) in a subject, including but not limited to rodents and mammals (e.g., humans), by administering to the subject an effective amount of a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the modulation of hepatocyte growth factor is activation of hepatocyte growth factor. In some embodiments, the percentage of modulation is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibition is greater than 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0226] In some embodiments, the present disclosure provides a method of regulating hepatocyte growth factor activity in a cell by contacting the cell with a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to regulate the activity of hepatocyte growth factor. In some embodiments, the present disclosure provides a method of regulating hepatocyte growth factor activity in a tissue by contacting the tissue with a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to regulate the activity of hepatocyte growth factor in the tissue. In some embodiments, the present disclosure provides a method of regulating hepatocyte growth factor activity in an organism by contacting the organism with a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to regulate the activity of hepatocyte growth factor in the organism. In some embodiments, the disclosure provides a method of modulating hepatocyte growth factor activity in an animal by contacting the animal with a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate the activity of hepatocyte growth factor in the animal. In some embodiments, the disclosure provides a method of modulating hepatocyte growth factor activity in a mammal by contacting the mammal with a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate the activity of hepatocyte growth factor in the mammal. In some embodiments, the disclosure provides a method of modulating hepatocyte growth factor activity in a human by contacting the human with a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate the activity of hepatocyte growth factor in the human. In other embodiments, the disclosure provides a method of treating a disease mediated by hepatocyte growth factor activity in a subject in need of such treatment.In some variations, the modulation of hepatocyte growth factor by a compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, involves activation of hepatocyte growth factor.

[0227] Other embodiments provide methods for combination therapy in which therapeutic agents known to modulate other pathways or other elements of the same pathway or overlapping target enzymes are used in combination with the compound of formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof. In one aspect, such therapy includes, but is not limited to, the combination of one or more compounds of formula (I) or Compound A19, or a pharma-ceutically acceptable salt, isotopic form, or stereoisomer thereof, with therapeutic agents, therapeutic antibodies, and other forms of therapy that provide synergistic or additive therapeutic effects.

[0228] Currently, many therapeutic agents are known in the art and can be used in combination with the compound of formula (I) or compound A19, or its pharma- ceutically acceptable salts, isotopic forms, or stereoisomers. In some embodiments, the therapeutic agent is selected from gabapentinoids (e.g., pregabalin or gabapentin), duloxetine, antidepressants (e.g., amitriptyline, desipramine, olimipramine), opioid-like drugs (e.g., tramadol or tapentadol), desvenlafaxine, topicals (e.g., lidocaine patches and capsaicin cream), opioids (e.g., oxycodone or morphine), or selective serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, citalopram, paroxetine, or escitalopram). In some embodiments, the therapeutic agent is selected from pregabalin, gabapentin, duloxetine, amitriptyline, tramadol, tapentadol, oxycodone, morphine, citalopram, paroxetine, or escitalopram.

[0229] In some embodiments, the therapeutic agent is selected from an antidepressant and / or an antipsychotic. Antidepressants may include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs). Some embodiments of the methods described herein may include the use or administration of antipsychotics such as aripiprazole (Abilify), haloperidol (Haldol), olanzapine (Zyprexa), and risperidone (Risperdal).

[0230] In some embodiments, the subject is being treated for diabetes. In some embodiments, the subject is being treated with a sodium glucose cotransporter-2 (SGLT-2) inhibitor, such as bexagliflozin, canagliflozin (INVOKANA®), dapagliflozin (FARXIGA®), empagliflozin (JARDIANCE®), ertugliflozin (STEGLATRO™), ipragliflozin (SUGLAT®), luseogliflozin (LUSEFI™), and tofogliflozin.

[0231] In some embodiments, the compound of formula (I) or compound A19, or its pharma- ceutically acceptable salt, isotopic form, or stereoisomer, is formulated or administered with a liquid or solid tissue barrier, also known as a lubricant. Examples of tissue barriers include, but are not limited to, polysaccharides, polyglycans, seprafilm, interceed, and hyaluronic acid.

[0232] In some embodiments, the therapeutic agent administered with the compound of formula (I) or compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, can include any suitable therapeutic agent, such as an analgesic, such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; an angina preparation, such as diltiazem; an antiallergic, such as cromoglycate, ketotifen, or nedocromil; an antiinfective, such as cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, or pentamidine; an antihistamine, such as methapyrilene; an anti-inflammatory, such as beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone; an antitussive, such as noscapine; a bronchodilator, such as ephedrine, adrenaline. , fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetharine, tulobuterol, orciprenaline or (-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol; diuretics, such as amiloride; anticholinergics, such as ipratropium, atropine or oxitropium; hormones, such as cortisone, hydrocortisone or prednisolone; xanthines, such as aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, such as insulin or glucagon. It will be apparent to those skilled in the art that therapeutic agents may be used, where appropriate, in the form of a salt (e.g., as an alkali metal or amine salt or an acid addition salt) or as an ester (e.g., a lower alkyl ester) or as a solvate (e.g., a hydrate) to optimize the activity and / or stability of the therapeutic agent.

[0233] Additional therapeutic agents that may be combined with the compound of Formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, can be found in Goodman and Gilman's "The Pharmacological Basis of Therapeutics" Tenth Edition, edited by Hardman, Limbird, and Gilman, or in the Physician's Desk Reference, both of which are incorporated herein by reference in their entireties.

[0234] The compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, can be used in combination with the therapeutic agents disclosed herein, depending on the condition being treated. Thus, in some embodiments, one or more compounds of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, are co-administered with other therapeutic agents as described above. When used in combination therapy, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, is administered simultaneously with the second therapeutic agent or separately. This combined administration can include simultaneous administration in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, and any of the therapeutic agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, and any of the above therapeutic agents can both be present in separate formulations and administered simultaneously. In another alternative, any of the above therapeutic agents can be administered immediately after the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, or vice versa. In some embodiments of the separate administration protocol, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, and any of the above therapeutic agents are administered minutes apart, or hours apart, or days apart.

[0235] The examples and preparations provided below further illustrate and demonstrate the compound of formula (I) or Compound A19, or a pharma- ceutically acceptable salt, isotopic form, or stereoisomer thereof, and methods for preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations. In the following examples, and throughout the specification and claims, molecules with a single stereocenter are present as racemic mixtures unless otherwise noted. Molecules with two or more stereocenters are present as racemic mixtures of diastereomers unless otherwise noted. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. EXAMPLES

[0236] The following examples are provided for illustrative purposes: Methods for the preparation of compounds of formula (I), or pharma-ceutically acceptable salts, isotopic forms, or stereoisomers thereof, are provided herein or can be derived by one skilled in the art.

[0237] The examples and preparations provided below further illustrate and demonstrate the compounds of the present disclosure and methods for testing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0238] The chemical reactions of the examples described 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 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 those 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.

[0239] Unless otherwise indicated in the examples below, the compounds are isolated as racemic mixtures.

[0240] In this application the following abbreviations apply: 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

[0241] 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]

[0242] 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 minutes, 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 hours. 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.

[0243] 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.

[0244] 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 minutes. 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 hours. 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.

[0245] 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.

[0246] Step 5: Synthesis of (6S)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (6.25 g, 83.8%) as a solid.

[0247] 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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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 compound 1a (0.340 g, 65.3%) as a solid. Preparative 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.

[0248] 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 compound 2a (380 mg 46%) as a solid. Prep HPLC conditions: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: Kromosil phenyl (150×25 mm 10μ); Flow rate: 25 mL / min. MS (ESI) m / z [M+H] + :424.11.

[0249] 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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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. The pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give compound 3a (0.180 g, 46.09%) as a solid. Preparative HPLC method: Mobile phase A: 10 mM ammonium bicarbonate in water; Mobile phase B: acetonitrile; Column: Kromosil phenyl (150×25 mm 10μ); Flow rate: 25 mL / min. MS (ESI) m / z [M+H] + :360.11.

[0250] 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 compound 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.

[0251] 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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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 compound 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: Kromosil C 18 (150×25mm 10μ);Flow rate: 25mL / min. MS(ESI)m / z[M+H] + :412.2.

[0252] 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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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 compound 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.

[0253] 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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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. The pure fractions were combined, concentrated under reduced pressure, and then lyophilized to give compound 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.

[0254] 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)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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. The crude material was analyzed by LC / MS showing 54.59% of the desired product. The crude material was used in the next step without purification.

[0255] Step 2: Synthesis of compound 8a. To a stirred solution of (6S)-1-(4-(benzyloxy)benzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-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 compound 8a (0.330 g, 82%) as a solid. MS (ESI) m / z [M+H] + :374.11.

[0256] 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 (2×150 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.

[0257] 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.

[0258] 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 hours. 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.

[0259] 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. When TLC showed complete consumption of starting material, the reaction mixture was concentrated and the resulting mass was diluted with water and extracted with dichloromethane (2×100 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.

[0260] 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 (2×50 mL) to remove non-polar impurities. Cold water was added and extracted with dichloromethane (2×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the pure product (8-(sec-butyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione (900 mg, 55.9%) as a solid.

[0261] 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. Crude The mixture 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) to elute the desired compound 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 compound 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.

[0262] 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 compound 10 (1-(4-chlorobenzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione) (150 mg, 0.383 mmol, 39.2% yield) as a solid. MS (ESI) m / z [M+H] + :392.05. 1 H NMR(400MHz,DMSO-d6)δ0.66-0.89(m,6H)0.91-1.42(m,4H)1.57-1.78(m,1H)2.16-2.35(m,2H)2.55-2.65(m,2 H)3.08-3.23(m,2H)3.28-3.40(m,1H)3.51-3.64(m,2H)4.76-4.89(m,1H)5.88-6.02(m,1H)7.46-7.56(m,4H).

[0263] 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 compound 11 (1-(4-fluorobenzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione) (140 mg, 0.37 mmol, 38.0% yield) as a solid. MS (ESI) m / z [M+H] + :376.05. 1 H NMR(400MHz,DMSO-d6)δ0.69-0.81(m,3H)0.86(t,J=7.23Hz,3H)0.95-1.14(m,2H)1.20-1.43(m,4H)1.59-1.80(m,2H)2.26(d,J=16.95Hz,1H) 2.55-2.72(m,1H)3.20-3.31(m,2H)3.35-3.39(m,1H)3.52-3.70(m,2H) 4.73-4.89(m,1H)7.33(t,J=8.73Hz,2H)7.61(dd,J=8.23,5.73Hz,2H).

[0264] 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 compound 12 (1-(3-chloro-4-(trifluoromethyl)benzoyl)-6-methyl-8-(2-methylbutyl)hexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione) (250 mg, 0.55 mmol, 55.2% yield) as a solid. MS (ESI) m / z [M+H] + :460.0. 1 H NMR(400MHz,DMSO-d6)δ0.74-0.93(m,6H)0.98-1.19(m,2H)1.28-1.46(m, 3H)1.64-1.81(m,1H)2.22(d,J=17.45Hz,1H)2.57-2.70(m,1H)3.14(dd,J= 13.21,6.23Hz,1H)3.25-3.31(m,2H)3.44-3.57(m,1H)3.61-3.87(m,2H)4. 78-4.90(m,1H)5.89-6.05(m,1H)7.72(d,J=7.98Hz,1H)7.90-8.02(m,2H).

[0265] 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 cooled at room temperature and to it was added EtOH (100 mL) 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 pressure. 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.

[0266] 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.

[0267] 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.

[0268] Step 4: Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-dimethoxyethyl)(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.

[0269] 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 was purified by column chromatography (silica 100-200 mesh; 30% EtOAc / 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.

[0270] 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) was added diethylamine (100 mL) 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.

[0271] 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. was added 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) 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.

[0272] 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(400MHz,DMSO-d6)δ1.25-1.46(m,3H)2.15-2.30(m,1H)2.56-2.69(m,1H)3.16(d,J=4.99Hz,1H)3.22-3.30(m,1 H)3.42-3.72(m,2H)4.70-4.87(m,1H)5.85-5.95(m,1H)7.75(d,J=7.98Hz,2H)7.86(d,J=7.98Hz,2H)8.11(brs,1H).

[0273] 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 tBu (1M in THF, 1.69 mmol, 1.69 mL) was added followed by the appropriate 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.

[0274] 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(400MHz,DMSO-d6)δ1.02-1.26(m,3H)1.28-1.42(m,2H)1.44-1.76(m,6H)1 .80-2.08-2.33(m,2H)2.55-2.71(m,1H)3.22(dd,J=12.96,7.48Hz,1H)3.26-3. 32(m,1H)3.39(d,J=6.98Hz,1H)3.49-3.57(m,1H)3.59-3.74(m,1H)3.76-3.91 (m,1H)4.80-4.90(m,1H)5.95-6.05(m,1H)7.72-7.79(m,2H)7.84-7.91(m,2H).

[0275] Example S18. Synthesis of compound 16.

[0276] Compound 16 was synthesized by general procedure A using bromomethylcyclobutane as the alkyl halide. MS (ESI) m / z [M+H] + :424.15. 1H NMR(400MHz,DMSO-d6)δ1.29-1.44(m,2H)1.58-1.89(m,4H)1.90-2.08(m, 2H)2.16-2.31(m,1H)2.55-2.70(m,2H)3.18-3.31(m,1H)3.25-3.26(m,1H) 3.34-3.42(m,1H)3.36-3.57(m,2H)3.60-3.69(n,1H)3.71-3.83(m,1H)4. 75-4.89(m,1H)5.90-6.05(m,1H)7.70-7.79(m,2H)7.87(d,J=8.31Hz,2H).

[0277] 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(400MHz,DMSO-d6)δ0.94-1.18(m,3H)1.26-1.61(m,9H)1.66-1.83(m,2H)2.16-2.31(m,1H)2.56-2.70(m,1H)3.16-3.28(m,1H)3. 35-3.56(m,3H)3.60-3.73(m,1H)3.77-3.90(m,1H)4.72-4.92(m,1H)5.94-6.06(m,1H)7.77(d,J=7.98Hz,2H)7.87(d,J=7.98Hz,2H).

[0278] 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(400MHz,DMSO-d6)δ1.27-1.44(m,3H)1.50-1.71(m,4H)1.71-1.88(m, 2H)1.93-2.09(m,2H)2.13-2.34(m,2H)2.56-2.70(m,2H)3.25-3.32(m,1H) 3.35-3.42(m,1H)3.45-3.55(m,1H)3.59-3.72(m,1H)3.74-3.90(m,1H)4. 75-4.89(m,1H)5.94-6.05(m,1H)7.71-7.79(m,2H)7.87(d,J=8.31Hz,2H).

[0279] 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(400MHz,DMSO-d6)δ0.81-0.97(m,3H)1.15-1.57(m,7H)2.15-2.31(m,1H)2.57-2.69(m,1H)3.14-3.28(m,1H)3.35-3.60 (m,3H)3.62-3.73(m,1H)3.74-3.92(m,1H)4.75-4.91(m,1H)5.94-6.06(m,1H)7.76(d,J=7.34Hz,2H)7.87(d,J=7.83Hz,2H).

[0280] 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(400MHz,DMSO-d6)δ1.28-1.45(m,3H)2.14-2.38(m,3H)2.55-2.69(m,1H)3.36-3.57(m,4H)3.58-3.72(m,1H)3.75-3.89 (m,1H)4.75-4.90(m,1H)4.98-5.19(m,2H)5.69-5.84(m,1H)5.93-6.05(m,1H)7.76(d,J=7.98Hz,2H)7.88(d,J=7.98Hz,2H).

[0281] 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(400MHz,DMSO-d6)δ0.80-0.96(m,6H)1.30-1.48(m,3H)1.85-2.03(m,1 H)2.15-2.31(m,1H)2.57-2.70(m,1H)3.06-3.16(m,1H)3.18-3.28(m,1H)3. 36-3.45(m,1H)3.44-3.57(m,1H)3.60-3.74(m,1H)3.73-3.87(m,1H)4.77- 4.92(m,1H)5.93-6.07(m,1H)7.76(d,J=7.48Hz,2H)7.87(d,J=7.48Hz,2H).

[0282] 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. 1 H NMR(400MHz,DMSO-d6)δ1.10(d,J=5.49Hz,6H)1.28-1.45(m,3H)2.16-2.24(m,1H)2.56-2.71(m,1H)3.34-3.40(m,1 H)3.44-3.79(m,3H)4.59-4.72(m,1H)4.75-4.90(m,1H)5.86-6.00(m,1H)7.79(d,J=7.98Hz,2H)7.83-7.92(m,2H).

[0283] 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. [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. was added 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) 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 / hexane) 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.

[0284] 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(400MHz,DMSO-d6)δ1.10-1.39(m,3H)2.17-2.18(m,1H)2.52-2.68(m,1H)3.18-3.27(m,2H)3.44-3.71(m,2H)4. 69-4.83(m,1H)5.75-5.92(m,1H)7.24(d,J=7.83Hz,2H)7.32(t,J=72.0Hz,1H)7.57(d,J=8.31Hz,2H)8.04(brs,1H).

[0285] 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, the appropriate 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.

[0286] 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(400MHz,DMSO-d6)δ1.07-1.16(m,3H)1.32(d,J=6.48Hz,3H)1.41-1.73(m ,7H)2.06-2.21(m,1H)2.21-2.34(m,1H)2.54-2.70(m,1H)3.14-3.29(m,1H)3. 35-3.45(m,1H)3.52-3.69(m,1H)3.75-3.93(m,1H)4.75-4.91(m,1H)5.88-5. 99(m,1H)7.27(d,J=8.48Hz,2H)7.35(t,J=72.0Hz,1H)7.61(d,J=8.98Hz,2H).

[0287] 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(400MHz,DMSO-d6)δ1.16-1.25(m,1H)1.27-1.43(m,3H)1.54-1.73(m,2H)1.73 -1.86(m,2H)1.89-2.03(m,2H)2.24(d,J=17.12Hz,1H)2.53-2.69(m,2H)3.20-3.28 (m,1H)3.29-3.40(m,1H)3.40-3.66(m,2H)3.69-3.87(m,1H)4.75-4.86(m,1H)5.74 -6.02(m,1H)7.26(d,J=8.31Hz,2H))7.33(t,J=72.0Hz,1H)7.59(d,J=8.31Hz,2H).

[0288] 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(400MHz,DMSO-d6)δ0.81-0.96(m,3H)1.15-1.39(m,4H)1.40-1.55(m,2 H)2.26(d,J=16.95Hz,1H)2.53-2.70(m,2H)3.12-3.30(m,2H)3.38-3.46(m ,1H)3.56-3.74(m,2H)3.75-3.92(m,1H)4.84(q,J=6.81Hz,1H)5.86-6.06( m,1H)7.28(d,J=7.98Hz,2H)7.36(t,J=72.0Hz,1H)7.62(d,J=8.48Hz,2H).

[0289] 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(400MHz,DMSO-d6)δ1.16-1.45(m,3H)2.18-2.33(m,3H)2.53-2.70(m,1H)3.36-3.46(m,3H)3.51-3.72(m,2H)3.74-3.90(m,1H)4.84(q ,J=6.65Hz,1H)4.91-5.15(m,2H)5.67-5.84(m,1H)5.86-6.03(m,1H)7.29(d,J=8.48Hz,2H)7.36(t,J=72.0Hz,1H)7.61(d,J=8.48Hz,2H).

[0290] 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, CDCl 3 )δ7.48-7.55(m,2H),7.20-7.30(m,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),4.06-4.17(m, 2H),3.82-3.92(m,4H),3.61-3.77(m,2H),2.83-2.99(m,1H),2.47-2.59(m,2H),2.01-2.12(m,4H),1.49(s,3H).

[0291] 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. 1 H NMR (400 MHz, CDCl 3)δ7.40-7.50(m,2H),7.20-7.28(m,2H),7.33-7.43(m,5H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72-3.96(m, 2H),3.44-3.52(m,1H),3.25-3.35(m,2H),2.83-2.99(m,2H),2.47-2.59(m,1H),2.42-2.60(m,1H),2.30-2.57(m,1H),1.49(s,3H).

[0292] 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, CDCl 3 )δ8.50-8.58(m,2H),7.24-7.46(m,4H),7.18(d,J=7.99Hz,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72-3.96( m,2H),3.44-3.52(m,1H),3.25-3.35(m,2H),2.83-2.99(m,2H),2.47-2.59(m,1H),2.42-2.60(m,1H),2.30-2.57(m,1H),1.49(s,3H).

[0293] 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. 1 H NMR (400 MHz, CDCl 3)δ8.50-8.58(m,2H),7.24-7.46(m,4H),7.18(d,J=7.99Hz,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72-3.96( m,2H),3.44-3.52(m,1H),3.25-3.35(m,2H),2.83-2.99(m,2H),2.47-2.59(m,1H),2.42-2.60(m,1H),2.30-2.57(m,1H),1.49(s,3H).

[0294] 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, CDCl 3 )δ7.48(d,J=8.01Hz,2H),7.20-7.28(m,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.16-5.26(m,1H),3.72- 3.96(m,1H),3.46-3.64(m,5H),2.46-2.64(m,2H),1.43-1.56(m,5H),0.43-0.65(m,2H),0.75-0.85(m,2H).

[0295] 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. 1 H NMR(400MHz,DMSO-d6)δ7.52-7.62(m,2H),7.16-7.34(m,3H),5.85-5.95(m,1H),4.80-4.90(m,1H),3.85-3.95 (m,1H),3.70-3.80(m,2H),3.25-3.46(m,5H),3.22(s,3H),2.62-2.72(m,1H),2.20-2.30(m,1H),1.49(s,3H).

[0296] 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(400MHz,DMSO-d6)δ7.52-7.62(m,2H),7.16-7.34(m,3H),5.85-5.95(m,1H),4.80-4.90(m,1H),3.85-3.95(m,1H),3 .70-3.80(m,2H),3.58-3.68(m,2H),3.45-3.55(m,4H),3.22(s,3H),2.62-2.72(m,1H),2.20-2.30(m,2H),1.49(s,3H).

[0297] 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. 1 H NMR(400MHz,CHLOROFORM)δ7.49(d,J=8.01Hz,2H),7.15-7.26(m,2H),6.40-6.76(m,1H),5.90-6.20(m,1H),5.15- 5.25(m,1H),3.86-3.97(m,3H),3.66-3.77(m,2H),3.38-3.49(m,3H),2.97(s,3H),2.59-2.69(m,2H),1.49(s,3H).

[0298] Example S39. Synthesis of compound 34. Step 1. Synthesis of 8-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 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.

[0299] Step 2. Synthesis of 1-(4-(difluoromethoxy)benzoyl)-8-(2-hydroxyethyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 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 warm to room temperature and stirred for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was slowly quenched with ice-cold water (5 mL) and extracted with EtOAc (2 x 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 compound 34 (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(400MHz,DMSO-d6)δ7.52-7.62(m,2H),7.16-7.34(m,3H),5.92-6.02(m,1H),6.78-6.88(m,2H),3.8 6-3.92(m,1H),3.47-3.62(m,6H),3.21-3.31(m,1H),2.57-2.67(m,1H),2.25-3.35(m,1H),1.49(s,3H).

[0300] Example S40. Synthesis of compound 35. Step 1. Synthesis of 2-(1-(4-(difluoromethoxy)benzoyl)-6-methyl-4,7-dioxooctahydro-8H-pyrazino[1,2-a]pyrimidin-8-yl)aceronitrile. To a solution of 1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidin-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 progress of the reaction 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 crude compound obtained 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.

[0301] Step 2. Synthesis of 8-(2-aminoethyl)-1-(4-(difluoromethoxy)benzoyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione. 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) was added concentrated HCl (0.100 mL) 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 compound 35 (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(400MHz,DMSOd6)δ7.96(s,2H),7.55-7.65(m,2H),7.20-7.35(m,3H),5.90-6.20(m,1H),4.85-4.95(m,1H),3.82-3. 92(m,1H),3.55.-3.85(m,2H),3.35-3.45(m,3H),2.95-3.05(m,2H),2.60-2.70(m,1H),2.20-2.30(m,1H),1.35(s,3H).

[0302] 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 the appropriate 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.

[0303] 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. 1 H NMR:δ7.40-7.50(m,2H),7.28-7.38(m,1H),7.15-7.25(m,2H),6.39-6.78(m,1H),6.25-6.35(m,1H),5.90-6.12(m,2H),5.25-5.35(m ,1H),5.10-5.20(m,1H),3.70-3.80(m,1H),3.50-3.60(m,1H),3.20-3.40(m,2H),2.95-3.05(m,3H),2.45-2.60(m,2H),1.59(s,3H).

[0304] 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, CDCl 3)δ7.40-7.48(m,2H),7.15-7.26(m,3H),6.85-6.95(m,2H),6.39-6.95(m,2H),5.90-6.20(m,1H),5.15-5.25(m, 1H),3.72-3.96(m,2H),3.47-3.54(m,1H),3.32-3.42(m,3H),3.10-3.20(m,2H),2.42-2.56(m,2H),1.49(s,3H).

[0305] 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.

[0306] 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.

[0307] 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) was added K2CO3 (1.58 g, 11.46 mmol) at room temperature and stirred for 10 min. To the resulting reaction mixture was added 1-(bromomethyl)-4-(difluoromethoxy)benzene (1.086 g, 4.584 mmol) 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.

[0308] 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.

[0309] 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, CDCl 3 ):δ1.41(d,J=7.13Hz,3H),1.71-1.86(m,2H),2.01-2.15(m,2H),2.26-2. 35(m,1H),2.60-2.67(m,1H),2.89-3.01(m,1H),3.07-3.15(m,1H),3.21-3 .34(m,2H),3.46-3.65(m,2H),3.81-3.95(m,2H),4.35-4.41(m,1H),5.20- 5.29(m,1H),6.53(t,J=72.0Hz,1H),7.08-7.16(m,2H),7.30-7.36(m,2H).

[0310] 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, CDCl 3 )δ1.01-1.15(m,2H),1.41(d,J=7.13Hz,3H),1.45-1.62(m,8H),1.66-1.80(m,2H),2. 23-2.34(m,1H),2.58-2.72(m,1H),2.89-2.98(m,1H),3.04-3.18(m,2H),3.23-3.33(m ,1H),3.43-3.54(m,1H),3.55-3.65(m,1H),3.78-3.93(m,1H),4.31-4.39(m,1H),5.1 5-5.26(m,1H),6.53(t,J=72.0Hz,1H),7.13(d,J=8.50Hz,2H),7.34(d,J=8.50Hz,2H).

[0311] 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, CDCl 3 )δ1.41(d,J=7.13Hz,3H),2.23-2.35(m,3H),2.60-2.71(m,1H),2.92-3.0 1(m,1H),3.06-3.14(m,1H),3.22-3.46(m,3H),3.53-3.64(m,1H),3.79-3. 93(m,2H),4.28-4.38(m,1H),4.91-5.00(m,2H),5.16-5.26(m,1H),5.64- 5.76(m,1H),6.52(t,J=72.0Hz,1H),7.10-7.16(m,2H),7.30-7.36(m,2H).

[0312] 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, CDCl 3 )δ1.41(d,J=7.13Hz,3H),1.56-1.65(m,4H),1.73-1.92(m,2H),1.95-2.07(m,2H),2. 14-2.25(m,1H),2.26-2.35(m,1H),2.59-2.72(m,1H),2.91-2.99(m,1H),3.04-3.14(m ,2H),3.23-3.43(m,2H),3.53-3.63(m,1H),3.87(q,J=13.38Hz,2H),4.29-4.39(m,1H) ,5.17-5.24(m,1H),6.53(t,J=72.0Hz,1H),7.13(d,J=8.63Hz,2H),7.30-7.37(m,2H).

[0313] 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. 1 H NMR(400MHz,DMSO-d6)δ0.86(t,J=7.34Hz,3H),1.14-1.24(m,2H),1.24-1.30(m,2H),1 .38-1.50(m,2H),1.98-2.10(m,1H),2.53-2.61(m,2H),2.64-2.77(m,2H),3.07-3.25( m,3H),3.32-3.41(m,1H),3.62-3.73(m,1H),3.87-3.93(m,2H),4.49-4.58(m,1H),4.8 4-4.94(m,1H),7.15(d,J=8.56Hz,2H),7.22(t,J=72.0Hz,1H),7.43(d,J=8.56Hz,1H).

[0314] 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, CDCl 3 )δppm7.31-7.38(m,2H),7.11-7.16(m,2H),6.31-6.73(m,1H),5.26(q,J=7.21Hz,1H), 4.23-4.44(m,2H),3.98-4.13(m,1H),3.80-3.93(m,3H),3.59(t,J=11.07Hz,1H),3.10 (dd,J=11.51,3.75Hz,1H),2.90-2.99(m,1H),2.62-2.72(m,1H),2.32(dd,J=4.38,2.3 8Hz,1H),2.28(dd,J=4.31,2.31Hz,1H),1.48(d,J=7.25Hz,1H),1.41(d,J=7.13Hz,3H).

[0315] 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 showed 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.

[0316] 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(400MHz,DMSO-d6)δ0.75-0.89(m,3H),0.82-0.87(m,3H),0.96-1.13(m,1H),1.23 -1.31(m,4H),1.64-1.75(m,1H),2.06-2.09(m,1H),2.55-2.62(m,1H),2.65-2.76(m,1 H),3.05-3.15(m,1H),3.15-3.26(m,3H),3.64-3.74(m,1H),3.84-3.95(m,2H),4.52- 4.60(m,1H),4.86-4.94(m,1H),7.17(t,J=8.76Hz,2H),7.41(dd,J=8.19,5.82Hz,2H).

[0317] 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(400MHz,DMSO-d6)0.72-0.80(m,3H),0.80-0.87(m,3H),0.96-1.10(m,1H),1.21-1.2 7(m,1H),1.28-1.34(m,3H),1.62-1.79(m,1H),2.00-2.13(m,1H),2.53-2.65(m,1H),2.66 -2.76(m,1H),3.00-3.10(m,1H),3.17-3.29(m,3H),3.62-3.72(m,1H),4.00-4.08(m,2H) ,4.55-4.65(m,1H),4.85-4.95(m,1H),7.52-7.60(m,1H),7.73(s,1H),7.80-7.88(m,1H).

[0318] 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 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(400MHz,DMSO-d6)δ0.70(t,J=7.09Hz,3H),0.75-0.82(m,3H),0.91-1.11(m,1H),1.22-1.31(m,3H), 1.57-1.72(m,1H),1.97-2.07(m,1H),2.55-2.70(m,2H),2.83(dt,J=10.91,2.74Hz,1H),2.95-3.07(m,1H ),3.10-3.26(m,3H),3.54-3.69(m,1H),3.96-4.04(m,1H),4.06-4.15(m,1H),4.54-4.64(m,1H),4.84-4. 95(m,1H),6.94-7.02(m,1H),7.04-7.13(m,1H),7.29-7.40(m,2H),7.65(d,J=7.95Hz,1H),10.95(s,1H).

[0319] 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.

[0320] 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)cyclobutane (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 compound 45 (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. 1H NMR(400MHz,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),2.1 5-2.40(m,2H),1.75-2.10(m,4H),1.55-1.65(m,4H),1.20-1.30(m,3H).

[0321] 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 compound 46 (8-(2-cyclopentylethyl)-1-(4-fluorobenzyl)-6-methylhexahydro-4H-pyrazino[1,2-a]pyrimidine-4,7(6H)-dione) as a gummy liquid.

[0322] 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 stirred untreated 2,2-diethoxyethan-1-amine (20.0 g, 0.137 mmol) was added 2-methylbutanal (11.60 g, 0.137 mmol) 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. Once the starting material was completely consumed (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(400MHz,DMSO-d6)δ0.80-0.89(m,6H)1.11(t,J=6.98Hz,6H)1.35-1.48(m,2H)2.28-2.32(m,1H) 2.41-2.45(m,1H)2.55(d,J=5.49Hz,2H)3.42-3.52(m,2H)3.57-3.65(m,2H)4.49(t,J=5.49Hz,1H).

[0323] 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.

[0324] 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. was added diethylamine (58 mL, 2.80 vol.) 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.

[0325] 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. was added 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) 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.

[0326] 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 (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.

[0327] 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. 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 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.

[0328] 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.

[0329] 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 tert-butyl 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.

[0330] 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), 4M HCl in dioxane (5 mL) was added at 0° C. 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 quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL×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.

[0331] 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) was added K2CO3 (0.381 g, 2.760 mmol) 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 compound 47 (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, CDCl 3 )δ7.34(d,J=8.01,2H),7.11(d,J=8.01,2H),6.32-6.69(m,1H),5.14-5. 25(m,2H),4.60-4.76(m,2H),3.84-3.97(m,2H),3.35-3.45(m,2H),3.12- 3.40(m,4H),2.85-3.05(m,1H),2.65-2.75(m,1H),2.29-2.34(m,1H),1. 65-1.75(m,1H),1.30-1.40(m,1H),1.05-1.18(m,1H),0.80-0.90(m,6H).

[0332] 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) was added Cs2CO3 (0.814 g, 2.506 mmol) 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 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 compound 48 (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, CDCl 3 )δ7.34(d,J=8.01,2H),7.11(d,J=8.01,2H),5.14-5.25(m,2H),4.60-4.76(m,2H),3.84-3.97(m,2H),3.35-3.45(m,2H),3.12-3.40(m,4 H),2.85-3.05(m,1H),2.65-2.75(m,1H),2.29-2.34(m,1H),1.65-1.75(m,1H),1.30-1.40(m,1H),1.05-1.18(m,1H),0.80-0.90(m,6H).

[0333] 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 was added N-(2,2-diethoxyethyl)-2-methylbutan-1-amine (3.50 g, 9.475 mmol), 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 HO (50 mL) followed by brine (50 mL), dried over NaSO 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.

[0334] Step 2: Synthesis of methyl 3-amino-4-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-oxobutanoate. To a solution of methyl 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) was added diethylamine (1.53 mL, 14.71 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 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.

[0335] 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. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with EtOAc (20 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 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.

[0336] 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) was added formic acid (1.5 mL) 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.

[0337] 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 (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) was added diethylamine (0.280 mL) 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 methyl 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.

[0338] 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.

[0339] 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 compound 49 (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, CDCl 3 )δ7.28-7.38(m,2H),7.11(d,J=7.99Hz,2H),6.33-6.71(m,1H),5.36-5.40(m ,1H),4.70-4.80(m,1H),4.65-4.75(m,1H),3.80-4.00(m,2H),3.55-3.65(m, 1H),3.35-3.45(m,1H),2.85-3.30(m,6H),2.70-2.80(m,1H),2.25-2.35(m,1 H),1.65-1.76(m,1H),1.25-1.35(m,1H),1.10-1.20(m,1H),0.8-0.9(m,6H).

[0340] 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 NH3 (10 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 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 compound 50 (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, CDCl 3 )δ7.30-7.40(m,2H),7.05-7.15(m,2H),6.39-6.70(m,1H),5.20-5.40(m,2H),4. 75-4.85(m,1H),3.95-4.05(m,1H),3.75-3.85(m,1H),3.50-3.60(m,1H),3.30-3. 40(m,1H),3.05-3.25(m,2H),2.85-2.95(m,2H),2.55-2.70(m,1H),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).

[0341] 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), potassium carbonate (1.13 g, 8.196 mmol) was added 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, it 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.

[0342] 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, then 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.

[0343] 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, CDCl 3 )δppm7.70(d,J=8.07Hz,1H),7.54(s,1H),7.33(d,J=8.68Hz,1H),4.34(dd,J=10 .64,3.55Hz,1H),3.87-3.99(m,2H),3.61(t,J=11.13Hz,1H),3.25-3.42(m,2H), 3.08-3.19(m,2H),2.89-2.98(m,1H),2.64-2.74(m,1H)2.29-2.38(m,1H)2.17-2 .27(m,1H)1.97-2.09(m,2H)1.72-1.92(m,3H)1.58-1.66(m,4H)1.55(br.s,3H).

[0344] 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. 1 H NMR (400 MHz, CDCl 3 )δppm7.69(d,J=8.11Hz,1H)7.52-7.56(m,1H)7.33(d,J=7.89Hz,1H),5.23(q,J=7.23Hz,1H),4.36(dd,J= 10.52,3.29Hz,1H),3.87-3.98(m,2H),3.63(t,J=11.07Hz,1H),3.46-3.56(m,1H),3.25-3.35(m,1H),3.1 2-3.23(m,2H),2.87-2.97(m,1H),2.60-2.70(m,1H),2.29-2.37(m,1H),1.66-1.82(m,2H),1.54-1.63(m, 1H),1.51(d,J=,2.63Hz,2H),1.42(d,J=7.23Hz,3H),1.26(br.s,2H)1.04-1.16(m,2H)0.80-0.92(m,2H).

[0345] 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.

[0346] 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) 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 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.

[0347] Step 3: Synthesis of (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-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 warm to 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.

[0348] 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 (9H-fluoren-9-yl)methyl (3-((1-((2,2-diethoxyethyl)(2-methylbutyl)amino)-4-methyl-1-oxopentan-2-yl)amino)-3-oxopropyl)carbamate (3.80 g, 6.231 mmol) was added formic acid (20 mL) at room temperature and the reaction mixture was stirred for 16 hours. 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.

[0349] 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) was added diethylamine (6.8 mL, 69.54 mmol) 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 / 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.

[0350] 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) was added K2CO3 (0.159 g, 1.152 mmol) at 0 °C and the reaction mixture was stirred for 10 min. To the resulting reaction mixture was added 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.150 g, 0.632 mmol) 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 compound 53 (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(400MHz,DMSOd6)δ7.42(d,J=8.8Hz,2H),7.14-7.24(m,3H),5.0-5.10(m,1H),4.50-4.60(m,1H),3.90-4.00(m,2H),3.60-3.70(m,1) H),3.02-3.40(m,4H),2.70-2.85(m,2H),2.0-2.10(m,1H),1.50-1.70(m,4H),1.20-1.35(m,1H),1.0-1.10(m,1H),0.70-0.98(m,12H).

[0351] Biological Examples Example B1. Mechanical allodynia and thermal hyperalgesia rescue assays. Common neuropathies include neuropathic pain associated with the diabetic state. Prolonged hyperglycemia causes persistent polyol pathway activation, cumulative oxidative stress, and neuronal hypoxia / ischemia. This neurotoxic environment leads to degeneration of peripheral sensory nerves, and blockade of sensory nerve endings is interpreted by the brain as pain. In rats, persistent hyperglycemia can be induced by treatment with streptozotocin (STZ), a toxic structural analogue of glucose that is preferentially taken up by pancreatic β-cells, causing cell death and resulting in reduced insulin secretion and hyperglycemia.

[0352] Hyperglycemic rats consistently develop neuropathic pain-related behaviors, including mechanical allodynia. Allodynia refers to a type of neuropathic pain characterized by increased sensitivity to normally non-painful stimuli. Mechanical allodynia in rats is quantified by measuring the force required to withdraw the paw, and is negatively correlated with allodynia, such that the lower the force required to elicit paw withdrawal, the greater the pain behavior.

[0353] A series of studies were conducted to confirm the ability of HGF / MET positive modulating compounds to reduce mechanical allodynia pain behavior in hyperglycemic rats. Male Sprague Dawley rats were administered a single dose of STZ (55 mg / kg intravenously (IV)) to induce type I diabetic hyperglycemia. Hyperglycemia was confirmed 4 days after STZ administration, and model induction was considered successful when blood glucose levels exceeded 200 mg / dL. Test compound treatment began 14 days after disease induction, and daily compound administration continued for the remainder of the study. The route of administration and dose of each compound were determined by pharmacokinetic and distribution modeling. Control groups included animals without induced diabetes (sham controls), animals that were diabetic but treated with formulation vehicle only (DNP (diabetic peripheral neuropathy) controls), and diseased animals treated with pregabalin (30 mg / kg orally), which is known to reduce neuropathic pain behavior.

[0354] Changes in neuropathic pain behavior were evaluated after 14 days of compound treatment, on study day 28. Mechanical allodynia was tested by placing each animal on an elevated wire mesh and stimulating the plantar surface of the right hind paw with a series of filaments of increasing force order, reaching a maximum force of 60 grams (AesthesiomanualVonFrey filaments). The force of the filament that caused paw withdrawal was considered as the paw withdrawal threshold in grams. Pain sensitivity to thermal hyperalgesia was measured using the hot plate method and expressed as paw withdrawal latency (PWL). Rats were placed on a hot plate (52.5°C) and the time it took for either paw to show nocifensive behavior (licking or jumping) was recorded. Statistical comparisons between treatment and DNP control groups were performed by one-way ANOVA followed by Dunnett's multiple comparison test.

[0355] Compounds 1a, 2a, 5a, and 6a demonstrated significant reversal of mechanical allodynia behavior as measured by paw withdrawal threshold in STZDNP rats, the results of which are shown in Table 2.

[0356] Compounds 1a, 2a, 5a, and 6a demonstrated significant reversal of thermal allodynia behavior as measured by paw withdrawal latency in STZDNP rats, the results of which are shown in Table 3. TIFF2025515044000060.tif72170TIFF2025515044000061.tif63170

[0357] Example B2. Comparison of dosing schedules using mechanical allodynia and thermal hyperalgesia rescue assays. An additional series of studies was conducted to compare the ability of compound 1a to reduce mechanical allodynia- and thermal hyperalgesia-induced pain behaviors in hyperglycemic rats administered once or twice daily. Briefly, male Sprague Dawley rats were administered a single dose of STZ (55 mg / kg intravenously (IV)) to induce type I diabetic hyperglycemia. Hyperglycemia was confirmed 4 days after STZ administration, and model induction was deemed successful when blood glucose levels exceeded 200 mg / dL. On day 14 after STZ administration, expression of the pain phenotype was confirmed through assessment of both mechanical allodynia and thermal hyperalgesia. Beginning on day 15 after disease induction, compound 1a (8 mg / kg) was administered orally once (QD) or twice (Q12h) daily from days 15 to 41. Control groups included animals without induced diabetes (sham controls) and animals that were diabetic but treated with the formulation vehicle only (DNP (diabetic peripheral neuropathy) controls).

[0358] Mechanical allodynia and thermal hyperalgesia were evaluated as described in Example B1. Briefly, on days 21, 27, 35, and 41 of the study, mechanical allodynia and thermal hyperalgesia were evaluated 1 hour after administration using vonFrey filaments (1.4, 4, 10, 15, 26, 48, and 60g) and hot plate test (52.5°C), respectively. To evaluate the durability of the administration effect of compound 1a, pain levels were also measured on day 48 after a 7-day washout period without compound administration.

[0359] The results are shown in Tables 4 and 5. Compound 1a effectively reversed the significant increase in pain-related behaviors in animals administered STZ, using assessments of mechanical allodynia and thermal hyperalgesia, beginning on day 27. This reversal of both pain-related behaviors improved throughout the treatment period. Importantly, these analgesic effects persisted on day 48, following a 7-day washout period without compound administration. These results also suggest that Q12h treatment with 8 mg / kg compound 1a moderately improved pain-related behaviors compared to QD. Taken together, compound 1a was found to significantly reduce both types of pain-related behaviors assessed in the rat model of STZ-induced DNP. TIFF2025515044000062.tif99170TIFF2025515044000063.tif99170

[0360] Example B3: Promotion of sensory neurite outgrowth and myelination of sensory neurons in primary cultures following treatment with compound 5a The primary pathological target of neuropathic manifestations is the neurite outgrowth of sensory neurons in the peripheral nervous system. Neurotransmission along sensory nerves depends both on the integrity of the neurite network originating from the sensory neurons themselves and on insulating myelination produced by peripheral Schwann cells.

[0361] To evaluate the effects of test compound treatment on these structures central to the pathology of neuropathies, peripheral sensory neurons were modeled using isolated primary cultures of neurons and Schwann cells harvested from fetal rats. Fetal rats were harvested from pregnant females after 15 days of gestation, and spinal ganglia were isolated by trypsin digestion and mechanical disruption. The resulting cells were cultured and allowed to grow for 7 days. On the 7th day of culture, ascorbic acid was added to the cultures at a concentration of 50 μM to promote myelination of sensory neurons by Schwann cells.

[0362] To model the effects of compound 5a in the normal peripheral nervous system, neuron-Schwann cell co-cultures were treated with compound 5a in combination with low doses of recombinant hepatocyte growth factor (HGF). On day 8 of culture, experimental treatments were added to the culture medium. These treatments included HGF with or without compound 5a. Some cultures were treated with the steroid hormone β-estradiol as a positive control. Treatments were performed every other day, and on day 21 of culture, cultures were fixed with ethanol and processed for immunodetection of both microtubule-associated protein 2 (MAP2) to reveal neurons and their neurites, and myelin-associated glycoprotein (MAG) to reveal the extent of myelination of Schwann cells and cultured neurites. To identify individual cells, cells were counterstained with Hoechst DNA dye.

[0363] To model the effects of neuropathic injury on sensory neurons and associated Schwann cells, cultures were injured with the chemotherapeutic drug cisplatin. These cultures were prepared similarly to those described above. In this system, compound 5a, HGF, and β-estradiol treatments were initiated on day 19 of culture. Also on day 19 of culture, cisplatin (10 μg / ml) was added to the cultures for 24 hours. On day 20 of culture, cisplatin was removed from the medium and replaced with test compound treatment for 24 hours. On day 21 of culture, cells were fixed and processed for immunodetection as described above.

[0364] Thirty fluorescent images were taken per treatment group and images were quantified by automated image analysis. Neurite network extension was quantified as the total length of MAP2-positive neurites per cell measured in μm. Schwann cell myelination was quantified as the overlapping area of ​​MAP2-positive neurites and MAG-positive myelin measured in μm2. Statistical analysis was performed as one-way ANOVA with Fisher's LSD post-hoc test for vehicle- or cisplatin-treated groups, respectively.

[0365] The results of this study are summarized in Table 6. Both healthy and injured cultures responded to treatment with the positive control β-estradiol by significantly promoting neurite network outgrowth and myelination of sensory neurons by Schwann cells. Administration of HGF alone at either 0.05 ng / ml or 5 ng / ml did not significantly promote neurite network outgrowth or myelination in either healthy or injured cultures. However, combining HGF (0.05 ng / ml) with 0.5 μM compound 5a in healthy cultures significantly promoted neurite network outgrowth and myelination. This effect was enhanced in injured cultures, where treatment with HGF (0.05 ng / ml) in combination with compound 5a significantly promoted neurite network outgrowth and myelination at concentrations of 0.1, 0.5, and 1 μM. These results led us to conclude that compound 5a may promote the elaboration of neurites in sensory neurons from patients with neuropathic injury and promote insulating myelination of those neurites by peripheral Schwann cells. TIFF2025515044000064.tif162170

Claims

1. A pharmaceutical composition for use in the treatment of neurological disorders, comprising a compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in the formula, 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 These are H and C, independently. １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ It is alkinyl, R １ａ and R １ｂ These are H and C, independently. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Alkoxy, halo, or C ６ ~C １０ It is an arylalkyl, R ２ is H, oxo, or thioxo, R ３ C ２ ~C ６ Alkyl, C ３ ~C ６ Alkenil, C ３ ~C ６ Alkinyl, C ３ ~C １２ Cycloalkyl, C ３ ~C ６ Cycloalkylalkyl, C ６ ~C １０ It is an arylalkyl, a 5-10 membered heteroarylalkyl, or a 5-10 membered heterocyclylalkyl. Here, the 5-10 membered heteroarylalkyl or 5-10 membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen. R ４ C ６ ~C １０ They are aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl. Here, the 5-10 membered heteroaryl or 5-10 membered heterocyclil contains 1 to 3 heteroatoms selected from nitrogen and oxygen. Each R ５ Independently, C １ ~C ６ Alkyl, oxo, or halo, R ６ H, C １ ~C ６ Alkyl or oxo, R ７ is H or oxo, m is either 1 or 2. n is an integer between 0 and 3. Here, each C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C ３ ~C １２ Cycloalkyl, C ３ ~C １２ Cycloalkylalkyl, C ６ ~C １０ Ariel, C ６ ~C １０ Arylalkyls, 5-10 membered heteroaryls, 5-10 membered heteroarylalkyls, 5-10 membered heterocyclyls, and 5-10 membered heterocyclylalkyls are hydroxyl, halo, amino, and 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 pharmaceutical composition, wherein the substituents are optionally substituted with 1 to 5 substituents selected from H.

2. The pharmaceutical composition according to claim 1, wherein L is -C(=O)- or -CH2-.

3. R １ａ and R １ｂ However, each is independent of H, methyl, fluoro, 2-methylbutyl, and -CH ２ F, Methoxy, -CH ２ CO ２ H, -CH ２ C(=O)NH ２ The pharmaceutical composition according to claim 1, wherein the composition is benzyl or 4-aminobenzyl.

4. R １ａ is methyl, R １ｂ The pharmaceutical composition according to claim 3, wherein is H.

5. R ３ However, the pharmaceutical composition according to claim 1 is as follows: 【Chemistry 2】

6. R ４ is phenyl substituted with 1 to 3 substituents selected from -CF ３ , -OCHF ２ , -OH, fluoro, and chloro, or pyridyl or indolyl optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy, the pharmaceutical composition according to claim 1.

7. R ４ However, the pharmaceutical composition according to claim 6 is as follows: 【Transformation 3】

8. -L-R ４ However, the pharmaceutical composition according to claim 1 is as follows: 【Chemistry 4】

9. The pharmaceutical composition according to claim 1, wherein n is 0, R2 is oxo, R6 is H, and R7 is oxo.

10. The aforementioned compound is of formula (V): 【Transformation 5】 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, During the ceremony, L is -C(=O)- or -CH2-, R1a and R1b are independently C1-C3 alkyl groups optionally substituted with H or -CO2H. R3 is a C1-C3 alkyl substituted with a C4-C5 alkyl, a C4-C5 alkenyl, or a C3-C5 cycloalkyl. The pharmaceutical composition according to claim 1, wherein R4 is a phenyl or pyridyl substituted with one to three substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.

11. A pharmaceutical composition for use in the treatment of neurological disorders, the following: 【Transformation 6】 【change】 【change】 The pharmaceutical composition comprising a compound selected from a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

12. The compound is 【Transformation 7】 The pharmaceutical composition according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

13. The compound is 【Transformation 8】 The pharmaceutical composition according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

14. The compound is 【Chemistry 9】 The pharmaceutical composition according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The compound is 【Chemistry 10】 The pharmaceutical composition according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

16. The compound is 【Chemistry 11】 The pharmaceutical composition according to claim 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the nerve disorder is mononeuropathy, polyneuropathy, sensory neuropathy, painful diabetic neuropathy, or idiopathic neuropathy.

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