Methods for treating inflammatory conditions

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 involving peripheral and / or systemic inflammatory conditions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 426,620, filed November 18, 2022, U.S. Provisional Patent Application No. 63 / 447,436, filed February 22, 2023, and U.S. Provisional Patent Application No. 63 / 463,742, filed May 3, 2023, each of which is incorporated by reference herein in its entirety for all purposes.

[0002] The present disclosure relates generally to compounds, compositions and methods for treating diseases such as peripheral and / or systemic inflammatory conditions. [Background technology]

[0003] Hepatocyte growth factor (HGF) is a pleiotropic protein involved in numerous biological processes, including embryonic and organ development, regeneration, and inflammation. HGF plays an important role in the development and maturation of cortical, motor, sensory, sympathetic, and parasympathetic neurons. HGF is translated and secreted as an inactive pro-HGF protein. Upon cleavage, the resulting α and β subunits are connected by disulfide bonds to form an active heterodimer. HGF expression is primarily found 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).

[0004] 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 various biological processes and has been shown to play roles in development, regeneration, and response to injury. HGF binding to the extracellular domain of MET leads to 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).

[0005] HGF is a key regulator of inflammation and autoimmunity. HGF activity reduces the expression of the pro-inflammatory cytokine IL-6 and promotes the expression of the anti-inflammatory cytokine IL-10 in monocytes (Molnarfi et al., 2015). Furthermore, HGF increases tolerogenic dendritic cells and attenuates cytotoxic T cell activity (Ilangumaran et al., 2016). These effects of HGF activity on inflammation and immune function are likely beneficial in inflammatory pathologies.

[0006] Despite advances in the field, there remains a need for improved compounds and methods for the treatment of peripheral and / or systemic inflammatory conditions. Summary of the Invention

[0007] Provided herein are compounds that modulate HGF for use in treating peripheral and / or systemic inflammatory conditions. Non-limiting exemplary embodiments include the following:

[0008] 1. A method of treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, comprising administering an effective amount of a compound of formula (I): [ka] (I) or a pharmaceutically 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 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 10 The arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl are optionally substituted with 1 to 5 substituents selected from hydroxyl, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, —(C═O)NH2, nitro, —SO2(C1-C6 alkyl), and —CO2H.

[0009] 2.L is -C(=O)- or -(CR a R b ) m 2. The method of embodiment 1, wherein

[0010] 3. The method of embodiment 1 or 2, wherein L is -C(=O)-.

[0011] 4.L is -(CR a R b ) m 3. The method of embodiment 1 or 2, wherein

[0012] 5.R a and R b 5. The method of embodiment 4, wherein each is H and m is 1.

[0013] 6.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-C6 optionally substituted with 1-3 substituents selected from halo and amino. 10 The method of any one of embodiments 1 to 5, wherein the alkyl is aryl.

[0014] 7.R 1a and R 1b is each independently H, methyl, fluoro, 2-methylbutyl, —CH 2 F, methoxy, —CH 2 CO 2 H, —CH 2 C(═O)NH 2 , benzyl, or 4-aminobenzyl.

[0015] 8.R 1a and R 1b is each independently H or C1-C3 alkyl.

[0016] 9.R 1a is methyl and R 1b 9. The method of embodiment 8, wherein

[0017] 10.R 1a and R 1b 9. The method of embodiment 8, wherein each is H.

[0018] 11.R 2 11. The method of any one of embodiments 1-10, wherein

[0019] 12.R 2 The method of any one of embodiments 1 to 10, wherein is thioxo.

[0020] 13.R 2 The method of any one of embodiments 1 to 10, wherein is oxo.

[0021] 14.R 3 C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C6 cycloalkyl alkyl, C6-C 10 14. The 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, C-C haloalkyl, C-C alkoxy, C-C haloalkoxy, cyano, —(C═O)NH, nitro, —SO(C-C alkyl), and —COH.

[0022] 15.R 3 is a C2-C6 alkyl optionally substituted with 1 to 3 substituents selected from halo, C1-C3 alkoxy, hydroxy, -NH2, -SO2(C1-C3 alkyl), and -C(=O)NH2; a C2-C6 alkenyl; a C3-C6 cycloalkylalkyl; a 5- to 6-membered heteroarylalkyl; a 5- to 6-membered heterocyclylalkyl; or a C6 arylalkyl.

[0023] 16.R 3 16. The method of embodiment 15, wherein is a C2 alkyl substituted with 1 to 3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(C1-C3 alkyl).

[0024] 17.R 3 17. The method of any one of embodiments 14-16, wherein: [ka]

[0025] 18.R 318. The method of embodiment 17, wherein: [ka]

[0026] 19.R 4 is a C6-C optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy; 10 The method of any one of embodiments 1 to 18, wherein the aryl is aryl.

[0027] 20.R 4 20. The method of embodiment 19, wherein is phenyl substituted with 1 to 3 substituents selected from -CF3, -OCHF2, -OH, fluoro, and chloro.

[0028] 21.R 4 21. The method of embodiment 20, wherein: [ka]

[0029] 22.R 4 22. The method of embodiment 21, wherein: [ka]

[0030] 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.

[0031] 24.R 4 24. The method of embodiment 23, wherein is pyridyl or indolyl optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0032] 25.R 4 but, [ka] 25. The method of embodiment 24, wherein

[0033] 26.R 4 but, [ka] 26. The method of embodiment 25, wherein

[0034] 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.

[0035] 28.R 4 28. The method of embodiment 27, wherein is indolinyl.

[0036] 29.R 4 but, [ka] 29. The method of embodiment 28, wherein

[0037] 30.-LR 4 27. The method of any one of embodiments 1-26, wherein: [ka]

[0038] 31. The method of any one of embodiments 1 to 30, wherein n is 0.

[0039] 32. The method of any one of embodiments 1 to 30, wherein n is 1.

[0040] 33.R5 33. The method of embodiment 32, wherein is oxo or halo.

[0041] 34.R 5 34. The method of embodiment 33, wherein is oxo or fluoro.

[0042] 35.R 6 35. The method of any one of embodiments 1-34, wherein

[0043] 36.R 6 36. The method of any one of embodiments 1-35, wherein is oxo.

[0044] 37. The compound has the formula (V): [ka] (V), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0045] 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 a C1-C3 alkyl substituted with a C4-C5 alkyl, a C4-C5 alkenyl, or a 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.

[0046] 39. A method for treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, comprising administering an effective amount of compound A19: [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0047] 40. A method of treating peripheral and / or systemic inflammatory conditions 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 a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0048] 41. The method of any one of the preceding embodiments, wherein the peripheral and / or systemic inflammatory disease is inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, Leber's hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis.

[0049] 42. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is inflammatory bowel disease.

[0050] 43. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is Crohn's disease.

[0051] 44. The method of embodiment 43, wherein the peripheral and / or systemic inflammatory condition is ulcerative colitis.

[0052] 45. The method of embodiment 43, wherein the peripheral and / or systemic inflammatory condition is celiac disease.

[0053] 46. ​​The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is rheumatoid arthritis.

[0054] 47. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is psoriasis.

[0055] 48. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory pathology is non-infectious uveitis.

[0056] 49. The method of any one of embodiments 1-41, wherein the peripheral and / or systemic inflammatory condition is type 2 diabetes.

[0057] 50. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is obesity.

[0058] 51. The method of any one of embodiments 1-41, wherein the peripheral and / or systemic inflammatory condition is coronary heart disease.

[0059] 52. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is gout.

[0060] 53. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is fatty liver disease.

[0061] 54. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory pathology is seasonal allergy.

[0062] 55. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is COPD.

[0063] 56. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is endometriosis.

[0064] 57. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is gout.

[0065] 58. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is dermatomyositis.

[0066] 59. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is polymyositis.

[0067] 60. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is optic neuritis.

[0068] 61. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is LHON.

[0069] 62. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is macular degeneration.

[0070] 63. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory pathology is retinal degeneration.

[0071] 64. The method of any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is myasthenia gravis.

[0072] 65. The method of any one of embodiments 1-64, wherein the compound reduces inflammation associated with the inflammatory condition.

[0073] 66. The method of any one of embodiments 1-65, wherein the compound reduces hypoxia associated with the inflammation.

[0074] 67. The method of any one of the preceding embodiments, wherein said compound alleviates pain associated with said inflammatory condition.

[0075] 68. The method of any one of the preceding embodiments, wherein said compound reduces the level of at least one pro-inflammatory molecule in said subject.

[0076] 69. The method of embodiment 68, wherein the compound reduces the level of at least one pro-inflammatory molecule selected from G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα, and IFNγ.

[0077] 70. The method of any one of the preceding embodiments, wherein said compound reduces the level of at least one pro-inflammatory molecule selected from IL-1β, IL-4, IL-6, TNF-α, and IFNγ.

[0078] 71. The method of any one of embodiments 1 to 70, wherein the peripheral and / or systemic inflammatory pathology does not result from neuroinflammation, or a disease or disorder of the central nervous system.

[0079] 72. The method of any one of embodiments 1-71, wherein the peripheral and / or systemic inflammatory condition does not result from Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensory hearing and vision loss.

[0080] 73. The method of any one of embodiments 1 to 70, wherein the peripheral and / or systemic inflammatory pathology is not associated with neuroinflammation, or a disease or disorder of the central nervous system.

[0081] 74. The method of any one of embodiments 1-73, wherein the peripheral and / or systemic inflammatory condition is not associated with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensory hearing and vision loss.

[0082] 75. The method of any one of embodiments 1-74, wherein the subject does not suffer from Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing loss and vision loss, or a disease or disorder of the central nervous system.

[0083] 76. The method of any one of the preceding embodiments, wherein the compound is formulated into a pharmaceutical composition. DETAILED DESCRIPTION OF THE INVENTION

[0084] 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, several specific details are set forth to provide a thorough understanding of various embodiments of the present disclosure. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting of any claimed subject matter. In the event that any material incorporated herein by reference contradicts the explicit content of the present disclosure, the explicit content shall control. In this application, the use of the singular includes the plural unless expressly stated otherwise. It must 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 expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0085] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0086] In describing the present invention, 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 with respect to 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 indicated.

[0087] 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.

[0088] "Amino" refers to the -NH2 radical.

[0089] "Carboxy" or "carboxyl" refers to the -CO2H radical.

[0090] "Cyano" refers to the -CN radical.

[0091] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0092] "Nitro" refers to the -NO2 radical.

[0093] "Oxo" refers to the =O substituent.

[0094] "Thioxo" refers to the =S substituent.

[0095] "Thiol" refers to an --SH substituent.

[0096] "Alkyl" means an unbranched or branched saturated hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, having from 1 to 12 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, etc. Unless stated otherwise in the specification, alkyl groups are optionally substituted.

[0097] "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 (C2-C6). 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 rest 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.

[0098] "Alkynyl" means an unbranched or branched unsaturated hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon triple bonds and having 2 to 12 carbon atoms (C2-C6). 12 Alkynyl), preferably having 2 to 8 carbon atoms (C2-C8 alkynyl) or 2 to 6 carbon atoms (C2-C6 alkynyl), and attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless stated otherwise in the specification, alkynyl groups are optionally substituted.

[0099] "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.

[0100] "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. Generally, aromatic rings contain covalently bonded, coplanar atoms and contain an even, but not multiple of four, number of pi electrons (e.g., alternating double and single bonds) (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 optionally substituted radicals.

[0101] "Aryl" refers to an alkyl group having 6 to 18 carbon atoms and at least one aromatic ring (i.e., C6-C 18 aryl), preferably containing 6 to 10 carbon atoms (i.e., C6 to C 10"aryl" refers to a carbocyclic ring system radical having a carbon atom, a carbonyl group, a cyclic ...

[0102] "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.

[0103] "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, and which has 3 to 15 carbon atoms (i.e., C3 to C6). 15 cycloalkyl), preferably 3 to 10 carbon atoms (i.e., C3 to C 10"cycloalkyl" refers to a group having 3 to 6 carbon atoms (i.e., C3-C6 cycloalkyl), saturated or unsaturated, and attached to the rest 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.

[0104] "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 to C6 12 C1-C connected to cycloalkyl radical 10 Alkylene chain (i.e., C3-C 12 C1-C connected to a cycloalkyl (alkyl) or C3-C6 cycloalkyl radical 10 It may contain an alkylene chain (i.e., C3-C6 cycloalkylalkyl). Unless stated otherwise in the specification, a cycloalkylalkyl group is optionally substituted.

[0105] "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.

[0106] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo.

[0107] "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 can all be the same, or the halo radicals can be different. Unless stated otherwise in the specification, haloalkyl groups are optionally substituted.

[0108] "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.

[0109] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or multiple fused rings (e.g., a 5- to 14-membered ring system) containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 1 to 10 ring carbon atoms and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur within the ring. Preferred heteroaryl groups have 5- to 10-membered ring systems containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., 5- to 10-membered heteroaryls) and 5- to 6-membered ring systems containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur (i.e., 5- to 6-membered heteroaryls). For purposes of embodiments of the present disclosure, heteroaryl radicals can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can 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 contain one or more N-oxide (NO-) moieties, such as pyridine-N-oxide. Unless otherwise specified herein, heteroaryl groups are optionally substituted.

[0110] "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- to 10-membered heteroarylalkyl) or a 5- to 6-membered heteroaryl group 10 It may contain an alkylene chain (i.e., a 5- to 6-membered heteroarylalkyl). Unless stated otherwise in the specification, a heteroarylalkyl group is optionally substituted.

[0111] "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 heterocyclyl, regardless of bonding (i.e., can be bonded via a carbon atom or a heteroatom). Furthermore, 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 heteroaryl ring, regardless of bonding to the rest of the molecule. As used herein, 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.

[0112] "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-C6 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 (ie, a 5- to 8-membered heterocyclylalkyl). Unless stated otherwise in the specification, a heterocyclylalkyl group is optionally substituted.

[0113] In some embodiments, the term "substituted" as used herein refers to any of the above groups or other substituents (e.g., C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 12 Cycloalkyl, C3-C 12In any of the cycloalkyl, alkyl, aryl, and heteroaryl, it means 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, such as, 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 containing one or more halogens, such as F, Cl, Br, and I (e.g., haloalkyl); and cyano.

[0114] 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 L, R is optionally substituted as above, unless otherwise specified, provided that all valences are satisfied by substitution. 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 Each selection 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).

[0115] "Peripheral inflammation" and "systemic inflammation" refer to the activation of the innate or adaptive immune system and the release of inflammatory cytokine signaling molecules in response to a variety of pathological stimuli outside the central nervous system. Tissues that produce or respond to peripheral inflammatory signals include muscle and connective tissue, the gastrointestinal tract and enteric nervous system, thoracic organs, blood, skin, and lymphatic tissue.

[0116] An "effective amount" or "therapeutically effective amount" of a compound or composition refers to the amount of the compound or composition that produces the desired intended result based on the disclosure herein. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, but not limited to, ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose 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.

[0117] "Treating" or "treatment" of a subject disease refers to 1) preventing the occurrence of the disease in a patient who is predisposed to or who 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 purposes of this disclosure, beneficial or desired results include one or more of the following, but are not limited to: alleviating one or more symptoms resulting from a disease or disorder of interest, reducing the severity of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the onset or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, improving the state of the disease or disorder, providing remission (whether partial or total) of the disease or disorder, reducing the dose of one or more other drugs required to treat the disease or disorder, enhancing the effectiveness of another drug used to treat the disease or disorder, delaying the progression of the disease or disorder, improving quality of life, and / or prolonging survival. Alleviation of the pathological consequences of a disease or disorder is also encompassed by "treatment." The methods of the present invention contemplate any one or more of these aspects of treatment.

[0118] 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.

[0119] As used herein, the term "therapeutic benefit" 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.

[0120] 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 a single composition in which both agents are present.

[0121] "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.

[0122] "Pharmaceutically acceptable salt" includes both acid and base addition salts.

[0123] "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, and including, 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, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, geraniol, methylparaben ... It is formed with organic acids such as antiseptic, glucoheptonic, gluconic, glucuronic, glutamic, glutaric, 2-oxoglutaric, 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.

[0124] A "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 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.

[0125] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

[0126] 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 various core structures. In addition, compounds for screening can be obtained from various natural sources, such as plant or animal extracts.

[0127] The term "in vivo" refers to events that take place inside a subject's body.

[0128] Embodiments of the present disclosure are also intended to encompass all pharmaceutically 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 incorporated 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 125These radiolabeled compounds may be useful to aid in determining or measuring the efficacy 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 due to its ease of incorporation and ready means of detection.

[0129] Deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may be preferable in some circumstances because they may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced required dosage.

[0130] 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 for examining 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 analogous to those described in the Examples set forth below, using appropriate isotopically labeled reagents in place of previously employed non-labeled reagents.

[0131] In certain embodiments, it is also intended to encompass in vivo metabolic products of the disclosed compounds. Such products may result primarily from enzymatic processes, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound. 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 a metabolic product thereof. 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 product from urine, blood, or other biological sample.

[0132] "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.

[0133] In many cases, crystallization produces a solvate of the compound of the present disclosure. As used herein, the term "solvate" refers to an aggregate containing 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 a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, etc., as well as the corresponding solvate. In some embodiments, the compound of formula (I) is a true solvate, while in other cases, the compound of the present disclosure simply retains adventitious water or is a mixture of water and some adventitious solvent.

[0134] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted and unsubstituted aryl radicals. It is not intended herein to encompass polymers or similar infinite structures that are reached by defining a substituent with an unlimited number of further substituents (e.g., a substituted aryl having a substituted alkyl, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group, etc.). Similarly, the above definitions are 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 of skill in the art.

[0135] A "pharmaceutical composition" or "pharmaceutically acceptable composition" refers to a formulation of a compound of the present disclosure with a vehicle generally accepted in the art for delivering biologically active compounds to mammals, e.g., humans. Such vehicles include any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0136] 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, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0137] A compound of Formula (I), or a pharmaceutically acceptable salt or isotopic form thereof, may contain one or more centers resulting in geometric asymmetry and may thus 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, 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 can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative), using, for example, chiral high-pressure 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 tautomeric forms.

[0138] "Stereoisomers" refer to compounds consisting of the same atoms joined by the same bonds but having different, incompatible three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0139] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0140] "Tautomer" refers to a 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.

[0141] The chemical naming protocols and structural diagrams used herein are modified IUPAC nomenclature using the ACD / Name Version 9.07 software program and / or the ChemDraw Ultra Version 11.0.1 software naming program (CambridgeSoft). In complex chemical names employed herein, substituents are typically named before the group to which they are attached. For example, cyclopropylethyl comprises an ethyl skeleton with a cyclopropyl substituent. Except as noted below, in the chemical structural diagrams herein, all bonds are identified, except for some carbon atoms, which are assumed to be connected to sufficient hydrogen atoms to satisfy the valence.

[0142] 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, for clarity, be described herein in the context of separate embodiments, the invention may also be practiced in a single embodiment.

[0143] compound Compounds of formula (I), or pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof, and methods for their preparation are described in PCT Publication No. WO2022 / 094400, which is incorporated herein by reference in its entirety for all purposes.

[0144] In one aspect, provided herein is a compound of formula (I): [ka] (I) or a pharmaceutically 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 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, wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12cycloalkyl, C3-C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 Arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl are hydroxyl, halo, amino, 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.

[0145] 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.

[0146] 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 bis independently H, C1-C3 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl. a and R b are each H. In some embodiments, R a is H. In some embodiments, R a is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R a is a C2-C6 alkenyl, such as vinyl or propenyl. a is a C2-C6 alkynyl, such as ethynyl or propynyl. b is H. In some embodiments, R b is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R b is a C2-C6 alkenyl, such as vinyl or propenyl. b is a C2-C6 alkynyl such as ethynyl or propynyl.

[0147] In some embodiments, R 1a and R 1b are independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, or C6-C 10 In some embodiments, R 1a is H. In some embodiments, R 1a is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 1a is a C2-C6 alkenyl, such as vinyl or propenyl. 1a is a C2-C6 alkynyl, such as ethynyl or propynyl. 1a is C1-C6 alkoxy, such as methoxy, ethoxy, or propoxy.1a is halo, such as fluoro, chloro, or bromo. 1a C6-C such as benzyl 10 In some embodiments, R 1b is H. In some embodiments, R 1b is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 1b is a C2-C6 alkenyl, such as vinyl or propenyl. 1b is a C2-C6 alkynyl, such as ethynyl or propynyl. 1b is C1-C6 alkoxy, such as methoxy, ethoxy, or propoxy. 1b is halo, such as fluoro, chloro, or bromo. 1b C6-C such as benzyl 10 It is arylalkyl.

[0148] 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-C6 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 to 3 -CO2H groups.

[0149] In some variations, R 1ais 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. In some embodiments, R 1a 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 1a is a C6-C substituted by 1 to 3 substituents selected from halo and amino 10 In some embodiments, R 1a is a C6-C substituted by 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. In some variations, R 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. In some embodiments, R 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 by 1 to 3 substituents selected from halo and amino 10 In some embodiments, R 1bis a C6-C substituted by 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 R 1b are each independently H, methyl, fluoro, 2-methylbutyl, —CHF, methoxy, —CHCOH, —CHC(═O)NH, benzyl, or 4-aminobenzyl. 1a and R 1b are each independently H or C1-C3 alkyl. In some embodiments, R 1a is methyl and 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 the groups is H, and the other is a C1-C3 alkyl such as methyl.

[0150] In some embodiments, R 2 is H, oxo, or thioxo. In some embodiments, R 2 is H. In some embodiments, R 2 is oxo. In some embodiments, R 2 is thioxo.

[0151] 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 10arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl, where the 5- to 10-membered heteroarylalkyl or 5- to 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. In some embodiments, R 3 is C4-C6 alkyl. In some embodiments, R 3 is C-C alkenyl. In some embodiments, R 3 is C4-C6 alkenyl. In some embodiments, R 3 is C3-C6 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 heteroarylalkyl 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.

[0152] In some embodiments, R 3 is C-C alkyl, C-C alkenyl, or C-C cycloalkylalkyl optionally substituted with 1-3 substituents selected from halo and C(=O)NH. In some embodiments, R 3 is a C2-C6 alkyl optionally substituted with 1-3 substituents selected from halo, C1-C3 alkoxy, hydroxy, —NH2, —SO2(C1-C3 alkyl), and —C(═O)NH2; a C2-C6 alkenyl; a C3-C6 cycloalkylalkyl; a 5-6 membered heteroarylalkyl; a 5-6 membered heterocyclylalkyl; or a C6 arylalkyl. In some embodiments, R 3 is a C2 alkyl substituted with 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(C1-C3 alkyl). 3 teeth, [ka] is.

[0153] In some embodiments, R 3 teeth, [ka] is.

[0154] In some embodiments, R 3 is 2-methylbutyl.

[0155] In some embodiments, R 4 C6~C 10aryl, 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. 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 a 5- to 10-membered heterocyclyl. 4 is a 5-9 membered heterocyclyl containing 1-2 nitrogen atoms. 4 is a 5-9 membered heterocyclyl containing 1-2 oxygen atoms. 4 is a 5-9 membered heterocyclyl containing one nitrogen atom and one oxygen atom.

[0156] In some embodiments, R 4 is a C6-C optionally substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy; 10 In some embodiments, R 4 is phenyl substituted with 1 to 3 substituents selected from -CF, -OCHF, -OH, fluoro, and chloro. 4 teeth, [ka] is.

[0157] In some embodiments, R 4 teeth, [ka] is.

[0158] In some embodiments, R4 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 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 teeth, [ka] In some embodiments, R 4 is pyridyl substituted with 1 to 3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 teeth, [ka] In some embodiments, R 4 is a 5-10 membered heterocyclyl optionally substituted with 1-3 substituents selected from halo, hydroxyl, C1-C6 haloalkyl, and C1-C6 haloalkoxy. 4 is indolinyl, [ka] is.

[0159] In some embodiments, -LR 4 is —CH2(phenyl) or —C(O)(phenyl), where phenyl is substituted with 1 to 3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. In some embodiments, —LR 4is —CH (pyridyl) or —C(O) (pyridyl), where the pyridyl is substituted with 1 to 3 substituents selected from C-C haloalkyl, C-C haloalkoxy, halo, and hydroxy. 4 is: [ka]

[0160] In some embodiments, each R 5 is independently C1-C6 alkyl, oxo, or halo. 5 is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 5 is oxo. In some embodiments, R 5 is halo, such as fluoro, chloro, or bromo. 5 is oxo or halo. In some embodiments, R 5 is oxo or fluoro.

[0161] In some embodiments, R 6 is H, C1-C6 alkyl, or oxo. In some embodiments, R 6 is H. In some embodiments, R 6 is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 6 is oxo.

[0162] In some embodiments, R 7 is H or oxo. In some embodiments, R 7 is H. In some embodiments, R 7 is oxo.

[0163] In some embodiments, m is 1. In other embodiments, m is 2.

[0164] 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.

[0165] In any embodiment of Formula (I) or variations thereof, each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 12 Cycloalkyl, C3-C 12 Cycloalkylalkyl, C6-C 10 Aryl, C6-C 10 The arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 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.

[0166] In some embodiments, the compound of Formula (I) is a compound of Formula (II), (IIa), (IIb), (IIc), (IId), or (IIe): [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein L, R 1a , R 1b , R 3 , R 4 , R 5 , R 6 , R 7and n are as described for Formula (I). In some embodiments, the compound is a compound of Formula (II), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIa), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIb), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIc), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IId), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IIe), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0167] In some embodiments, the compound of Formula (I) is a compound of Formula (IIIa), (IIIb), (IIIc), or (IIId): [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein R 1a , R 1b , R 3 , R 5 , R 6and n are as described for Formula (I), and R represents one or more optional substituents, such as hydroxyl, halo, amino, C-C haloalkyl, C-C haloalkoxy, as described for Formula (I). In some embodiments, the compound is of Formula (IIIa), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of Formula (IIIb), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of Formula (IIIc), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is of Formula (IIId), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0168] In some embodiments, the compound of Formula (I) is a compound of Formula (IVa), (IVb), (IVc), or (IVd): [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, wherein R 5 and n are as described for Formula (I), and R represents one or more optional substituents, such as hydroxyl, halo, amino, C-C haloalkyl, C-C haloalkoxy, as described for Formula (I). In some embodiments, the compound is a compound of Formula (IVa), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IVb), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IVc), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the compound is a compound of Formula (IVd), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0169] In some embodiments, the compound of formula (I) is a compound of formula (V): [ka] (V) or a pharmaceutically 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 -CH2-, and R 1a and R 1b are independently H, or C-C alkyl optionally substituted with —COH, and 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 to 3 substituents selected from -CF, -OCHF, -OH, fluoro, and chloro. 1a and R 1b One of the groups is H, and the other is a C1-C3 alkyl such as methyl.

[0170] In the description herein, it is understood that any description, variation, embodiment, or aspect of one 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 listed. 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 7and n may be combined with any and all descriptions, variations, embodiments, or aspects 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 to and are similarly described with respect 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 relating to formula (I) equally applies to and is equally described, where applicable, for 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 relating to all formulas were individually and independently listed.

[0171] In some embodiments, provided is a compound selected from Table 1, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. Some compounds described in this disclosure, including those in Table 1, are depicted as particular stereoisomeric and / or non-stereochemical forms, but it is understood that any and 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. TIFF2025538382000026.tif232170TIFF2025538382000027.tif225170TIFF2025538382000028.tif244170TIFF2025538382000029.tif246170TIFF2025538382000030.tif248170TIFF2025538382000031.tif224170TIFF2025538382000032.tif245170TIFF2025538382000033.tif100170 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0172] 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.

[0173] In some embodiments, provided is a compound selected from Table 1A, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. Some compounds described in this disclosure, including those in Table 1A, are depicted as particular stereoisomeric and / or non-stereochemical forms, but it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms, of any of the compounds of this disclosure, including those in Table 1A, are also described herein. TIFF2025538382000034.tif238170TIFF2025538382000035.tif248170TIFF2025538382000036.tif104170 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0174] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0175] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0176] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0177] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0178] 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.

[0179] Furthermore, all compounds of formula (I) that exist in free base or free acid form can be converted into their pharmaceutically 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 into their free base or free acid forms by standard techniques.

[0180] Phosgonimeton and related compounds Fosgonimeton is a prodrug that is rapidly converted in plasma after subcutaneous injection to the active drug ATH-1001 (Dihexa; see US 2014 / 0094413), which acts as a positive regulator of the hepatocyte growth factor (HGF) receptor and its tyrosine kinase, MET, receptor system.

[0181] Phosgonimeton is compound A19: [ka] is a pharmaceutically acceptable salt of

[0182] Non-limiting exemplary pharmaceutically acceptable salts of Compound A19 include: [ka]

[0183] Unless otherwise indicated, phosgonimeton refers to the monosodium salt of compound A19, shown below: [ka]

[0184] Compound A19 and its pharmaceutically acceptable salts, isotopic forms, or stereoisomers, e.g., phosgonimetone, can be synthesized and characterized using methods known to those skilled in the art, such as those described in PCT Publication No. WO2017 / 210489A1.

[0185] In some embodiments, fosgonimeton is formulated for subcutaneous administration.

[0186] Synthesis method The compounds of formula (I), or pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof, can be prepared by using organic chemical synthesis methods known in the art. Generally, 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 (e.g., Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5 thedition (Wiley, December 2000), may be prepared as described herein.

[0187] General reaction scheme 1. [ka] General Reaction Scheme 1 provides an exemplary method for preparing compounds of formula (I). 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, and n are as defined herein. X is a reactive moiety (e.g., halo) selected to facilitate the desired reaction. P1 and P2 are suitable protecting groups. L' is a group selected from L'-R 4 The desired L moiety is selected to result from the reaction between A1 and a secondary amine. Compounds of structure A1 are either commercially available or prepared according to methods known in the art. A1 and A2 are reacted under suitable coupling conditions (e.g., T3P and a base) to provide the coupling reaction product A3 between A1 and A2. A3 is then reacted with A4 under suitable coupling conditions (e.g., T3P and a base) to provide compound A5. Compound A5 is then cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to provide compound A6. Compound A6 is then reacted with compound A7 to provide the final compound of formula (I) shown.

[0188] General reaction scheme 2. [ka] An alternative synthesis of compounds of formula (I) is shown in General Reaction Scheme 2. In General Reaction Scheme 2, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R6 , R 7 , L, and n are as defined herein. P2 is a suitable protecting group. Each X is a reactive moiety (e.g., halo) selected to facilitate the desired reaction. L' is a group selected from L'-R 4 Intermediate A5 is selected to yield the desired L moiety from the reaction between R 3 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).

[0189] General Reaction Scheme 3. [ka] A method related to that shown in General Reaction Scheme 2 is shown in General Reaction Scheme 3. In this method, the two amine nitrogen atoms of the bicyclic core are deprotected to 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).

[0190] 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 analogous methods using appropriate starting materials.

[0191] Those skilled in the art will understand that in the processes for preparing the compounds described herein, it may be necessary to protect the functional groups of intermediate compounds with 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 as described herein. The use of protecting groups is described in detail in Green, T W and P G M Hutz, Protective Groups in Organic Synthesis (1999). , 3 rd 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.

[0192] Pharmaceutical Compositions and Formulations In a further aspect, provided herein are pharmaceutical compositions. The pharmaceutical compositions comprise any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are formulated for oral administration. In other embodiments, the pharmaceutical compositions are formulated for injection. In even more embodiments, the pharmaceutical compositions comprise a compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and an additional therapeutic agent. Non-limiting examples of such therapeutic agents are described herein below.

[0193] 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 injection, as well as intrathecal, intravenous, intraperitoneal, intralymphatic, and intranasal injection.

[0194] In certain embodiments, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered locally rather than systemically, for example, by directly injecting the compound into an organ, often in a depot preparation or sustained-release formulation. In certain embodiments, a long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In yet 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 and selectively taken up by the organ. In yet other embodiments, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0195] The compounds of formula (I) or Compound A19, or pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof, are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg per day, 0.5 to 100 mg per day, 1 to 50 mg per day, and 5 to 40 mg per day are exemplary dosages used in some embodiments. An exemplary dosage is 10 to 30 mg per day. The exact dosage may depend on the route of administration, the form in which the compound is administered, the subject being treated, the subject's weight, and the preference and experience of the attending physician.

[0196] In some embodiments, the compound of formula (I) or compound A19, or its pharmaceutically 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.

[0197] In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered in multiple doses. In some embodiments, dosing is about once, twice, three times, four times, five times, six times, or more than six times per day. In other embodiments, 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 pharmaceutically 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, administration of the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and the therapeutic agent continues for less than about 7 days. In yet another embodiment, administration continues for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous administration is possible and is maintained for as long as necessary.

[0198] Administration of the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, can be continued for as long as necessary. In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered continuously, for example, chronically, for the treatment of chronic effects (e.g., peripheral or systemic inflammatory conditions).

[0199] In some embodiments, the 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 variability in the pharmacokinetics of compounds between subjects, optimal treatment requires individualized administration regimens.The dosage of compound can be found by routine experimentation in light of the present disclosure.

[0200] In some embodiments, the compound of formula (I) or compound A19, or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, is formulated into a pharmaceutical composition. In a specific embodiment, the pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries, that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the selected route of administration. Any pharmaceutically 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).

[0201] 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).

[0202] In certain embodiments, the compound is administered as a pharmaceutical composition in which the compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is mixed with other therapeutic agents as a combination therapy. All combinations of active ingredients described in the methods section below and throughout this disclosure are encompassed herein. In specific embodiments, the pharmaceutical composition comprises one or more compounds of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0203] As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided herein is administered in a pharmaceutical composition to a mammal having the disease, disorder, or medical condition to be treated. In specific embodiments, 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 mixtures in combination with one or more therapeutic agents.

[0204] In one embodiment, one or more compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are formulated in an aqueous solution. In a specific embodiment, the aqueous solution is selected from a physiologically compatible buffer, 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are formulated for transmucosal administration. In a specific embodiment, the transmucosal formulation includes a penetrant appropriate for the barrier to be permeated (e.g., the blood-brain barrier). In yet other embodiments, in which the compounds described herein are formulated for parenteral injection, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0205] In another embodiment, the compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, 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 a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated into oral dosage forms, including, but not limited to, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0206] 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 pharmaceutically acceptable salts, isotopic forms, or stereoisomers, and optionally grinding the resulting mixture, processing the granular mixture, and optionally adding suitable excipients 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 certain embodiments, disintegrants are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0207] In one embodiment, dosage forms such as dragee cores and tablets are provided with one or more suitable coatings. In a specific embodiment, a concentrated sugar solution is used to coat the dosage form. The sugar solution optionally contains additional ingredients such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, Carbopol® gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. 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.

[0208] In certain embodiments, a therapeutically effective amount of at least one of the compounds of Formula (I) or Compound A19, or a pharmaceutically 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 specific embodiments, the push-fit capsules contain the active ingredient mixed with one or more fillers. Fillers include, by way of example only, binders such as lactose or 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.

[0209] In other embodiments, a therapeutically effective amount of at least one of the compounds of Formula (I) or Compound A19 described herein, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels. In still other embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated for parenteral injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, the injectable formulation is provided in a unit dosage form (e.g., an ampule) or in a multi-dose container. Preservatives are optionally added to the injection. 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 formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In additional embodiments, suspensions of one or more active compounds (e.g., a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof) 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, allowing for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0210] In yet another embodiment, the compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered topically. The compound is formulated into a variety of topically administrable compositions, such as a solution, suspension, lotion, gel, paste, medicated stick, balm, cream, or ointment. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancers, buffers, and preservatives.

[0211] In yet other embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically 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 polymers or adhesives. In various embodiments, such patches can 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is achieved 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In specific embodiments, the absorption rate is slowed by using rate-controlling membranes or by entrapment of the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to enhance absorption. The absorption enhancer or carrier comprises a pharmaceutically acceptable absorbable solvent that aids 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, predetermined rate over an extended period of time, and a means for securing the device to the skin.

[0212] In other embodiments, the compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of the compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas). In specific embodiments, 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 mix of the compound and a suitable powder base, such as lactose or starch.

[0213] In yet other embodiments, the compound of formula (I) or Compound A19, or a pharmaceutically 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 suppository forms of the composition, a low melting point wax, such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter, is first melted.

[0214] 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 pharmaceutically usable preparations.The appropriate formulation depends on the selected administration route.Any pharmaceutically acceptable technology, carrier, and excipient are optionally used suitably.Pharmaceutical compositions containing a compound of formula (I), or its pharmaceutically acceptable salt, isotopic form, or stereoisomer, are prepared in a conventional manner, such as, for example, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0215] Pharmaceutical compositions comprise at least one pharmaceutically acceptable carrier, diluent, or excipient and at least one compound of Formula (I) or Compound A19 described herein, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, as an active ingredient. The active ingredient may be in the form of a free acid or free base, or a pharmaceutically 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 that have the same type of activity. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Furthermore, compounds of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, encompass unsolvated forms as well as solvates with pharmaceutically 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, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0216] Methods for preparing compositions containing a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, include formulating the compound with one or more pharmaceutically 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 containing the compound, emulsions containing the compound, or solutions containing liposomes, micelles, or nanoparticles containing a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The pharmaceutical compositions described herein may be in the form of a liquid solution or suspension, a solid form suitable for solution or suspension in a liquid prior to use, or an emulsion. These compositions also optionally contain minor amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and the like.

[0217] In some embodiments, pharmaceutical compositions comprising at least one compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are illustratively in the form of a liquid in which the agent is present in solution, suspension, or both. Typically, when the composition is administered as a solution or suspension, a first portion of the agent is present in solution, and a second portion of the agent is present in a particulate form suspended in a liquid matrix. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

[0218] 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 a mucoadhesive polymer selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate, and dextran.

[0219] Useful pharmaceutical compositions also optionally contain a solubilizing agent to aid in the dissolution of the compound of formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. "Solubilizing agents" generally include agents that result in a micellar or true solution of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizing agents, as are ophthalmologically acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers.

[0220] In addition, useful pharmaceutical compositions optionally contain one or more pH adjusters or buffers, 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 within an acceptable range.

[0221] Additionally, useful compositions also optionally contain one or more salts in an amount necessary to bring the osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium, or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

[0222] 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.

[0223] 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.

[0224] Still other useful compositions optionally include one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium disulfite.

[0225] 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.

[0226] 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is delivered using a sustained-release system, such as a semipermeable matrix of solid hydrophobic polymers containing a therapeutic agent. Various 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.

[0227] 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) cyclodextrin, (l) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc, or (n) combinations thereof.

[0228] In some embodiments, the concentration of the compound of Formula (I) or Compound A19 provided in the 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 less than 0.0001% w / w, w / v or v / v.

[0229] 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%, 15.75%, 16.50%, 16.25%, 16%, 15.75%, 16.50%, 16.25%, 16%, 16.50%, 16 ...50%, 16.75%, 16.50%, 16.25%, 16%, 16.50%, 16.50%, 16.75%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, 16.50%, %, 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.

[0230] In some embodiments, the concentration of the compound of Formula (I) or Compound A19, or a pharmaceutically 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 The range is from 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.

[0231] In some embodiments, the concentration of the compound of Formula (I) or Compound A19, or a pharmaceutically 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.

[0232] In some embodiments, the amount of the compound of Formula (I) or Compound A19, or a pharmaceutically 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.

[0233] In some embodiments, the amount of the compound of Formula (I) or Compound A19, or a pharmaceutically 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 , 0.0009g, 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 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.

[0234] In some embodiments, the amount of the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, provided in the pharmaceutical composition is in the range of 0.0001 to 10 g, 0.0005 to 9 g, 0.001 to 8 g, 0.005 to 7 g, 0.01 to 6 g, 0.05 to 5 g, 0.1 to 4 g, 0.5 to 4 g, or 1 to 3 g.

[0235] In some embodiments, the method comprises administering compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, by subcutaneous injection.

[0236] In some embodiments, the methods comprise administering the HGF / MET positive modulator via an oral dosage form.

[0237] In some embodiments, the method comprises administering compound 2a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0238] In some embodiments, the method comprises administering compound 1a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0239] In some embodiments, the method comprises administering compound 5a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0240] In some embodiments, the method comprises administering compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0241] In some embodiments, the method comprises administering compound 7a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, via an oral dosage form.

[0242] 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 compartmentalized to receive one or more containers, such as vials, tubes, etc., each of which contains one of the individual elements used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials, such as glass or plastic.

[0243] The products provided herein contain packaging materials. Packaging materials used to package 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 pierceable by a hypodermic needle). Such kits optionally contain the compound along with identifying information or a label or instructions for use in the methods described herein.

[0244] For example, a kit typically includes one or more additional containers, each containing one or more of a variety of materials desirable from a commercial and user standpoint for use of a compound of Formula (I), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, such as reagents (optionally in concentrated form) and / or devices. 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 describing the contents and / or instructions for use, as well as package inserts describing the instructions for use. A set of instructions is also typically included. A label is optionally on or associated with the container. For example, a label is on a container when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself, or when the label is present in a receptacle or carrier that holds the container, e.g., as a package insert. Additionally, labels are used to indicate that the contents are to be used for a particular therapeutic application. Additionally, the label provides instructions for use of the contents, such as the methods described herein. In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device containing one or more unit dosage forms containing a compound provided herein. The pack contains, for example, metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may be accompanied by labeling attached to the container in a format prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which labeling reflects the agency's approval of the drug form for human or veterinary administration. Such labeling is, for example, labeling 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, formulated in a compatible pharmaceutical carrier is prepared, placed in an appropriate container, and labeled for treatment of a designated condition.

[0245] How to use / treat Embodiments of the present disclosure provide methods for modulating hepatocyte growth factor in a subject in need thereof, the method 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 pharmaceutically 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 variety of ways known in the art. Kits and commercially available assays are available for determining whether and to what extent hepatocyte growth factor is modulated (e.g., inhibited or activated).

[0246] In some embodiments, provided herein is a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, for use in positively regulating hepatocyte growth factor in a subject in need thereof. In some embodiments, provided herein is a compound of Formula (I) or Compound A19, or a pharmaceutically 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.

[0247] Applicant has discovered that the compound of Formula (I) or Compound A19 exhibits promising activity in connection with certain diseases of interest. Accordingly, in one aspect, provided herein is a method for modulating hepatocyte growth factor in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) or Compound A19, or a pharmaceutically 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, the method comprising administering to the subject an effective amount of a compound of Formula (I) or Compound A19, or a pharmaceutically 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, the method comprising administering to the subject an effective amount of a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0248] In more specific embodiments, positively modulating includes treating or alleviating a disease, condition, or injury. In some embodiments, the disease, condition, or injury is a peripheral and / or systemic inflammatory condition. The peripheral and / or systemic inflammatory condition may be associated with gastrointestinal, skin, ophthalmological, metabolic, or respiratory disorders.

[0249] In some embodiments, the peripheral and / or systemic inflammatory condition can be inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, Leber's hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis.

[0250] In some embodiments, the peripheral and / or systemic inflammatory condition can be inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, Leber's hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0251] In some embodiments, provided herein are methods for treating inflammatory bowel disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0252] In some embodiments, provided herein are methods for treating Crohn's disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0253] In some embodiments, provided herein are methods for treating ulcerative colitis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0254] In some embodiments, provided herein are methods for treating celiac disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0255] In some embodiments, provided herein are methods for treating rheumatoid arthritis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0256] In some embodiments, provided herein are methods for treating psoriasis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0257] In some embodiments, provided herein are methods for treating non-infectious uveitis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0258] In some embodiments, provided herein are methods for treating type 2 diabetes in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0259] In some embodiments, provided herein are methods for treating obesity in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0260] In some embodiments, provided herein are methods for treating coronary heart disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0261] In some embodiments, provided herein are methods for treating gout in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0262] In some embodiments, provided herein is a method for treating fatty liver disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0263] In some embodiments, provided herein are methods for treating seasonal allergies in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0264] In some embodiments, provided herein are methods for treating COPD in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0265] In some embodiments, provided herein are methods for treating endometriosis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0266] In some embodiments, provided herein are methods for treating systemic lupus erythematosus in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0267] In some embodiments, provided herein are methods for treating dermatomyositis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0268] In some embodiments, provided herein are methods for treating polymyositis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0269] In some embodiments, provided herein are methods for treating optic neuritis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0270] In some embodiments, provided herein are methods for treating LHON in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0271] In some embodiments, provided herein are methods for treating macular degeneration in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0272] In some embodiments, provided herein are methods for treating retinal degeneration in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0273] In some embodiments, provided herein are methods for treating myasthenia gravis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1, a compound of Table 1a, Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0274] In some embodiments, the peripheral and / or systemic inflammatory condition can be inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, Leber's hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0275] In some embodiments, provided herein are methods for treating inflammatory bowel disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0276] In some embodiments, provided herein are methods for treating Crohn's disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0277] In some embodiments, provided herein are methods for treating ulcerative colitis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0278] In some embodiments, provided herein are methods for treating celiac disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0279] In some embodiments, provided herein are methods for treating rheumatoid arthritis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0280] In some embodiments, provided herein are methods for treating psoriasis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0281] In some embodiments, provided herein are methods for treating non-infectious uveitis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0282] In some embodiments, provided herein are methods for treating type 2 diabetes in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0283] In some embodiments, provided herein are methods for treating obesity in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0284] In some embodiments, provided herein are methods for treating coronary heart disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0285] In some embodiments, provided herein are methods for treating gout in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0286] In some embodiments, provided herein is a method for treating fatty liver disease in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0287] In some embodiments, provided herein are methods for treating seasonal allergies in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0288] In some embodiments, provided herein are methods for treating COPD in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0289] In some embodiments, provided herein are methods for treating endometriosis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0290] In some embodiments, provided herein are methods for treating systemic lupus erythematosus in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0291] In some embodiments, provided herein are methods for treating dermatomyositis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0292] In some embodiments, provided herein are methods for treating polymyositis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0293] In some embodiments, provided herein are methods for treating optic neuritis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0294] In some embodiments, provided herein are methods for treating LHON in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0295] In some embodiments, provided herein are methods for treating macular degeneration in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0296] In some embodiments, provided herein are methods for treating retinal degeneration in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0297] In some embodiments, provided herein are methods for treating myasthenia gravis in a subject. The method includes administering to the subject an effective amount of a compound of Table 1a, a compound of Table 2a, a compound of Table 5a, a compound of Table 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0298] In some embodiments, the peripheral and / or systemic inflammatory condition is not due to neuroinflammation or a disease or disorder of the central nervous system. In some embodiments, the peripheral and / or systemic inflammatory condition is not due to dementia. In some embodiments, the peripheral and / or systemic inflammatory condition is not due to a neurodegenerative disease. In some embodiments, the peripheral and / or systemic inflammatory condition is not due to Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensory hearing and vision loss. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory condition does not suffer from dementia. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory condition does not suffer from a neurodegenerative disease. In some embodiments, the subject being treated for a peripheral and / or systemic inflammatory condition does not suffer from Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, and / or sensory hearing and vision loss.

[0299] In some embodiments, the peripheral and / or systemic inflammatory condition is not associated with neuroinflammation or a disease or disorder of the central nervous system. In some embodiments, the peripheral and / or systemic inflammatory condition is not associated with dementia. In some embodiments, the peripheral and / or systemic inflammatory condition is not associated with a neurodegenerative disease. In some embodiments, the peripheral and / or systemic inflammatory condition is not associated with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensory hearing and vision loss. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory condition does not suffer from dementia.

[0300] In some embodiments, the present disclosure provides methods 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 pharmaceutically 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%.

[0301] In some embodiments, the present disclosure provides methods for modulating hepatocyte growth factor activity in a cell by contacting the cell with a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate the activity of hepatocyte growth factor. In some embodiments, the present disclosure provides methods for modulating hepatocyte growth factor activity in a tissue by contacting the tissue with a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate the activity of hepatocyte growth factor in the tissue. In some embodiments, the present disclosure provides methods for modulating hepatocyte growth factor activity in an organism by contacting the organism with a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate the activity of hepatocyte growth factor in the organism. In some embodiments, the present 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate hepatocyte growth factor activity in the animal. In some embodiments, the present 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate hepatocyte growth factor activity in the mammal. In some embodiments, the present 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, in an amount sufficient to modulate hepatocyte growth factor activity in the human. In other embodiments, the present 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, involves activation of hepatocyte growth factor.

[0302] In some embodiments, a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one proinflammatory molecule in a subject. In some embodiments, a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one proinflammatory molecule selected from G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα, and IFNγ. In some embodiments, a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one proinflammatory molecule selected from IL-1β, IL-4, IL-6, TNF-α, and IFNγ. In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one pro-inflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), eotaxin (CCL11), IL-2R, LIF, MIP-1 beta (CCL4), and MIP-1 alpha (CCL3).

[0303] In some embodiments, a compound of Table 1, Table 1A, or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one proinflammatory molecule in a subject. In some embodiments, a compound of Table 1, Table 1A, or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one proinflammatory molecule selected from G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα, and IFNγ. In some embodiments, a compound of Table 1, Table 1A, or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one proinflammatory molecule selected from IL-1β, IL-4, IL-6, TNF-α, and IFNγ. In some embodiments, a compound of Table 1, Table 1A, or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one pro-inflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), eotaxin (CCL11), IL-2R, LIF, MIP-1 beta (CCL4), and MIP-1 alpha (CCL3).

[0304] In some embodiments, Compound 1a, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one pro-inflammatory molecule in a subject. In some embodiments, Compound 1a, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one pro-inflammatory molecule selected from G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα, and IFNγ. In some embodiments, Compound 1a, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one pro-inflammatory molecule selected from IL-1β, IL-4, IL-6, TNF-α, and IFNγ. In some embodiments, Compound 1a, Compound 2a, Compound 5a, Compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, reduces the level of at least one pro-inflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), eotaxin (CCL11), IL-2R, LIF, MIP-1 beta (CCL4), and MIP-1 alpha (CCL3).

[0305] Other embodiments provide methods for combination therapy in which therapeutic agents known to modulate other pathways or other components of the same pathway or overlapping target enzymes are used in combination with a compound of Formula (I) or Compound A19, or a pharmaceutically 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 pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, with therapeutic agents, therapeutic antibodies, and other forms of therapy that provide a synergistic or additive therapeutic effect.

[0306] Many therapeutic agents are currently known in the art and can be used in combination with a compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. In some embodiments, the subject with a peripheral and / or systemic inflammatory condition is also treated with another anti-inflammatory agent, such as a steroid.

[0307] In some embodiments, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, 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®, and hyaluronic acid.

[0308] Additional therapeutic agents that can be combined with the compounds of Formula (I) or Compound A19, or a pharmaceutically 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 the Physician's Desk Reference, both of which are incorporated herein by reference in their entireties.

[0309] The compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, 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 a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, are co-administered with the other therapeutic agents described above. When used in combination therapy, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, 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 a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and any of the above therapeutic agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and any of the above therapeutic agents can be present in separate formulations and administered simultaneously. In another alternative, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, can be administered immediately followed by any of the above therapeutic agents, or vice versa. In some embodiments of the separate administration protocol, the compound of Formula (I) or Compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, and any of the above therapeutic agents are administered minutes apart, or hours apart, or days apart.

[0310] The examples and preparations provided below further illustrate and demonstrate the compounds of Formula (I) or Compound A19, or pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof, and methods for preparing such compounds. It is 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 examples below, and throughout the specification and claims, molecules with a single stereocenter exist as a racemic mixture unless otherwise noted. Molecules with two or more stereocenters exist as a racemic mixture of diastereomers unless otherwise noted. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art. [Example]

[0311] The following examples are provided for illustrative purposes. Methods for preparing compounds of formula (I), or pharmaceutically acceptable salts, isotopic forms, or stereoisomers thereof, are provided in PCT Publication No. WO2022 / 094400, which is incorporated herein by reference, or can be derived by one of ordinary skill in the art.

[0312] Example B1: Reduction of inflammatory pain-related behaviors and inflammatory biomarkers after treatment in the rodent CFA inflammatory pain model Responses to peripheral inflammatory stimuli can be modeled by subcutaneous injection of a suspension of dried actinomycetes in complete Freund's adjuvant (CFA), paraffin oil, and mannide monooleate into the footpad of rats. Introduction of CFA into peripheral nerve tissue results in a rapid and sustained inflammatory response in the exposed tissue within 24 hours. Subcutaneous administration of CFA in the plantar region induces inflammatory pain-related behaviors that persist for at least 8 days. CFA treatment also results in the accumulation of inflammatory cytokines at the site of injury in paw tissue. The extent of the inflammatory response to CFA can be assessed by quantification of inflammatory cytokines in paw skin homogenates and inflammatory pain-related behaviors using tests of mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test).

[0313] On test day 1, compound 2a was tested for its ability to reduce inflammatory pain-related behavior in the CFA inflammation model. On test day 0, 50 μg of CFA was administered subcutaneously into the plantar hind paw. Animals were treated daily with compound 2a in solution via oral gavage (PO) at doses of 1 mg / kg, 0.1 mg / kg, and 0.025 mg / kg. This treatment began on test day 1 before CFA injection and continued until test day 8.

[0314] Mechanical allodynia was measured using the von Frey test. In this test, rats were placed on a wire mesh, and a series of filaments designed to deliver investigation pressures ranging from 4 to 26 grams were applied to the center of the plantar surface of the rat's hind right paw. Animals demonstrated a pain response by lifting the investigated paw. The minimum force required to elicit a withdrawal response was recorded as the paw withdrawal threshold (PWT). von Frey tests were performed 1 hour after administration of compound 2a on test days 1, 3, and 7, and also before administration on test day 7. Statistical analysis was performed using one-way analysis of variance with Tukey's post-hoc test. A p value of less than 0.05 was considered statistically significant. The results are summarized in Table 2. Control animals stimulated with CFA but treated with vehicle alone had increased sensitivity to mechanical stimuli compared to normal control animals. Treatment with 1 mg / kg of compound 2a resulted in a reduction in mechanical allodynia at the post-administration test on test day 7.

[0315] Thermal hyperalgesia was measured using the Hargreaves test. A heat lamp was applied to the right hind paw via a direct light beam, and paw withdrawal latency (PWL) was recorded as a measure of sensitivity to thermal stimuli. Testing was performed 1 hour post-dose on test days 1, 3, and 7, and also pre-dose on test day 7. Statistical analysis was performed using one-way ANOVA with Tukey's post-hoc test. A p value of less than 0.05 was considered statistically significant. The results are summarized in Table 2. Control animals stimulated with CFA but treated with vehicle alone had increased sensitivity to thermal stimuli compared with normal control animals. Treatment with 1 mg / kg of compound 2a resulted in decreased thermal sensitivity on pre-dose testing on days 3 and 7. TIFF2025538382000047.tif119170

[0316] In another test, Compound 1a, Compound 5a, and Compound 6a were similarly tested for their ability to reduce pain-related behavior in response to CFA-induced inflammatory stimulation of the right hind paw. This test also included quantifying the expression of inflammatory cytokines in paw skin homogenates. Inflammatory pain stimulation by CFA injection, as well as mechanical and thermal pain-related behavioral assessments, were carried out as described above.

[0317] Intraplantar CFA injections were performed on day 0. Treatment with Compound 1a, Compound 5a, and Compound 6a was administered daily from day -1 to day 8. Rats were sacrificed on day 8, and cytokine levels in paw skin were measured. Tissues from the paw bones, joints, and muscles were obtained for H&E staining and analysis. Cytokine levels in CFA-stimulated test compound-treated animals were compared with CFA-stimulated vehicle-treated animals. Analyses included interleukin 4 (IL-4), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ). Statistical analysis consisted of one-way analysis of variance followed by Dunnett's multiple comparison post-hoc test. Mechanical allodynia and thermal hyperalgesia were tested 1 hour after administration on days 1, 3, and 7. PWT indicates the lower limit of paw withdrawal latency, with higher values ​​corresponding to a higher pain threshold. PWL indicates the lower limit of paw withdrawal latency, with higher values ​​corresponding to a higher pain threshold.

[0318] As shown in Table 3, compound 1a significantly reduced sensitivity to mechanical stimuli on test days 1, 3, and 7, as well as thermal sensitivity on test days 1, 3, and 7. Treatment with compound 5a reduced mechanical sensitivity on test day 1 and thermal sensitivity on test days 1 and 7. Compound 6a reduced thermal sensitivity on test day 7. TIFF2025538382000048.tif126170

[0319] Compounds 1a and 5a showed statistically significant increases in PWT on day 1, and compound 1a showed statistically significant increases in PWT on days 3 (8 mg / kg and 16 mg / kg) and 7 (16 mg / kg) (Table 3 and data not shown).

[0320] Compound 1a, Compound 5a and Compound 6a showed a statistically significant increase in PWL at each dose on day 7 (Table 3 and data not shown).

[0321] On day 5, mechanical allodynia and thermal hyperalgesia were assessed 1 hour before administration. The thresholds for each compound were tested on day 5. Compound 1a and Compound 6a showed a statistically significant increase in PWL (data not shown).

[0322] Despite the observable pain reduction, treatment had no significant effect on paw skin thickness (data not shown). On study day 8, significant reductions in IL-4, TNF-α, and IFN-γ were detected in the paw skin (Table 4 and data not shown).

[0323] All test compounds reduced the expression of the evaluated cytokines at at least one dose tested, except for compound 6a, which had no effect on IFN-γ expression (Table 4). These results suggest that the test compounds exert meaningful anti-inflammatory effects in response to CFA-stimulated peripheral inflammation. TIFF2025538382000049.tif78170

[0324] Example B2: Reduction of inflammation after pulmonary LPS challenge. Acute pneumonia can be effectively modeled in rats by intratracheal administration of bacterial lipopolysaccharide (LPS). The severity of the inflammatory response can be measured by quantifying the amount of immune cell infiltration in bronchoalveolar lavage fluid (BALF) and the secretion of cytokine signaling proteins. Activation of the HGF / MET signaling pathway by positive regulators of HGF / MET is predicted to reduce the inflammatory response. Two test compounds, compound 1a and compound 5a, were evaluated for their ability to reduce acute pneumonia in this intranasal LPS model.

[0325] In this study, acute pneumonia was induced in healthy male Sprague-Dawley rats (7–9 weeks old at the start of the study) by intratracheal instillation of 20 μg of LPS in saline. Test animals were treated twice with the test compound via intravenous (IV) injection, 24 h and 0.5 h before LPS treatment. Dexamethasone (Dex), an anti-inflammatory corticosteroid, was used as a positive control and administered at 3 mg / kg via intraperitoneal (IP) injection 1 h before LPS treatment. Four hours after LPS administration, animals were euthanized by intraperitoneal injection of thiopental, and 20 mL of cold Hank's balanced salt solution, pH 7.2, was instilled into the lungs via tracheal cannulation. BALF was then collected.

[0326] Immune cell infiltration in BALF was quantified as an assessment of the inflammatory response, and the results are shown in Table 5. Immune cell infiltration was measured by counting total leukocytes using a MUSE® mini flow cytometer and manually counting neutrophil cells in cytospin smears stained with Leishman's staining reagent. Treatment with Compound 1a and Compound 5a reduced both total leukocyte and neutrophil counts compared with the LPS-only control. TIFF2025538382000050.tif79170

[0327] Cytokine expression in BALF supernatants was quantified by multiplex immunoassay using a MAGPIX multiplex unit with a cytokine multiplex kit (Merck-Millipore, Cat# RECYMAG65K27PMX). The panel of cytokines tested included growth factors (G-CSF, GM-CSF, EGF, VEGF, TNF-α), chemokines (CCL2, CCL3, CCL5, CCL11, CXCL1, CXCL2, CXCL5, CXCL10, CX3CL1), interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A), and interferon-γ (IFNγ). The results of this analysis are shown in Table 6. Statistically significant changes from levels in animals treated with LPS alone were determined by Student's t-test, with p<0.05 indicating a statistically significant change in cytokine expression levels. Treatment with compound 1a resulted in significant changes in the expression of G-CSF, CXCL2, CXCL10, IFN-γ, and IL-1β. Treatment with compound 5a resulted in significant changes in the expression of CCL3, CXCL1, IFN-γ, IL-1α, IL-1β, IL-10, IL-12p70, and IL-17A. These results indicate that treatment with the test compound had a significant impact on acute lung inflammation in response to LPS by reducing the levels of proinflammatory molecules. The normal process of inflammation is regulated and promoted by the expression, secretion, and delivery of inflammatory signaling proteins. Therapies intended to reduce inflammation are generally distinguished by their ability to alter the expression levels of inflammatory signaling molecules, either by directly disrupting inflammatory pathways or by disrupting inflammatory signaling cascades. The compounds provided herein are expected to be able to interrupt inflammatory signaling based on their demonstrated effects on the expression of notable inflammatory cytokines. TIFF2025538382000051.tif228170

[0328] Example B3: Reduction of pro-inflammatory cytokine expression in macrophage-like cell cultures Inflammation plays a pivotal role in disease progression and is a complex phenomenon involving various cells, affecting numerous extracellular and intracellular signaling pathways and cytokine production. Macrophages are tissue-resident or infiltrating immune cells important for innate immunity, normal tissue development, homeostasis, and repair of damaged tissues. Activated macrophages are involved in the development of systemic and peripheral inflammation and respond to toxic exogenous substances (such as LPS) or endogenous substances. Here, we used THP-1 cells as an in vitro cell model to evaluate mechanisms related to systemic and peripheral inflammation. PMA-induced differentiation induces THP-1 mononuclear cells to acquire macrophage-like functionality and morphology. LPS interacts with THP-1 differentiated macrophages via Toll-like receptor 4, triggering an inflammatory response, stimulating the release of pro-inflammatory cytokines, and ultimately leading to cell death. We investigated whether test compounds have anti-inflammatory effects on LPS-challenged macrophage cultures. THP-1 differentiated macrophages were treated with test compounds for 20 min followed by a 24-h LPS challenge, and culture supernatants were then collected and analyzed for the presence of proinflammatory cytokines, namely interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α).

[0329] Quantification of cytokines in cell culture supernatants was performed by homogeneous time-resolved fluorescence (HTRF) kits to assess the levels of IL-1β (human IL-1β kit, #62HIL1BPEG, Cisbio) and IL-6 (human IL-6 kit, 62HIL06PET, Cisbio), and ELISA to determine the levels of TNF-α (human TNF-α ELISA kit, KHC3011, ThermoFisher).

[0330] Data analysis was performed using Prism statistical software (GraphPad) via one-way ANOVA with Tukey's post-hoc test compared to LPS-treated cultures. Table data show the significance of the reduction of the indicated analytes in culture supernatants at the indicated doses.

[0331] The results are shown in Table 7. Treatment with Compound 1a, Compound 5a, Compound 6a, and the active metabolite of A19 (ATH-1001) all significantly reduced the expression of IL-1β and TNF-α at at least one dose tested. Treatment with Compound 1a, Compound 5a, and the active metabolite of A19 all significantly reduced the expression of IL-6 at at least one dose tested. "NS" indicates a non-significant reduction in the indicated cytokine. "+" indicates a p-value of <0.05 by Tukey's post-hoc test. "++" indicates a p-value of <0.01 by Tukey's post-hoc test. TIFF2025538382000052.tif140170

[0332] Example B4: Reduction of streptozotocin-induced inflammatory cytokines in response to compound treatment. Administration of streptozotocin, a chemotherapeutic agent with specific toxic effects on pancreatic islet cells, induces a severe systemic inflammatory response in animals. Streptozotocin enters pancreatic B cells via glucose transporters and disrupts the function of these cells by cross-linking their DNA, resulting in the production of uncontrollable hyperglycemia. This condition leads to a strong and chronic induction of inflammatory pathways and is widely used as a model of peripheral inflammation associated with the symptoms of diabetes.

[0333] To evaluate the ability of test compounds to reduce systemic inflammation in a streptozotocin-induced diabetic model in Sprague-Dawley rats, disease was induced by a single intravenous dose of streptozotocin (STZ, 55 mg / kg) on ​​study day 0, and induction of diabetic disease was confirmed by estimating blood glucose levels on day 4. Rats with blood glucose levels above 200 mg / dL were considered successfully induced and included in the study. Treatment with test compounds began on study day 15 and continued with a single daily dose administered by oral gavage (PO) until study day 28, when plasma was collected for cytokine expression analysis.

[0334] Cytokines were quantified using a bead capture detection system (ProcartaPlex, ThermoFisher, catalog number: PPX-090MXKA44V) with a Luminex multiplex detection system. Each analyte was quantified against a standard curve, and plasma content was measured in pg / ml. Interferon gamma (IFN-γ) and interleukin-4 (IL-4) were strongly upregulated by STZ stimulation and decreased in response to test compound treatment. IFN-γ is expressed in response to other inflammatory cytokines and promotes inflammation by activating the JAK / STAT signaling pathway. IL-4 is a proinflammatory cytokine that activates several types of inflammatory macrophage cells. Therefore, a decrease in the expression of any of these analytes represents a decreased inflammatory response to disease challenge. Statistical analysis was performed by one-way analysis of variance followed by Dunnett's multiple comparison post-hoc test relative to untreated disease controls.

[0335] Three test compounds were evaluated in this study: Compound 1a, Compound 5a, and Compound 6a. The results are summarized in Table 8. Daily treatment with Compound 1a significantly reduced the expression of both IFN-γ and IL-4 at doses of 8 mg / kg and 16 mg / kg, respectively. Daily treatment with Compound 5a reduced the expression of IFN-γ and IL-4 at a dose of 20 mg / kg. Daily treatment with Compound 6a reduced the expression of IFN-γ and IL-4 at a dose of 10 mg / kg. These results demonstrate that the indicated test compounds have the ability to reduce peripheral inflammation caused by chronic hyperglycemia. Statistical outliers were identified by the ROUT method (Q = 1%) and excluded before statistical analysis. Statistical analysis consisted of one-way ANOVA with Dunnett's multiple comparison post-hoc test compared to untreated STZ disease controls. ++ = p < 0.01, +++ = p < 0.001, ++++ = p < 0.0001.

[0336] Example B5: Reduction of pro-inflammatory cytokine expression in a mouse model of LPS-induced inflammation. Administration of bacterial lipopolysaccharide (LPS) induces an inflammatory response, stimulating the release of proinflammatory cytokines and ultimately leading to cell death. In this study, we evaluated the ability of compound A19 to reduce systemic inflammation in an LPS inflammation model in 8-10 week-old male C57B / 6N mice.

[0337] The study design was as follows: [Table 10] IP-intraperitoneal, LPS-lipopolysaccharide, QD-once daily, SC-subcutaneous, WFI-water for injection Animals in Groups 1 and 2 served as controls and received vehicle (saline-0.9% NaCl). Starting on Day 0 (D), animals in both groups received 10 mL / kg subcutaneously (SC) once daily (QD). All animals in Group 1 were treated for four consecutive days, while the first 16 animals in Group 2 received a single dose, the next eight animals were treated for two consecutive days, and the remaining eight animals were treated for four consecutive days. Animals were weighed before administration, and the amount of vehicle administered was adjusted according to their individual body weights.

[0338] The test article, Compound A19, was dissolved in saline (0.9% NaCl), pH 7.4–7.7, to give final concentrations of 0.125, 0.5, and 1.25 mg / kg for groups 3–5, respectively. Starting on Day 0, animals in groups 3–5 were administered Compound A19 at 0.125, 0.5, or 1.25 mg / kg once daily (QD) at 10 mL / kg via the subcutaneous (SC) route. The first 16 animals in each group received a single dose, the next 8 animals were treated for two consecutive days, and the remaining 8 animals were treated for four consecutive days. Animals were weighed prior to administration, and the dose was adjusted according to individual body weight.

[0339] Twenty minutes after the first administration of Compound A19, animals in groups 2-5 were challenged with a single 5 mg / kg LPS (derived from E. coli O111:B4) dose administered intraperitoneally (IP) at 10 mL / kg. Group 1 served as the control group and received an equivalent volume of water for injection (WFI). Animals were weighed prior to administration, and the amount of LPS administered was adjusted according to individual body weight.

[0340] At designated time points after the LPS challenge, animals were euthanized, and blood was collected by carotid artery phlebotomy under ketamine and xylazine anesthesia. Serum samples were then separated by centrifugation. Brain and liver samples were also collected (data not shown). Eight animals in groups 2–5 were sampled at 1.5, 6, 24, and 72 hours, while control animals in group 1 were sampled only at 72 hours postchallenge (20 minutes after the last dose).

[0341] Blood samples were collected into marked tubes containing protease inhibitors (8:1 v / v; whole blood:protease inhibitors, no EDTA) and allowed to clot for 30 minutes after collection. After clotting, samples were centrifuged at 2500 × g for 15 minutes at 21–22°C, divided into sets of aliquots, flash-frozen, and stored at -80°C until multiplex cytokine analysis. At 72 hours postchallenge (20 minutes after the last dose), an additional 20 μL of serum was isolated from groups 3–5, flash-frozen, and used for cytokine analysis.

[0342] Cytokines were quantified by multiplex analysis using the Invitrogen Immune Monitoring 48-Plex Mouse ProcartaPlex™ Panel kit according to the manufacturer's instructions, and amounts were calculated by interpolation from a standard curve. The panel determines the levels of specific cytokines, chemokines, growth factors / regulatory factors, and soluble receptors. The panel includes pro-inflammatory, anti-inflammatory, and other molecules. The cytokines, chemokines, growth factors / regulatory factors, and soluble receptors tested were as follows: Cytokines: BAFF, G-CSF (CSF-3), GM-CSF, IFNα, IFNγ, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12p70, IL-13, IL-15 / IL-15R, IL-17A (CTLA-8), IL-18, IL-19, IL-22, IL-23, IL-25 (IL-17E), IL-27, IL-28, IL-31, IL-4, IL-5, IL-6, IL-7, IL-8 ... -33, LIF, M-CSF, RANKL, and TNF alpha; chemokines: ENA-78 (CXCL5), eotaxin (CCL11), GRO alpha (CXCL1), IP-10 (CXCL10), MCP-1 (CCL2), MCP-3 (CCL7), MIP-1 alpha (CCL3), MIP-1 beta (CCL4), MIP-2, and RANTES (CCL5); growth factors / regulatory factors: betacellulin (BTC), leptin, and VEGF-A; soluble receptors: IL-2R, IL-7R alpha, IL-33R (ST2).

[0343] As shown in Table 10, at 1.5 hours after LPS administration, mice treated with Compound A19 at 1.5 mg / kg had significantly lower levels of the inflammatory mediators BAFF, G-CSF, ENA-78, eotaxin, IL-2R, LIF, MIP-1 Beta, and MIP-1 Alpha compared with vehicle-treated LPS animals. Mice treated with Compound A19 at 0.125 mg / kg also showed significant decreases in G-CSF and ENA-78 levels at this time point. At 6 hours after LPS administration, BAFF, ENA-78, and IL-2R levels remained lower compared with LPS-treated vehicle mice. In some instances, LPS challenge resulted in a small, non-significant increase in inflammatory mediator levels compared with Group 1 controls, but Compound A19 was able to significantly reduce these levels. These events are indicated by asterisks in Table 10. These results indicate that treatment with compound A19 can attenuate the increase in inflammatory mediators after LPS challenge, suggesting the immunomodulatory potential of compound A19. [Table 11]

Claims

1. 1. A method of treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, comprising administering an effective amount of a compound of formula (I): 【Chemistry 1】 (I) or a pharmaceutically 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, C １ ~C ６ Alkyl, C ２ ~C ６ alkenyl, or C ２ ~C ６ is alkynyl, R １ａ and R １ｂ are independently H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Alkoxy, halo, or C ６ ~C １０ is arylalkyl, R ２ is H, oxo, or thioxo; R ３ is C ２ ~C ６ Alkyl, C ３ ~C ６ Alkenyl, C ３ ~C ６ Alkynyl, C ３ ~C １２ Cycloalkyl, C ３ ~C ６ Cycloalkylalkyl, C ６ ~C １０ arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl; wherein the 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocyclylalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; R ４ is C ６ ~C １０ aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl; wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen; Each R ５ are independently １ ~C ６ alkyl, oxo, or halo; R ６ is H, C １ ~C ６ alkyl, or oxo; R ７ is H or oxo, m is 1 or 2; n is an integer from 0 to 3, Here, each C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C １２ cycloalkyl, C ３ -C １２ Cycloalkylalkyl, C ６ -C １０ Aryl, C ６ -C １０ Arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclyl, and 5- to 10-membered heterocyclylalkyl are hydroxyl, halo, amino, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, cyano, —(C═O)NH ２ , nitro, -SO ２ (C １ -C ６ alkyl), and —CO ２ The foregoing method, wherein the alkyl group is optionally substituted with 1 to 5 substituents selected from H.

2. L is —C(═O)— or —(CR ａ R ｂ ) ｍ The method of claim 1, wherein

3. The method of claim 1 or 2, wherein L is -C(=O)-.

4. L is -(CR ａ R ｂ ) ｍ The method according to claim 1 or 2, wherein

5. R ａ and R ｂ 5. The method of claim 4, wherein each is H and m is 1.

6. R １ａ and R １ｂ are each independently H; halo, —CO ２ H, and —C(═O)NH ２ C optionally substituted with 1 to 3 substituents selected from １ ~C ６ Alkyl; C １ ~C ６ C optionally substituted by 1 to 3 substituents selected from alkoxy; halo; or halo and amino ６ ~C １０ The method according to any one of claims 1 to 5, wherein the alkyl group is arylalkyl.

7. R １ａ and R １ｂ are each independently H, methyl, fluoro, 2-methylbutyl, —CH ２ F, methoxy, —CH ２ CO ２ H, —CH ２ C(=O)NH ２ , benzyl, or 4-aminobenzyl.

8. R １ａ and R １ｂ are each independently H or C １ ~C ３ The method of claim 6, wherein the alkyl is alkyl.

9. R １ａ is methyl, and R １ｂ The method of claim 8 , wherein is H.

10. R １ａ and R １ｂ The method of claim 8 , wherein each is H.

11. R ２ The method of any one of claims 1 to 10, wherein is H.

12. R ２ The method of any one of claims 1 to 10, wherein is thioxo.

13. R ２ The method of any one of claims 1 to 10, wherein is oxo.

14. R ３ But C ３ ~C ６ Alkyl, C ３ ~C ６ Alkenyl, C ３ ~C ６ Alkynyl, C ３ ~C １２ Cycloalkyl, C ３ ~C ６ Cycloalkylalkyl, C ６ ~C １０ arylalkyl, 5- to 10-membered heteroarylalkyl, or 5- to 10-membered heterocyclylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclylalkyl is selected from the group consisting of hydroxyl, halo, amino, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, cyano, —(C═O)NH ２ , nitro, -SO ２ (C １ ~C ６ alkyl), and —CO ２ 14. The method of any one of claims 1 to 13, optionally substituted with 1 to 5 substituents selected from H.

15. R ３ But, Halo, C １ -C ３ Alkoxy, hydroxy, -NH ２ , -SO ２ (C １ -C ３ alkyl), and —C(═O)NH ２ C optionally substituted with 1 to 3 substituents selected from ２ -C ６ Alkyl; C ２ -C ６ Alkenyl; C ３ -C ６ cycloalkylalkyl; 5- to 6-membered heteroarylalkyl; 5- to 6-membered heterocyclylalkyl; or C ６ The method according to any one of claims 1 to 13, wherein the alkyl is aryl.

16. R ３ But C １ ~C ３ Alkoxy, hydroxy, -NH ２ , and -SO ２ (C １ ~C ３ C substituted by 1 to 3 substituents selected from ２ 16. The method of claim 15, wherein the alkyl is alkyl.

17. R ３ The method according to any one of claims 14 to 16, wherein is: 【Chemistry 2】

18. R ３ 18. The method of claim 17, wherein: 【Transformation 3】

19. R ４ But halo, hydroxyl, C １ ~C ６ Haloalkyl, and C １ ~C ６ C optionally substituted with 1 to 3 substituents selected from haloalkoxy ６ ~C １０ The method according to any one of claims 1 to 18, wherein the aryl is aryl.

20. R ４ But, -CF ３ , -OCHF ２ 20. The method of claim 19, wherein the phenyl is phenyl substituted with 1 to 3 substituents selected from -OH, fluoro, and chloro.

21. R ４ 21. The method of claim 20, wherein: 【Chemistry 4】

22. R ４ 22. The method of claim 21 , wherein: 【Transformation 5】

23. R ４ But halo, hydroxyl, C １ ~C ６ Haloalkyl, and C １ ~C ６ The method of any one of claims 1 to 18, wherein the heteroaryl is 5 to 10 membered, optionally substituted with 1 to 3 substituents selected from haloalkoxy.

24. R ４ But halo, hydroxyl, C １ ~C ６ Haloalkyl, and C １ ~C ６ 24. The method of claim 23, wherein the alkoxy group is pyridyl or indolyl optionally substituted with 1 to 3 substituents selected from haloalkoxy.

25. R ４ but, 【Transformation 6】 25. The method of claim 24, wherein:

26. R ４ but, 【Transformation 7】 26. The method of claim 25, wherein:

27. R ４ But halo, hydroxyl, C １ ~C ６ Haloalkyl, and C １ ~C ６ The method of any one of claims 1 to 18, wherein the heterocyclyl is a 5- to 10-membered heterocyclyl optionally substituted with 1 to 3 substituents selected from haloalkoxy.

28. R ４ 28. The method of claim 27, wherein is indolinyl.

29. R ４ but, 【Transformation 8】 29. The method of claim 28, wherein:

30. -L-R ４ The method of any one of claims 1 to 26, wherein is: 【Chemistry 9】

31. The method of any one of claims 1 to 30, wherein n is 0.

32. The method of any one of claims 1 to 30, wherein n is 1.

33. R ５ 33. The method of claim 32, wherein is oxo or halo.

34. R ５ 34. The method of claim 33, wherein is oxo or fluoro.

35. R ６ The method of any one of claims 1 to 34, wherein is H.

36. R ７ The method of any one of claims 1 to 35, wherein is oxo.

37. The compound has the formula (V): 【Chemistry 10】 (V), or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

38. L is —C(═O)— or —CH ２ - and R １ａ and R １ｂ are independently H or —CO ２ C optionally substituted with H １ ~C ３ is alkyl, R ３ But C ４ ~C ５ Alkyl, C ４ ~C ５ alkenyl, or C ３ ~C ５ Cycloalkyl-substituted C １ ~C ３ is alkyl, R ４ But, -CF ３ , -OCHF ２ 38. The method of claim 37, wherein the aryl group is phenyl or pyridyl substituted with 1 to 3 substituents selected from -OH, fluoro, and chloro.

39. 1. A method of treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, comprising administering to a subject an effective amount of Compound A19: 【Chemistry 11】 or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

40. 1. A method of treating a peripheral and / or systemic inflammatory condition in a subject in need thereof, comprising administering to a subject an effective amount of a compound of Table 1A and Compound A19: 【Chemistry 12】 and a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

41. 10. The method of any one of the preceding claims, wherein the peripheral and / or systemic inflammatory disease is inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, Leber's hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver disease, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis.

42. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is inflammatory bowel disease.

43. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is Crohn's disease.

44. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is ulcerative colitis.

45. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is celiac disease.

46. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is rheumatoid arthritis.

47. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is psoriasis.

48. 42. The method according to any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is non-infectious uveitis.

49. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is type 2 diabetes.

50. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is obesity.

51. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is coronary heart disease.

52. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is gout.

53. 42. The method according to any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is fatty liver disease.

54. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is seasonal allergy.

55. The method according to any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is COPD.

56. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is endometriosis.

57. 42. The method according to any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is gout.

58. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is dermatomyositis.

59. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is polymyositis.

60. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is optic neuritis.

61. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is LHON.

62. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is macular degeneration.

63. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is retinal degeneration.

64. 42. The method of any one of claims 1 to 41, wherein the peripheral and / or systemic inflammatory condition is myasthenia gravis.

65. 10. The method of any one of the preceding claims, wherein the compound reduces inflammation associated with the inflammatory condition.

66. 10. The method of any one of the preceding claims, wherein the compound reduces hypoxia associated with the inflammation.

67. 10. The method of any one of the preceding claims, wherein the compound reduces pain associated with the inflammatory condition.

68. 10. The method of any one of the preceding claims, wherein the compound reduces the level of at least one pro-inflammatory molecule in the subject.

69. 69. The method of claim 68, wherein the compound reduces the level of at least one pro-inflammatory molecule selected from G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα, and IFNγ.

70. 70. The method of claim 68 or 69, wherein the compound reduces the level of at least one pro-inflammatory molecule selected from IL-1β, IL-4, IL-6, TNF-α, and IFNγ.

71. 71. The method of any one of claims 1 to 70, wherein the peripheral and / or systemic inflammatory condition does not result from neuroinflammation or a disease or disorder of the central nervous system.

72. 72. The method of any one of embodiments 1-71, wherein said peripheral and / or systemic inflammatory condition does not result from Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensory hearing and vision loss.

73. 71. The method of any one of embodiments 1-70, wherein said peripheral and / or systemic inflammatory condition is not associated with neuroinflammation, or a disease or disorder of the central nervous system.

74. 71. The method of any one of embodiments 1-70, wherein said peripheral and / or systemic inflammatory condition is not associated with Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensory hearing and vision loss.

75. 75. The method of any one of embodiments 1-74, wherein the subject does not suffer from Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing loss and vision loss, or a disease or disorder of the central nervous system.

76. 10. The method of any one of the preceding claims, wherein the compound is formulated into a pharmaceutical composition.

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