Methods of treating inflammatory conditions

Abstract

Provided herein are compounds and compositions thereof for modulating hepatocyte growth factor. In some embodiments, the compounds and the compositions are provided for the treatment of diseases, including peripheral and / or systemic inflammatory diseases.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority benefit of U.S. Provisional Application No. 63 / 426,620, filed on November 18, 2022; U.S. Provisional Application No. 63 / 447,436, filed on February 22, 2023; and U.S. Provisional Application No. 63 / 463,742, filed on May 3, 2023, each of which is hereby incorporated by reference in its entirety for any purpose. Technical Field

[0003] The present disclosure generally relates to compounds, compositions, and methods for treating diseases such as peripheral and / or systemic inflammatory conditions. Background Art

[0004] Hepatocyte growth factor (HGF) is a pleiotropic protein factor involved in multiple biological processes including embryonic and organ development, regeneration, and inflammation. HGF is a key contributor to the development and maturation of cortical, motor, sensory, sympathetic, and parasympathetic neurons. HGF is translated and secreted as inactive pro - HGF, but upon cleavage, the resulting α - and β - subunits are joined by a disulfide bond to form an active heterodimer. The expression of HGF occurs mainly in mesenchymal cells such as fibroblasts, chondrocytes, adipocytes, and endothelial cells. Expression has also been demonstrated in the central nervous system (CNS) including neurons, astrocytes, and ependymal cells (Nakamura and Mizuno, 2010).

[0005] 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 a demonstrated role in development, regeneration, and response to injury. After the binding of HGF to the extracellular domain of MET, the homodimerization of MET protein causes autophosphorylation of the intracellular domain. Phosphorylation of the MET intracellular domain causes 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, etc. to affect a series of cellular components including gene regulation, cytoskeletal rearrangement, cell cycle progression, cell adhesion, survival, and proliferation (Organ and Tsao, 2011).

[0006] HGF is a key regulator of inflammation and autoimmunity. Reduced HGF activity promotes the expression of the pro-inflammatory cytokine IL-6 and the expression of the anti-inflammatory cytokine Il-10 in monocytes (Molnarfi et al., 2015). Additionally, 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 may be beneficial for inflammatory conditions.

[0007] Despite the progress made in the art, there remains a need for improved compounds and methods for treating peripheral and / or systemic inflammatory conditions. Summary of the Invention

[0008] Compounds that modulate HGF are provided herein for treating peripheral and / or systemic inflammatory conditions. Non-limiting exemplary embodiments include:

[0009] 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):

[0010]

[0011] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein:

[0012] 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 -;

[0013] Each R a and R b is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0014] 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 arylalkyl;

[0015] R 2 is H, oxo or thio;

[0016] R 3is a C2-C6 alkyl group, C3-C6 alkenyl group, C3-C6 alkynyl group, C3-C 12 cycloalkyl group, C3-C6 cycloalkylalkyl group, C6-C 10 arylalkyl group, 5- to 10-membered heteroarylalkyl group or 5- to 10-membered heterocycloalkylalkyl group,

[0017] wherein the 5- to 10-membered heteroarylalkyl group or the 5- to 10-membered heterocycloalkylalkyl group contains 1-3 heteroatoms selected from nitrogen and oxygen;

[0018] R 4 is a C6-C 10 aryl group, 5- to 10-membered heteroaryl group or 5- to 10-membered heterocyclic group,

[0019] wherein the 5- to 10-membered heteroaryl group or the 5- to 10-membered heterocyclic group contains 1-3 heteroatoms selected from nitrogen and oxygen;

[0020] Each R 5 is independently a C1-C6 alkyl group, oxo group or halo group;

[0021] R 6 is H, a C1-C6 alkyl group or an oxo group;

[0022] R 7 is H or an oxo group;

[0023] m is 1 or 2; and

[0024] n is an integer from 0 to 3;

[0025] wherein each C1-C6 alkyl group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C 12 cycloalkyl group, C3-C 12 cycloalkylalkyl group, C6-C 10 aryl group, C6-C 10 arylalkyl group, 5- to 10-membered heteroaryl group, 5- to 10-membered heteroarylalkyl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heterocycloalkylalkyl group is optionally substituted with one to five substituents selected from the following: hydroxy group, halo group, amino group, C1-C6 haloalkyl group, C1-C6 alkoxy group, C1-C6 haloalkoxy group, cyano group, -(C=O)NH2, nitro group, -SO2(C1-C6 alkyl) and -CO2H.

[0026] 2. The method according to embodiment 1, wherein L is -C(=O)- or -(CR a R b ) m -.

[0027] 3. The method according to embodiment 1 or 2, wherein L is -C(=O)-.

[0028] 4. The method according to embodiment 1 or 2, wherein L is -(CR a R b ) m -.

[0029] 5. The method according to embodiment 4, wherein R a and R b are each H, and m is 1.

[0030] 6. The method according to any one of embodiments 1 to 5, wherein R 1a and R 1b are each independently H; C1-C6 alkyl optionally substituted with 1-3 substituents selected from halo, -CO2H, and -C(=O)NH2; C1-C6 alkoxy; halo; or C6-C 10 arylalkyl optionally substituted with 1-3 substituents selected from halo and amino.

[0031] 7. The method according to embodiment 6, wherein R 1a and R 1b are each independently H, methyl, fluoro, 2-methylbutyl, -CH2F, methoxy, -CH2CO2H, -CH2C(=O)NH2, benzyl, or 4-aminobenzyl.

[0032] 8. The method according to embodiment 6, wherein R 1a and R 1b are each independently H or C1-C3 alkyl.

[0033] 9. The method according to embodiment 8, wherein R 1a is methyl and R 1b is H.

[0034] 10. The method according to embodiment 8, wherein R 1a and R 1b are each H.

[0035] 11. The method according to any one of embodiments 1 to 10, wherein R 2 is H.

[0036] 12. The method according to any one of embodiments 1 to 10, wherein R 2 is thio.

[0037] 13. The method according to any one of embodiments 1 to 10, wherein R 2 is oxo.

[0038] 14. The method according to any one of embodiments 1 to 13, wherein R 3is a C3-C6 alkyl group, C3-C6 alkenyl group, C3-C6 alkynyl group, C3-C 12 cycloalkyl group, C3-C6 cycloalkylalkyl group, C6-C 10 arylalkyl group, 5- to 10-membered heteroarylalkyl group or 5- to 10-membered heterocyclicalkyl group, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkylalkyl group, arylalkyl group, heteroarylalkyl group or heterocyclicalkyl group is optionally substituted with one to five substituents selected from the following: hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl) and -CO2H.

[0039] 15. The method according to any one of embodiments 1 to 13, wherein R 3 is a C2-C6 alkyl group optionally substituted with 1-3 substituents selected from halo, C1-C3 alkoxy, hydroxy, -NH2, -SO2(C1-C3 alkyl) and -C(=O)NH2; C2-C6 alkenyl group; C3-C6 cycloalkylalkyl group; 5- to 6-membered heteroarylalkyl group; 5- to 6-membered heterocyclicalkyl group; or C6 arylalkyl group.

[0040] 16. The method according to embodiment 15, wherein R 3 is a C2 alkyl group substituted with 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2 and -SO2(C1-C3 alkyl).

[0041] 17. The method according to any one of embodiments 14 to 16, wherein R 3 is:

[0042]

[0043] 18. The method according to embodiment 17, wherein R 3 is:

[0044]

[0045] 19. The method according to any one of embodiments 1 to 18, wherein R 4 is a C6-C 10 aryl group optionally substituted with 1-3 substituents selected from halo, hydroxy, C1-C6 haloalkyl and C1-C6 haloalkoxy.

[0046] 20. The method according to embodiment 19, wherein R 4 is a phenyl group substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluorine and chlorine.

[0047] 21. The method according to embodiment 20, wherein R4 is:

[0048]

[0049] 22. The method according to embodiment 21, wherein R 4 is:

[0050]

[0051] 23. The method according to any one of embodiments 1 to 18, wherein R 4 is a 5- to 10-membered heteroaryl group optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0052] 24. The method according to embodiment 23, wherein

[0053] R 4 is a pyridyl or indolyl group optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0054] 25. The method according to embodiment 24, wherein

[0055] R 4 is

[0056] 26. The method according to embodiment 25, wherein

[0057] R 4 is

[0058] 27. The method according to any one of embodiments 1 to 18, wherein R 4 is a 5- to 10-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

[0059] 28. The method according to embodiment 27, wherein R 4 is indolinyl.

[0060] 29. The method according to embodiment 28, wherein R 4 is

[0061] 30. The method according to any one of embodiments 1 to 26, wherein -L-R 4 is:

[0062]

[0063] 31. The method according to any one of embodiments 1 to 30, wherein n is 0.

[0064] 32. The method according to any one of embodiments 1 to 30, wherein n is 1.

[0065] 33. The method according to embodiment 32, wherein R 5 is an oxo group or a halo group.

[0066] 34. The method according to embodiment 33, wherein R 5 is an oxo group or fluorine.

[0067] 35. The method according to any one of embodiments 1 to 34, wherein R 6 is H.

[0068] 36. The method according to any one of embodiments 1 to 35, wherein R 7 is an oxo group.

[0069] 37. The method according to any one of embodiments 1 to 10, 13 to 31, 35 and 36, wherein the compound is a compound of formula (V):

[0070] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0071] 38. The method according to embodiment 37, wherein:

[0072] L is -C(=O)- or -CH2-;

[0073] R 1a and R 1b are independently H or C1-C3 alkyl optionally substituted with -CO2H;

[0074] R 3 is C4-C5 alkyl, C4-C5 alkenyl or C1-C3 alkyl substituted with C3-C5 cycloalkyl; and

[0075] R 4 is phenyl or pyridyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluorine and chlorine.

[0076] 39. A method of treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, comprising administering an effective amount of compound A19:

[0077]

[0078] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0079] 40. A method of treating a subject in need of treatment for a peripheral and / or systemic inflammatory condition, the method comprising administering an effective amount of a compound selected from the compounds of Table 1A and compound A19:

[0080]

[0081] and pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof.

[0082] 41. The method according to any one of the preceding embodiments, wherein the peripheral and / or systemic inflammatory condition 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 hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver, seasonal allergy, chronic obstructive pulmonary disease (COPD) or endometriosis.

[0083] 42. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is inflammatory bowel disease.

[0084] 43. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is Crohn's disease.

[0085] 44. The method according to embodiment 43, wherein the peripheral and / or systemic inflammatory condition is ulcerative colitis.

[0086] 45. The method according to embodiment 43, wherein the peripheral and / or systemic inflammatory condition is celiac disease.

[0087] 46. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is rheumatoid arthritis.

[0088] 47. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is psoriasis.

[0089] 48. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is non-infectious uveitis.

[0090] 49. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is type 2 diabetes.

[0091] 50. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is obesity.

[0092] 51. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is coronary heart disease.

[0093] 52. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is gout.

[0094] 53. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is fatty liver.

[0095] 54. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is seasonal allergy.

[0096] 55. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is COPD.

[0097] 56. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is endometriosis.

[0098] 57. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is systemic lupus erythematosus.

[0099] 58. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is dermatomyositis.

[0100] 59. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is polymyositis.

[0101] 60. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is optic neuritis.

[0102] 61. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is LHON.

[0103] 62. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is macular degeneration.

[0104] 63. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is retinal degeneration.

[0105] 64. The method according to any one of embodiments 1 to 41, wherein the peripheral and / or systemic inflammatory condition is myasthenia gravis.

[0106] 65. The method according to any one of embodiments 1 to 64, wherein the compound reduces the inflammation associated with the inflammatory condition.

[0107] 66. The method according to any one of embodiments 1 to 65, wherein the compound reduces the hypoxia associated with the inflammation.

[0108] 67. The method according to any one of the foregoing embodiments, wherein the compound reduces the pain associated with the inflammatory condition.

[0109] 68. The method according to any one of the foregoing embodiments, wherein the compound reduces the level of at least one pro-inflammatory molecule in the subject.

[0110] 69. The method according to 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.

[0111] 70. The method according to any one of the foregoing embodiments, 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.

[0112] 71. The method according to any one of embodiments 1 to 70, wherein the peripheral and / or systemic inflammatory condition is not caused by neuroinflammation or a disease or disorder of the central nervous system.

[0113] 72. The method according to any one of embodiments 1 to 71, wherein the peripheral and / or systemic inflammatory condition is not caused by Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss.

[0114] 73. The method according to any one of embodiments 1 to 70, wherein the peripheral and / or systemic inflammatory condition is not associated with neuroinflammation or a disease or disorder of the central nervous system.

[0115] 74. The method according to any one of embodiments 1 to 73, wherein the peripheral and / or systemic inflammatory conditions are 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 sensorineural hearing and vision loss.

[0116] 75. The method according to any one of embodiments 1 to 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 and vision loss, or a disease or disorder of the central nervous system.

[0117] 76. The method according to any one of the foregoing embodiments, wherein the compound is formulated in a pharmaceutical composition. Detailed Description

[0118] Definitions

[0119] 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 pertains. In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments of the disclosure. It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit any claimed subject matter. In the event of any conflict between any material incorporated herein by reference and the present disclosure, the present disclosure shall control. In this application, unless otherwise specifically stated, the use of the singular includes the plural. 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, unless otherwise stated, the use of "or" means "and / or". Further, the use of the term "including" and other forms (such as "include / includes / included") is not limiting.

[0120] Unless the context otherwise requires, throughout this specification and the claims, the word "comprise" and variations thereof (such as "comprises / comprising") shall be construed in an open, inclusive sense, i.e., "including but not limited to".

[0121] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and, when appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer). Additionally, unless otherwise indicated, any quantity range related to any physical characteristic such as polymer subunits, size, or thickness described herein should be understood to include any integer within the recited range. As used herein, unless otherwise indicated, the terms "about" and "substantially" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0122] References to "an embodiment" or "an embodiment" throughout this specification mean that the particular features, structures, or characteristics described in connection with the embodiment are included in at least one embodiment of the present disclosure. Thus, the phrases "in an embodiment" or "in an embodiment" that appear in various places throughout this specification do not necessarily all refer to the same embodiment. Additionally, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0123] "Amino" refers to the -NH2 group.

[0124] "Carboxy / carboxyl" refers to the -CO2H group.

[0125] "Cyano" refers to the -CN group.

[0126] "Hydroxy / hydroxyl" refers to the -OH group.

[0127] "Nitro" refers to the -NO2 group.

[0128] "Oxo" refers to the ═O substituent.

[0129] "Thioxo" refers to the ═S substituent.

[0130] "Thiol" refers to the -SH substituent.

[0131] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain group consisting only of carbon and hydrogen atoms, having from one to twelve carbon atoms (C1-C 12alkyl), preferably an alkyl having one to eight carbon atoms (C1-C8 alkyl), one to six carbon atoms (C1-C6 alkyl) or one to three carbon atoms (C1-C3 alkyl), and which is attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, etc. Unless specifically stated otherwise in this specification, the alkyl is optionally substituted.

[0132] "Alkenyl" means an unbranched or branched unsaturated hydrocarbon chain group consisting only of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds and has two to twelve carbon atoms (C2-C 12 alkenyl), preferably two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl), and which is attached to the remainder of the molecule by a single bond, such as vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless specifically stated otherwise in this specification, the alkenyl is optionally substituted.

[0133] "Alkynyl" means an unbranched or branched unsaturated hydrocarbon chain group consisting only of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds and has two to twelve carbon atoms (C2-C 12 alkynyl), preferably two to eight carbon atoms (C2-C8 alkynyl) or two to six carbon atoms (C2-C6 alkynyl), and which is attached to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless specifically stated otherwise in this specification, the alkynyl is optionally substituted.

[0134] "Alkoxy" means a group of the formula -OR a wherein R a is an alkyl as defined above having one to twelve carbon atoms. Preferred alkoxy groups have one to six carbon atoms in the alkyl (i.e., C1-C6 alkoxy) or one to three carbon atoms (i.e., C1-C3 alkoxy). Unless specifically stated otherwise in this specification, the alkoxy is optionally substituted.

[0135] "Aromatic ring" refers to the cyclic planar portion of a molecule (i.e., a group) of a ring having resonating bonds, which exhibits increased stability relative to other connectivity arrangements of atoms of the same set. Generally, an aromatic ring contains a set of coplanar atoms linked by covalent bonds and contains a plurality of π-electrons (e.g., alternating double and single bonds) that are even but not a multiple of 4 (i.e., 4n + 2 π-electrons, where n = 0, 1, 2, 3, etc.). Aromatic rings include, but are not limited to, phenyl, naphthenyl, imidazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridone, pyridazinyl, pyrimidinone. Unless otherwise specifically stated in this specification, "aromatic ring" includes all groups that are optionally substituted.

[0136] "Aryl" refers to a carbocyclic ring system group containing 6 to 18 carbon atoms and at least one aromatic ring (i.e., C6-C 18 aryl), preferably having 6 to 10 carbon atoms (i.e., C6-C 10 aryl). For the purposes of the embodiments of this disclosure, aryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl includes, but is not limited to, aryls derived from: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, (chrysene), fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, phenyl, pleiadene, pyrene, and triphenylene. Unless otherwise specifically stated in this specification, aryl is optionally substituted.

[0137] "Arylalkyl" refers to a group of the formula –R b -R c wherein R b is an alkylene chain and R c is one or more aryls as defined above, such as benzyl, diphenylmethyl, etc. Arylalkyl may contain a C1-C 10 alkylene chain linked to a C6-C 10 aryl (i.e., C6-C 10 arylalkyl). Unless otherwise specifically stated in this specification, arylalkyl is optionally substituted.

[0138] "Cycloalkyl" means a stable non-aromatic monocyclic or polycyclic carbocyclic group consisting only of carbon and hydrogen atoms, which may include fused or bridged ring systems, having from three to fifteen carbon atoms (i.e., C3-C 15 cycloalkyl), preferably having from three to ten carbon atoms (i.e., C3-C 10 cycloalkyl) or from three to six carbon atoms (i.e., C3-C6 cycloalkyl), and which is saturated or unsaturated and is attached to the remainder of the molecule by a single bond. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When there are two substitution positions on the same carbon atom, cycloalkyl also includes "spirocycloalkyl". Polycyclic groups include, for example, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless specifically stated otherwise in this specification, cycloalkyl is optionally substituted.

[0139] "Cycloalkylalkyl" means a group of the formula –R b -R c wherein R b is an alkylene chain and R c is one or more cycloalkyls as defined above, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, etc. Cycloalkylalkyl may contain a C1-C 12 alkylene chain linked to a C3-C 12 cycloalkyl (i.e., C3-C 10 cycloalkylalkyl) or a C1-C 10 alkylene chain linked to a C3-C6 cycloalkyl (i.e., C3-C6 cycloalkylalkyl). Unless specifically stated otherwise in this specification, cycloalkylalkyl is optionally substituted.

[0140] "Fused" means that any ring structure described herein is fused to an existing ring structure in the compounds of the present disclosure. When the fused ring is a heterocyclic group ring or a heteroaryl ring, any carbon atom on the existing ring structure that becomes part of the fused heterocyclic group ring or the fused heteroaryl ring is replaced by a nitrogen atom.

[0141] "Halogen" or "halide" means bromine, chlorine, fluorine or iodine.

[0142] "Haloalkyl" means an alkyl as defined above substituted with one or more halogen substituents as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Preferred haloalkyls include alkyls having from one to six carbon atoms and substituted with one or more halogen substituents (i.e., C1-C6 haloalkyl). The halogen substituents may all be the same or the halogen substituents may be different. Unless specifically stated otherwise in this specification, haloalkyl is optionally substituted.

[0143] "Haloalkoxy" means a group of the formula -OR a wherein R a is a haloalkyl group having from one to twelve carbon atoms as defined herein. Preferred haloalkoxy groups include alkoxy groups having from one to six carbon atoms (i.e., C1-C6 haloalkoxy) or having from one to three carbon atoms (C1-C3 haloalkoxy) and substituted with one or more halogen atoms. The halogen atoms may all be the same or the halogen atoms may all be different. Unless specifically stated otherwise in this specification, the haloalkoxy group is optionally substituted.

[0144] "Heteroaryl" means an aromatic group having a single ring, multiple rings, or multiple fused rings (e.g., a 5-14 membered ring system), wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur within the ring. Preferred heteroaryl groups have a 5- to 10-membered ring system (i.e., 5- to 10-membered heteroaryl) containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and a 5- to 6-membered ring system (i.e., 5- to 6-membered heteroaryl) containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. For the purposes of the embodiments of this disclosure, an aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Examples of heteroaryl groups include pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and benzothiolyl (i.e., thienyl). The heteroaryl group may contain one or more N-oxide (N-O-) moieties, such as pyridine-N-oxide. Unless specifically stated otherwise in this specification, the heteroaryl group is optionally substituted.

[0145] "Heteroarylalkyl" means a group of the formula –R b -R c wherein R b is an alkylene chain and R c is one or more heteroaryl groups as defined above. The heteroarylalkyl group may contain a C1-C 10 alkylene chain linked to a 5- to 10-membered heteroaryl group (i.e., 5- to 10-membered heteroarylalkyl) or a C1-C 10 alkylene chain linked to a 5- to 6-membered heteroaryl group (i.e., 5- to 6-membered heteroarylalkyl). Unless specifically stated otherwise in this specification, the heteroarylalkyl group is optionally substituted.

[0146] "Heterocyclic group" means a saturated or unsaturated cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heteroalkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spiro heterocyclic groups. The heterocyclic group can be a single ring or multiple rings, where the multiple rings can be fused, bridged, or spiro, and can contain one or more oxo groups (C=O) or N-oxide (N-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of the connection (i.e., it can be bonded via a carbon atom or a heteroatom). In addition, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom that can be fused to an aryl ring or a heteroaryl ring, regardless of the connection to the rest of the molecule. As used herein, the heterocyclic group 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 heterocyclic groups have five to ten members (i.e., 5- to 10-membered heterocyclic groups) in a ring system including one to four heteroatoms selected from nitrogen and oxygen or five to eight members (i.e., 5- to 8-membered heterocyclic groups) in a ring system including one to four heteroatoms selected from nitrogen and oxygen. Examples of heterocyclic groups include dioxolanyl, thienyl[1,3]dithialanyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithialanyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in this specification, the heterocyclic group is optionally substituted.

[0147] "Heterocyclic group alkyl" means a group of the formula –R b -R c wherein R b is an alkylene chain and R c is one or more heterocyclic groups as defined above. The heterocyclic group alkyl can contain a C1-C 10 alkylene chain linked to a 5- to 10-membered heterocyclic group (i.e., 5- to 10-membered heterocyclic group alkyl) or a C1-C 10 alkylene chain linked to a 5- to 8-membered heterocyclic group (i.e., 5- to 8-membered heterocyclic group alkyl). Unless specifically stated otherwise in this specification, the heterocyclic group alkyl is optionally substituted.

[0148] In some embodiments, the term "substituted" as used herein means any of the above groups or other substituents (e.g., C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7-C6 alkyl, C8-C6 alkyl, C9-C6 alkyl, C10-C6 alkyl, C11-C6 alkyl, C12-C6 alkyl, C13-C6 alkyl, C14-C6 alkyl, C15-C6 alkyl, C16-C6 alkyl, C17-C6 alkyl, C18-C6 alkyl, C19-C6 alkyl, C21-C6 alkyl, C22-C6 alkyl, C23-C6 alkyl, C24-C6 alkyl, C25-C6 alkyl, C26-C6 12 Cycloalkyl, C3-C 12 cycloalkylalkyl, aryl and heteroaryl) in which at least one hydrogen atom (e.g., 1, 2, 3 or all of the hydrogen atoms) is replaced by a bond to a non-hydrogen atom such as, but not limited to, a halogen atom such as F, Cl, Br and I (i.e., a "halo"); an oxygen atom in a group such as a hydroxyl or alkoxy group (e.g., an alkoxy or haloalkoxy group); a nitrogen atom in a group such as an amine (e.g., -NH2), an amide (e.g., -(C=O)NH2) and a nitro group; an alkyl group including one or more halogens such as F, Cl, Br and I (e.g., a haloalkyl); and a cyano group.

[0149] It should be understood that unless otherwise specified, L, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each selection of is optionally substituted as described above, with the proviso that all valences are satisfied by substitution. Specifically, unless otherwise specifically stated, L, R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each selection of is optionally substituted, and provided such substitution results in a stable molecule (eg, groups such as H and halo are not optionally substituted).

[0150] "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, gastrointestinal tract and enteric nervous system, thoracic organs, blood, skin, and lymphoid tissue.

[0151] 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 result as needed based on the disclosure herein. The effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to by measuring ED 50 (the dose that is 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 the compound causes alleviation or suppression of symptoms or an increase in survival time in a subject (i.e., a human patient). Multiple doses of the compound may be required for the results.

[0152] "Treating / treatment" a subject for a disease means 1) preventing the disease from occurring in a patient who is predisposed to the disease or who has not yet shown symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating the disease or causing the disease to regress. As used herein, "treatment / treating" is a method for obtaining a beneficial or desired result, including a clinical result. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: alleviating one or more symptoms caused by a disease or disorder; reducing the degree 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 condition of the disease or disorder; causing the disease or disorder to (partially or completely) remit; reducing the dosage of one or more other drugs required to treat the disease or disorder; enhancing the effect of another drug used to treat the disease or disorder; delaying the progression of the disease or disorder; improving the quality of life; and / or increasing the survival time of the subject. "Treatment" also encompasses alleviation of the pathological consequences of a disease or disorder. The methods of the present invention encompass any one or more of these aspects of treatment.

[0153] As used herein, the terms "individual", "subject", and "patient" mean 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.

[0154] As the term is used herein, "treatment effect" encompasses the treatment benefits and / or prophylactic benefits as described herein. Treatment effects include 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 the disease or condition to (partially or completely) regress; or any combination thereof.

[0155] As used herein, the terms "co-administer", "administer in combination with", and their grammatical equivalents encompass administering two or more agents to an animal, including a human, such that both the agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration in separate compositions at different times, or administration in a composition in which both agents are present.

[0156] "Pharmaceutically acceptable" means a compound, salt, composition, dosage form, and other materials that are suitable for preparing a pharmaceutical composition for veterinary or human pharmaceutical use.

[0157] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts.

[0158] "Pharmaceutically acceptable acid addition salts" are those salts that retain the biological effectiveness and properties of the free base, which are not undesirable biologically or otherwise, and are formed by: inorganic acids, such as but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and organic acids, such as but not limited to acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0159] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not otherwise undesirable in a biological or other context. These salts are prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, 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, methylglucosamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0160] In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (e.g., methyl bromide).

[0161] As used herein, "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, such as small molecules and oligomers (e.g., oligopeptides and oligonucleotides), as well as synthetic organic compounds based on various core structures. Additionally, various natural sources can provide compounds for screening, such as plant or animal extracts, etc.

[0162] The term "in vivo" refers to events that occur within a subject.

[0163] Embodiments of the present disclosure also intend to cover all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number (i.e., "isotope forms" of the compounds of formula (I)). Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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 125 I. These radiolabeled compounds can be used to assist in determining or measuring the effectiveness of a compound, which is done by characterizing, for example, the site or mode of action or the binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of formula (I) (e.g., those incorporating a radioisotope) are suitable for drug and / or substrate tissue distribution studies. The radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly suitable for this purpose in view of their ease of incorporation and ready means of detection.

[0164] Replacement with heavier isotopes such as deuterium (i.e., 2 H) can provide certain therapeutic advantages resulting from greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement, and is thus preferred in some cases.

[0165] Replacement with positron-emitting isotopes such as 11 C, 18 F, 15 O and 13 N can be suitable for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples set forth below, using appropriate isotopically labeled reagents in place of the unlabeled reagents previously used.

[0166] Certain embodiments also intend to cover the in vivo metabolites of the disclosed compounds. Such products can be produced, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes. Accordingly, the embodiments include compounds produced by a method comprising administering the disclosed compound to a mammal for a period of time sufficient to produce its metabolites. Such products are typically identified by administering a detectable dose of a radiolabeled disclosed compound to an animal (such as a rat, mouse, guinea pig, monkey) or to a human, allowing metabolism to proceed for a sufficient time, and separating the conversion products from urine, blood, or other biological samples.

[0167] "Stable compounds" and "stable structures" are intended to denote compounds that are sufficiently stable to survive isolation to useful purity from a reaction mixture and formulation into an effective therapeutic agent.

[0168] Solvents typically employed to crystallize the compounds of the present disclosure produce solvates of the compounds. As used herein, the term "solvate" refers to an aggregate that comprises one or more molecules of a compound of formula (I) and 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. Accordingly, the compounds of formula (I) may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvated forms. In some aspects, the compounds of formula (I) are true solvates, while in other cases, the compounds of the present disclosure merely retain adventitious water or are a mixture of water plus some adventitious solvent.

[0169] "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where it does not. For example, "optionally substituted aryl" means that the aryl may or may not be substituted and the description includes both substituted aryl and aryl that does not have a substitution. Polymers or similar infinite structures obtained by defining substituents with infinitely additional other substituents (e.g., a substituted aryl having a substituted alkyl, the substituted alkyl itself being substituted by a substituted aryl, the substituted aryl further being substituted by a substituted heteroalkyl, etc.) are not intended to be included herein. Similarly, the above definitions are not intended to include non-permissible substitution patterns (e.g., a methyl substituted with five fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such non-permissible substitution patterns are well known to those skilled in the art.

[0170] "Pharmaceutical composition" or "pharmaceutically acceptable composition" means a formulation of a compound of the present disclosure and a medium generally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). Such media include all of its pharmaceutically acceptable carriers, diluents, or excipients.

[0171] "Pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, lubricant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the United States Food and Drug Administration as acceptable for use in humans or livestock.

[0172] The compounds of formula (I), or pharmaceutically acceptable salts or isotopic forms thereof, may contain one or more centers that give rise to geometric asymmetry and may thus provide enantiomers, diastereomers and other stereoisomeric forms that are defined as (R)- or (S)- in terms of absolute stereochemistry or as (D)- or (L)- for amino acids. Embodiments thus include all such possible isomers, as well as their racemic and optically pure forms. The 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 / separation 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 performance liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compounds are intended to include both the E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0173] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0174] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0175] "Tautomers" refer to the transfer of a proton from one atom of a molecule to another atom of the same molecule. Embodiments thus include the tautomers of the disclosed compounds.

[0176] The chemical nomenclature and structural diagrams used herein are a modified form of the I.U.P.A.C. nomenclature system, which uses the ACD / Naming 9.07 software program and / or the ChemDraw Ultra 11.0.1 software naming program (CambridgeSoft). For the complex chemical names employed herein, substituents are generally named before the group to which they are attached. For example, cyclopropyl ethyl contains an ethyl backbone with a cyclopropyl substituent. Unless otherwise described below, in the chemical structural diagrams herein, all bonds, except for all bonds on some carbon atoms, are assumed to be bonded to sufficient hydrogen atoms to complete the valency.

[0177] Although the various features of the present 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 for clarity the present invention may be described herein in the context of separate embodiments, the present invention may also be implemented in a single embodiment form.

[0178] Compound

[0179] The compound of formula (I), or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, and a process for its preparation are described in PCT Publication WO2022 / 094400, which is incorporated herein by reference in its entirety for any purpose.

[0180] In one aspect, there is provided herein a compound of formula (I):

[0181]

[0182] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein:

[0183] 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 -;

[0184] Each R a and R b is independently H, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0185] 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 arylalkyl;

[0186] R 2 is H, oxo or thio;

[0187] R 3 is C2-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10 arylalkyl, 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocycloalkylalkyl,

[0188] wherein the 5- to 10-membered heteroarylalkyl or the 5- to 10-membered heterocycloalkylalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen;

[0189] R 4 is C6-C 10 aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl,

[0190] wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heterocycloalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen;

[0191] each R 5 is independently C1-C6 alkyl, oxo or halo;

[0192] R 6 is H, C1-C6 alkyl or oxo;

[0193] R 7 is H or oxo;

[0194] m is 1 or 2; and

[0195] n is an integer from 0 to 3;

[0196] wherein 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 arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocycloalkyl and 5- to 10-membered heterocycloalkylalkyl is optionally substituted with one to five substituents selected from: hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl) and -CO2H.

[0197] 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 -C(=O)-. In some embodiments, L is -C(=O)-(CR a R b ) m -.

[0198] In some embodiments, each R a and R b is independently H, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group. In some embodiments, each R a and R b is independently H, a C1-C3 alkyl group, a C2-C4 alkenyl group, or a C2-C4 alkynyl group. In some embodiments, R a and R b are each H. In some embodiments, R a is H. In some embodiments, R a is a C1-C6 alkyl group, such as a methyl, ethyl, or propyl group. In some embodiments, R a is a C2-C6 alkenyl group, such as a vinyl or propenyl group. In some embodiments, R a is a C2-C6 alkynyl group, such as an ethynyl or propynyl group. In some embodiments, R b is H. In some embodiments, R b is a C1-C6 alkyl group, such as a methyl, ethyl, or propyl group. In some embodiments, R b is a C2-C6 alkenyl group, such as a vinyl or propenyl group. In some embodiments, R b is a C2-C6 alkynyl group, such as an ethynyl or propynyl group.

[0199] In some embodiments, R 1a and R 1b are independently H, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a halogenated group, or a C6-C 10 arylalkyl group. In some embodiments, R 1a is H. In some embodiments, R 1a is a C1-C6 alkyl group, such as a methyl, ethyl, or propyl group. In some embodiments, R 1a is a C2-C6 alkenyl group, such as a vinyl or propenyl group. In some embodiments, R 1a is a C2-C6 alkynyl group, such as an ethynyl or propynyl group. In some embodiments, R 1a is a C1-C6 alkoxy group, such as a methoxy, ethoxy, or propoxy group. In some embodiments, R 1ais a halogen group, such as fluorine, chlorine or bromine. In some embodiments, R 1a is a C6-C 10 arylalkyl, such as benzyl. In some embodiments, R 1b is H. In some embodiments, R 1b is a C1-C6 alkyl group, such as methyl, ethyl or propyl. In some embodiments, R 1b is a C2-C6 alkenyl group, such as vinyl or propenyl. In some embodiments, R 1b is a C2-C6 alkynyl group, such as ethynyl or propynyl. In some embodiments, R 1b is a C1-C6 alkoxy group, such as methoxy, ethoxy or propoxy. In some embodiments, R 1b is a halogen group, such as fluorine, chlorine or bromine. In some embodiments, R 1b is a C6-C 10 arylalkyl, such as benzyl.

[0200] In some embodiments, R 1a and R 1b are each independently H; a C1-C6 alkyl group optionally substituted with 1-3 substituents selected from halogen groups, -CO2H and -C(=O)NH2; a C1-C6 alkoxy group; a halogen group; or a C6-C 10 arylalkyl optionally substituted with 1-3 substituents selected from halogen groups and amino groups. In some embodiments, R 1a is a C1-C6 alkyl group substituted with 1-3 halogen groups (such as fluorine or chlorine). In some embodiments, R 1a is a C1-C6 alkyl group substituted with 1-3 -CO2H groups. In some variations, R 1a is a C1-C3 alkyl group substituted with 1-2 CO2H groups (such as -CH2CO2H or -CH2CH2CO2H). In some embodiments, R 1a is a C1-C6 alkyl group substituted with 1-3 -C(=O)NH2 groups. In some embodiments, R 1a is a C1-C3 alkyl group substituted with 1-2 -C(=O)NH2 groups (such as -CH2C(=O)NH2 or -CH2CH2C(=O)NH2). In some embodiments, R 1a is a C6-C 10 arylalkyl substituted with 1-3 substituents selected from halogen groups and amino groups. In some embodiments, R 1a is a C6-C 10 arylalkyl substituted with 1-3 halogen groups (such as fluorine, chlorine or bromine). In some embodiments, R 1a is a C6-C substituted with 1-3 amino groups10 Arylalkyl. In some embodiments, R 1b is a C1-C6 alkyl group substituted with 1-3 halogen groups (such as fluorine or chlorine). In some embodiments, R 1b is a C1-C6 alkyl group substituted with 1-3 -CO2H groups. In some variations, R 1b is a C 21 -C3 alkyl group substituted with 1-2 CO2H groups (such as -CH2CO2H or -CH2CH2CO2H). In some embodiments, R 1b is a C1-C6 alkyl group substituted with 1-3 -C(=O)NH2 groups. In some embodiments, R 1b is a C1-C3 alkyl group substituted with 1-2 -C(=O)NH2 groups (such as -CH2C(=O)NH2 or -CH2CH2C(=O)NH2). In some embodiments, R 1b is a C6-C 10 arylalkyl group substituted with 1-3 substituents selected from halogen groups and amino groups. In some embodiments, R 1b is a C6-C 10 arylalkyl group substituted with 1-3 halogen groups (such as fluorine, chlorine or bromine). In some embodiments, R 1b is a C6-C 10 arylalkyl group substituted with 1-3 amino groups. In some embodiments, R 1a and R 1b are each independently H, methyl, fluorine, 2-methylbutyl, -CH2F, methoxy, -CH2CO2H, -CH2C(=O)NH2, benzyl or 4-aminobenzyl. In some embodiments, R 1a and R 1b are each independently H or a C1-C3 alkyl group. 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, one of R 1a and R 1b is H and the other is a C1-C3 alkyl group, such as methyl.

[0201] In some embodiments, R 2 is H, an oxo group or a thio group. In some embodiments, R 2 is H. In some embodiments, R 2 is an oxo group. In some embodiments, R 2 is a thio group.

[0202] In some embodiments, R3 is a C3-C6 alkyl group, C3-C6 alkenyl group, C3-C6 alkynyl group, C3-C 12 cycloalkyl group, C3-C6 cycloalkylalkyl group, C6-C 10 arylalkyl group, 5- to 10-membered heteroarylalkyl group or 5- to 10-membered heterocycloalkylalkyl group, wherein the 5- to 10-membered heteroarylalkyl group or 5- to 10-membered heterocycloalkylalkyl group contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R 3 is a C3-C6 alkyl group, such as propyl, butyl, pentyl or hexyl. In some embodiments, R 3 is a C4-C6 alkyl group. In some embodiments, R 3 is a C3-C6 alkenyl group. In some embodiments, R 3 is a C4-C6 alkenyl group. In some embodiments, R 3 is a C3-C6 alkynyl group. In some embodiments, R 3 is a C4-C6 alkynyl group. In some embodiments, R 3 is a C3-C 12 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R 3 is a C3-C6 cycloalkyl group. In some embodiments, R 3 is a C3-C6 cycloalkylalkyl group, such as -(CH2) 1-3 (C3-C6 cycloalkyl). In some embodiments, R 3 is a C6-C 10 arylalkyl group, such as benzyl. In some embodiments, R 3 is a 5- to 10-membered heteroarylalkyl group, such as -(CH2) 1-3 (5- to 10-membered heteroaryl) or -(CH2) 1-3 (5- to 6-membered heteroaryl). In some embodiments, the 5- to 10-membered heteroarylalkyl group contains 1-2 nitrogen atoms. In some embodiments, R 3 is a 5- to 10-membered heterocycloalkylalkyl group, such as -(CH2) 1-3 (5- to 10-membered heterocycloalkyl) or -(CH2) 1-2 (5- to 6-membered heterocycloalkyl). In some embodiments, the 5- to 10-membered heterocycloalkylalkyl group contains 1-2 nitrogen atoms.

[0203] In some embodiments, R 3 is a C3-C6 alkyl group, C2-C6 alkenyl group or C3-C6 cycloalkylalkyl group optionally substituted with 1-3 substituents selected from halo and -C(=O)NH2. In some embodiments, R 3C2-C6 alkyl optionally substituted with 1-3 substituents selected from halo, C1-C3 alkoxy, hydroxy, -NH2, -SO2(C1-C3 alkyl), and -C(=O)NH2; C2-C6 alkenyl; C3-C6 cycloalkylalkyl; 5- to 6-membered heteroarylalkyl; 5- to 6-membered heterocycloalkylalkyl; or C6 arylalkyl. In some embodiments, R 3 is C2 alkyl substituted with 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2, and -SO2(C1-C3 alkyl). In some embodiments, R 3 is:

[0204]

[0205] In some embodiments, R 3 is:

[0206]

[0207] In some embodiments, R 3 is 2-methylbutyl.

[0208] In some embodiments, R 4 is C6-C 10 aryl, 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclo, wherein the 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclo contains 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, R 4 is C6-C 10 aryl, such as phenyl. In some embodiments, R 4 is 5- to 10-membered heteroaryl containing 1-2 nitrogen atoms. In some embodiments, R 4 is 5- to 10-membered heterocyclo. In some embodiments, R 4 is 5- to 9-membered heterocyclo containing 1-2 nitrogen atoms. In some embodiments, R 4 is 5- to 9-membered heterocyclo containing 1-2 oxygen atoms. In some embodiments, R 4 is 5- to 9-membered heterocyclo containing 1 nitrogen atom and 1 oxygen atom.

[0209] In some embodiments, R 4 is C6-C 10 aryl optionally substituted with 1-3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, R 4 is phenyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluorine, and chlorine. In some embodiments, R 4 is:

[0210]

[0211] In some embodiments, R 4 is:

[0212]

[0213] In some embodiments, R 4 is a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, R 4 is pyridyl or indolyl optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, R 4 is In some embodiments, R 4 is pyridyl substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, R 4 is In some embodiments, R 4 is a 5- to 10-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy. In some embodiments, R 4 is indolinyl.

[0214] In some embodiments, -L-R 4 is -CH2(phenyl) or -C(O)(phenyl), wherein the phenyl is substituted with 1 to 3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. In some embodiments, -L-R 4 is -CH2(pyridyl) or -C(O)(pyridyl), wherein the pyridyl is substituted with 1 to 3 substituents selected from C1-C3 haloalkyl, C1-C3 haloalkoxy, halo, and hydroxy. In some embodiments, -L-R 4 is:

[0215]

[0216] In some embodiments, each R 5 is independently C1-C6 alkyl, oxo, or halo. In some embodiments, R 5 is C1-C6 alkyl, such as methyl, ethyl, or propyl. In some embodiments, R 5 is oxo. In some embodiments, R 5is a halogen group, such as fluorine, chlorine or bromine. In some embodiments, R 5 is an oxo group or a halogen group. In some embodiments, R 5 is an oxo group or fluorine.

[0217] In some embodiments, R 6 is H, C1-C6 alkyl or an oxo group. 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 an oxo group.

[0218] In some embodiments, R 7 is H or an oxo group. In some embodiments, R 7 is H. In some embodiments, R 7 is an oxo group.

[0219] In some embodiments, m is 1. In other embodiments, m is 2.

[0220] 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.

[0221] In any embodiment of formula (I) or a variant 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 arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclic group and 5- to 10-membered heterocyclic group alkyl is optionally substituted by one to three substituents selected from the following: hydroxyl, halogen group (such as fluorine, chlorine or bromine), 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.

[0222] In one embodiment, the compound of formula (I) is a compound of formula (II), (IIa), (IIb), (IIc), (IId) or (IIe):

[0223]

[0224] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein L, R 1a 、R1b , R 3 , R 4 , R 5 , R 6 , R7 and 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.

[0225] In one embodiment, the compound of formula (I) is a compound of formula (IIIa), (IIIb), (IIIc) or (IIId):

[0226]

[0227] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein R 1a , R 1b , R 3 , R 5 , R6 and n are as described for formula (I), and R represents one or more optional substituents such as hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, as described for formula (I). In some embodiments, the compound is a compound of formula (IIIa) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIIb) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIIc) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In some embodiments, the compound is a compound of formula (IIId) or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0228] In one embodiment, the compound of formula (I) is a compound of formula (IVa), (IVb), (IVc) or (IVd):

[0229]

[0230] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein R5 and n are as described for formula (I), and R represents one or more optional substituents such as hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 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.

[0231] In one embodiment, the compound of formula (I) is a compound of formula (V):

[0232]

[0233] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein L, R 1a , R 1b , R 3 and R4 are as described for formula (I). In some embodiments, L is -C(=O)- or -CH2-; R 1a and R 1b are independently H or C1-C3 alkyl optionally substituted with -CO2H; R 3 is C4-C5 alkyl, C4-C5 alkenyl or C1-C3 alkyl optionally substituted with C3-C5 cycloalkyl; and R 4 is phenyl or pyridyl substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluorine and chlorine. In some variations, one of R 1a and R 1b is H and the other is C1-C3 alkyl such as methyl.

[0234] In the descriptions herein, it should be understood that each description, variation, embodiment or aspect of one part can be combined with each description, variation, embodiment or aspect of other parts, as if each combination described was specifically and individually listed. For example, each description, variation, embodiment or aspect provided herein regarding L of formula (I) can be combined with R 1a , R 1b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7Each description, variation, embodiment or aspect of m and n is combined as if each combination were specifically and individually listed. It should also be understood that, where applicable, all descriptions, variations, embodiments or aspects of formula (I) apply equally to the other formulas detailed herein and are described equally as if each description, variation, embodiment or aspect were individually and specifically listed for all formulas. For example, where applicable, all descriptions, variations, embodiments or aspects of formula (I) apply equally to any one of the formulas detailed herein, such as formulas (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIIa), (IIIb), (IIIc), (IIId), (IVa), (IVb), (IVc), (IVd) and (V), and are described equally as if each description, variation, embodiment or aspect were individually and specifically listed for all chemical formulas.

[0235] In some embodiments, there is provided a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. Although certain compounds described in the present disclosure (including the compounds in Table 1) are presented in a particular stereoisomeric and / or non-stereochemical form, it should be 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 the present disclosure (including the compounds in Table 1) are described herein.

[0236] Table 1.

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0245] 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.

[0246] In some embodiments, a compound is provided that is selected from the compounds in Table 1A or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. Although certain compounds described in the present disclosure (including the compounds in Table 1A) are presented in a specific stereoisomeric and / or non-stereochemical form, 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 described herein (including the compounds in Table 1A) are contemplated.

[0247] Table 1A.

[0248]

[0249]

[0250]

[0251] or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0252] In some embodiments, the compound is or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0253] In some embodiments, the compound is or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0254] In some embodiments, the compound is or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0255] In some embodiments, the compound is or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0256] It is understood that in this specification, combinations of substituents and / or variables of the depicted chemical formulas are permitted only if such combinations result in stable compounds.

[0257] In addition, all compounds of formula (I) in free base or free acid form can be converted to their pharmaceutically acceptable salts by treatment with a suitable inorganic or organic base or inorganic or organic acid by methods known to those skilled in the art. The salts of the compounds of formula (I) can be converted to their free base or free acid form by standard techniques.

[0258] Fosgonimeton and related compounds

[0259] Fogelnitone is a prodrug that rapidly converts to the active drug ATH-1001 (Dihexa; see US2014 / 0094413) in plasma after subcutaneous injection. The active drug ATH-1001 acts as a positive modulator of the hepatocyte growth factor (HGF) receptor and its tyrosine kinase MET receptor system.

[0260] Fogelnitone is the pharmaceutically acceptable salt of compound A19:

[0261]

[0262] Non-limiting exemplary pharmaceutically acceptable salts of compound A19 include:

[0263]

[0264] Unless otherwise indicated, fogelnitone refers to the monosodium salt of compound A19, as follows:

[0265]

[0266] Compound A19 and its pharmaceutically acceptable salts, isotopic forms or stereoisomers (including fogelnitone) can be synthesized and characterized using methods known to those skilled in the art (such as the methods described in PCT Publication No. WO 2017 / 210489 A1).

[0267] In some embodiments, fogelnitone is formulated for subcutaneous administration.

[0268] Synthesis method

[0269] The compound of formula (I), or its pharmaceutically acceptable salt, isotopic form or stereoisomer can be prepared by using organic chemical synthesis methods known in the art. Generally, the starting components can be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI and Fluorochem USA or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition (Wiley, December 2000)) or prepared as described herein.

[0270] General reaction scheme 1.

[0271]

[0272] General Reaction Scheme 1 provides an exemplary method for preparing compounds of formula (I). R in General Reaction Scheme 1 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 selected reactive moiety that facilitates the desired reaction (e.g., a halogen group). P1 and P2 are suitable protecting groups. L' is selected such that the desired L moiety is produced by the reaction between L'-R 4 and a secondary amine. Compounds of structure A1 are purchased or prepared according to methods known in the art. The reaction of A1 with A2 under appropriate coupling conditions (e.g., T3P and a base) gives the product of the coupling reaction between A1 and A2, A3. Then A3 is reacted with A4 under suitable coupling conditions (e.g., T3P and a base) to give compound A5. Then compound A5 is cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to give compound A6. Then compound A6 is reacted with compound A7 to give the final compound of formula (I) as shown.

[0273] General Reaction Scheme 2.

[0274]

[0275] General Reaction Scheme 2 depicts an alternative method for synthesizing compounds of formula (I). R in General Reaction Scheme 2 1a 、R 1b 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、L and n are as defined herein. P2 is a suitable protecting group. Each X is a selected reactive moiety that facilitates the desired reaction (e.g., a halogen group). L' is selected such that the desired L moiety is produced by the reaction between L'-R 4 and a secondary amine. Intermediate A5 is prepared using a removable protecting group P 3 (e.g., p-methoxybenzyl) as the R 3 group to give intermediate A8. Then A8 is cyclized (e.g., using formic acid) and deprotected (e.g., using piperidine) to give compound A9. Then compound A9 is reacted with A7 to give compound A10. Then compound A10 is deprotected (e.g., with ammonium cerium(IV) nitrate) to give compound A11. Then compound A11 is reacted with A12 to provide the final compound of formula (I).

[0276] General reaction scheme 3.

[0277]

[0278] A method related to that shown in General Reaction Scheme 2 is depicted in General Reaction Scheme 3. In this method, the two amine nitrogen atoms of the bicyclic core are deprotected to provide compound A10, which is then reacted with A7 to give compound A11. Subsequent reaction with A12 provides the final compound of formula (I).

[0279] It should be noted that various alternative strategies for preparing compounds of formula (I) are available to those of ordinary skill in the art. For example, other compounds of formula (I) can be prepared according to similar methods using appropriate starting materials.

[0280] It will also be appreciated by those skilled in the art that in the method for preparing the compounds described herein, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. Such functional groups may include hydroxyl, amino and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino and amidino include tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable protecting groups for carboxylic acids include alkyl, aryl or arylalkyl esters. Protecting groups are optionally added or removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, TW and PGM Wutz, Protective Groups in Organic Synthesis (1999), 3rd edition, Wiley. As will be appreciated by those skilled in the art, protecting groups may also be polymer resins, such as Wang resin, Rink resin or 2-chlorotrityl chloride resin.

[0281] Pharmaceutical compositions and formulations

[0282] On the other hand, provided herein is a pharmaceutical composition. The pharmaceutical composition comprises any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. In other more embodiments, the pharmaceutical composition comprises 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 below.

[0283] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, mucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0284] In certain embodiments, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered in a local rather than a systemic manner, e.g., often in the form of a depot formulation or a sustained release formulation by directly injecting the compound into an organ. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Additionally, in other embodiments, the drug is delivered in a targeted drug delivery system, e.g., in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ. In still other embodiments, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is provided in a rapid release formulation, an extended release formulation, or an intermediate release formulation. In still other embodiments, the compounds described herein are administered topically.

[0285] The compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is effective over a wide range of doses. For example, in treating adults, doses of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg / day, and 5 to 40 mg / day are examples of doses used in some embodiments. An exemplary dose is 10 to 30 mg / day. The exact dose will depend on the route of administration, the form of the compound administered, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.

[0286] In some embodiments, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof, is administered in a single dose form. Generally, such administration will be by injection, e.g., intravenous injection, to rapidly introduce the agent. However, other routes are used when appropriate. The single dose of the compounds of the present disclosure can also be used to treat acute conditions.

[0287] 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 dose forms. In some embodiments, the administration is about once, twice, three times, four times, five times, six times or more than six times per day. In other embodiments, the administration is about once per 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 to about 6 times per day. In another embodiment, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, and a therapeutic agent are administered for less than about 7 days. In yet another embodiment, the administration continues for more than about 6 days, 10 days, 14 days, 28 days, two months, six months or one year. In some cases, continuous administration is achieved and maintained as long as needed.

[0288] The compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, can be administered continuously as long as needed. 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 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days 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 days, 14 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days 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 long-term on an uninterrupted basis, for example, for treating chronic effects (e.g., peripheral and / or systemic inflammatory conditions).

[0289] In some embodiments, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, is administered in doses. It is known in the art that due to variability in the pharmacokinetics of the compound among subjects, optimal therapy requires personalization of the dosing regimen. The dosing of the compound can be found by routine experimentation in view of the present disclosure.

[0290] In some embodiments, a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, 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, which include excipients and auxiliaries that assist in processing the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the chosen route of administration. Any pharmaceutically acceptable techniques, carriers and excipients are suitable for formulating the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, 19th Edition (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, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999).

[0291] The present disclosure provides 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, excipient or carrier. The present disclosure also provides 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, excipient or carrier.

[0292] In certain embodiments, the compound is administered as a pharmaceutical composition, wherein the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, is mixed with other therapeutic agents, such as in combination therapy. All combinations of the active ingredients set forth in the following method sections and throughout the present disclosure are encompassed herein. In a specific embodiment, the pharmaceutical composition comprises one or more compounds of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

[0293] 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, thickening agents and / or excipients. In certain embodiments, the pharmaceutical composition facilitates the administration of the compound to an organism. In some embodiments, for practicing 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 is administered to a mammal having a disease, disorder or medical condition to be treated in the form of a pharmaceutical composition. In a specific embodiment, the mammal is a human. In some embodiments, the therapeutically effective amount depends on factors such as 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 in combination with one or more therapeutic agents as components of a mixture.

[0294] 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, by way of example only, the aqueous solution is selected from physiologically compatible buffers such as Hank's solution, Ringer's solution or saline buffer. In other embodiments, 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 suitable for the barrier to be penetrated (e.g., the blood-brain barrier). In still other embodiments where the compounds described herein are formulated for other parenteral injections, suitable formulations include aqueous or non-aqueous solutions. In a specific embodiment, such solutions include physiologically compatible buffers and / or excipients.

[0295] In some embodiments, a 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 an oral dosage form which includes, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, etc.

[0296] In certain embodiments, a pharmaceutical preparation for oral use is obtained by mixing one or more solid excipients with one or more of the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof; optionally grinding the resulting mixture; and, if desired, treating the mixture of granules with suitable auxiliaries to obtain tablets or dragee cores. Specifically, suitable excipients are fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In a particular embodiment, a disintegrant is optionally added. Disintegrants include (by way of example only) croscarmellose sodium, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate.

[0297] In one embodiment, dosage forms such as dragee cores and tablets have one or more suitable coatings. In a particular embodiment, the dosage form is coated with a concentrated sugar solution. The sugar solution optionally contains additional components such as, by way of example only, gum arabic, talc, polyvinylpyrrolidone, gelatin, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes and / or pigments are also optionally added to the coating for identification purposes. Additionally, different combinations of the active compound dose are optionally characterized using dyes and / or pigments.

[0298] In certain embodiments, a therapeutically effective amount of at least one of the compound 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 soft-sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. In a particular embodiment, the push-fit capsules contain the active ingredient admixed with one or more fillers. Fillers include, by way of example only, lactose, binders such as starch and / or lubricants such as talc or magnesium stearate and optionally selected 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 oils, liquid paraffin or liquid polyethylene glycol. Additionally, stabilizers are optionally added.

[0299] 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 formulations for injection are provided in unit dosage forms (e.g., in ampoules) or in multi-dose containers. An antiseptic is optionally added to the injection formulation. In still other embodiments, the pharmaceutical composition is formulated in a form suitable for parenteral injection, such as a sterile suspension, solution or emulsion in an oily or aqueous vehicle. The parenteral injection formulation optionally contains formulatory agents such as suspending agents, stabilizers and / or dispersing agents. In specific embodiments, the pharmaceutical formulation for parenteral administration comprises an aqueous solution of the active compound in water-soluble form. In additional embodiments, a suspension of one or more active compounds (e.g., the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof) is prepared as an oily injection suspension where appropriate. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fats such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, the aqueous injection suspension contains 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 compound to allow the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0300] In still other embodiments, 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 solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compositions optionally contain solubilizing agents, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0301] In still other embodiments, a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof is formulated for transdermal administration. In a specific embodiment, the transdermal formulation employs a transdermal delivery device and a transdermal delivery patch and may be a lipophilic emulsion or a buffered aqueous solution dissolved and / or dispersed in a polymer or adhesive. In various embodiments, such patches are constructed for continuous, pulsatile or on-demand delivery of the medicament. In additional embodiments, transdermal delivery of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof is accomplished by means of an iontophoretic patch or the like. In certain embodiments, the transdermal patch provides controlled delivery of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. In a specific embodiment, the rate of absorption is slowed by using a rate controlling membrane or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, the transdermal device is in the form of a bandage that includes a backing member, a reservoir containing the compound optionally with a carrier, an optional rate controlling barrier that delivers the compound to the host skin at a controlled and predetermined rate over an extended period of time, and a member that secures the device to the skin.

[0302] In other embodiments, a 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, sprays or powders. A pharmaceutical composition of any of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof is suitably delivered in aerosol spray presentation form from a pressurized pack or a nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In a specific embodiment, the dosage unit for a pressurized aerosol is determined by providing a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for an inhaler or insufflator, such as (by way of example only) gelatin, are formulated to contain a powder mixture of the compound with a suitable powder base such as lactose or starch.

[0303] In still other embodiments, a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, is formulated as a rectal composition containing a conventional suppository base such as cocoa butter or other glycerides, such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, gelatin suppositories or retention enemas, and synthetic polymers such as polyvinylpyrrolidone, PEG, etc. In the suppository form of the composition, a low melting wax such as, but not limited to, a mixture of fatty acid glycerides optionally combined with cocoa butter is first melted.

[0304] In certain embodiments, the pharmaceutical composition is formulated in any conventional manner using one or more physiologically acceptable carriers, which carriers include excipients and auxiliaries that assist in processing the active compound into a pharmaceutically usable preparation. The appropriate formulation depends on the chosen route of administration. Where appropriate, any pharmaceutically acceptable techniques, carriers and excipients are optionally used. A pharmaceutical composition containing a compound of formula (I), or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, is manufactured in a conventional manner, such as (by way of example only) by means of conventional mixing, dissolving, granulating, pill-making, levigating, emulsifying, encapsulating, entrapping or compressing methods.

[0305] The pharmaceutical composition contains at least one pharmaceutically acceptable carrier, diluent or excipient and at least one compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, described herein as the active ingredient. The active ingredient is in the free acid or free base form, or in a pharmaceutically acceptable salt form. Additionally, the methods and pharmaceutical compositions described herein include the use of N-oxides, crystalline forms (also known as polymorphs) and active metabolites of these compounds having the same type of activity. All tautomeric forms of the compounds described herein are included within the scope of the compounds presented herein. Additionally, a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, encompasses non-solvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein. Additionally, the pharmaceutical composition optionally contains other medical or pharmaceutical agents, carriers, adjuvants (such as preservatives, stabilizers, wetting agents or emulsifying agents), solubilizing agents, salts for regulating osmotic pressure, buffers and / or other therapeutically valuable substances.

[0306] A method for preparing a composition comprising a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, comprises formulating the compound with one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets and suppositories. Liquid compositions include solutions in which the compound is dissolved; emulsions containing the compound; or solutions containing liposomes, micelles or nanoparticles comprising 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 forms of the pharmaceutical compositions described herein include liquid solutions or suspensions, solid forms suitable for dissolving or suspending in a liquid prior to use, or emulsions. These compositions also optionally contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifying agents, pH buffering agents, and the like.

[0307] In some embodiments, when the agent is present in solution form, suspension form or both, a pharmaceutical composition comprising at least one compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, illustratively takes a liquid form. Generally, when the composition is administered in solution or suspension form, a first portion of the agent is present in solution form and a second portion of the agent is present as fine particles suspended in the liquid matrix. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is an aqueous solution.

[0308] In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers, e.g., hydroxypropyl methylcellulose, and water-insoluble polymers such as cross-linked carboxyl-containing polymers. Certain pharmaceutical compositions described herein contain mucoadhesive polymers selected from, for example, carboxymethylcellulose, carbomer (acrylic acid polymer), poly(methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid / butyl acrylate copolymer, sodium alginate and polydextrose.

[0309] Useful pharmaceutical compositions also optionally contain solubilizing agents to assist the solubility of the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof. The term "solubilizing agent" generally includes agents that result in the formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants (e.g., polysorbate 80) are suitable as solubilizing agents, and ophthalmically acceptable diols, polyethylene glycols (e.g., polyethylene glycol 400) and glycol ethers are also suitable as solubilizing agents.

[0310] In addition, useful pharmaceutical compositions optionally contain one or more pH regulators or buffers, including 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 tris(hydroxymethyl)aminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in the amounts required to maintain the pH of the composition within an acceptable range.

[0311] Additionally, useful compositions also optionally contain one or more salts in the amounts required to bring the osmolality of the composition within an acceptable range. Such salts include salts 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.

[0312] Other useful pharmaceutical compositions optionally contain one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as phenylmercuric borate (merfen) and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

[0313] Other useful compositions also contain one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers such as octoxynol 10 and octoxynol 40.

[0314] Other useful compositions also optionally contain one or more antioxidants to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite.

[0315] In certain embodiments, aqueous suspension compositions are packaged in single-dose non-reclosable containers. Alternatively, multi-dose reclosable containers are used, in which case preservatives are typically included in the composition.

[0316] In alternative embodiments, other delivery systems for hydrophobic pharmaceutical compounds are employed. Liposomes and emulsions are examples of useful delivery vehicles or carriers herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also employed. In additional embodiments, sustained release systems such as semipermeable matrices of solid hydrophobic polymers containing a therapeutic agent are used to deliver a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. A variety of sustained release materials are suitable herein. In some embodiments, the sustained release capsule releases the compound for weeks up to over 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies may be employed for protein stabilization.

[0317] In certain embodiments, the formulations described herein contain one or more antioxidants, metal chelators, thiol-containing compounds, and / or other common stabilizers. 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.

[0318] In some embodiments, the concentration of the compound of formula (I) or compound A19 provided in the pharmaceutical compositions of the present disclosure is less than 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%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w / w, w / v, or v / v.

[0319] In some embodiments, the concentration of the compound of formula (I) or compound A19 provided in the pharmaceutical composition of the present disclosure is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v.

[0320] In some embodiments, the concentration range 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 approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12% or approximately 1% to approximately 10% w / w, w / v or v / v.

[0321] In some embodiments, the concentration range 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 approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1% or approximately 0.1% to approximately 0.9% w / w, w / v or v / v.

[0322] 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 equal to or less than 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, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

[0323] In some embodiments, the amount of the compound of formula (I) or compound A19 provided in the pharmaceutical composition of the present disclosure, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, is greater than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g or 10 g.

[0324] In some embodiments, the amount of the compound of formula (I) or compound A19 provided in the pharmaceutical composition, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, ranges from 0.0001 - 10 g, 0.0005 - 9 g, 0.001 - 8 g, 0.005 - 7 g, 0.01 - 6 g, 0.05 - 5 g, 0.1 - 4 g, 0.5 - 4 g or 1 - 3 g.

[0325] In some embodiments, the method comprises administering compound A19 or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof by subcutaneous injection.

[0326] In some embodiments, the method comprises administering an HGF / MET positive modulator by an oral dosage form.

[0327] In some embodiments, the method comprises administering compound 2a or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof by an oral dosage form.

[0328] In some embodiments, the method comprises administering Compound 1a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof via an oral dosage form.

[0329] In some embodiments, the method comprises administering Compound 5a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof via an oral dosage form.

[0330] In some embodiments, the method comprises administering Compound 6a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof via an oral dosage form.

[0331] In some embodiments, the method comprises administering Compound 7a or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof via an oral dosage form.

[0332] Kit / Article

[0333] Kits and articles for use in the therapeutic applications described herein are also provided. In some embodiments, such kits include a carrier, a package, or a container divided to receive one or more containers (such as vials, tubes, etc.), each of the containers including one of the individual elements to be used in the methods described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers are formed from a variety of materials such as glass or plastic.

[0334] The articles provided herein contain packaging materials. Packaging materials for packaging pharmaceutical products include, for example, the packaging materials 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 the intended mode of administration and treatment. For example, the container includes one or more of the compounds described herein, optionally in the form of a composition or in combination with another agent as disclosed herein. The container optionally has a sterile access port (e.g., the container is an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). Such kits optionally include a compound with an identifying description, label, or instructions related to its use in the methods described herein.

[0335] For example, a kit typically includes one or more additional containers, each additional container having one or more of a variety of materials (such as reagents, and / or devices, optionally in concentrated form) that are needed from a commercial and user perspective for the use of the compound of formula (I) or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof. Non-limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes, carriers, packaging, containers, vials, and / or tube labels listing the contents and / or instructions for use, as well as package inserts with instructions for use. A set of instructions is also typically included. The label is optionally attached to or associated with the container. For example, the label is attached to the container when letters, numbers, or other characters forming the label are attached, molded, or etched into the container itself; or the label is associated with the container when the label is present in a receptacle or carrier that also holds the container, such as a package insert. Additionally, the label is used to indicate the contents for a particular therapeutic application. Additionally, the label indicates the instructions for use of the contents, such as in the methods described herein. In certain embodiments, the pharmaceutical composition is presented in a packaging or dispenser device in one or more unit dosage forms containing the compounds provided herein. The packaging contains, for example, a metal or plastic foil, such as a blister pack. The packaging or dispenser device may be accompanied by instructions for administration. The packaging or dispenser may be accompanied by precautions associated with the container, in a form specified by a government agency that regulates the manufacture, use, or sale of the pharmaceutical, which precautions reflect the approval of the agency for the use of the pharmaceutical form for human or veterinary administration. Such precautions are, for example, the labels approved by the U.S. Food and Drug Administration for prescription drugs, or approved product inserts. 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 a suitable container, and labeled for the treatment of the indicated condition.

[0336] Method of Use / Treatment

[0337] Embodiments of the present disclosure provide 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 as 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 evaluated and confirmed by a wide variety of ways known in the art. Kits and commercially available assays can be utilized to determine whether hepatocyte growth factor has been modulated (e.g., inhibited or activated) and to what extent hepatocyte growth factor has been modulated.

[0338] In some embodiments, provided herein are compounds of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, which are used to positively regulate hepatocyte growth factor in a subject in need thereof. In some embodiments, provided herein are compounds of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, which are used to manufacture a medicament for regulating hepatocyte growth factor in a subject in need thereof.

[0339] The applicant has found that the compounds of formula (I) or compound A19 exhibit promising activities related to certain target diseases. Thus, in one aspect, provided herein is a method for regulating 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 positively regulating 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.

[0340] In certain more specific embodiments, positive regulation includes treating a disease, condition or injury, or reducing the symptoms of 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 a gastrointestinal condition, a dermatological condition, an ophthalmological condition, a condition associated with a metabolic disease or a pulmonary condition.

[0341] In some embodiments, the peripheral and / or systemic inflammatory condition may 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 hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver, seasonal allergy, chronic obstructive pulmonary disease (COPD) or endometriosis.

[0342] In some embodiments, provided herein are methods of treating the following conditions in a subject: inflammatory bowel disease, Crohn's disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, Leber hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0343] In some embodiments, provided herein are methods of treating inflammatory bowel disease in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0344] In some embodiments, provided herein are methods of treating Crohn's disease in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0345] In some embodiments, provided herein are methods of treating ulcerative colitis in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0346] In some embodiments, provided herein are methods of treating celiac disease in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0347] In some embodiments, provided herein are methods of treating rheumatoid arthritis in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0348] In some embodiments, provided herein are methods of treating psoriasis in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0349] In some embodiments, provided herein are methods of treating non-infectious uveitis in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0350] In some embodiments, provided herein are methods of treating type 2 diabetes in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0351] In some embodiments, provided herein are methods of treating obesity in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0352] In some embodiments, provided herein are methods of treating coronary heart disease in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0353] In some embodiments, provided herein are methods of treating gout in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0354] In some embodiments, provided herein are methods of treating fatty liver in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0355] In some embodiments, provided herein are methods of treating seasonal allergies in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0356] In some embodiments, provided herein are methods of treating COPD in a subject. The methods comprise administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0357] In some embodiments, provided herein are methods of treating endometriosis in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0358] In some embodiments, provided herein are methods of treating systemic lupus erythematosus in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0359] In some embodiments, provided herein are methods of treating dermatomyositis in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0360] In some embodiments, provided herein are methods of treating polymyositis in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0361] In some embodiments, provided herein are methods of treating optic neuritis in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0362] In some embodiments, provided herein are methods of treating LHON in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0363] In some embodiments, provided herein are methods of treating macular degeneration in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0364] In some embodiments, provided herein are methods of treating retinal degeneration in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0365] In some embodiments, provided herein are methods of treating myasthenia gravis in a subject. The methods include administering to the subject an effective amount of a compound in Table 1, a compound in Table 1a, compound A19, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0366] In some embodiments, provided herein are methods of treating the following conditions in a subject: inflammatory bowel disease, Crohn’s disease, ulcerative colitis, celiac disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, dermatomyositis, polymyositis, non-infectious uveitis, optic neuritis, leber hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver, seasonal allergies, chronic obstructive pulmonary disease (COPD), or endometriosis. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0367] In some embodiments, provided herein are methods of treating inflammatory bowel disease in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0368] In some embodiments, provided herein are methods of treating Crohn’s disease in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0369] In some embodiments, provided herein are methods of treating ulcerative colitis in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0370] In some embodiments, provided herein are methods of treating celiac disease in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0371] In some embodiments, provided herein are methods of treating rheumatoid arthritis in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0372] In some embodiments, provided herein are methods of treating psoriasis in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0373] In some embodiments, provided herein are methods of treating non-infectious uveitis in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0374] In some embodiments, provided herein are methods of treating type 2 diabetes in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0375] In some embodiments, provided herein are methods of treating obesity in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0376] In some embodiments, provided herein are methods of treating coronary heart disease in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0377] In some embodiments, provided herein are methods of treating gout in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0378] In some embodiments, provided herein are methods of treating fatty liver in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0379] In some embodiments, provided herein are methods of treating seasonal allergies in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0380] In some embodiments, provided herein are methods of treating COPD in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0381] In some embodiments, provided herein are methods of treating endometriosis in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0382] In some embodiments, provided herein are methods of treating systemic lupus erythematosus in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0383] In some embodiments, provided herein are methods of treating dermatomyositis in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0384] In some embodiments, provided herein are methods of treating polymyositis in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0385] In some embodiments, provided herein are methods of treating optic neuritis in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0386] In some embodiments, provided herein are methods of treating LHON in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0387] In some embodiments, provided herein are methods of treating macular degeneration in a subject. The methods comprise administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0388] In some embodiments, provided herein are methods of treating retinal degeneration in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0389] In some embodiments, provided herein are methods of treating myasthenia gravis in a subject. The methods include administering to the subject an effective amount of compound 1a, compound 2a, compound 5a, compound 6a, or a pharmaceutically acceptable salt, isotopic form, or stereoisomer thereof.

[0390] In some embodiments, the peripheral and / or systemic inflammatory conditions are not caused by neuroinflammation or a disease or disorder of the central nervous system. In some embodiments, the peripheral and / or systemic inflammatory conditions are not caused by dementia. In some embodiments, the peripheral and / or systemic inflammatory conditions are not caused by neurodegenerative diseases. In some embodiments, the peripheral and / or systemic inflammatory conditions are not caused by Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory conditions does not have dementia. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory conditions does not have a neurodegenerative disease. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory conditions does not have Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss.

[0391] In some embodiments, the peripheral and / or systemic inflammatory conditions are not associated with neuroinflammation or a disease or disorder of the central nervous system. In some embodiments, the peripheral and / or systemic inflammatory conditions are not associated with dementia. In some embodiments, the peripheral and / or systemic inflammatory conditions are not associated with neurodegenerative diseases. In some embodiments, the peripheral and / or systemic inflammatory conditions are 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 sensorineural hearing and vision loss. In some embodiments, the subject being treated for the peripheral and / or systemic inflammatory conditions does not have dementia.

[0392] In some embodiments, the present disclosure provides a method of modulating protein activity (e.g., hepatocyte growth factor activity) in a subject including but not limited to a rodent and a mammal (e.g., a human) 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 the activation of hepatocyte growth factor. In some embodiments, the percentage of modulation is more than 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. In some embodiments, the percentage of inhibition is more than 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

[0393] In some embodiments, the present disclosure provides a method for modulating hepatocyte growth factor activity in a cell by contacting the cell with an amount of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor. In some embodiments, the present disclosure provides a method for modulating hepatocyte growth factor activity in a tissue by contacting the tissue with an amount of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the tissue. In some embodiments, the present disclosure provides a method for modulating hepatocyte growth factor activity in an organism by contacting the organism with an amount of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the organism. In some embodiments, the present disclosure provides a method for modulating hepatocyte growth factor activity in an animal by contacting the animal with an amount of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the animal. In some embodiments, the present disclosure provides a method for modulating hepatocyte growth factor activity in a mammal by contacting the mammal with an amount of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the mammal. In some embodiments, the present disclosure provides a method for modulating hepatocyte growth factor activity in a human by contacting the human with an amount of a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, sufficient to modulate the activity of hepatocyte growth factor in the human. In other embodiments, the present disclosure provides a method for treating a disease mediated by hepatocyte growth factor activity in a subject in need of such treatment. In some variations, modulating hepatocyte growth factor by a compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, involves activating hepatocyte growth factor.

[0394] 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 in a subject. 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 G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα 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 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), eosinophil activating chemokine (Eotaxin) (CCL11), IL-2R, LIF, MIP-1β (CCL4) and MIP-1α (CCL3).

[0395] In some embodiments, the compounds 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 in a subject. In some embodiments, the compounds 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 G-CSF, CCL3, CXCL1, CXCL2, CXCL10, IL-1α, IL-1β, IL-4, IL-10, IL-12p70, IL-17A, TNFα and IFNγ. In some embodiments, the compounds 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 IL-1β, IL-4, IL-6, TNF-α and IFNγ. In some embodiments, the compounds 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), eosinophil activating chemokine (CCL11), IL-2R, LIF, MIP-1β (CCL4) and MIP-1α (CCL3).

[0396] In some embodiments, Compound 1a, Compound 2a, Compound 5a, Compound 6a, 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 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 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 reduces the level of at least one pro-inflammatory molecule selected from BAFF, G-CSF, ENA-78 (CXCL5), eosinophil activating chemokine (CCL11), IL-2R, LIF, MIP-1β (CCL4), and MIP-1α (CCL3).

[0397] Other embodiments provide methods for combination therapy, wherein therapeutic agents known to modulate other pathways, or other components of the same pathway, or even overlapping sets of 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 therapies include, but are not limited to, combinations 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 to provide a synergistic or additive therapeutic effect.

[0398] 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, a subject having a peripheral and / or systemic inflammatory condition is also treated with another anti-inflammatory agent such as a steroid.

[0399] In some embodiments, a 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, polycarbohydrates, and hyaluronic acid.

[0400] Other therapeutic agents that can be combined with the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, can be found in the tenth edition of Goodman and Gilman's “The Pharmacological Basis of Therapeutics” edited by Hardman, Limbird and Gilman or the Physician's Desk Reference, both of which are incorporated herein by reference in their entirety.

[0401] Depending on the condition being treated, 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. Thus, in some embodiments, one or more compounds of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, will be co-administered with other therapeutic agents as 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 or separately from the second therapeutic agent. This combination 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 one of the therapeutic agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof and any one of the therapeutic agents described above can be administered simultaneously, where both are present in separate formulations. 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 after any one of the therapeutic agents described above, or vice versa. In some embodiments of the separate administration scenario, the compound of formula (I) or compound A19, or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof and any one of the therapeutic agents described above are administered minutes, or hours, or days apart.

[0402] The examples and preparations provided below further illustrate and exemplify 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 following examples and throughout the specification and claims, unless otherwise indicated, molecules having a single stereocenter are present in the form of a racemic mixture. Unless otherwise indicated, those molecules having two or more stereocenters are present in the form of a racemic mixture of diastereoisomers. The single enantiomers / diastereoisomers can be obtained by methods known to those skilled in the art.

[0403] Example

[0404] The following examples are provided for illustrative purposes. Methods for preparing the compounds of formula (I), or pharmaceutically acceptable salts, isotopic forms or stereoisomers thereof, are provided in PCT publication WO2022 / 094400, which is incorporated herein by reference or can be derived by those of ordinary skill in the art.

[0405] Example B1: Reduction of inflammatory pain-related behaviors and inflammatory biomarkers after treatment in a rodent CFA inflammatory pain model

[0406] The response to a peripheral inflammatory stimulus can be modeled by administering complete Freund's adjuvant (CFA) (a suspension of dried Mycobacterium in paraffin oil and mannitol monooleate) via subcutaneous injection into the plantar surface of the rat hind paw. Introduction of CFA into the peripheral tissue results in a rapid and sustained inflammatory response in the exposed tissue within 24 hours. Subcutaneous administration of CFA in the plantar region of the paw induces inflammatory pain-related behaviors that persist for at least 8 days. CFA treatment also results in the accumulation of inflammatory cytokines in the paw tissue at the site of injury. The degree of the inflammatory response to CFA can be evaluated by quantifying the inflammatory cytokines in the paw skin homogenate, and the inflammatory pain-related behaviors can be evaluated by tests of mechanical allodynia (von Frey test) and thermal hyperalgesia (Hargreaves test).

[0407] In one study, the ability of compound 2a to reduce inflammatory pain-related behaviors in a CFA inflammatory model was tested. On day 0 of the study, 50 μg of CFA was administered subcutaneously into the plantar surface of the right hind paw. The animals were treated daily via oral gavage (PO) with a solution of compound 2a at doses of 1, 0.1 and 0.025 mg / kg. The treatment started before the CFA injection on day -1 of the study and continued until day 8 of the study.

[0408] The von Frey test was used to measure mechanical allodynia. In this test, rats were placed on a wire mesh, and a series of filaments designed to deliver a probing force of 4 to 26 grams were applied to the plantar surface of the right hind paw. The animals indicated a pain response by lifting the paw being probed. The minimum force required to elicit a withdrawal response was recorded as the paw withdrawal threshold (PWT). On days 1, 3, and 7 of the study, the Von Frey test was performed 1 hour after compound 2a administration, and also before dosing on day 7. Statistical analysis was performed using one-way ANOVA and Tukey's post hoc test. A p-value less than 0.05 was considered statistically significant. The results are summarized in Table 2. Compared with normal control animals, control animals stimulated with CFA but treated only with vehicle were hypersensitive to mechanical stimuli. Treatment with compound 2a at a dose of 1 mg / kg resulted in a reduction in mechanical allodynia in the post-dose test on day 7 of the study.

[0409] Thermal hyperalgesia was measured using the Hargreaves method. A temperature ramp was applied to the right hind paw via a directed beam, and the paw withdrawal latency (PWL) was recorded as a measure of sensitivity to thermal stimuli. Post-dose one-hour tests were performed on days 1, 3, and 7 of the study, and a pre-dose test was performed on day 7. Statistical analysis was performed using one-way ANOVA and Tukey's post hoc test. A p-value less than 0.05 was considered statistically significant. The results are summarized in Table 2. Compared with normal control animals, control animals stimulated with CFA but treated only with vehicle were hypersensitive to thermal stimuli. Treatment with compound 2a at a dose of 1 mg / kg resulted in a reduction in thermal sensitivity in the pre-dose tests on days 3 and 7.

[0410] Table 2. Compound 2a reduced mechanical allodynia and thermal hyperalgesia in response to CFA-based inflammatory pain stimuli.

[0411]

[0412] NS = No statistically significant change in sensitivity compared to CFA alone

[0413] + = Statistically significant change in sensitivity compared to CFA alone, p < 0.05

[0414] In another study, compounds 1a, 5a, and 6a were also similarly tested for their ability to reduce pain-related behaviors against CFA-induced inflammatory stimuli in the right hind paw. This study also included quantification of the expression of inflammatory cytokines in paw skin homogenates. Inflammatory pain stimuli using CFA injection and assessment of mechanical and thermal pain-related behaviors were performed as described above.

[0415] Intraplantar CFA injection was performed on day 0. Compounds 1a, 5a, and 6a were administered daily from day -1 to day 8. On day 8, the rats were sacrificed and cytokine levels in the paw skin were measured. Tissues of the paw bone, joint, and muscle were obtained for H&E staining and analysis. Cytokine levels in CFA-stimulated test compound-treated animals were compared with those in CFA-stimulated vehicle-treated animals. Analytes included interleukin 4 (IL-4), tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Statistical analysis included one-way ANOVA, followed by Dunnett's multiple comparison post hoc test. Mechanical allodynia and thermal hyperalgesia were tested 1 hour after dosing on days 1, 3, and 7. PWT refers to the paw withdrawal threshold, where a higher value corresponds to a higher pain threshold. PWL refers to the paw withdrawal latency, where a higher value corresponds to a higher pain threshold.

[0416] As shown in Table 3, compound 1a significantly reduced sensitivity to mechanical stimuli on days 1, 3, and 7 of the study, and similarly reduced thermal sensitivity on days 1, 3, and 7 of the study. Treatment with compound 5a reduced mechanical sensitivity on day 1 of the study and reduced thermal sensitivity on days 1 and 7 of the study. Compound 6a reduced thermal sensitivity on day 7 of the study.

[0417] Table 3. Significant reduction in mechanical and thermal pain behaviors

[0418]

[0419] NS = No statistically significant change in sensitivity compared to CFA alone

[0420] + = Statistically significant change in sensitivity compared to CFA alone, p < 0.05

[0421] Compounds 1a and 5a showed a statistically significant increase in PWT on day 1, and compound 1a showed a statistically significant increase in PWT on days 3 (8 and 16 mg / kg) and 7 (16 mg / kg) (Table 3 and data not shown).

[0422] Compounds 1a, 5a, and 6a showed a statistically significant increase in PWL at each dose on day 7 (Table 3 and data not shown).

[0423] On day 5, mechanical allodynia and thermal hyperalgesia were evaluated 1 hour before dosing. On day 5, the threshold levels of each compound were tested. Compounds 1a and 6a both showed a statistically significant increase in PWL (data not shown).

[0424] Although a reduction in pain was observable, the treatment had no significant effect on paw thickness (data not shown). On day 8 of the study, a significant decrease in IL-4, TNF-α, and IFN-γ was detected in the paw skin (Table 4 and data not shown).

[0425] All tested compounds reduced the expression of the evaluated cytokines at at least one tested dose, except that compound 6a had no effect on IFN-γ expression (Table 4). These results suggest that the tested compounds produced a meaningful anti-inflammatory effect in response to the peripheral inflammation stimulated by CFA.

[0426] Table 4. Quantification of cytokine expression in the paw skin of CFA-stimulated animals treated with the indicated test compounds

[0427]

[0428] NS = no statistically significant change in expression compared to CFA alone

[0429] + = statistically significant change in expression compared to CFA alone, p < 0.05

[0430] Example B2: Reduction of inflammation after pulmonary LPS challenge.

[0431] Acute pulmonary inflammation 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 and the secretion of cytokine signaling proteins in bronchoalveolar lavage fluid (BALF). Activation of the HGF / MET signaling system by positive modulators of HGF / MET is expected to reduce the inflammatory response. The ability of two tested compounds (compound 1a and compound 5a) to reduce acute pulmonary inflammation in the intranasal LPS model was evaluated.

[0432] In this study, acute pulmonary inflammation was induced in healthy male Sprague-Dawley rats (7-9 weeks old at the start of the study) by intratracheal instillation of 20 μg LPS in saline. The test animals were treated twice with the test compounds at 24 hours and 0.5 hours before treatment by intravenous (IV) injection of LPS. The anti-inflammatory corticosteroid dexamethasone (Dex) was used as a positive control and administered at 3 mg / kg by intraperitoneal (IP) injection 1 hour before LPS treatment. Four hours after LPS administration, the animals were euthanized by intraperitoneal injection of sodium thiopental, and 20 mL of cold Hanks Balanced Salt Solution (pH 7.2) was injected into the lungs through tracheal intubation. Then BALF was collected.

[0433] The immune cell infiltration in BALF was quantified as an assessment of the inflammatory response, and the results are shown in Table 5. The immune cell infiltration was performed by counting total white blood cells using a miniature flow cytometer and by manually counting neutrophils in cytocentrifuge smears stained with Leishman staining reagent. Treatment with Compound 1a and Compound 5a reduced the total white blood cell count and the neutrophil count compared to the LPS control only.

[0434] Table 5. Immune cell infiltration in BALF of rats stimulated with pulmonary LPS

[0435]

[0436] NS indicates not significant

[0437] + = cell count decreased by >5% compared to the disease control

[0438] ++ = cell count decreased by >25% compared to the disease control

[0439] +++ = cell count decreased by >75% compared to the disease control

[0440] The cytokine expression in the BALF supernatant was quantified by multiplex immunoassay using a MAGPIX multiplexing unit with a cytokine multiplex kit (Merck-Millipore, catalog number RECYMAG65K27PMX). The panel of cytokines tested included growth factors (G-CSF, GM-CSF, EGF, VEGF, TNF-α), chemokines (CCL2, CCL3, CCL5, CCL11, CXCL 1, CXCL 2, 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 compared to LPS-only animals were determined by Student's T-test, with p < 0.05 indicating a statistically significant change in cytokine expression levels. Treatment with compound 1a led to significant changes in the expression of G-CSF, CXCL2, CXCL10, IFN-γ, and IL-1β. Treatment with compound 5a led to significant changes in the expression of CCL3, CXCL1, IFN-γ, IL-1α, IL-1β, IL-10, IL-12p70, and IL-17A. These results suggest that treatment with the test compounds had a meaningful impact on acute pulmonary inflammation in response to LPS by reducing the levels of pro-inflammatory molecules. The normal process of inflammation is regulated and promoted by the expression, secretion, and distribution of inflammatory signaling proteins. Therapeutic approaches aimed at reducing inflammation are typically identified by their ability to alter the expression levels of inflammatory signaling molecules, either by directly disrupting the inflammatory pathway or by resolving the inflammatory signaling cascade. The compounds provided herein are expected to be able to block inflammatory signaling, based on their demonstrated significant effects on the expression of notable inflammatory cytokines.

[0441] Table 6. Significant changes in cytokine expression in the BALF supernatant of LPS-stimulated rats in the lung

[0442]

[0443]

[0444] + = significant change in cytokine quantification, p < 0.05 according to Student's T-test; blank cells indicate results are not statistically significant.

[0445] Example B3: Reduction of pro-inflammatory cytokine expression in macrophage-like cell cultures.

[0446] Inflammation plays a crucial role in disease progression and is a complex phenomenon involving various cells that affect many extracellular and intracellular signaling pathways and the production of cytokines. Macrophages are tissue-resident or infiltrating immune cells that are essential for innate immunity, normal tissue development, homeostasis, and the repair of damaged tissues. Activated macrophages are involved in the development of systemic and peripheral inflammation in response to toxic exogenous substances (such as LPS) or endogenous substances. Here, we used THP-1 cells as an in vitro cell model to evaluate the mechanisms associated with systemic and peripheral inflammation. Differentiation using PMA led to the acquisition of functional and morphological similarities of THP-1 monocytes to macrophages. LPS interacted with THP-1 differentiated macrophages through Toll-like receptor 4, triggering an inflammatory response and stimulating the release of pro-inflammatory cytokines, ultimately leading to cell death. Here, we investigated whether the test compound had an anti-inflammatory effect on LPS-challenged macrophage cultures. THP-1 differentiated macrophages were treated with the test compound for 20 minutes, followed by a 24-hour LPS challenge. Then, the culture supernatants were collected and analyzed for the presence of pro-inflammatory cytokines: interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α).

[0447] Cytokines in the cell culture supernatants were quantified using a homogeneous time resolved fluorescence (HTRF) kit to evaluate the levels of IL-1β (human IL-1β kit, #62HIL1BPEG, Cisbio) and IL-6 (human IL-6 kit, 62HIL06PET, Cisbio), and the level of TNF-α (human TNF-α ELISA kit, KHC3011, ThermoFisher) was determined by ELISA.

[0448] Data analysis was performed using Prism statistical software (GraphPad) by one-way ANOVA and Tukey's post hoc test compared to LPS-treated cultures. Tabular data indicated a significant reduction in the culture supernatants of the indicated analytes at the indicated doses.

[0449] The results are shown in Table 7. Treatment with compounds 1a, 5a, 6a, and the A19 active metabolite (ATH-1001) significantly reduced the expression of IL-1β and TNF-α at at least one test dose. Treatment with compounds 1a, 5a, and the A19 active metabolite significantly reduced the expression of IL-6 at at least one test dose. "NS" indicates no significant reduction in the indicated cytokine. "+" indicates a p-value < 0.05 in Tukey's post hoc test. "++" indicates a p-value < 0.01 in Tukey's post hoc test.

[0450] Table 7: Significantly reduced expression of pro-inflammatory cytokines in THP-1 immune cells in vitro

[0451]

[0452] Example B4: Reduction of streptozotocin-induced inflammatory cytokines in response to compound treatment.

[0453] Administration of streptozotocin, a chemotherapeutic agent with specific toxic effects on pancreatic islet cells, produces a severe systemic inflammatory response in animals. Streptozotocin enters pancreatic β-cells via glucose transporters, disrupts the function of these cells through cross-linking in DNA, and produces uncontrolled hyperglycemia. This condition leads to the induction of strong chronic inflammatory pathways and is a widely used model of peripheral inflammation associated with diabetic manifestations.

[0454] To evaluate the ability of test compounds to mitigate systemic inflammation in a streptozotocin-diabetes model in Sprague Dawley rats, the disease was induced on day 0 of the study by a single intravenous dose of streptozotocin (STZ, 55 mg / kg), and diabetes induction was confirmed on day 4 by estimating blood glucose levels. Rats with blood glucose levels higher than 200 mg / dl were considered successfully induced and included in the study. Treatment with the test compound was initiated on day 15 of the study and continued as a single daily dose via oral gavage (PO) until day 28 of the study, at which time plasma was collected for cytokine expression analysis.

[0455] Cytokines were quantified using a Luminex multiplex detection system with a bead capture detection system (ProcartaPlex, ThermoFisher, catalog number: PPX-090MXKA44V). Each analyte was quantified according to a standard curve, and the abundance in plasma was measured in pg / ml. Interferon γ (IFN-γ) and interleukin 4 (IL-4) were strongly upregulated upon STZ stimulation and decreased upon treatment with the test compound. IFN-γ is expressed in response to other pro-inflammatory cytokines and promotes inflammation by activating the JAK / STAT signaling pathway. IL-4 is a pro-inflammatory cytokine that activates several types of inflammatory macrophages. Thus, the reduced expression of these analytes represents a reduction in the disease-induced inflammatory response. Statistical analysis was performed by one-way ANOVA, followed by Dunnett's multiple comparison post hoc test against untreated disease controls.

[0456] In this study, three test compounds were evaluated: Compound 1a, Compound 5a, and Compound 6a. The results are summarized in Table 8. Treatment with Compound 1a at doses of 8 and 16 mg / kg daily significantly reduced the expression of IFN-γ and IL-4. Treatment with Compound 5a at a dose of 20 mg / kg daily reduced the expression of IFN-γ and IL-4. Treatment with Compound 6a at a dose of 10 mg / kg daily reduced the expression of IFN-γ and IL-4. These results indicate that the indicated test compounds have the ability to alleviate peripheral inflammation caused by chronic hyperglycemia.

[0457] Table 8: Reduction of plasma cytokines in STZ-induced rats after treatment with the indicated test compounds daily

[0458]

[0459] Statistical outliers were identified by the ROUT method (Q = 1%) and removed prior to statistical analysis. Statistical analysis included one-way ANOVA and Dunnett's multiple comparison post-test against untreated STZ disease controls. ++ = p < 0.01, +++ = p < 0.001, ++++ = p < 0.0001

[0460] Example B5: Reduction of pro-inflammatory cytokine expression in a LPS-induced inflammatory mouse model.

[0461] Administration of bacterial lipopolysaccharide (LPS) induces an inflammatory response and stimulates the release of pro-inflammatory cytokines, and ultimately leads to cell death. In this study, the ability of Compound A19 to alleviate systemic inflammation in a LPS inflammatory model of 8- to 10-week-old male C57B / 6N mice was evaluated.

[0462] The study design was as follows:

[0463] Table 9. Study design for LPS-induced inflammation

[0464]

[0465] IP – Intraperitoneal, LPS – Lipopolysaccharide, QD – Once daily, SC – Subcutaneous, WFI – Water for injection

[0466] Animals in Groups 1 and 2 served as control groups and received vehicle (saline - 0.9% NaCl). Starting from Day 0 (D0), animals in both groups were treated via the subcutaneous (SC) route at 10 mL / kg once daily (QD). All animals in Group 1 were treated continuously for 4 days, while the first 16 animals in Group 2 received a single dose, the next 8 animals were treated continuously for 2 days, and the remaining 8 animals were treated continuously for 4 days. Before dosing, the animals were weighed and the amount of vehicle administered was adjusted according to the individual body weight.

[0467] The test compound A19 was dissolved in saline (0.9% NaCl) at pH 7.4 - 7.7 and prepared at final concentrations of 0.125, 0.5, and 1.25 mg / kg for groups 3 - 5. Starting from D0, the animals in groups 3 - 5 were treated with compound A19 at 0.125, 0.5, or 1.25 mg / kg once daily (QD) via the subcutaneous (SC) route at 10 mL / kg. The first 16 animals in each group received a single dose treatment, the next 8 animals were treated for two consecutive days, and the remaining 8 animals were treated for 4 consecutive days. Before dosing, the animals were weighed and the administered amount was adjusted according to the individual body weight.

[0468] Twenty minutes after the first administration of compound A19, a single dose of 5 mg / kg of LPS (from Escherichia coli 0111:B4) was administered intraperitoneally (IP) at 10 mL / kg to the animals in groups 2 - 5. Group 1 served as the control and received an equal volume of water for injection (WFI). Before dosing, the animals were weighed and the administered amount of LPS was adjusted according to the individual body weight.

[0469] At the predetermined time points after the LPS challenge, the animals were euthanized and blood was collected by carotid exsanguination under anesthesia with ketamine hydrochloride and xylazine. Serum samples were then separated by centrifugation. Brain and liver sampling was also performed (data not shown). Eight animals in groups 2 - 5 were sampled at each time point as follows: 1.5 h, 6 h, 24 h, and 72 h, while the control animals in group 1 were sampled only at 72 h after the challenge (20 min after the last dosing).

[0470] Blood samples were collected in labeled tubes containing protease inhibitor (8:1 v / v; whole blood: protease inhibitor - without EDTA) and allowed to stand for 30 min after collection to clot. After clotting, the samples were centrifuged at 2500×g for 15 min at 21 - 22 °C, aliquoted into a set of aliquots, snap - frozen, and stored at - 80 °C until multiplex cytokine analysis. At 72 h after the challenge (20 min after the last dosing), an additional 20 μL of serum was isolated from groups 3 - 5, snap - frozen, and used for cytokine analysis.

[0471] According to the manufacturer's instructions, Invitrogen Immune Monitoring 48 - Plex Mouse ProcartaPlex was used TMThe Panel kit quantifies cytokines by multiplex analysis and calculates the quantity by interpolation of a standard curve. The panel determines the levels of certain cytokines, chemokines, growth factors / regulators, and soluble receptors. The factors include pro-inflammatory and anti-inflammatory molecules and other molecules. The cytokines, chemokines, growth factors / regulators, and soluble receptors tested are 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-33, LIF, M-CSF, RANKL, and TNFα; Chemokines: ENA-78 (CXCL5), Eotaxin (CCL11), GROα (CXCL1), IP-10 (CXCL10), MCP-1 (CCL2), MCP-3 (CCL7), MIP-1α (CCL3), MIP-1β (CCL4), MIP-2, and RANTES (CCL5); Growth factors / regulators: Betacellulin (BTC), Leptin, and VEGF-A; and Soluble receptors: IL-2R, IL-7Rα, IL-33R (ST2).

[0472] As shown in Table 10, at 1.5 hours after LPS administration, the levels of the inflammatory mediators BAFF, G-CSF, ENA-78, Eotaxin, IL-2R, LIF, MIP-1Beta, and MIP-1α in mice treated with compound A19 at 1.5 mg / kg were significantly reduced compared to LPS animals treated with vehicle. Mice treated with compound A19 at 0.125 mg / kg also showed significantly reduced levels of G-CSF and ENA-78 at this time. At 6 hours after LPS administration, the levels of BAFF, ENA-78, and IL-2R were still lower compared to LPS-treated vehicle mice. In some cases, relative to the Group 1 control, LPS challenge led to a nominal but not significant increase in the levels of inflammatory mediators, but compound A19 was able to significantly reduce these levels. These events are indicated by asterisks in Table 10. These results suggest that treatment with compound A19 reduces the increase in inflammatory mediators after LPS challenge, indicating the immunomodulatory ability of compound A19.

[0473] Table 10. Reduction of Pro-inflammatory Mediator Levels

[0474]

[0475] + = p < 0.05; ++ = p < 0.01; +++ = p < 0.001; ++++ = p < 0.0001; * = the model effect is not significant

Claims

1. A method for treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, which comprises administering an effective amount of a compound of formula (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 -; Each R a and R b is 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 arylalkyl; R 2 is H, an oxo group or a thio group; R 3 is a C2-C6 alkyl group, C3-C6 alkenyl group, C3-C6 alkynyl group, C3-C 12 cycloalkyl group, C3-C6 cycloalkylalkyl group, C6-C 10 arylalkyl group, 5- to 10-membered heteroarylalkyl group or 5- to 10-membered heterocyclicalkyl group, wherein the 5- to 10-membered heteroarylalkyl or the 5- to 10-membered heterocycloalkyl contains 1-3 heteroatoms selected from nitrogen and oxygen; R 4 is C6-C 10 aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclic group, wherein the 5- to 10-membered heteroaryl or the 5- to 10-membered heterocycle contains 1-3 heteroatoms selected from nitrogen and oxygen; Each R 5 independently is a C1-C6 alkyl group, an oxo group or a halogenated group; R 6 is H, a C1-C6 alkyl group or an oxo group; R 7 is H or an oxo group; m is 1 or 2; and n is an integer from 0 to 3; wherein 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 arylalkyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylalkyl, 5- to 10-membered heterocyclic group, and 5- to 10-membered heterocyclic group alkyl are optionally substituted with one to five substituents selected from the group consisting of hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl), and -CO2H.

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

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

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

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

6. The method according to any one of claims 1 to 5, wherein R 1a and R 1b are each independently H; C1-C6 alkyl optionally substituted with 1-3 substituents selected from halo, -CO2H and -C(=O)NH2; C1-C6 alkoxy; halo; or C6-C 10 arylalkyl optionally substituted with 1-3 substituents selected from halo and amino.

7. The method according to claim 6, wherein R 1a and R 1b are each independently H, methyl, fluoro, 2-methylbutyl, -CH2F, methoxy, -CH2CO2H, -CH2C(=O)NH2, benzyl or 4-aminobenzyl.

8. The method according to claim 6, wherein R 1a and R 1b are each independently H or C1-C3 alkyl.

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

10. The method according to claim 8, wherein R 1a and R 1b are each H.

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

12. The method according to any one of claims 1 to 10, wherein R 2 is a thio group.

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

14. The method according to any one of claims 1 to 13, wherein R 3 is C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C 12 cycloalkyl, C3-C6 cycloalkylalkyl, C6-C 10 arylalkyl, 5- to 10-membered heteroarylalkyl or 5- to 10-membered heterocycloalkylalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl or heterocycloalkylalkyl is optionally substituted with one to five substituents selected from the group consisting of: hydroxy, halo, amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cyano, -(C=O)NH2, nitro, -SO2(C1-C6 alkyl) and -CO2H.

15. The method according to any one of claims 1 to 13, wherein 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; C2-C6 alkenyl; C3-C6 cycloalkylalkyl; 5- to 6-membered heteroarylalkyl; 5- to 6-membered heterocycloalkylalkyl; or C6 arylalkyl.

16. The method according to claim 15, wherein R 3 is a C2 alkyl group substituted with 1-3 substituents selected from C1-C3 alkoxy, hydroxy, -NH2 and -SO2(C1-C3 alkyl).

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

18. The method according to claim 17, wherein R 3 is:

19. The method according to any one of claims 1 to 18, wherein R 4 is a C6-C 10 aryl optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

20. The method according to claim 19, wherein R 4 is a phenyl group substituted with 1-3 substituents selected from -CF3, -OCHF2, -OH, fluorine, and chlorine.

21. The method according to claim 20, wherein R 4 is:

22. The method according to claim 21, wherein R 4 is:

23. The method according to any one of claims 1 to 18, wherein R 4 is a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

24. The method according to claim 23, wherein R 4 is a pyridyl or indolyl group optionally substituted with 1 to 3 substituents selected from halo groups, hydroxy groups, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups.

25. The method according to claim 24, wherein R 4 For 26. The method according to claim 25, wherein R 4 For 27. The method according to any one of claims 1 to 18, wherein R 4 is a 5- to 10-membered heterocyclic group optionally substituted with 1 to 3 substituents selected from halo, hydroxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

28. The method according to claim 27, wherein R 4 is an indolinyl group.

29. The method according to claim 28, wherein R 4 is 30. The method according to any one of claims 1 to 26, wherein -L-R 4 is:

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

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

33. The method according to claim 32, wherein R 5 is an oxo group or a halogen group.

34. The method according to claim 33, wherein R 5 is an oxo group or fluorine.

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

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

37. The method according to any one of claims 1 to 10, 13 to 31, 35 and 36, wherein the compound is a compound of formula (V): or a pharmaceutically acceptable salt, isotope form or stereoisomer thereof.

38. The method according to claim 37, wherein: L is -C(=O)- or -CH2-; R 1a and R 1b are independently H or a C1-C3 alkyl group optionally substituted with -CO2H; R 3 is a C4-C5 alkyl group, a C4-C5 alkenyl group or a C1-C3 alkyl group substituted by a C3-C5 cycloalkyl group; and R 4 is phenyl or pyridyl substituted by 1 to 3 substituents selected from -CF3, -OCHF2, -OH, fluorine and chlorine.

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

40. A method for treating peripheral and / or systemic inflammatory conditions in a subject in need thereof, which comprises administering an effective amount of a compound selected from the compounds in Table 1A and compound A19: and a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof.

41. The method according to any one of the preceding claims, wherein the peripheral and / or systemic inflammatory condition 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 hereditary optic neuropathy (LHON), macular degeneration, retinal degeneration, myasthenia gravis, type 2 diabetes, obesity, coronary heart disease, gout, fatty liver, seasonal allergy, chronic obstructive pulmonary disease (COPD) or endometriosis.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

69. The method according to 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, TNF-α, and IFNγ.

70. The method according to 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. The method according to any one of claims 1 to 70, wherein the peripheral and / or systemic inflammatory condition is not caused by neuroinflammation or a disease or disorder of the central nervous system.

72. The method according to any one of embodiments 1 to 71, wherein the peripheral and / or systemic inflammatory condition is not caused by Alzheimer's disease, mild cognitive impairment, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, or sensorineural hearing and vision loss.

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

74. The method according to any one of embodiments 1 to 70, 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 sensorineural hearing and vision loss.

75. The method according to any one of embodiments 1 to 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 and vision loss, or a disease or disorder of the central nervous system.

76. The method according to any one of the preceding claims, wherein the compound is formulated in a pharmaceutical composition.

Images