Bicyclic pyrrolotriazolone compounds and methods of use thereof

Abstract

Some embodiments of the invention provide compounds having the general formula (I): wherein R 1 , R 2 , R 3a , and R 3b are as described herein; also provided are pharmaceutical compositions comprising the compounds, and uses of the compounds in methods of treating diseases.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 791,118, filed January 11, 2019, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This invention relates to organic compounds that can be used for treatment and / or prevention in subjects, and more particularly to RIP1 kinase inhibitors that can be used to treat diseases and disorders associated with inflammation, cell death and other related conditions. Background Technology

[0004] Receptor-interacting protein-1 (“RIP1”) kinase is a serine / threonine protein kinase. RIP1 is a cell signaling regulator involved in mediating programmed cell death pathways, particularly necrosis. While the best-studied form of necrotizing cell death is induced by TNF α (tumor necrosis factor), necrosis can also be induced by other members of the TNF α death ligand family (Fas and TRAIL / Apo2L), interferon, Toll-like receptor (TLR) signaling, and viral infection via the DNA sensor DAI (DNA-dependent interferon regulator activator) [1-3]. TNF α binding to TNFR1 (TNF receptor 1) promotes TNFR1 trimerization and the formation of an intracellular complex, namely complex-I. TRADD (TNF receptor-associated death domain protein) binds to the intracellular death domain of TNFR1 and recruits the protein kinase RIP1 (receptor-interacting protein 1) via the death domain present in both proteins [4]. After initial recruitment to the TNFR1-associated signaling complex, RIP1 translocates to a second cytoplasmic complex, namely complex-II [5-7]. Complex II is formed by the protein FADD (Fas-associated protein), which contains a death domain, RIP1, cysteine ​​protease-8, and cFLIP. If cysteine ​​protease-8 is not fully activated or its activity is blocked, protein kinase RIP3 is recruited to the complex to form the necrosis complex, which triggers necrotizing cell death [8-10]. Once the necrosis complex is formed, RIP1 and RIP3 immediately participate in a series of autophosphorylation and crossphosphorylation events that are essential for necrotizing cell death. Necrosis can be inactivated by mutations in either of the two kinases, or chemically blocked by either a RIP1 kinase inhibitor (necrostatin) or a RIP3 kinase inhibitor [11-13]. Phosphorylation of RIP3 allows for the binding and phosphorylation of a key component of necrotizing cell death—the pseudokinase MLKL (mixed lineage kinase domain-like) [14,15].

[0005] Necrosis is pathophysiologically critical for myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory bowel disease, retinal degeneration, and many other common clinical disorders

[16] . Therefore, selective inhibitors of RIP1 kinase activity are needed as potential treatments for diseases mediated by this pathway and associated with inflammation and / or necrotic cell death.

[0006] RIP1 kinase inhibitors have been described previously. The first publicly disclosed inhibitor of RIP1 kinase activity was necroptosis inhibitor 1 (Nec-1)

[17] . Following its initial discovery, modified forms of Nec-1 were found to possess various abilities to block RIP1 kinase activity [11,18]. Recently, additional RIP1 kinase inhibitors that are structurally different from necroptosis inhibitors have been described [19,20,21,22].

[0007] The references cited above are each incorporated into this paper in their entirety through citation:

[0008] 1)Vanden Berghe,T.,Linkermann,A.,Jouan-Lanhouet,S.,Walczak,H.andVandenabeele,P.(2014)Regulated necrosis: the expanding network of non-apoptotic cell death pathways.Nat.Rev.Mol.Cell Biol.15,135-147.

[0009] 2) Newton, K. (2015) RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends Cell Biol. 25, 347-353.

[0010] 3) de Almagro, MC and Vucic, D. (2015) Necroptosis: Pathway diversity and characteristics. Semin. Cell Dev. Biol. 39, 56-62.

[0011] 4)Chen,ZJ(2012)Ubiquitination in signaling to and activation ofIKK.Immunological reviews.246,95-106.

[0012] 5)O'Donnell,M.A.,Legarda-Addison,D.,Skountzos,P.,Yeh,W.C.and Ting,A.T.(2007)Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling.Curr.Biol.17,418-424.

[0013] 6)Feoktistova,M.,Geserick,P.,Kellert,B.,Dimitrova,D.P.,Langlais,C.,Hupe,M.,Cain,K.,MacFarlane,M.,Hacker,G.and Leverkus,M.(2011)cIAPs blockRipoptosome formation,a RIP1 / caspase-8 containing intracellular cell deathcomplex differentially regulated by cFLIP isoforms.Mol.Cell 43,449-463.

[0014] 7)Bertrand,M.J.,Milutinovic,S.,Dickson,K.M.,Ho,W.C.,Boudreault,A.,Durkin,J.,Gillard,J.W.,Jaquith,J.B.,Morris,S.J.and Barker,P.A.(2008)cIAP1 andcIAP2 facilitate cancer cell survival by functioning as E3 ligases thatpromote RIP1 ubiquitination.Mol.Cell 30,689-700.

[0015] 8)Wang,L.,Du,F.and Wang,X.(2008)TNF-alpha induces two distinctcaspase-8 activation pathways.Cell 133,693-703.

[0016] 9)He,S.,Wang,L.,Miao,L.,Wang,T.,Du,F.,Zhao,L.and Wang,X.(2009)Receptor interacting protein kinase-3 determines cellular necrotic responseto TNF-alpha.Cell 137,1100-1111.

[0017] 10)Cho,Y.S.,Challa,S.,Moquin,D.,Genga,R.,Ray,T.D.,Guildford,M.andChan,F.K.(2009)Phosphorylation-driven assembly of the RIP1-RIP3complexregulates programmed necrosis and virus-induced inflammation.Cell 137,1112-1123.

[0018] 11)Degterev,A.,Hitomi,J.,Germscheid,M.,Ch'en,I.L.,Korkina,O.,Teng,X.,Abbott,D.,Cuny,G.D.,Yuan,C.,Wagner,G.,Hedrick,S.M.,Gerber,S.A.,Lugovskoy,A.and Yuan,J.(2008)Identification of RIP1 kinase as a specific cellulartarget of necrostatins.Nat.Chem.Biol.4,313-321.

[0019] 12)Newton,K.,Dugger,D.L.,Wickliffe,K.E.,Kapoor,N.,de Almagro,M.C.,Vucic,D.,Komuves,L.,Ferrando,R.E.,French,D.M.,Webster,J.,Roose-Girma,M.,Warming,S.and Dixit,V.M.(2014)Activity of protein kinase RIPK3 determineswhether cells die by necroptosis or apoptosis.Science 343,1357-1360.

[0020] 13)Kaiser,W.J.,Sridharan,H.,Huang,C.,Mandal,P.,Upton,J.W.,Gough,P.J.,Sehon,C.A.,Marquis,R.W.,Bertin,J.and Mocarski,E.S.(2013)Toll-like receptor 3-mediated necrosis via TRIF,RIP3,and MLKL.J.Biol.Chem.288,31268-31279.

[0021] 14)Zhao,J.,Jitkaew,S.,Cai,Z.,Choksi,S.,Li,Q.,Luo,J.and Liu,Z.G.(2012)Mixed lineage kinase domain-like is a key receptor interacting protein3downstream component of TNF-induced necrosis.Proc.Nat.Acad.Sci.U.S.A.109,5322-5327.

[0022] 15)Sun,L.,Wang,H.,Wang,Z.,He,S.,Chen,S.,Liao,D.,Wang,L.,Yan,J.,Liu,W.,Lei,X.and Wang,X.(2012)Mixed Lineage Kinase Domain-like Protein MediatesNecrosis Signaling Downstream of RIP3 Kinase.Cell 148,213-227.

[0023] 16)Linkermann,A.and Green,D.R.(2014)Necroptosis.N.Engl.J.Med.370,455-465.

[0024] 17)Degterev,A.,Huang,Z.,Boyce,M.,Li,Y.,Jagtap,P.,Mizushima,N.,Cuny,GD,Mitchison,TJ,Moskowitz,MAand Yuan,J.(2005)Chemical inhibitor ofnonapoptotic cell death with therapeutic potential for ischemic braininjury.Nat.Chem.Biol.1,112-119.

[0025] 18)Takahashi,N.,Duprez,L.,Grootjans,S.,Cawwels,A.,Nerinckx,W.,DuHadaway,JB,Gossens,V.,Roelandt,R.,Van Hauwermeiren,F.,Libert,C.,Declercq,W.,Callewaert,N.,Prendergast,GC,Degterev,A.,Yuan,J.andVandenabeele,P.(2012)Necrostatin-1 analogues:critical issues on thespecificity, activity and in vivo use of Cell disease experiments. Dec. 3,e437.

[0026] 19) Harris, P.A., Bandyopadhyay, D., Berger, S.B., Campobasso, N., Capriotti, C.A., Cox, J.A., Dare, L., Finger, J.N., Hoffman, S.J., Kahler, K.M., Lehr, R., Lich, J.D., Nagilla, R., Nolte, R.T., Ouellette, M.T., Pao, C.S., Schaeffer, M.C., Smallwood, A., Sun, H.H., Swift, B.A., Totoritis, R.D., Ward, P., Marquis, R.W., Bertin, J. and Gough, P.J. (2013) Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS Med. Chem. Lett. 4, 1238 - 1243.

[0027] 20) Najjar, M., Suebsuwong, C., Ray, S.S., Thapa, R.J., Maki, J.L., Nogusa, S., Shah, S., Saleh, D., Gough, P.J., Bertin, J., Yuan, J., Balachandran, S., Cuny, G.D. and Degterev, A. (2015) Structure Guided Design of Potent and Selective Ponatinib - Based Hybrid Inhibitors for RIPK1. Cell Rep. 24, 1850 - 60.

[0028] 21) International Patent Publication No. WO 2014 / 125444.

[0029] 22) International Patent Publication No. WO 2017 / 004500. Summary of the Invention

[0030] The present invention provides compounds of formula I:

[0031]

[0032] Or its medicinal salt, in which

[0033] R 1 Choose from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R) N 2. Phenyl, benzyl, 4- to 8-membered heterocyclic groups and 5- to 6-membered heteroaryl groups; wherein R 1 It bonds to the adjacent carbonyl group via a carbon atom, and R in it 1 Optionally substituted by one or two substituents selected from the group consisting of: F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R) N )2. Hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C1-C6 alkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), 5- to 6-membered heteroaryl and CH2-(5- to 6-membered heteroaryl);

[0034] Each R N Independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; or two R N It can form a 4-6 element ring with the adjacent N;

[0035] R 2 Selected from the group consisting of: phenyl, pyrazolyl and pyridinyl, each group may be unsubstituted or substituted by one to three substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano;

[0036] R 3a and R 3b Each is independently hydrogenated or halogenated; and

[0037] The compounds mentioned therein are selected from:

[0038]

[0039] Cyclopropyl(7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone;

[0040]

[0041] (2,2-Dimethyl-3-oxabicyclo[3.1.0]hexane-1-yl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone;

[0042]

[0043] 3-Hydroxy-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one;

[0044]

[0045] 3-(difluoromethoxy)-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one;

[0046]

[0047] 1-[racemic-(5S,7S)-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one;

[0048]

[0049] 1-(3-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl)azacyclobutane-1-yl)ethane-1-one;

[0050]

[0051] 3-[racemic-(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile;

[0052]

[0053] Cyclopropyl-[racemic-(5S,7S)-5-(3-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone;

[0054]

[0055] Cyclopropyl-[racemic-(7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; and

[0056]

[0057] Cyclopropyl((5S,7S)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; and

[0058]

[0059] Cyclopropyl((5R,7R)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone.

[0060] This document also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutical salt thereof, and one or more pharmaceutical carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

[0061] This article also provides oral formulations comprising a compound of formula I or a pharmaceutical salt thereof, and one or more pharmaceutical carriers or excipients, suitable for oral delivery.

[0062] This article also provides methods for treating diseases and disorders related to inflammation, cell death, and other conditions associated with RIP1 kinase.

[0063] This article also provides compounds of formula I or their pharmaceutical salts, which are used as therapeutically active substances.

[0064] This article also provides compounds of formula I or their pharmaceutical salts for the treatment of diseases or disorders selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndrome, taupathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0065] This document also provides a compound of formula I or a pharmaceutical salt thereof, or a combination thereof, according to any one of the embodiments provided herein, for the treatment of diseases or disorders selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, Tau disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0066] This article also provides a compound of formula I or a pharmaceutical salt thereof for the preparation of a medicament for the treatment of diseases or disorders selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, Tau disease, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration and demyelinating diseases.

[0067] This article also provides compounds of formula I or their pharmaceutical salts for the treatment of diseases or disorders selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, glaucoma, psoriasis, pyoderma gangrenosa, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

[0068] This document also provides a compound of formula I or a pharmaceutical salt thereof, or a combination thereof, according to any one of the embodiments provided herein, for the treatment of diseases or disorders selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, glaucoma, psoriasis, pyoderma gangrenosa, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

[0069] This article also provides a compound of formula I or a pharmaceutical salt thereof for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, glaucoma, psoriasis, pyoderma gangrenosa, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

[0070] This article also provides compounds of formula I or pharmaceutical salts thereof for the treatment of diseases or disorders selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, solid organ ischemia-reperfusion injury, delayed graft function recovery (DGF), cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS).

[0071] This document also provides a compound of formula I or a pharmaceutical salt thereof, or a combination thereof, according to any one of the embodiments provided herein, for the treatment of diseases or disorders selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, solid organ ischemia-reperfusion injury, delayed graft function recovery (DGF), cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS).

[0072] This article also provides a compound of formula I or a pharmaceutical salt thereof for the preparation of a medicament for the treatment of diseases or disorders selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, solid organ ischemia-reperfusion injury, delayed graft function recovery (DGF), cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS). Detailed Implementation

[0073] definition

[0074] As will be understood by those skilled in the art, all chemical formulas and general chemical structures provided herein should be interpreted as providing appropriate valences and chemically stable bonds between atoms. Where appropriate, substituents may be bonded to more than one adjacent atom (e.g., alkyl groups include methylene groups with two bonds).

[0075] In the chemical formulas provided in this article, "halogen" or "halogenated" refers to fluorine, chlorine, and bromine (i.e., F, Cl, B).

[0076] Unless otherwise specifically defined, alkyl refers to a straight-chain or branched C1-C alkyl group that is optionally substituted. 12Alkyl. In some embodiments, alkyl refers to C1-C6 alkyl. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. The substituted alkyl groups provided herein are substituted with one or more substituents selected from the group consisting of: halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, OH, CO2H, CO2(C1-C4 alkyl), NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl)2, S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)2, and NHSO2(C1-C4 alkyl). In some embodiments, the substituted alkyl group has one or two substituents. In some embodiments, the alkyl group is unsubstituted.

[0077] Unless otherwise specifically defined, cycloalkyl refers to optionally substituted C3-C 12 The cycloalkyl group includes fused, spirocyclic, and bridged bicyclic groups, wherein the substituents are selected from the group consisting of: halogen, cyano, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, C3-C6 cycloalkyl, phenyl, OH, CO2H, CO2(C1-C4 alkyl), NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C=O)C1-C4 alkyl, (C=O)NH(C1-C4 alkyl), (C=O)N(C1-C4 alkyl)2, S(C1-C4 alkyl), SO(C1-C4 alkyl), SO2(C1-C4 alkyl), SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)2, and NHSO2(C1-C4 alkyl). In some embodiments, the cycloalkyl group refers to a C3-C6 cycloalkyl group. In some embodiments, the C3-C6 cycloalkyl group is optionally substituted with 1 to 3 halogen atoms. In some embodiments, the C3-C6 cycloalkyl group is optionally substituted with 1 to 3 fluorine atoms. Exemplary C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 12The cycloalkyl group further includes bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl, cycloheptyl, bicyclo[4.1.0]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro[4.3]octyl, spiro[5.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, decahydronaphthyl, and spiro[5.4]decyl. Where appropriate, the cycloalkyl group may be fused with other groups so that there is more than one chemical bond between the cycloalkyl group and another ring system (e.g., the C ring of Formula I). ​​In some embodiments, the cycloalkyl group is unsubstituted.

[0078] Unless otherwise defined, a haloalkyl group refers to a straight-chain or branched C1-C group in which one or more hydrogen atoms have been halogenated. 12 Alkyl group. In some embodiments, a haloalkyl group refers to a C1-C6 haloalkyl group. In some embodiments, one to three hydrogen atoms of the haloalkyl group are halogenated. In some embodiments, each hydrogen atom of the haloalkyl group is halogenated (e.g., trifluoromethyl). In some embodiments, the haloalkyl group is as defined herein, wherein the halogen in each case is fluorine. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and pentafluoroethyl.

[0079] Unless otherwise specifically defined, an alkoxy group refers to a straight-chain or branched C1-C group in which, in each case, one or more oxygen atoms are present between two carbon atoms. 12 Alkyl group. In some embodiments, alkoxy group refers to C1-C6 alkoxy group. In some embodiments, the C1-C6 alkoxy group provided herein has one oxygen atom. Exemplary alkoxy groups include methoxy, ethoxy, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2CH2OCH2CH3, CH2OCH2CH2CH3, CH2CH2CH2OCH3, CH2OCH(CH3)2, CH2OC(CH3)3, CH(CH3)OCH3, CH2CH(CH3)OCH3, CH(CH3)OCH2CH3, CH2OCH2OCH3, CH2CH2OCH2CH2OCH3, and CH2OCH2OCH2OCH3.

[0080] Unless otherwise specifically defined, cycloalkoxy refers to C4-C as defined above. 10 Or a C4-C6 alkoxy group, wherein the group is cyclic and contains one oxygen atom. Exemplary cycloalkoxy groups include oxetane, tetrahydrofuran, and tetrahydropiperanyl.

[0081] Unless otherwise specifically defined, a haloalkoxy group refers to a C1-C6 haloalkyl group as defined above, wherein in each case there is one or two oxygen atoms between the two carbon atoms. In some embodiments, the C1-C6 haloalkoxy groups provided herein have one oxygen atom. Exemplary haloalkoxy groups include OCF3, OCHF2, and CH2OCF3.

[0082] Unless otherwise specifically defined, thioalkyl refers to C1-C as defined above. 12 Or a C1-C6 alkoxy group, wherein the oxygen atom is replaced by a sulfur atom. In some embodiments, the thioalkyl group may include a sulfur atom substituted with one or two oxygen atoms (i.e., alkyl sulfones and alkyl sulfoxides). Exemplary thioalkyl groups are groups exemplified in the above definition of alkoxy groups, wherein in each case each oxygen atom is replaced by a sulfur atom.

[0083] Unless otherwise specifically defined, thiocycloalkyl refers to C4-C as defined above. 10 Or a C4-C6 thioalkyl group, wherein the group is cyclic and contains one sulfur atom. In some embodiments, the sulfur atom of the thiocycloalkyl group is substituted with one or two oxygen atoms (i.e., cyclic sulfones or sulfoxides). Exemplary thiocycloalkyl groups include thiocyclobutane, thiocyclopentane, thiocyclohexane, 1,1-di-side-oxythiocyclopentane, and 1,1-di-side-oxythiocyclohexane.

[0084] Unless otherwise specifically defined, a heterocyclic group refers to a single saturated or partially unsaturated 4- to 8-membered ring having at least one atom other than carbon, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; the term also includes multi-condensed ring systems having at least one such saturated or partially unsaturated ring having 7 to 12 atoms, as further described below. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, 7-, or 8-membered ring) having about 1 to 7 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be C-branched (i.e., substituted with C1-C4 alkyl groups). The ring may be substituted with one or more (e.g., 1, 2, or 3) side oxygen groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Exemplary heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, tetrahydrofuranyl, and piperidinyl. Where valence requirements permit, the rings of a multi-condensed ring system may be connected to each other via fusion, spirolysis, and bridging bonds. It should be understood that the individual rings of a polycyclic ring system can be connected in any order relative to each other. It should also be understood that the attachment points of a polycyclic ring system (as defined above for heterocycles) can be at any position within the polycyclic ring system. Furthermore, it should be understood that the attachment points of a heterocycle or a heterocyclic polycyclic ring system can be at any suitable atom of the heterocyclic group, including carbon and nitrogen atoms. Exemplary heterocycles include (but are not limited to) azahexylpropenyl, azahexylbutyl, pyrrolidyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazine, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropiperanyl, tetrahydrothiopiperanyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazine, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzo-m-dioxacyclopentenyl, 1,4-benzodioxyl, spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptyl, imidazolide -2-one N-methylpiperidine, imidazoline, pyrazolidine, butyrolactam, valproic acid, imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperan, 3-pyrrololine, thiopiperanone, piperanone, tetrahydrothiophene, quinine ring, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidone-2-one.

[0085] In some embodiments, the heterocyclic group is a C4-C heteroatom having one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. 10Heterocyclic group. In some embodiments, the heterocyclic group is neither bicyclic nor spirocyclic. In some embodiments, the heterocyclic group is a C5-C6 heterocyclic group having 1 to 3 heteroatoms, wherein if 3 heteroatoms are present, at least 2 are nitrogen.

[0086] Unless otherwise specifically defined, aryl refers to a single all-carbon aromatic ring or an all-carbon polycyclic condensation ring system in which at least one ring is an aromatic ring and the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl. Aryl also includes polycyclic condensation ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), in which at least one ring is an aromatic ring and the other rings may be aromatic or non-aromatic (i.e., carbocyclic). Such polycyclic condensation ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) side oxygen groups on any carbocyclic portion of the polycyclic condensation ring system. Where valence requirements permit, the rings of the polycyclic condensation ring system may be connected to each other via fusion, spirolysis, and bridging bonds. It should be understood that the attachment point of a polycyclic condensation ring system as defined above can be at any location in the ring system, including the aromatic or carbocyclic portion of the ring. Exemplary aryl groups include phenyl, indene, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracene, and similar groups.

[0087] Unless otherwise specifically defined, a heteroaryl refers to a 5- to 6-membered aromatic ring having at least one atom other than carbon, wherein the atom is selected from the group consisting of oxygen, nitrogen, and sulfur; "heteroaryl" also includes a polycondensed ring system having 8 to 16 atoms having at least one such aromatic ring, which is further described below. Thus, "heteroaryl" includes a single aromatic ring having about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized forms, provided that the ring is an aromatic ring. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "Heteroaryl" also includes multi-cyclic condensation systems (e.g., cyclic systems comprising 2 or 3 rings), wherein the heteroaryl group as defined above condenses with one or more rings selected from: heteroaryl (forming, for example, naphthidyl, such as 1,8-naphthidyl), heterocycle (forming, for example, 1,2,3,4-tetrahydronaphthidyl, such as 1,2,3,4-tetrahydro-1,8-naphthidyl), carbocyclic (forming, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (forming, for example, indazole), forming a multi-cyclic condensation system. Thus, a heteroaryl group (single aromatic ring or multi-cyclic condensation system) has 1 to 15 carbon atoms and about 1 to 6 heteroatoms within the heteroaromatic ring. Such multi-cyclic condensation systems may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) side oxygen groups on the carbocyclic or heterocyclic portion of the condensation ring. Where valence requirements permit, the rings of the multi-cyclic condensation system may be connected to each other via fusion, spirolysis, and bridging bonds. It should be understood that the individual rings of a polycyclic condensation system can be connected in any order relative to each other. It should also be understood that the attachment point of a polycyclic condensation system (as defined above for heteroaryl groups) can be at any position within the polycyclic condensation system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portion of the polycyclic condensation system. Furthermore, it should be understood that the attachment point of a heteroaryl or heteroaryl polycyclic condensation system can be at any suitable atom within the heteroaryl or heteroaryl polycyclic condensation system, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiophenyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzooxazolyl, indazole, quinoxolinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzoimidazolyl, thiaindyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropano[3,4]cyclopentano[1,2-c]pyrazole.

[0088] As used in this article, the term "opposites" refers to molecules that do not overlap with their mirror image counterparts, while the term "non-opposites" refers to molecules that overlap with their mirror image counterparts.

[0089] As used herein, the term “stereoisomer” refers to a compound that has a consistent chemical composition but differs in the spatial arrangement of its atoms or groups.

[0090] As used in this article, the waveform lines that intersect with one bond in the chemical structure. Indicates the attachment point of a wave-shaped bond in a chemical structure where it intersects with the rest of the molecule.

[0091] As used herein, the term "C-link" refers to the group described by the term being attached to the rest of the molecule via a ring carbon atom.

[0092] As used herein, the term “N-link” refers to the group described by the term being attached to the rest of the molecule via a cyclic nitrogen atom.

[0093] "Diabeta-isomers" are stereoisomers that have two or more diastereomeric centers and whose molecules are not mirror images of each other. Diabeta-isomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical procedures such as electrophoresis and chromatography.

[0094] "Enantiomers" refer to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0095] Stereochemical definitions and conventions used herein generally follow those of SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or enantiomeric centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of this invention form part of this invention, including but not limited to diastereomers, enantiomers, and transisomers, as well as mixtures thereof, such as racemic mixtures. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its enantiomeric center. The prefixes d and l or (+) and (-) are used to specify the direction in which the compound rotates plane-polarized light, where (-) or 1 indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or processes where there is no stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0096] When the bonds in the compound formulas herein are drawn in a non-stereochemical manner (e.g., flat), the atoms bonded to the bonds include all stereochemical possibilities. When the bonds in the compound formulas herein are drawn in a defined stereochemical manner (e.g., bold, bold-wedge, dashed, or dashed-wedge), it should be understood that, unless otherwise stated, the atoms bonded to the stereochemical bonds are enriched in the depicted absolute stereoisomers. In one embodiment, the compound may be at least 51% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 80% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 90% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 95% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 97% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 98% of the depicted absolute stereoisomers. In another embodiment, the compound may be at least 99% of the depicted absolute stereoisomers.

[0097] As used herein, the terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via a low-energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enine isomerization. Valence tautomers include interconversions through a rearrangement of some bonding electrons.

[0098] As used herein, the term "solvent" refers to the association or complex of one or more solvent molecules with the compounds of the present invention. Examples of solvents that form solvates include (but are not limited to) water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. In some embodiments, the hydrates of the compounds provided herein are ketone hydrates.

[0099] As used herein, the term "protecting group" refers to a substituent commonly used to block or protect a specific functional group on a compound. For example, an "amino protecting group" is a substituent attached to an amino group in a compound that blocks or protects the amino functional group. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzoxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a hydroxyl substituent that blocks or protects the hydroxyl functional group. Suitable protecting groups include acetyl and silyl groups. A "carboxyl protecting group" refers to a carboxyl substituent that blocks or protects the carboxyl functional group. Common carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfinyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and similar groups. For an overview of protecting groups and their use, see PGMWuts and TWGreene, Greene's Protective Groups in Organic Synthesis, 4th edition, Wiley-Interscience, New York, 2006.

[0100] As used herein, the term “mammal” includes (but is not limited to) humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cattle, pigs, and sheep.

[0101] As used in this article, the term “subject” includes (but is not limited to) mammals.

[0102] As used herein, the term "pharmaceutical salt" refers to a salt of an active compound prepared with a relatively non-toxic acid or base, depending on the specific substituents found on the compound described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of the desired base in a solvent-free environment or in a suitable inert solvent. Examples of salts derived from pharmaceutical inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, and the like. Salts derived from pharmaceutical organic bases include salts of primary, secondary, and tertiary ammonia, including substituted ammonia, cyclic ammonia, naturally occurring ammonia, and analogues such as arginine, betaine, caffeine, choline, N,N'-diphenylmethylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, thiocyanate, and analogues. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid in a solvent-free environment or in a suitable inert solvent. Examples of pharmaceutical acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid and their analogues; and salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and their analogues. Also included are salts of amino acids such as arginine salts and their analogues, and salts of organic acids such as glucuronic acid or galacturonic acid and their analogues (see, for example, Berge, SM et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain basic and acidic functional groups that allow the compounds to become base addition salts or acid addition salts.

[0103] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from many salts in certain physical properties, such as solubility in polar solvents, but in other respects, for the purposes of this invention, such salts are equivalent to the parent form of the compound.

[0104] In addition to salt forms, the present invention provides compounds in prodrug form. As used herein, the term "prodrug" refers to a compound that readily undergoes chemical changes under physiological conditions to yield the compounds of the present invention. Furthermore, prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biological methods. For example, when placed in a percutaneous patch reservoir with a suitable enzyme or chemical reagent, a prodrug can be slowly converted into the compounds of the present invention.

[0105] The prodrugs of this invention comprise compounds in which a polypeptide chain of amino acid residues or two or more (e.g., two, three, or four) amino acid residues is covalently bonded to a free amino, hydroxy, or carboxylic acid group of a compound of this invention via an amide or ester bond. The amino acid residues include, but are not limited to, 20 naturally occurring amino acids, which are generally named with three-letter symbols and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosin, isodesmosin, γ-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, pepsinine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, valine, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, methylalanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

[0106] Additional types of prodrugs are also covered. For example, the free carboxyl group of the compounds of the present invention can be derived into an amide or alkyl ester. As another example, the compounds of the present invention containing a free hydroxyl group can be derived into prodrugs by converting the hydroxyl group into a group such as, but not limited to, a phosphate ester group, a hemisuccinate group, a dimethylaminoacetate group, or a phosphoryloxymethoxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Also included are urethane prodrugs containing hydroxyl and amino groups, as well as carbonate prodrugs, sulfonates, and sulfates containing hydroxyl groups. Also covered are hydroxyl groups derived into (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may be an alkyl ester optionally substituted with a group including (but not limited to) ether, amino, and carboxylic acid functional groups, or wherein the acyl group is an amino acid ester as described above. This type of prodrug is described in J. Med. Chem., (1996), 39:10. More specific examples include hydrogen atoms in alcohol groups via structures such as (C 1-6 )alkyl oxymethyl, 1-((C 1-6 )alkylyloxy)ethyl, 1-methyl-1-((C 1-6)alkylyloxy)ethyl, (C 1-6 )alkoxycarbonyloxymethyl, N-(C 1-6 Alkoxycarbonylaminomethyl, succinyl, (C 1-6 ) alkyl acyl group, α-amino (C 1-4 Substitution of alkyl, aromatic, and α-aminoacyl or α-aminoacyl-α-aminoacyl groups, wherein each α-aminoacyl group is independently selected from naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C)2, ... 1-6 Alkyl group or glycosyl group (a group produced by removing the hydroxyl group from the hemiacetal form of a carbohydrate).

[0107] For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309–396, edited by K. Widder et al., (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, “Design and Application of Prodrugs”, H. Bundgaard, pp. 113–191, (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1–38 (1992); d) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N. Kakeya et al., Chem. Pharm. Bull., 32:692 (1984), are each expressly incorporated herein by reference.

[0108] Furthermore, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced in vivo by the metabolism of a specified compound or its salt. Such products can be produced by, for example, oxidation, reduction, hydrolysis, acylation, deacylation, esterification, deesterification, enzymatic cleavage, and similar processes of the compound.

[0109] Metabolite products are typically identified by the following: radioactive isotope labeling used to prepare the compounds of this invention (e.g., 14 C or 3H) isotopes are administered non-enterally to animals such as rats, mice, guinea pigs, monkeys, or humans at detectable doses (e.g., exceeding about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and for the metabolites to be separated from urine, blood, or other biological samples. These products are readily separated because they are labeled (by using antibodies capable of binding to antigenic determinants remaining in the metabolites to separate other products). The metabolite structure is determined in a conventional manner, for example by MS, LC / MS, or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. The metabolite products are suitable for diagnostic analysis of therapeutic administration of the compounds of the present invention, provided that they are not otherwise found in vivo.

[0110] Some of the compounds of this invention may exist in both unsolvated and solvated forms, including hydrated forms. Generally, the solvated form is equivalent to the unsolvated form and is intended to be covered within the scope of this invention. Some of the compounds of this invention may exist in various crystalline or amorphous forms. Generally, all physical forms are used equivalently for the purposes covered by this invention and are intended to be within the scope of this invention.

[0111] Some of the compounds of this invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., single enantiomers) are all intended to be covered within the scope of this invention.

[0112] As used herein, the term "composition" is intended to cover products containing specified amounts of specified ingredients, and any products produced directly or indirectly from combinations of specified amounts of specified ingredients. "Pharmaceutical" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and harmless to its recipient.

[0113] The terms "treat" and "treatment" refer to therapeutic treatment and / or preventive treatment or preventive measures in which the goal is to prevent or slow (mitigate) undesirable physiological changes or conditions, such as the onset or spread of cancer. For the purposes of this invention, beneficial or desired clinical outcomes include (but are not limited to) relief of symptoms, reduction of the severity of the disease or condition, stabilization of the state of the disease or condition (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease or condition, and symptom relief (whether partial or overall), whether detectable or undetectable. "Treatment" may also refer to prolonged survival compared to expected survival without treatment. Those in need of treatment include those who already have the disease or condition, those who are prone to developing the disease or condition, or those who wish to prevent the disease or condition.

[0114] The phrase “therapeutic effective amount” or “effective amount” refers to the amount of the compound of the present invention that (i) treats or prevents the specific disease, symptom, or disorder described herein, (ii) reduces, improves, or eliminates one or more symptoms of the specific disease, symptom, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the specific disease, symptom, or disorder. For cancer therapies, efficacy can be measured, for example, by assessing time to disease progression (TTP) and / or determining response rate (RR).

[0115] The term "bioavailability" refers to the rate at which a given amount of drug is utilized throughout a patient's body (i.e., blood / plasma levels). Bioavailability is an absolute term that measures the time (rate) and total amount of a drug from its administered dosage form into the overall circulation.

[0116] RIP1 kinase inhibitors

[0117] Some embodiments of the present invention provide compounds having the general formula (I):

[0118]

[0119] Or its medicinal salt, in which

[0120] R 1 Choose from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R) N 2. Phenyl, benzyl, 4- to 8-membered heterocyclic groups and 5- to 6-membered heteroaryl groups; wherein R 1 It bonds to the adjacent carbonyl group via a carbon atom, and R in it 1 Optionally substituted by one or two substituents selected from the group consisting of: F, Cl, Br, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-N(R) N )2. Hydroxyl, hydroxymethyl, cyano, cyanomethyl, cyanoethyl, C(O)C1-C6 alkyl, phenyl, benzyl, CH2-(C3-C6 cycloalkyl), 5- to 6-membered heteroaryl and CH2-(5- to 6-membered heteroaryl);

[0121] Each R N Independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; or two R N It can form a 4-6 element ring with the adjacent N;

[0122] R 2Selected from the group consisting of: phenyl, pyrazolyl and pyridinyl, each group may be unsubstituted or substituted by one to three substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and cyano;

[0123] R 3a and R 3b Each is independently hydrogenated or halogenated; and

[0124] The compounds mentioned therein are selected from:

[0125]

[0126] Cyclopropyl(7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone;

[0127]

[0128] (2,2-Dimethyl-3-oxabicyclo[3.1.0]hexane-1-yl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone;

[0129]

[0130] 3-Hydroxy-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one;

[0131]

[0132] 3-(difluoromethoxy)-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one;

[0133]

[0134] 1-[racemic-(5S,7S)-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one;

[0135]

[0136] 1-(3-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl)azacyclobutane-1-yl)ethane-1-one;

[0137]

[0138] 3-[racemic-(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile;

[0139]

[0140] Cyclopropyl-[racemic-(5S,7S)-5-(3-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone;

[0141]

[0142] Cyclopropyl-[racemic-(7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; and

[0143]

[0144] Cyclopropyl((5S,7S)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone.

[0145] In some embodiments, this document provides pharmaceutical compositions comprising a compound of formula I according to any one of the above embodiments or a pharmaceutical salt thereof, and one or more pharmaceutical carriers or excipients. Specific embodiments include pharmaceutical compositions suitable for oral delivery.

[0146] This document also provides oral formulations of the compound of formula I or a pharmaceutical salt thereof according to any one of the above embodiments, and one or more pharmaceutical carriers or excipients, which are suitable for oral delivery.

[0147] In some embodiments, this document provides the use of a compound of formula I or a pharmaceutical salt thereof according to any one of the above embodiments for the treatment of neurodegenerative diseases and disorders. In some embodiments, the diseases and disorders to be treated are synucleinopathies, such as Parkinson's disease, Lewy body dementia, multiple system atrophy, and Parkinson's plus syndrome. In some embodiments, the diseases and disorders to be treated are tau diseases, such as Alzheimer's disease and frontotemporal dementia. In some embodiments, the diseases and disorders to be treated are demyelinating diseases, such as multiple sclerosis.

[0148] In some embodiments, the diseases and disorders to be treated are such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and other neurodegenerative diseases of stroke. Additional exemplary neurodegenerative diseases for treatment as provided herein include (but are not limited to) intracranial hemorrhage, cerebral hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0149] In some embodiments, the disease or condition to be treated is Alzheimer's disease. In some embodiments, the disease or condition to be treated is Parkinson's disease. In some embodiments, the disease or condition to be treated is Huntington's disease. In some embodiments, the disease or condition to be treated is multiple sclerosis. In some embodiments, the disease or condition to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition to be treated is spinal muscular atrophy (SMA).

[0150] In some embodiments, this document provides the use of the compound of formula I or a pharmaceutical salt thereof according to any one of the above embodiments for the treatment of inflammatory diseases and disorders. In some embodiments, the disease or disorder to be treated is selected from the group consisting of: inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), psoriasis, pyoderma gangrenosa, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjögren's syndrome. Systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver damage / disease (non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage / injury (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type 1 diabetes, Wegener's granulomatosis. Granulomatosis, sarcoidosis, Behcet's disease, interleukin-1 convertase (ICE, also known as cysteine ​​protease-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO deficiency syndrome (F-κ-B essential regulatory gene (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency (also known as RBCK1 oxidized heme IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency, hematologic and solid organ malignancies, bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (especially Gaucher disease).This includes GM2, ganglioside storage diseases, alpha-mannoside hyperasthenia, asparagine glucosamineuria, cholesterol ester storage diseases, chronic hexosamine A deficiency, cystine diseases, Danon disease, Fabry disease, Farber disease, fucoside storage diseases, galactosylsialic acid storage diseases, GM1 ganglioside storage diseases, mucolipid storage diseases, infantile free sialic acid storage diseases, juvenile hexosamine A deficiency, Krabbedisease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharide storage diseases, polysulfatase deficiency, Niemann-Pick disease, neuronal cerebroid lipofuscinosis, Pompe disease, osteogenesis imperfecta, Sandhoff disease, and Schindler disease. Diseases including sialic acid storage disorders, Tay-Sachs disease, and Wolman's disease.

[0151] In some embodiments, the disease or condition to be treated is inflammatory bowel disease (IBD). In some embodiments, the disease or condition to be treated is irritable bowel syndrome (IBS). In some embodiments, the disease or condition to be treated is Crohn's disease. In some embodiments, the disease or condition to be treated is ulcerative colitis. In some embodiments, the disease or condition to be treated is glaucoma. In some embodiments, the disease or condition to be treated is psoriasis. In some embodiments, the disease or condition to be treated is pyoderma gangrenosa. In some embodiments, the disease or condition to be treated is rheumatoid arthritis. In some embodiments, the disease or condition to be treated is spondyloarthritis. In some embodiments, the disease or condition to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or condition to be treated is osteoarthritis.

[0152] In some embodiments, this document provides a method for treating or preventing a disease or ailment with a therapeutically effective amount of a compound of formula I or a pharmaceutical salt thereof, wherein the disease or ailment is associated with inflammation and / or necrosis. In some embodiments, the disease or ailment is selected from the specific diseases and ailments described herein.

[0153] In some embodiments, this document provides a method for inhibiting RIP1 kinase activity by contacting cells with a compound of formula I or a pharmaceutical salt thereof.

[0154] Pharmaceutical composition and administration

[0155] This document provides pharmaceutical compositions or agents containing compounds of the present invention (or their stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutical salts, or prodrugs) and therapeutically inert carriers, diluents, or excipients, as well as methods for preparing such compositions and pharmaceuticals using compounds of the present invention. In one example, a compound of formula I can be formulated into a galenical administration form by mixing it at ambient temperature, at a suitable pH, and at the desired purity with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dose and concentration used. The pH of the formulation depends primarily on the specific use and concentration of the compound, but preferably varies in the range of about 3 to about 8. In one example, the compound of formula I is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I is sterile. The compound can be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0156] The composition is formulated, administered, and applied in accordance with good medical practice. Factors considered in this context include the specific disease being treated, the specific subject being treated, the individual patient's clinical condition, the cause of the disease, the site of drug delivery, the method of administration, the timing of administration, and other factors known to the practicing physician. In some embodiments, the "effective amount" of the compound to be administered will depend on such considerations and the minimum amount required to inhibit RIP1 kinase activity to provide a therapeutic effect in the treated subject. Furthermore, such effective amount may be below amounts that would be toxic to normal cells or, overall, the subject.

[0157] In one instance, the pharmaceutically effective amount of each dose of the compound of the invention administered intravenously or non-enterally will be in the range of about 0.1 to 100 mg / kg, or alternatively about 0.1 to 20 mg / kg of patient body weight per day, or alternatively about 0.3 to 15 mg / kg per day.

[0158] In another embodiment, oral unit dosage forms such as tablets and capsules preferably contain about 1 to about 1000 mg (e.g., 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 100 mg, 200 mg, 250 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg) of the compound of the present invention. In some embodiments, the daily dose is given as a single daily dose or in divided doses, two to six times a day, or in a continuous release form. In the case of a 70 kg adult, the total daily dose will generally be about 7 mg to about 1,400 mg. This dosing regimen can be adjusted to provide the best therapeutic response. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily.

[0159] In some embodiments, low doses of the compounds of the present invention are administered to provide therapeutic benefits while minimizing or preventing side effects.

[0160] The compounds of the present invention can be administered by any suitable method, including oral, local (including buccal and sublingual), rectal, vaginal, percutaneous, non-intestinal, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration, and intralesional administration when local treatment is required. Non-intestinal infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the compound of formula I is administered orally. In other specific embodiments, the compound of formula I is administered intravenously.

[0161] The compounds of the present invention can be administered in any suitable form, such as lozenges, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain conventional components found in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, build-up agents, and other activators.

[0162] Typical formulations are prepared by mixing the compounds of the present invention with a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also include one or more buffers, stabilizers, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other additives known to provide an attractive presentation of a medicine (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a medicine (i.e., a drug).

[0163] Suitable carriers, diluents, and excipients are well known to those skilled in the art and include substances such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like. The specific carrier, diluent, or excipient used will depend on the manner and purpose of applying the compounds of the invention. Solvents are generally selected based on solvents deemed by those skilled in the art to be safe for administration to subjects (GRAS). Generally, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, humectants, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-blocking agents, flow aids, processing aids, colorants, sweeteners, flavorings, and other additives known to provide an attractive presentation of a medicine (i.e., the compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of a medicine (i.e., a drug).

[0164] Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to recipients at the doses and concentrations used and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexahydroxyquaternary ammonium chloride; benzyl ethoxymmonium chloride; phenol, butanol, or benzyl alcohol; alkyl p-hydroxybenzoates, such as methyl p-hydroxybenzoate or propyl p-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 1) (0 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming ions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN. TM PLURONICS TMOr polyethylene glycol (PEG). The active pharmaceutical ingredients of the present invention (e.g., compounds of formula I or examples thereof) may also be encapsulated in microcapsules prepared, for example, by coagulation techniques or by interfacial polymerization (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in crude emulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005), 21st edition, Lippincott Williams & Wilkins, Philipelphia, PA.

[0165] Sustained-release formulations of the compounds of the present invention (e.g., compounds of Formula I or examples thereof) can be prepared. Suitable examples of sustained-release formulations include semi-permeable matrices containing solid hydrophobic polymers of Formula I or examples thereof, in the form of molded articles such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid esters (Sidman et al., Biopolymers 22:547,1983), non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater. Res. 15:167,1981), and degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT. TM (Injectable microspheres composed of a lactic-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid (EP 133,988A). The sustained-release composition also includes liposome-encapsulated compounds that can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. USA 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. USA 77:4030, 1980; U.S. Patents 4,485,045 and 4,544,545; and EP 102,324A). Typically, the liposomes are small (approximately 200–800 Å) monolayers containing more than approximately 30 mol% cholesterol, the selected ratio adjusted for optimal therapeutic effect.

[0166] In one example, a compound of formula I or an embodiment thereof may be formulated into a galenate dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the dose and concentration used, at ambient temperature, at a suitable pH, and at the desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but preferably varies in the range of about 3 to about 8. In one example, the compound of formula I (or an embodiment thereof) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula I or an embodiment thereof is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0167] An example of a suitable oral dosage form provided herein is a tablet containing about 1 to about 500 mg (e.g., about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg, and 500 mg) of the compound of the present invention mixed with suitable amounts of anhydrous lactose, croscarmellose sodium, polyvinylpyrrolidone (PVP) K30, and magnesium stearate. The powdered components are first mixed together and then mixed with a PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment.

[0168] Formulations of the compounds of the present invention (e.g., compounds of Formula I or examples thereof) may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents mentioned above, according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, non-enteric-acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable mediators and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils may be commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid may also be used to prepare injectable formulations.

[0169] The amount of active ingredient that can be combined with a delivery vehicle to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a delayed-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of the active ingredient mixed with an appropriate and suitable amount of delivery vehicle, which may vary from approximately 5% to approximately 95% (by weight) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain approximately 3 to 500 μg of the active ingredient per milliliter of solution, allowing an appropriate volume to be infused at a rate of approximately 30 mL / h.

[0170] Suitable formulations for non-enteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0171] The formulations can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under lyophilized (freeze-dried) conditions, requiring only the addition of a sterile liquid carrier, such as water, for injection just before use. Injectable solutions and suspensions can be prepared from the previously described types of sterile powders, granules, and tablets.

[0172] Therefore, one embodiment includes a pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof. Another embodiment includes a pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof, together with a pharmaceutical carrier or excipient.

[0173] When the target of binding is located in the brain, certain embodiments of the invention provide compounds of formula I (or embodiments thereof) that cross the blood-brain barrier. In these embodiments, the compounds provided herein exhibit sufficient brain penetration and can serve as potential therapeutic agents in neurological diseases. In some embodiments, brain penetration is assessed by measuring, for example, the free brain / plasma ratio (B / P ratio) in an in vivo pharmacokinetic study in rodents. u / P u Or by other methods known to those skilled in the art (see, for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008).

[0174] Certain neurological disorders are associated with increased permeability of the blood-brain barrier, thus allowing compounds of formula I (or embodiments thereof) to be readily introduced into the brain. When the blood-brain barrier remains intact, several methods known in the art exist for delivering molecules across it, including (but not limited to) physical methods, lipid-based methods, and receptor- and channel-based methods. Physical methods for delivering compounds of formula I (or embodiments thereof) across the blood-brain barrier include (but are not limited to) completely bypassing the blood-brain barrier or by creating an opening in the blood-brain barrier.

[0175] Bypass methods include (but are not limited to) direct injection into the brain (see, for example, Papanastassiou et al., GeneTherapy 9:398-406, 2002), interstitial infusion / convection-enhanced delivery (see, for example, Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of the delivery device into the brain (see, for example, Gill et al., Nature Med. 9:589-595, 2003; and Gliadel Wafers). TM (Guildford).

[0176] Methods for creating openings in the barrier include (but are not limited to) ultrasound (see, for example, U.S. Patent Publication No. 2002 / 0038086), osmotic pressure (e.g., by application of hypertonic mannitol (Neuwelt, EA, Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, NY, 1989)), and permeation by, for example, bradykinin or permeabilizer A-7 (see, for example, U.S. Patents Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0177] Lipid-based methods for delivering a Formula I compound (or an embodiment thereof) across the blood-brain barrier include (but are not limited to) encapsulating a Formula I or II compound (or an embodiment thereof) in a liposome coupled with an antibody-binding fragment of a receptor bound to the vascular endothelium of the blood-brain barrier (see, for example, U.S. Patent Publication No. 2002 / 0025313) and coating a Formula I compound (or an embodiment thereof) in low-density lipoprotein particles (see, for example, U.S. Patent Publication No. 2004 / 0204354) or apolipoprotein E (see, for example, U.S. Patent Publication No. 2004 / 0131692).

[0178] Receptor- and channel-based methods for delivering a Formula I compound (or an embodiment thereof) across the blood-brain barrier include (but are not limited to) increasing the permeability of the blood-brain barrier using a glucocorticoid blocker (see, for example, U.S. Patent Publications 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533); activating potassium channels (see, for example, U.S. Patent Publication 2005 / 0089473); inhibiting ABC drug delivery proteins (see, for example, U.S. Patent Publication 2003 / 0073713); coating a Formula I or II compound (or an embodiment thereof) with transferrin and modulating the activity of one or more transferrin receptors (see, for example, U.S. Patent Publication 2003 / 0129186); and cationizing an antibody (see, for example, U.S. Patent No. 5,004,697).

[0179] For intracerebral use, in some embodiments, the compound can be administered continuously via a reservoir infused into the CNS, although rapid concentration is acceptable. The inhibitor can be administered into the ventricles or otherwise introduced into the CNS or cerebrospinal fluid. Administration can be performed using indwelling catheters and continuous administration devices (such as pumps), or it can be administered via implantation, such as an intracerebral implantation of a continuously releasing agent. More specifically, the inhibitor can be injected via a long-term implanted cannula or infused long-term with the aid of a permeable miniature vacuum pump. Subcutaneous pumps can be used, which deliver proteins to the ventricles via small tubing. Highly sophisticated pumps can be refilled through the skin, and their delivery rate can be set without surgical intervention. Examples of suitable administration protocols and delivery systems involving subcutaneous pump devices or continuous intraventricular infusion via fully implanted drug delivery systems include protocols and systems for administering dopamine, dopamine agonists, and cholinergic agonists to patients with Alzheimer's disease and animal models of Parkinson's disease, as described below: Harbaugh, J. Neural Transm., Supplement 24:271, 1987; and DeYebenes et al., Mov. Disord. 2:143, 1987.

[0180] Indications and treatment methods

[0181] In some embodiments, the compounds of the present invention inhibit RIP1 kinase activity. Therefore, the compounds of the present invention can be used to treat diseases and disorders mediated by this pathway and associated with inflammation and / or necrotic cell death.

[0182] In some embodiments, the disease or condition to be treated is a neurodegenerative disease or condition. In some embodiments, the disease or condition to be treated is a synucleinic disease, such as Parkinson's disease, Lewy body dementia, multiple system atrophy, or Parkinson's plus syndrome. In some embodiments, the disease or condition to be treated is a tau disease, such as Alzheimer's disease or frontotemporal dementia. In some embodiments, the disease or condition to be treated is a demyelinating disease, such as multiple sclerosis.

[0183] In some embodiments, the diseases and disorders to be treated are such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, and other neurodegenerative diseases of stroke. Additional exemplary neurodegenerative diseases for treatment as provided herein include (but are not limited to) intracranial hemorrhage, cerebral hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

[0184] In some embodiments, the disease or condition to be treated is Alzheimer's disease. In some embodiments, the disease or condition to be treated is Parkinson's disease. In some embodiments, the disease or condition to be treated is Huntington's disease. In some embodiments, the disease or condition to be treated is multiple sclerosis. In some embodiments, the disease or condition to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or condition to be treated is spinal muscular atrophy (SMA).

[0185] In some embodiments, the disease or condition to be treated is an inflammatory disease or condition. In some embodiments, the disease or condition to be treated is selected from the group consisting of: inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), psoriasis, pyoderma gangrenosa, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondyloarthritis, gout, systemic juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), and Sjögren's syndrome. Systemic scleroderma, antiphospholipid syndrome (APS), vasculitis, liver damage / disease (non-alcoholic steatohepatitis, alcoholic steatohepatitis, autoimmune hepatitis, autoimmune hepatobiliary disease, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxicity), kidney damage / injury (nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs such as cisplatin, acute kidney injury (AKI)), celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, solid organ ischemia-reperfusion injury, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), allergic diseases (including asthma and atopic dermatitis), multiple sclerosis, type 1 diabetes, Wegener's granulomatosis. Granulomatosis, sarcoidosis, Behcet's disease, interleukin-1 convertase (ICE, also known as cysteine ​​protease-1)-associated fever syndrome, chronic obstructive pulmonary disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO deficiency syndrome (F-κ-B essential regulatory gene (also known as IKKγ or IKKG) deficiency syndrome), HOIL-1 deficiency (also known as RBCK1 oxidized heme IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency, hematologic and solid organ malignancies, bacterial and viral infections (such as tuberculosis and influenza), and lysosomal storage diseases (especially Gaucher disease).This includes GM2, ganglioside storage diseases, alpha-mannoside hyperasthenia, asparagine glucosamineuria, cholesterol ester storage diseases, chronic hexosamine A deficiency, cystinosis, Danondisease, Fabry disease, Farber disease, fucoside storage diseases, galactosylsialic acid storage diseases, GM1 ganglioside storage diseases, mucolipid storage diseases, infantile free sialic acid storage diseases, juvenile hexosamine A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharide storage diseases, polysulfatase deficiency, Niemann-Pick disease, neuronal cerebroid lipofuscinosis, Pompe disease, osteogenesis imperfecta, Sandhoff disease, and Schindler disease. (Diseases including sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0186] In some embodiments, the disease or condition to be treated is inflammatory bowel disease (IBD). In some embodiments, the disease or condition to be treated is irritable bowel syndrome (IBS). In some embodiments, the disease or condition to be treated is Crohn's disease. In some embodiments, the disease or condition to be treated is ulcerative colitis. In some embodiments, the disease or condition to be treated is glaucoma. In some embodiments, the disease or condition to be treated is psoriasis. In some embodiments, the disease or condition to be treated is pyoderma gangrenosa. In some embodiments, the disease or condition to be treated is rheumatoid arthritis. In some embodiments, the disease or condition to be treated is spondyloarthritis. In some embodiments, the disease or condition to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or condition to be treated is osteoarthritis.

[0187] In some embodiments, the treatment methods provided herein treat one or more symptoms of the aforementioned diseases or conditions.

[0188] This document also provides the use of the compounds of the invention in therapeutic applications. In some embodiments, this document provides the use of the compounds of the invention for treating or preventing the above-mentioned diseases and conditions. This document also provides the use of the compounds of the invention for manufacturing medicaments for treating or preventing the above-mentioned diseases and conditions.

[0189] This article also provides a method for treating a subject with the disease or ailment described above that requires such treatment, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a human.

[0190] This article also provides a method for treating symptoms of a disease or disorder in a subject who requires such treatment, the disease or disorder being selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), Crohn's disease, ulcerative colitis, myocardial infarction, stroke, traumatic brain injury, atherosclerosis, ischemia-reperfusion injury of the kidney, liver and lungs, cisplatin-induced kidney injury, sepsis, systemic inflammatory response syndrome (SIRS), pancreatitis, psoriasis, pyoderma gangrenosa, retinitis pigmentosa, retinal degeneration, chronic kidney disease, acute respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD), wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0191] This article also provides a method for treating a disease or ailment in a human patient requiring such treatment, the disease or ailment being selected from the diseases or ailments provided above, wherein the method comprises orally administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in the form of an orally acceptable pharmaceutical composition.

[0192] Combination therapy

[0193] In some embodiments, the compounds of the present invention may be combined with one or more other compounds of the present invention or one or more other therapeutic agents in any combination for the treatment of the diseases and ailments described herein. For example, the compounds of the present invention may be combined with other known therapeutic agents for the treatment of diseases or ailments selected from those described above, administered simultaneously, sequentially, or alone.

[0194] As used herein, “combination” means any mixture or arrangement of one or more compounds of the present invention and one or more other compounds of the present invention or one or more additional therapeutic agents. Unless the context otherwise requires, “combination” may include the simultaneous or sequential delivery of compounds of the present invention with one or more therapeutic agents. Unless the context otherwise requires, “combination” may include a dosage form of compounds of the present invention with another therapeutic agent. Unless the context otherwise requires, “combination” may include a route of administration of compounds of the present invention with another therapeutic agent. Unless the context otherwise requires, “combination” may include a formulation of compounds of the present invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include (but are not limited to) the dosage forms, routes of administration, and pharmaceutical compositions described herein.

[0195] In some embodiments, the compounds provided herein may be combined with another therapeutic agent as described in WO 2016 / 027253, the contents of which are incorporated herein by reference in their entirety. In such embodiments, the RIP1 kinase inhibitor in the combination described in WO 2016 / 027253 is replaced with the compound of Formula I of the present invention.

[0196] In some embodiments, the compounds provided herein may be combined with DLK inhibitors for the treatment of neurodegenerative diseases and disorders, such as those listed elsewhere herein, and including, but not limited to, the following: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndrome, Alzheimer's disease, frontotemporal dementia, demyelinating diseases (such as multiple sclerosis), amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, and corticobasal degeneration. DLK inhibitors are described, for example, in WO 2013 / 174780, WO 2014 / 177524, WO 2014 / 177060, WO2014 / 111496, WO 2015 / 091889 and WO 2016 / 142310.

[0197] Example

[0198] The invention will be more fully understood by referring to the following examples. However, these examples should not be construed as limiting the scope of the invention.

[0199] These examples are intended to guide those skilled in the art in the preparation and use of the compounds, compositions, and methods of the present invention. While specific embodiments of the invention have been described, those skilled in the art will understand that many changes and modifications can be made without departing from the spirit and scope of the invention.

[0200] The chemical reactions described in the examples are readily adaptable to prepare many other compounds of the present invention, and alternative methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of compounds not described according to the present invention can be successfully carried out by modifications readily apparent to those skilled in the art, such as by appropriately protecting the interfering groups with other suitable reagents known in the art, for example by appropriately protecting the interfering groups with other suitable reagents known in the art besides the aforementioned reagents, and / or by conventional modifications to the reaction conditions.

[0201] In the following examples, all temperatures are expressed in degrees Celsius unless otherwise indicated. Commercially available reagents were purchased from suppliers such as Aldrich Chemical Company, Lancaster, TCI, or Maybridge, and were used without further purification unless otherwise indicated. The reactions described below are generally carried out under positive pressure nitrogen or argon or in a dry tube (unless otherwise specified) in anhydrous solvents, and reaction flasks are typically equipped with rubber septa for introducing the matrix and reagents via syringe. Glassware is dried and / or heat-dried. 1 ¹H NMR spectra were obtained using trimethylsilane (TMS) or residual undeuterated solvent peaks as reference standards in CDCl₃, d⁶-DMSO, CH₃OD, or d⁶-acetone solvent solutions (reported in ppm). When reporting peak multiplicity, the following abbreviations are used: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). Coupling constants are reported in Hz (Hertz).

[0202] All abbreviations used to describe reagents, reaction conditions, or equipment are intended to be used according to their definitions as set forth in the following abbreviation table. The chemical names of the discrete compounds of this invention are typically obtained using the structural naming component of the ChemDraw naming program.

[0203] abbreviation

[0204] ACN Acetonitrile

[0205] Boc tert-butyloxycarbonyl

[0206] DAST diethylaminosulfonium trifluoride

[0207] DCE 1,2-Dichloroethane

[0208] DCM dichloromethane

[0209] DMF N,N-dimethylformamide

[0210] DMSO (dimethyl sulfoxide)

[0211] DPPH 2,2-diphenyl-1-picrylhydrazine

[0212] HPLC (High-Performance Liquid Chromatography)

[0213] LCMS (Liquid Chromatography-Mass Spectrometry) analysis

[0214] PCC pyridyl chloride

[0215] RP reverse phase

[0216] RT or R T Duration of stay

[0217] SEM 2-(trimethylsilyl)ethoxymethyl

[0218] SFC supercritical fluid chromatography

[0219] TFA (trifluoroacetic acid)

[0220] THF Tetrahydrofuran

[0221] Synthesis process

[0222] In addition to the specific synthetic methods of the examples below, additional compounds of the present invention may be prepared, for example, according to the procedure of process 1, wherein R is a low-carbon alkyl group and may be the same or different each time it appears, TBS is tert-butyldimethylchlorosilyl, THP is tetrahydropiperanyl, Piv is tert-pentanoic acid ester, and R 1 and R 2 As defined in this article.

[0223] Process 1

[0224]

[0225] In step 1 of process 1, the ester compound is subjected to a strong base such as lithium bis(trimethylsilyl)amino in the presence of a base. a Treatment with acetates such as ethyl acetate yields β-keto ester compounds. b According to the invention, the group R 2 It may contain, for example, phenyl, pyridyl, pyrazolyl or other aryl or heteroaryl groups.

[0226] In step 2, compound b is reduced to form the corresponding β-hydroxy ester compound. c This reduction can be carried out using NaBH4 or a similar reducing agent.

[0227] In step 3, treatment with tert-butyldimethylchlorosilane c Formation of compounds c tert-butyl dimethyl chlorosilyl ester d .

[0228] In step 4, the ester compound d The reaction with N,O-dimethylhydroxylamine hydrochloride yields the corresponding N-methoxyamide compound. e The reaction in this step can be carried out in the presence of a Grignard reagent, such as magnesium isopropyl halide.

[0229] Next, in step 5, the N-methoxyamide compound from step 4... e The reaction with 3,5-dibromo-1-tetrahydropiperan-2-yl-1,2,4-triazole yields a triazolone compound. f3,5-Dibromo-1-tetrahydropiperan-2-yl-1,2,4-triazole is available from Sigma-Aldrich (L158747 ALDRICH) and other sources.

[0230] In step 6, the compound is treated with NaBH4 or a similar reducing agent. f Reduction was performed to obtain the corresponding hydroxyl compound g.

[0231] In step 7, pivalate ester is formed by treating compound g with pivaloyl halogen. h .

[0232] In step 8, the self-compound h Removing the tert-butyldimethylchlorosilane yields the corresponding hydroxyl compound. i .

[0233] In step 9, the compound is treated with methanesulfonyl chloride in the presence of a base. i A ring is formed, yielding a pyrrolotriazole compound. j .

[0234] In step 10, from j Removing the pentanoyl group yields the corresponding hydroxy-pyrrolotriazole compound k.

[0235] In step 11, the compound k Reaction with fluorinating agents such as diethylaminosulfonium trifluoride yields the corresponding fluoro-pyrrolotriazole compounds. m .

[0236] In step 12, the compound m The reaction with N-methoxyamide compound n yields compound n. o It is a compound of formula I according to the present invention. Group R 1 It could be, for example, cyclopropyl, or as described in this article for R. 1 Other defined groups.

[0237] Many variations of the procedure in process 1 are possible, and those skilled in the art will recognize these variations. In some embodiments, the order of the steps in process 1 may vary, and R 1 and R 2 The value can be varied as defined in this article.

[0238] Examples 1 and 2

[0239] Cyclopropyl-[(5R,7R)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[(5S,7S)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone.

[0240]

[0241] Step 1: Methyl 5-fluoropyridine-3-carboxylate

[0242]

[0243] Thionyl chloride (31 mL, 425 mmol) was added to a solution of 5-fluoronicotinic acid (40 g, 283 mmol) in methanol (200 mL). The mixture was stirred at 90 °C for 18 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate (400 mL) and washed with saturated sodium bicarbonate aqueous solution (100 mL) and brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude methyl 5-fluoropyridine-3-carboxylate (32 g, 73%) as a light brown solid.

[0244] Step 2: Ethyl 3-(5-fluoro-3-pyridyl)-3-sideoxy-propionate

[0245]

[0246] Ethyl acetate (35 mL, 358 mmol) was added to a solution of lithium bis(trimethylsilyl)amino (1.0 M tetrahydrofuran solution, 500 mL, 500 mmol) in tetrahydrofuran (500 mL) at -78 °C under a nitrogen atmosphere. After stirring for 15 minutes, methyl 5-fluoropyridinium-3-carboxylate (50 g, 322 mmol) in tetrahydrofuran (50 mL) was added dropwise. The mixture was stirred for 2 hours and quenched by adding saturated ammonium chloride aqueous solution (300 mL). The resulting solution was extracted with ethyl acetate (3 × 500 mL). The combined organic layers were washed with potassium bisulfate (500 mL) and brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude ethyl 3-(5-fluoro-3-pyridyl)-3-sideoxy-propionate (64 g, 94%) as a brown oil.

[0247] Step 3: Ethyl 3-(5-fluoro-3-pyridyl)-3-hydroxypropionate

[0248]

[0249] Sodium borohydride (5.73 g, 151 mmol) was added to a solution of ethyl 3-(5-fluoro-3-pyridyl)-3-hydroxy-propionate (64 g, 303 mmol) in methanol (400 mL) at 0 °C. The mixture was stirred for 1.5 h and then quenched by adding saturated aqueous ammonium chloride solution (200 mL). The mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude ethyl 3-(5-fluoro-3-pyridyl)-3-hydroxy-propionate (60 g, 93%) as a brown oil.

[0250] Step 4: Ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propionate

[0251]

[0252] tert-butyldimethylchlorosilane (47 g, 309 mmol) was added to a mixture of ethyl 3-(5-fluoro-3-pyridyl)-3-hydroxypropionate (60 g, 281 mmol) and imidazole (38 g, 562.83 mmol) in N,N-dimethylformamide (500 mL) at 20 °C. After addition, the mixture was stirred at 20 °C for 18 hours and filtered. The filtrate was diluted with water (1000 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (2 × 300 mL), brine (200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate in petroleum ether) to give ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propionate (40 g, 44%) as a colorless oil.

[0253] Step 5: 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)-N-methoxy-N-methylpropionamide

[0254]

[0255] Magnesium isopropyl chloride (2.0 M tetrahydrofuran solution, 183.2 mL, 366.4 mmol) was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (24 g, 244.3 mmol) and ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propionate (40 g, 122.2 mmol) in tetrahydrofuran (400 mL) at -78 °C under a nitrogen atmosphere. The mixture was stirred at -70 °C for 16 hours and then quenched by adding saturated aqueous ammonium chloride solution (400 mL). The resulting solution was extracted with ethyl acetate. The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)-N-methoxy-N-methylpropionamide (25 g, 60%) as a colorless oil.

[0256] Step 6: 1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propane-1-one

[0257]

[0258] Magnesium isopropyl chloride (2.0 M tetrahydrofuran solution, 47.5 mL, 95.0 mmol) was added to a solution of 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)-N-methoxy-N-methylpropionamide (25.0 g, 73.0 mmol) and 3,5-di-bromo-1-tetrahydropiperan-2-yl-1,2,4-triazole (29.5 g, 94.9 mmol) in tetrahydrofuran (300 mL) under a nitrogen atmosphere at -70 °C. Following the addition, the mixture was stirred at 30 °C for 18 hours and then quenched by adding water (200 mL). The mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give 1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propane-1-one (15.0 g, 40%), which was a light brown oil.

[0259] Step 7: 1-(3-bromo-1-(tetrahydro-2H-piperan-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(5-fluoropyridin-3-yl)propane-1-ol

[0260]

[0261] Sodium borohydride (829 mg, 21.9 mmol) was added to a mixture of 1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propane-1-one (15.0 g, 29.2 mmol) in ethanol (225 mL) at 0 °C. After the addition, the mixture was stirred at 0 °C for 16 hours and concentrated to dryness. The residue was diluted with water (500 mL) and extracted with ethyl acetate (2 × 300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude 1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridinyl)propane-1-ol (14.0 g, 93%), which was a brown oil.

[0262] Step 8: 1-(3-bromo-1-(tetrahydro-2H-piperan-2-yl)-1H-1,2,4-triazol-5-yl)-3-((tert-butyldimethylsilyl)oxy)-3-(5-fluoropyridin-3-yl)propyl tert-valerate

[0263]

[0264] A solution of 1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propane-1-ol (14.0 g, 27.2 mmol) in dichloromethane (175 mL) and triethylamine (11.4 mL, 81.5 mmol) was added with pentanoyl chloride (5 mL, 40.74 mmol) and 4-dimethylaminopyridine (3.3 g, 27.2 mmol). After the addition, the mixture was stirred at 25 °C for 1.5 h and quenched by adding water (300 mL). The mixture was extracted with dichloromethane (3 × 500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give a colorless oily [1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridinyl)propyl]2,2-dimethylpropionate (16 g, 98%).

[0265] Step 9: 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(5-fluoropyridin-3-yl)-3-hydroxypropyl tervaponate

[0266]

[0267] Hydrochloric acid (4.0 M methanol solution, 40.0 mL, 16.7 mmol) was added to a solution of [1-(5-bromo-2-tetrahydropiperan-2-yl-1,2,4-triazol-3-yl)-3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridinyl)propyl]2,2-dimethylpropionate (10.0 g, 16.7 mmol) in methanol (20 mL) at 0 °C. The resulting solution was stirred at 25 °C for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(5-fluoropyridin-3-yl)-3-hydroxypropyl tert-pentanoic acid (3.6 g, 54%) as a yellow solid. LC-MS R T =0.749min, m / z=401.0[M+H] + .

[0268] The LCMS (after 1.5 minutes of water + 0.03% trifluoroacetic acid with 5% to 95% acetonitrile) retention time was 0.749 min, and the ESI+ experimental value [M+H] = 401.0.

[0269] Step 10: Pteropenic acid (trans)-2-bromo-5-(5-fluoropyridin-3-yl)-6,7-di-hydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl ester

[0270]

[0271] Triethylamine (25 mL, 6.23 mmol) and methanesulfonyl chloride (4.23 g, 36.93 mmol) were added to a solution of 1-(3-bromo-1H-1,2,4-triazol-5-yl)-3-(5-fluoropyridin-3-yl)-3-hydroxypropyl terephthalate (2.5 g, 6.23 mmol) in dichloromethane (50 mL) at 25 °C. The mixture was stirred for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give [trans-2-bromo-5-(5-fluoro-3-pyridinyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]-2,2-dimethylpropionate (600 mg, 25%) as a white solid. LC-MS R T=0.845min, m / z=383.1[M+H] + .

[0272] The LCMS (after 1.5 minutes of water + 0.03% trifluoroacetic acid with 5% to 95% acetonitrile) retention time was 0.845 min, and the ESI+ experimental value [M+H] = 383.1.

[0273] Step 11: trans-2-bromo-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol

[0274]

[0275] Sodium hydroxide (63 mg, 1.57 mmol) was added to a solution of [trans-2-bromo-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-yl]2,2-dimethylpropionate (200 mg, 0.52 mmol) in methanol (5 mL) and water (2 mL) at 25 °C. The resulting mixture was stirred for 2 hours and concentrated under reduced pressure. A mixture of dichloromethane / methanol (20:1) (50 mL) was added to the residue and filtered. The filtrate was concentrated under reduced pressure to give crude trans-2-bromo-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (180 mg, 90%) as a white solid. LC-MS R T =0.609min, m / z=299.9[M+H] + .

[0276] LCMS (after 1.5 min of water + 0.03% trifluoroacetic acid with 5% to 95% acetonitrile) retention time: 0.609 min; ESI+ experimental value [M+H] = 299.0

[0277] Step 12: (cis-2-bromo-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole)

[0278]

[0279] Diethylaminosulfonium trifluoride (1.3 g, 7.62 mmol) was added to a solution of trans-2-bromo-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol (570 mg, 1.91 mmol) in toluene (10 mL) at -78 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was diluted with dichloromethane (50 mL) and poured into ice water (50 mL). The separated organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give a white solid (cis-2-bromo-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (170 mg, 30%).

[0280] Step 13: Cyclopropyl-[(5R,7R)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone and cyclopropyl-[(5S,7S)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone

[0281]

[0282] A solution of cis-2-bromo-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (80 mg, 0.27 mmol) and N-methoxy-N-methylcyclopropaneformamide (100 mg, 0.77 mmol) in tetrahydrofuran (5 mL) was added to magnesium isopropyl chloride (2.0 M tetrahydrofuran solution, 0.35 mL, 0.70 mmol). The mixture was stirred at 0 °C for 1 hour and quenched by adding saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (75% ethyl acetate in petroleum ether, Rf = 0.5) to give cyclopropyl-[cis-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (17 mg, 20%) as a yellow solid. Furthermore, the racemic mixture was separated by palmar SFC to give the following compounds in arbitrary partitions:

[0283] Cyclopropyl-[(5R,7R)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 1, retention time = 4.154 min) (8.3 mg, 51%) 1 H NMR (400MHz, CD3OD) δ8.54-8.53 (m, 1H), 8.46 (s, 1H), 7.60-7.55 (m, 1H), 6.25-6.08 (m, 1H), 5.86-5.83 (m, 1H), 3.85-3.76 (m, 1H), 3.32-2.88 (m, 2H), 1.30-1.12 (m, 4H). LC-MSR T =0.807min,m / z=290.9[M+H] + .

[0284] The LCMS (after 1.5 minutes of water + 0.03% trifluoroacetic acid with 5% to 95% acetonitrile) retention time was 0.807 min, and the ESI+ experimental value [M+H] = 290.9.

[0285] Cyclopropyl-[(5S,7S)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone (peak 2, retention time = 4.835 min). (8.2 mg, 48%) 1 H NMR (400MHz, CD3OD) δ8.54-8.52 (m, 1H), 8.46 (s, 1H), 7.59-7.55 (m, 1H), 6.24-6.08 (m, 1H), 5.85-5.82 (m, 1H), 3.86-3.82 (m, 1H), 3.07-2.95 (m, 2H), 1.29-1.11 (m, 4H).

[0286] LC-MS R T =0.812min, m / z=291.0[M+H] + .

[0287] The LCMS (after 1.5 minutes of water + 0.03% trifluoroacetic acid with 5% to 95% acetonitrile) retention time was 0.812 min, and the ESI+ experimental value [M+H] = 291.0.

[0288] SFC conditions: Column: Phenomenex-Amylose-1 (250 mm × 30 mm, 5 μm); Mobile phase A: CO2; B: Ethanol (0.1% NH3 H2O). Gradient from 5% to 35% B. Flow rate: 50 mL / min.

[0289] Example 3-10

[0290] Additional compounds were prepared using variations of the above procedure by replacing the fluoropyridyl ester in step 1 with a suitable phenyl ester or pyrazolyl ester and replacing the N-methoxy-N-methyl-cyclopropaneformamide in step 13 with a suitable carboxamide. These compounds, along with the compounds of Examples 1 and 2, are shown in Table 1, along with their proton NMR, mass spectra, and Ki values ​​(determined as described below). Unless otherwise stated, the stereochemistry shown in each structure represents the relative configuration of a single stereoisomer, and the absolute configurations (i.e., “R” and / or “S”) are arbitrarily assigned.

[0291] Table 1

[0292]

[0293]

[0294]

[0295] RIP1 kinase inhibition analysis (biochemical analysis)

[0296] The ability of the compounds of the present invention to inhibit RIP1K activity is tested as follows.

[0297] Enzyme analysis:

[0298] The ability of receptor-interacting protein kinase 1 (RIPK1) to catalyze the hydrolysis of adenosine-5′-triphosphate (ATP) was monitored using a Transcreener ADP (adenosine-5′-bisphosphate) assay (BellBrook Labs). A purified human RIP1 kinase domain (2-375) (50 nM) derived from a baculovirus-infected insect cell expression system was incubated with the test compound for 2 hours in 50 mM Epes buffer (pH 7.5) containing 30 mM MgCl2, 1 mM dithiothreitol, 50 μM ATP, 0.002% Brii-35, and 0.5% dimethyl sulfoxide (DMSO). The assay was then performed by adding an additional 12 mM EDTA and 55 μg / mL ADP2 antibody and 4 nM... The 633 tracer was quenched using 1X Bell Brooks stop buffer B (20 mM Hepes (pH 7.5), 40 mM EDTA, and 0.02% Brij-35). ADP generated during the RIP1K reaction replaces the tracer bound to the antibody, causing a decrease in fluorescence polarization, which can be measured using a FP microquantitative disc reader M1000 by laser excitation at 633 nm. Partial activity was plotted against test item concentration. Data were fitted to a tight-binding epigenetic inhibition constant (K0) using Genedata Screener software (Genedata; Basel, Switzerland). i app Morrison's equation [Williams, JW and Morrison, JF (1979) The kinetics of reversible tight-binding inhibition. Methods Enzymol 63: 437-67]. The following equation is used to calculate partial activity and K. i app :

[0299]

[0300] [E]T and [I]T represent the total concentrations of the active enzyme and the test sample, respectively.

[0301] Table 1 provides exemplary compounds of the present invention, along with their physiological and chemical characterization and in vitro RIP1 kinase inhibitory activity data. The "Method" in the first column of each table refers to the synthetic method used to prepare the compounds shown in the examples above.

[0302] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety.

[0303] While the invention has been described in considerable detail for ease of understanding, it will be apparent that certain variations and modifications may be made within the scope of the appended claims. Therefore, the embodiments described are to be considered illustrative rather than restrictive, and the invention is not limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

Claims

1. Compound, Or its medicinal salt, The compounds mentioned therein are selected from: Cyclopropyl(7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone; (2,2-Dimethyl-3-oxabicyclo[3.1.0]hexane-1-yl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; 3-Hydroxy-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one; 3-(difluoromethoxy)-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one; 1-[racemic-(5S,7S)-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one; 1-(3-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl)azacyclobutane-1-yl)ethane-1-one; 3-[racemic-(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile; Cyclopropyl-[racemic-(5S,7S)-5-(3-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] ketone; Cyclopropyl-[racemic-(7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; and Cyclopropyl((5S,7S)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone.

2. The compound according to claim 1, wherein the compound is: (2,2-Dimethyl-3-oxabicyclo[3.1.0]hexane-1-yl)-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone; Or its medicinal salt.

3. The compound according to claim 1, wherein the compound is: 3-Hydroxy-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one; Or its medicinal salt.

4. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: 3-(difluoromethoxy)-2,2-dimethyl-1-[racemic-(5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one.

5. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: 1-[racemic-(5S,7S)-7-fluoro-5-(1-methylpyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl]propane-1-one.

6. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: 1-(3-((5S,7S)-7-fluoro-5-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-carbonyl)azacyclobutane-1-yl)ethane-1-one.

7. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: 3-[racemic-(5S,7S)-2-(cyclopropanecarbonyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-5-yl]benzonitrile.

8. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: Cyclopropyl-[racemic-(5S,7S)-5-(3-chlorophenyl)-7-fluoro-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone.

9. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: Cyclopropyl-[racemic-(7S)-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl] methyl ketone.

10. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: Cyclopropyl((5S,7S)-7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone.

11. The compound according to claim 1 or a pharmaceutical salt thereof, wherein the compound is: Cyclopropyl(7-fluoro-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl) methyl ketone.

12. A pharmaceutical composition comprising the compound according to any one of claims 1-11 or a pharmaceutical salt thereof and a therapeutically inert carrier.

13. The compound or its pharmaceutical salt according to any one of claims 1-11, which is used as a therapeutically active substance.

14. The compound or pharmaceutical salt thereof according to any one of claims 1-11, for the treatment of diseases or disorders selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndrome, taupathy, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

15. The compound or its pharmaceutical salt according to any one of claims 1-11, for the treatment of diseases or disorders selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

16. The compound or pharmaceutical salt thereof according to any one of claims 1-11, for the treatment of diseases or disorders selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, solid organ ischemia-reperfusion injury, cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS).

17. Use of the compound or pharmaceutical salt thereof according to any one of claims 1-11, for the preparation of a medicament for treating diseases or disorders selected from the group consisting of: Parkinson's disease, Lewy body dementia, multiple system atrophy, Parkinson's plus syndrome, Tau proteinosis, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, muscular atrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.

18. Use of the compound or pharmaceutical salt thereof according to any one of claims 1-11 for the preparation of a medicament for treating diseases or disorders selected from the group consisting of: inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), glaucoma, psoriasis, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.

19. Use of the compound or pharmaceutical salt thereof according to any one of claims 1-11, for the preparation of a medicament for treating diseases or disorders selected from the group consisting of: acute kidney injury (AKI), transplant rejection or injury, solid organ ischemia-reperfusion injury, cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS).

20. The compound of claim 14 or the use of claim 17, wherein the disease is intracranial hemorrhage.

21. The compound or use according to claim 20, wherein the intracranial hemorrhage is a brain hemorrhage.

22. The compound of claim 14 or the use of claim 17, wherein the disease or ailment is Alzheimer's disease.

23. The compound of claim 14 or the use of claim 17, wherein the disease or ailment is multiple sclerosis.

24. The compound of claim 14 or the use of claim 17, wherein the disease or ailment is Parkinson's disease.

25. The compound of claim 14 or the use of claim 17, wherein the disease or ailment is amyotrophic lateral sclerosis (ALS).

26. The compound of claim 14 or the use of claim 17, wherein the disease or ailment is Huntington's disease.

27. The compound of claim 14 or the use of claim 17, wherein the disease or ailment is spinal muscular atrophy.

28. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is inflammatory bowel syndrome or inflammatory bowel disease (IBD).

29. The compound or use according to claim 28, wherein the IBD is Crohn's disease.

30. The compound or use according to claim 28, wherein the IBD is ulcerative colitis.

31. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is irritable bowel syndrome (IBS).

32. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is psoriasis.

33. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is psoriatic arthritis.

34. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is rheumatoid arthritis.

35. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is spondylitis.

36. The compound of claim 15 or the use of claim 18, wherein the disease or ailment is juvenile idiopathic arthritis.

37. The compound of claim 16 or the use of claim 19, wherein the disease or ailment is acute kidney injury (AKI).

38. The compound of claim 16 or the use of claim 19, wherein the disease or ailment is transplant rejection or injury.

39. The compound of claim 16 or the use of claim 19, wherein the disease or ailment is solid organ ischemia-reperfusion injury.

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