Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• the invention relates to organic compounds useful for therapy and/or prophylaxis in a subject, and in particular to inhibitors of RIP1 kinase useful for treating diseases and disorders associated with inflammation, cell death and others.
• Receptor-interacting protein- 1 (“RIP1”) kinase is a serine/threonine protein kinase.
• RIP1 is a regulator of cell signaling that is involved, among other things, in the mediation of programmed cell death pathways, e.g., necroptosis. The best studied form of necroptotic cell death is initiated by TNFa
• TNFa death ligand family Fas and TRAIL/ Apo2L
• interferons TLRs
• TLRs Toll-like receptors
• DAI DNA-dependent activator of interferon regulatory factor
• Complex-II is formed by the death domain containing protein FADD (Fas-associated Protein), RIP1, easpase-8 and cFLIP. If caspase-8 is not fully activated or its activity is blocked, the protein kinase
• necrosome gets recruited to the complex, forming a necrosome, which will lead to necroptotic cell death initiation [8-10]
• RIPI and RIPS engage in a series of auto and cross phosphorylation events that are essential for necroptotic cell death Necroptosis can be completely blocked either by the kinase inactivating mutation in any of the two kinases, or chemically by RIPI kinase inhibitors (necrostatins), or RIP3 kinase inhibitors [1 1-13].
• Phosphorylation of RIPS allows the binding and phosphorylation of pseudokinase MLKL (mixed lineage kinase domain-like), a key component of necroptotic cell death [14, 15]
• Necroptosis has crucial pathophysiological relevance in myocardial infarction, stroke, atherosclerosis, ischemia-reperfusion injury, inflammatory' bowel diseases, retinal degeneration and a number of other common clinical disorders [16] Therefore, selective inhibitors of RIPI kinase activity are therefore desired as a potential treatment of diseases mediated by this pathway and associated with inflammation and/or necroptotic cell death.
• Inhibitors of RIP 1 kinase have been previously described. The first published inhibitor of RIP 1 kinase activity was necrostatin I (Nec-I) [17].
• Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus- induced inflammation.
• R ! is selected from the group consisting of C -Cc, alkyl, C -Ce cycloalkyl, C -Ce alkoxy, Ci-Ce haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkyl-N(R N ) 2 , phenyl, benzyl, 4 to 8 memhered heterocyclyl and 5 to 6 memhered heteroaryl; wherein R 1 is bound to the adjacent carbonyl by a carbon atom, and wherein R !
• each R N is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-CY alkoxy, and Ci-CY haloalkyl; or two R N may together with the adjacent N form a 4-6 membered ring;
• R 3 is selected from the group consisting of phenyl, pyrazolyl and pyridinyl , each of which may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, Ci- C4 alkyl, C 1 -C 4 haloalkyl, C -C4 alkoxy, Ci-Ci haloalkoxy, and cyano;
• R 3a and R 3b are each independenly hydrogen or halo
• compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
• Specific embodiments include pharmaceutical compositions suitable for oral deliver ⁇ '.
• oral formulations of a compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery' are also provided herein.
• a compound of formula I or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.
• a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder selected from the group consisting of Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes, taupathies, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.
• a disease or disorder selected from the group consisting of Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes, taupathies, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.
• Parkinson's Disease Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes, taupathies, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage
• a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson -plus syndromes, taupathies, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.
• Parkinson's Disease Lewy body dementia, multiple system atrophy, Parkinson -plus syndromes, taupathies, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis,
• a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disorder or disease (IBD), irritable bowel syndrome (IBS), Crohn’s disease, ulcerative colitis, glaucoma, psoriasis, pyoderma gangrenosum, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.
• IBD inflammatory bowel disorder or disease
• IBS irritable bowel syndrome
• a compound of formula I or a pharmaceutically acceptable salt thereof, or composition thereof for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disorder or disease (IBD), irritable bowel syndrome (IBS), Crohn’s disease, ulcerative colitis, glaucoma, psoriasis, pyoderma gangrenosum, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.
• IBD inflammatory bowel disorder or disease
• IBS irritable bowel syndrome
• Crohn’s disease ulcerative colitis
• glaucoma psoriasis
• pyoderma gangrenosum psoriatic arthritis
• rheumatoid arthritis rheumatoid arthritis
• juvenile idiopathic arthritis juvenile idiopathic arthritis
• osteoarthritis selected from the group consisting of inflammatory bowel disorder or disease (I
• a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of inflammatory bowel disorder or disease (IBD), irritable bowel syndrome (IBS), Crohn’s disease, ulcerative colitis, glaucoma, psoriasis, pyoderma gangrenosum, psoriatic arthritis, rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, and osteoarthritis.
• IBD inflammatory bowel disorder or disease
• IBS irritable bowel syndrome
• Crohn’s disease ulcerative colitis
• glaucoma psoriasis
• pyoderma gangrenosum psoriatic arthritis
• rheumatoid arthritis rheumatoid arthritis
• juvenile idiopathic arthritis juvenile idiopathic arthritis
• osteoarthritis selected from the group consisting of inflammatory bowel disorder or
• a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder selected from the group consisting of acute kidney injury (AK1), transplant rejection or injury', ischemia reperfusion injury' of solid organs, delayed graft function (DGF), cisplatin-induced kidney injury, nephritis-induced kidney injury, sepsis, and systemic inflammatory' response syndrome (SIRS)
• AK1 acute kidney injury
• transplant rejection or injury' ischemia reperfusion injury' of solid organs
• DGF delayed graft function
• cisplatin-induced kidney injury nephritis-induced kidney injury
• sepsis sepsis
• systemic inflammatory' response syndrome SIRS
• a compound of formula I or a pharmaceutically acceptable salt thereof, or composition thereof for the treatment of a disease or disorder selected from the group consisting of acute kidney injury (AKI), transplant rejection or injury, ischemia reperfusion injury' of solid organs, delayed graft function (DGF), cisplatin- induced kidney injury', nephritis-induced kidney injury, sepsis, and systemic inflammatory response syndrome (SIRS).
• AKI acute kidney injury
• DGF delayed graft function
• SIRS systemic inflammatory response syndrome
• a compound of formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or disorder selected from the group consisting of acute kidney injury (AKI), transplant rejection or injury, ischemia reperfusion injury of solid organs, delayed graft function (DGF), cisplatin-induced kidney injury, nephritis-induced kidney inj ry, sepsis, and systemic inflammatory response syndrome (SIRS).
• AKI acute kidney injury
• DGF delayed graft function
• SIRS systemic inflammatory response syndrome
• halogen or“halo” refers to fluorine, chlorine, and bromine (i.e., F, Cl, Br).
• Alkyl refers to an optionally substituted, straight-chain or branched Ci-Cn alkyl group in some embodiments, alkyl refers to a Ci-Ce alkyl group.
• Exemplary alkyl groups include methyl, ethyl, propyl, Ao-propyl, re-butyl, Ao-butyl, fcrt-butyl, sec-butyl, re-pentyl, re-hexyl, re-heptyl, and re-oxtyl.
• eycioalkyl refers to a Ca-Cs cycloalkyl group.
• the C3-C6 cycloalkyl group is optionally substituted with 1 to three halogen atoms.
• the Ca-Ce eycioalkyl group is optionally substituted with 1 to three fluorine atoms.
• Exemplary Ca-Ce eycioalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• Exemplar ⁇ ' Ca-Cn cycloalkyl groups further include bicyc!o[3 l 0]hexyl, bicyclo[2.1.1]hexyl, cyeloheptyl, bicycie[4 l Q]heptyl, spiro[4.2]heptyl, cyclooctyl, spiro [4.3] octyl, spiro[5.2]octyl, bicyclo[2.2.1]heptanyl, bicycle[2.2.2]octanyl, adamantanyl, decalinyl, and spiro[5.4jdecanyl.
• eycioalkyl groups may be fused to other groups such that more than one chemical bond exists between the eycioalkyl group and another ring system (e.g., the C ring of formula I).
• the cycloalkyl group is unsubstituted.
• Haloalkyi refers to a straight-chain or branched C1-C12 alkyl group, wherein one or more hydrogen atoms are replaced by a halogen.
• haloalkyi refers to a C1-C5 haloalkyi group in some embodiments, 1 to 3 hydrogen atoms of the haloaikyl group are replaced by a halogen.
• every hydrogen atom of the haloaikyl group is replaced by a halogen (e.g, trifluoromethyl).
• the haloaikyl is as defined herein wherein the halogen in each instance is fluorine.
• Exemplary haloaikyl groups include fluoromethyl, difluoromeihyl, trifiuromethyl, trifluoroethyl, and pentafluoroethyl.
• Alkoxy refers to a straight-chain or branched C3-C32 alkyl group, wherein one or more oxygen atoms are present, in each instance between two carbon atoms.
• alkoxy refers to a CYCe alkoxy group.
• CYCe alkoxy groups provided herein have one oxygen atom.
• Exemplary' alkoxy groups include methoxy, ethoxy, CH2OCH3, CH2CH2OCH3, CH2OCH2CH3, CH2CH2OCH2CH3, CH2OCH2CH2CH3, CH2CH2CH2OCH3, ( ⁇ I . ⁇ (C ' P ⁇ ( ⁇ i ) . ⁇ . ( i 1 *( ) C i ( ! E ) ( ⁇ 1(( ⁇ I .KC ⁇ ! . CH 2 CH(C3 ⁇ 4)OC3 ⁇ 4, P ⁇ ⁇ UOP EP U
• Cycloalkoxy refers to a C4-C30 or a GYCe alkoxy group as defined above wherein the group is cyclic and contains one oxygen atom.
• Exemplary' cycloalkoxy groups include oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.
• Haloalkoxj' refers to a (YG, haloaikyl group as defined above, wherein one or two oxygen atoms are present, in each instance between two carbon atoms.
• CYCe haloalkoxy groups provided herein have one oxygen atom.
• Exemplary haloalkoxy groups include OCF 3 , OCHF 2 and CH 2 GCF 3 .
• Thioalkyl refers to a C3-C32 or a CYO, alkoxy group as defined above wherein the oxygen atom is replaced by a sulfur atom.
• thioalkyl groups may include sulfur atoms substituted by one or two oxygen atoms (i.e., alkylsulfones and alkylsulfoxides).
• Exemplary' thioalkyl groups are those exemplified in the definition of alkoxy above, wherein each oxygen atom is replaced by a sulfur atom in each instance.
• Thiocycloalkyl refers to a C4-C30 or a Ci-Ce thioalkyl group as defined above wherein the group is cyclic and contains one sulfur atom.
• the sulfur atom of the thiocycloalkyl group is substituted by one or two oxygen atoms (i.e., a cyclic sulfone or sulfoxide).
• Exemplary' thiocycloalkyl groups include thietany!, thiolany!, thianyl, 1,1- dioxothiolanyl, and 1,1-dioxothianyl.
• Heterocyclyl referes to a single saturated or partially unsaturated 4 to 8 membered ring that has at least one atom other than carbon m the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems have from 7 to 12 atoms and are further described below.
• the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6, 7 or 8 membered rings) from about 1 to 7 carbon atoms and from about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and stdfur in the ring.
• the ring may be C-branched (i.e., substituted by C -C4 alkyl).
• the ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
• Exemplary heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl
• the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another.
• the point of attachment of a multiple condensed ring system (as defined above for a heterocycle) can be at any position of the multiple condensed ring system. It is also to be understood that the point of attachment for a heterocycle or heterocycle multiple condensed ring system can be at any suitable atom of the heterocyclyl group including a carbon atom and a nitrogen atom.
• heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1, 2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1 ,2-dihydropyridinyl, 2,3- dihy drobenzofuranyl, 1 ,3 -benzodioxoly 1, 1 ,4-benzodioxanyl, spiro [cyclopropane- 1 , 1 '-isoindolinyl] -3 '- one, isoindolinyl-I-one, 2-oxa-6-
• the heterocyclyl is a C4-C10 heterocyclyl having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
• the heterocyclyl group is neither bicyclic nor spiroeyclie.
• the heterocyclyl is a CV Ce heterocylcyl having 1 to 3 heteroatoms, wherein at least 2 are nitrogen if 3 heteroatoms are present.
• Aryl includes a phenyl radical.
• Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle).
• Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system.
• the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring sy stem, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring.
• Exemplary aryl groups include phenyl, indenyl, naphthyl, 1 , 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
• Heteroaryl refers to a 5 to 6 membered aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur;“heteroaryl” also includes multiple condensed ring systems having 8 to 16 atoms that have at least one such aromatic ring, which multiple condensed ring systems are further described below .
• “heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
• heteroaryl ring systems include but are not limited to pyridyl, pyrimidiny!, oxazolyl or furyl.
• “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3, 4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-l ,8- naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroqumolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system.
• heteroaryls to form for example a naphthyrid
• a heteroaryl (a single aromatic ring or multiple condensed ring system) has 1 to 15 carbon atoms and about 1 -6 heteroatoms within the heteroaryl ring.
• Such multiple condensed ring s stems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring.
• the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another.
• the point of attachment of a multiple condensed ring system can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system. It is also to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen).
• heteroaryls include but are not limited to pyridyl, pyrroly!, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indoiy!, imidazoly!, oxazolyl, isoxazolyl, thiazoiyl, furyl, oxadiazolyl, thiadiazolyi, quinoiyl, isoquinolyi, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoqumolinyl benzofuranyl, benzimidazolyi, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl ⁇ 4(3H) ⁇ one, triazolyl, 4, 5,6,7- tetraliydro-lH-indazole
• chiral refers to molecules which have the property of non- superimposability of the mirror image partner, while the term '‘achiral" refers to molecules which are superimposable on their mirror image partner.
• stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
• a wavy line“ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.
• C-linked means that the group that the term describes is attached the remainder of the molecule through a ring carbon atom.
• N-linked means that the group that the term describes is attached to the remainder of the molecule through a ring nitrogen atom.
• Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral propesties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.
• Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
• the compounds of the in vention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
• optically active compounds i.e., they have the ability to rotate the plane of plane- polarized light.
• the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
• the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
• a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
• a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
• a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
• the terms“racemic mixture” and“racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
• the atom to which the bond is attached includes all stereochemical possibilities.
• a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. , bold, bold-wedge, dashed or dashed-wedge)
• a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. , bold, bold-wedge, dashed or dashed-wedge)
• the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted.
• the compound may be at least 51% the absolute stereoisomer depicted.
• the compound may be at least 80% the absolute stereoisomer depicted.
• the compound may be at least 90% the absolute stereoisomer depicted.
• the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 97% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 98% the absolute stereoisomer depicted in another embodiment, the compound may he at least 99% the absolute stereoisomer depicted.
• tautomer or“tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy bander.
• proton tautomers also known as prototropic tautomers
• Valence tautomers include interconversions by reorganization of some of the bonding electrons.
• solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
• solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
• hydrate refers to the complex where the solvent molecule is water in some embodiments, a hydrate of a compound provided herein is a ketone hydrate.
• the term“protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound.
• an“amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
• Suitable amino-protecting groups include acetyl trifluoroacetyl, t-butoxy carbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmelhylenoxy carbonyl (Fmoe).
• a “hydroxy- protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl.
• A“carboxy-protecting group” refers to a substituent of the earboxy group that blocks or protects the carboxy functionality.
• Common carboxy-protecting groups include phenylsulfonylethyl, eyanoethyl, 2-(trimethylsiiyl)ethyi, 2- (trimethylsilyl)ethoxymetltyl, 2-(p-toluenesulfonyl)elhyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like.
• protecting groups and their use see P.G.M. Wuts and T.W. Greene, Greene’s Protective Groups in Organic Synthesis 4 th edition, Wiley-Interscience, New York, 2006.
• the term“mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
• the term“subject” includes, but is not limited to, mammals.
• salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
• base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• salts derived from pharmaceutically -acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
• Saits derived from pharmaceutically-acceptable organic bases include salts of primary, secondary' and tertiary' amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N !
• dibenzylethylenediamine diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethyl amine, trimethylamine, tripropylamine, tromethamme and the like.
• acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydxobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelie, phthalic, benzenesulfomc, p-tolylsulfonic, citric, tartaric, me thane sulfonic, and the like.
• salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. ML, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19).
• Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
• the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
• the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equi valent to the parent form of the compound for the p urposes of the present invention.
• the present invention provides compounds which are in a prodrug form.
• prodrug refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
• prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e g , two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention.
• the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxy proline, hydroxylysine, demosine, isodemosine, gamma -carboxy glutamate, hippuric acid, octahydroindole-2 -carboxylic acid, statine, l ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
• prodrugs are also encompassed.
• a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester.
• compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et ai., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery ' Reviews, 19: 115.
• Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
• Derivatizaiion of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrags of this type are described in .1. Med. Chem., (1996), 39: 10.
• More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci ⁇ )alkanoyloxymethyl, 1 -((Ci- 6 )alkanoyloxy)ethyl, 1 -methyl-1 -((C - 6 )aikanoyloxy)ethyi, (C ]-6 )alkoxycarbonyloxymethyl, N - (Ci-6)alkoxycarbonylaminomethyl, succinoyl, (Ci-6)alkanoyl, alpha-amino(Cw)alkanoyl, aryiacyi and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, R(0)(OH)> ; , -P(0)(0(C -6)alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl
• prodrug derivatives see, for example, a) Design of Prodrugs, edi ted by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Voi. 42, p. 309-396, edited by K Widder, et ai. (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," by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drag Delivery ' Review's, 8: 1-38 (1992); d) H.
• a‘"metabolite ” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
• Metabolite products typically are identified by preparing a radiolabelled (e. g., 14 C or 3 H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
• a detectable dose e.g., greater than about 0.5 mg/kg
• metabolites In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art.
• the metabolite products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
• Certain compounds of the present invention can exist in unsolvated forms as well as sol vated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
• Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
• composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.
• Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.
• terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (it) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
• efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
• bioavailability refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.
• R 1 is selected from the group consisting of Ci-Ce alkyl, C3-C6 cycloalkyl, C -Ce alkoxy, C -Ce, haloalkyl, Ci-Ce haloalkoxy, Ci-Ce alkyl-N(R N ) 2 , phenyl, benzyl, 4 to 8 membered heterocyclyl and 5 to 6 membered heteroaryl; wherein R ! is bound to the adj cent carbonyl by a carbon atom, and wherein R !
• each R N is independently selected from the group consisting of H, Ci-Ce alkyl, Ca-Ce cycloalkyl, C -fA alkoxy, and C i-Ce haloalkyl; or two R N may together with the adjacent N form a 4- 6 membered ring;
• R 2 is selected from the group consisting of phenyl, pyrazolyl and pyridinyl, each of which may be unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and cyano;
• R 3a and R 3b are each independenly hydrogen or halo
• compositions comprising a compound of formula 1 as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable earners or excipients.
• Specific embodiments include pharmaceutical compositions suitable for oral delivery.
• oral formulations of a compound of formula I as described in any one of the above embodiments, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients suitable for oral delivery are also provided herein.
• the diseases and disorders to be treated are synueleopathies such as Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes in some embodiments, the diseases and disorders to be treated are taupathies such as Alzheimer's Disease and frontotemporal dementia. In some embodiments, the diseases and disorders to be treated are demyelination diseases such as multiple sclerosis.
• the diseases and disorders to be treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington’s disease, ischemia, and stroke.
• Additional exemplary neurodegenerative diseases to be treated as provided herein include, but are not limited to, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy , pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelmating diseases.
• the disease or disorder to be treated is Alzheimer’s disease in some embodiments, the disease or disorder to be treated is Parkinson's disease. In some embodiments, the disease or disorder to be treated is Huntington's disease. In some embodiments, the disease or disorder to be treated is multiple sclerosis. In some embodiments, the disease or disorder to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder to be treated is spinal muscular atrophy (SMA).
• ALS amyotrophic lateral sclerosis
• SMA spinal muscular atrophy
• the disease or disorder to be treated is selected from the group consisting of inflammatory bowel disorder or disease (IBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), psoriasis, pyoderma gangrenosum, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vascu
• IBD inflammatory bowel disorder or disease
• IBS irritable bowel syndrome
• psoriasis pyoderma gangrenosum
• retinal detachment retin
• cisplatin acute kidney injury (AKG), Celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia reperfusion injury of solid organs, 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 I diabetes, Wegener's granulomatosis, pulmonary sarcoidosis, Behcet's disease, interleukin-!
• ICE converting enzyme
• COPD chronic obstructive pulmonary disease
• TRAPS tumor necrosis factor receptor-associated periodic syndrome
• periodontitis NEMQ-deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or 1KKG) deficiency syndrome)
• HOIL-1 deficiency (also known as RBCKl) heme-oxidized IRP2 ubiquitin ligase-1 deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome
• hematological and solid organ malignancies bacterial infections and viral infections (such as tuberculosis and influenza)
• Lysosomal storage diseases particularly, Gaucher Disease, and including GM2, Gangliosidosis, Alpha-mannosidosis, Aspartylglucosammuria, Cholesteryl Ester storage disease, Clrronie Hexosaminidase A Deficiency, Cystinos
• the disease or disorder to be treated is an inflammator' bowel disorder or disease (IBD).
• the disease or disorder to be treated is an inflammatory bowel syndrome (IBS).
• the disease or disorder to be treated is Crohn’s disease.
• the disease or disorder to be treated is ulcerative colitis.
• the disease or disorder to be treated is glaucoma.
• the disease or disorder to be treated is psoriasis.
• the disease or disorder to be treated is pyoderma gangrenosum.
• the disease or disorder to be treated is rheumatoid arthritis.
• the disease or disorder to be treated is spondyloarthritis.
• the disease or disorder to be treated is juvenile idiopathic arthritis.
• the disease or disorder to be treated is osteoarthritis.
• provided herein are methods for the treatment or prevention of a disease or disorder with a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is associated with inflammation and/or necroptosis.
• said disease or disorder is selected from the specific diseases and disorders recited herein.
• provided herein are methods of inhibiting RIP1 kinase activity by contacting a cell with a compound of formula I or a pharmaceutically acceptable salt thereof.
• compositions or medicaments containing the compounds of the invention or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof), and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments.
• compounds of formula 1 may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e , carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
• the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8.
• a compound of formula I is formulated in an acetate buffer, at pH 5.
• the compounds of formula I are sterile.
• the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
• compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
• Factors for consideration in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
• the“effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit RIP1 kinase activity in order to provide a therapeutic effect in the subject being treated.
• such an effective amount may be below the amount that is toxic to normal cells, or the subject as a whole.
• the pharmaceutically effective amount of the compound of the invention administered intravenously or parenterally will he in the per dose range of about 0.1 to 100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, or alternatively about 0.3 to 15 mg/kg/ day.
• oral unit dosage forms such as tablets and capsules, preferably contain from 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 invention.
• the daily does is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
• the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
• a low dose of the compound of the invention is administered in order to provide therapeutic benefit while minimizing or preventing adverse effects.
• the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intraderma!, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
• Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
• the compound of formula I is administered orally.
• the compound of formula I is administered intravenously .
• the compounds of the present invention may be administered in any convenient administrati ve form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
• Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
• a typical formulation is prepared by mixing a compound of the present: invention and a carrier or excipient.
• Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et a!., 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.
• the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaqidng agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, wuxes, water soluble and/or sw'ellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
• the particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present invention is being applied.
• Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a subject.
• 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 w'ater, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc and mixtures thereof.
• the formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
• Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine,
• a active pharmaceutical ingredient of the invention can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcel!ulose or gelatin-microcapsules and poly- (methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
• colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
• Sustained-release preparations of a compound of the invention can be prepared.
• suitable examples of sustained-release preparations include semipermeabie matrices of solid hydrophobic polymers containing a compound of formula I or an embodiment thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
• sustained-release matrices include polyesters, hydrogels (for example, poly (2- hydroxyethyl-methacrylate), or poly (vinyl alcohol)), polylactides (U.S. Patent No.
• Sustained release compositions also include liposomally entrapped compounds, which can be prepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A. 82:3688, 1985; Hwang et al affect Proc. Natl. Acad. Sci. U.S.A. 77:4030, 1980; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102, 324 A).
• the liposomes are of the small (about 200-800 Angstroms) unilamelar type in which the lipid content is greater than about 30 mol % cholesterol, the selected proportion being adjusted for the optimal therapy.
• compounds of formula 1 or an embodiment thereof may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
• physiologically acceptable carriers i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form.
• the pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges any where from about 3 to about 8 in one example, a compound of formula I (or an embodiment thereof) is formulated in an acetate buffer, at pH 5.
• the compounds of formula I or an embodiment thereof are sterile.
• the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
• 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, 25mg, 30mg, 50mg, 80mg, l OOmg, 150mg, 250mg, 300mg and 500mg) of the compound of the invention compounded with suitable amounts of anhydrous lactose, sodium croscarmellose, polyvinylpyrrolidone (PVP) K30, and magnesium stearate.
• PVP polyvinylpyrrolidone
• the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
• the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment.
• Formulations of a compound of the invention can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
• a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
• This suspension can be formulated according to the known art usin those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
• the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder.
• the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile fixed oils can conventionally be employed as a solvent or suspending medium.
• any bland fixed oil can be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid can likewise be used in the preparation of injectables.
• a time-release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight: weight).
• the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
• an aqueous solution intended for intravenous infusion can contain from about 3 to 500 gg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
• Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of tire intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
• the formulations can be packaged in unit-dose or multi -dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid canier, for example water, for injection immediately prior to use.
• sterile liquid canier for example water
• Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
• An embodiment therefore, includes a pharmaceutical composition comprising a compound of formula I, or pharmaceutically acceptable salt thereof.
• a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
• certain embodiments of the invention provide for a compound of formula I (or an embodiment thereof) to traverse the blood-brain barrier.
• the compounds provided herein exhibit sufficient brain penetration as potential therapeutics in neurological diseases.
• brain penetration is assessed by evaluating free brain/plasma ratio (B u /PRON) as measured in vivo pharmacokinetic studies in rodents or by other methods knowm to persons skilled in the art (see, e.g., Liu, X. et al , I Pharmacol. Exp. Therap., 325:349-56, 2008).
• Certain neurological diseases are associated with an increase in permeability of the blood-brain barrier, such that a compound of formula 1 (or an embodiment thereof) can be readily introduced to the brain.
• a compound of formula 1 or an embodiment thereof
• several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods.
• Physical methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, circumventing the blood- brain barrier entirely, or by creating openings in the blood-brain barrier.
• Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al, Gene Therapy 9:398-406, 2002), interstitial infusion/convection-enhanced delivery (see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91 :2076-2080, 1994), and implanting a delivery device in the brain (see, e.g.. Gill et al, Nature Med. 9:589-595, 2003; and Gliadel WafersTM, Guildford.
• Methods of creating openings in the barrier include, but are not limited to, ultrasound (see, e.g., LIS. Patent Publication No. 2002/0038086), osmotic pressure (e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y., 1989)), and permeabilization by, e.g., bradykinin or penneabilizer A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).
• ultrasound see, e.g., LIS. Patent Publication No. 2002/0038086
• osmotic pressure e.g., by administration of hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N
• Lipid-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, encapsulating the a compound of formula I or I-I (or an embodiment thereof) in liposomes that are coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood- brain barrier (see, e.g. , U.S. Patent Publication No. 2002/0025313), and coating a compound of formula I (or an embodiment thereof) in low-density lipoprotein particles (see, e.g., U.S. Patent Publication No. 2004/0204354) or apolipoprotein E (see, e.g., U .S Patent Publication No. 2004/0131692).
• Receptor and channel-based methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, using glucocorticoid blockers to increase permeability of the blood-brain barrier (see, e.g., U.S. Patent Publication Nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. Patent Publication No. 2005/0089473), inhibiting ABC drug transporters (see, e.g. , U.S. Patent Publication No.
• the compounds can be administered continuously by infusion into the fluid reservoirs of the CNS, although bolus injection may be acceptable.
• the inhibitors can be administered into the ventricles of the brain or otherwise introduced into the CNS or spinal fluid. Administration can be performed by use of au indwelling catheter and a continuous administration means such as a pump, or it can be administered by implantation, e.g., intracerebral implantation of a sustained-release vehicle. More specifically, the inhibitors can be injected through chronically implanted cannulas or chronically infused with the help of osmotic minipumps. Subcutaneous pumps are available dial deliver proteins through a small tubing to the cerebral ventricles.
• Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set without surgical intervention.
• suitable administration protocols and delivery systems involving a subcutaneous pump device or continuous intracerebroventricular infusion through a totally implanted drug delivery' system are those used for the administration of dopamine, dopamine agonists, and cholinergic agonists to Alzheimer's disease patients and animal models for Parkinson's disease, as described by Harbaugh, 1. Neural Transm. Suppl. 24:271 , 1987; and DeYebenes et al , Mov. Disord. 2: 143, 1987.
• the compounds of the invention inhibit R1P1 kinase activity.
• the compounds of the invention are useful for the treatment of diseases and disorders mediated by this pathway and associated with inflammation and/or necroptotic cell death.
• the disease or disorder to be treated is a neurodegenerative disease or disorder.
• the diseases and disorders to be treated are synucleopathies such as Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndromes.
• the diseases and disorders to be treated are taupathies such as Alzheimer's Disease and frontotemporal dementia.
• the diseases and disorders to be treated are demyelination diseases such as multiple sclerosis.
• the diseases and disorders to be treated are other neurodegenerative diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, primary' lateral sclerosis, Huntington's disease, ischemia, and stroke.
• Additional exemplary neurodegenerative diseases to be treated as provided herein include, but are not limited to, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy , progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, and demyelinating diseases.
• the disease or disorder to be treated is Alzheimer’s disease. In some embodiments the disease or disorder to be treated is Parkinson's disease. In sotne embodiments, the disease or disorder to be treated is Huntington’s disease. In some embodiments, the disease or disorder to be treated is multiple sclerosis. In some embodiments, the disease or disorder to be treated is amyotrophic lateral sclerosis (ALS). In some embodiments, the disease or disorder to be heated is spinal muscular atrophy (SMA).
• SMA spinal muscular atrophy
• the disease or disorder to be treated is an inflammatory disease or disorder.
• the disease or disorder to be treated is selected from the group consisting of inflammatory' bowel disorder or disease (TBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), psoriasis, pyoderma gangrenosum, retinal detachment, retinitis pigmentosa, macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, osteoarthritis, spondylarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, liver damage/diseases (non-alcohol steatohepatitis, alcohol
• TBD inflammatory'
• cisplatin acute kidney injury (AKI), Celiac disease, autoimmune idiopathic thrombocytopenic purpura, transplant rejection, ischemia reperfusion injury of solid organs, 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, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also know'n as caspase-1) associated fever syndrome, chronic obstructive pulmonary' disease (COPD), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), periodontitis, NEMO-deficiency syndrome (F-kappa-B essential
• Ester storage disease Chronic Hexosaminidase A Deficiency, Cystinosis, Danon disease, Fabry disease, Farber disease, Fucosidosis, Galactosialidosis, GM 1 gangliosidosis, Mucolipidosis, Infantile Free Sialic Acid Storage Disease, Juvenile Hexosaminidase A Deficiency, Krabbe disease, Lysosomal acid lipase deficiency, Metaehromatic Leukodystrophy, Mucopolysaccharidoses disorders, Multiple sulfatase deficiency, Niemann-Pick Disease, Neuronal Ceroid Lipofuscinoses, Pompe disease, Pycnodysostosis, Sandhoff disease, Schindler disease, Sialic Acid Storage Disease, Tay-Sachs and Wolman disease).
• the disease or disorder to be treated is an inflammatory bowel disorder or disease (IBD). in some embodiments, the disease or disorder to be treated is an irritable bowel syndrome (IBS). In some embodiments, the disease or disorder to be treated is Crohn’s disease. In some embodiments, the disease or disorder to be treated is ulcerative colitis. In some embodiments, the disease or disorder to be treated is glaucoma. In some embodiments, the disease or disorder to be treated is psoriasis. In some embodiments, the disease or disorder to be treated is pyoderma gangrenosum. In some embodiments, the disease or disorder to be treated is rheumatoid arthritis. In some embodiments, the disease or disorder to be treated is spondyloarthritis. hi some embodiments, the disease or disorder to be treated is juvenile idiopathic arthritis. In some embodiments, the disease or disorder to be treated is osteoarthritis.
• IBD inflammatory bowel disorder or disease
• IBS irritable bowel syndrome
• the method of treatment provided herein is the treatment of one or more symptoms of a disease or disorder listed above.
• a compound of the invention in therapy.
• pro vided herein is the use of a compound of the invention for the treatment or prevention of the above diseases and disorders.
• IBD inflammatory bowel disorder or disease
• IBS irritable
• Also provided herein is a method of treating a disease or disorder in a human patient in need of such treatment, said disease or disorder being selected from those provided above, wherein the method comprises orally administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, as an orally acceptable pharmaceutical composition.
• compounds of the invention are combined with one or more other compounds of the invention or one or more other therapeutic agent as any combination thereof, in the treatment of the diseases and disorders provided herein.
• a compound of the invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents known to be useful for the treatment of a disease or disorder selected from those recited above.
• “combination” refers to any mixture or permutation of one or more compounds of the invention and one or more other compounds of the invention or one or more additional therapeutic agent. Unless the context makes clear otherwise, “combination” may include simultaneous or sequentially delivery' of a compound of the invention with one or more therapeutic agents. Unless the context makes clear otherwise, “combination” may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise “combination” may include routes of administration of a compound of the invention with another therapeutic agent. Unless the context makes clear otherwise, “combination” may include formulations of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration and pharmaceutical compositions include, but are not limited to, those described herein.
• a compound provided herein may be combined with another therapeutically active agent as recited in WO 2016/027253, the contents of which are hereby incorporated by reference in their entirely.
• the compound that inhibits RIP1 kinase in the combinations recited in WO 2016/027253 is replaced by a compound of formula I of the present disclosure.
• a compound provided herein may be combined with a DLK inhibitor for the treatment of neurode generative 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 syndromes, Alzheimer's Disease, frontotemporal dementia, demyelination diseases such as multiple sclerosis, amyotrophic lateral sclerosis, spinal muscular atrophy, primary' lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, and corticobasal degeneration.
• DLK inhibitors are described, for example, in WO 2013/174780, WO 2014/177524, WO 2014/177060, WO 2014/11 1496, WO 2015/091889
• R is lower alkyl and may be same or different in each occurrence
• TBS is tert- butyidimethylchlorosilyl
• ⁇ R is tetrahydropyranyl
• Piv is pivalaie
• R 1 and R 2 are as defined herein.
• ester compound a is treated with acetate ester such as ethyl acetate, in the presence of strong base such as lithium bis(trimethysilyl)amide, to afford a beta keto ester compound b.
• the group R 2 may comprise, for example, phenyl, pyridyl, pyrazolyi or other aryl or heteroaryl in accordance with the invention.
• a reduction of compound b is carried out in step 2 to form the corresponding beta hydroxyl ester compound c.
• This reduction may be carried out using NaBIR or like reducing agent.
• a tert-butyldimethylchlorosilyl ester d of compound c is formed by treating c with ter t-buty ldime thy lchlorosilane .
• ester compound d is reacted with N,O-dimethylhydroxylamine hydrochloride to provide the corresponding N-methoxy amide compound e.
• the reaction of the step may be performed in the presence of a Grignard reagent such as isopropymagnesium halide.
• N-methoxy amide compound e of step 4 is then reacted with 3,5-dibromo-l - tetrahydropyran-2-yl-l, 2, 4-triazole in step 5 to afford the triazole ketone compound f.
• 3,5-Dibromo-l- tetrahydropyran-2-yl-l, 2, 4-triazole is commercially available from Sigma Aldrich (1,158747 ALDRICH) and other soiuces.
• step 6 a reduction is made by treatment of compound f with NaBIL or like reducing agent to provide the corresponding hydroxy l compound g
• step 7 a pfvalate ester h is formed by treatment of compound g with pivaloyl halide.
• step 8 the tert-butyldimethylchlorosilyl group is removed from compound h to afford the corresponding hydroxyl compound i.
• a ring formation is carried out in step 9 by treatment of compound i with methanesulfonyl chloride in the presence of base to afford pyrrolotriazole compound j.
• step 10 the pivalyol group is removed from j to yield the corresponding hydroxy - pyrrolotriazole compound k.
• step I I the compound k is reacted with a fluorinating reagent such as diethylaminosulfur trifluoride to provide the corresponding fluoro-pyrrolotriazole compound m.
• a fluorinating reagent such as diethylaminosulfur trifluoride
• step 12 compound m is reacted with N-methoxy amide compound n to afford compound o, which is a compound of formula I in accordance with the invention.
• the group R 1 may be cyclopropyl, for example, or other group as defined herein for R 5 .
• Step 1 methyl 5-fluoropyridine-3-carboxylate
• Step 2 ethyl 3-(5-fluoro-3-pyridyl)-3-oxo-propanoate
• Step 3 ethyl 3-(5-fluoiO-3-pyridyl)-3-hydiOxy-propanoate
• Step 4 ethyl 3-[tert-butyl(dimethyl)silyl]oxy-3-(5-fluoro-3-pyridyl)propanoate
• Tire 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 to 20% ethyl acetate in petroleum ether) to afford 3-[ tert-buty l(dimethy l)sily fjoxy- 3-(5-iluoro-3-pyridyi)-N-methoxy-N-methyl-propanamide (25 g, 60%) as colorless oil.
• Step 6 l-(5-bromo-2-tetrahydropyran-2-yl-l ,2,4-tri azo!-3-yl)-3- [tert- butyI(dimethyI)silyI]oxy-3- (5 ⁇ f!uoro-3-pyridy!propan-l ⁇ one
• Tire residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 30% ethyl acetate in petroleum ether) to afford l-(5-bromo-2-tetrahydropyran-2-yl-l,2,4-1riazol-3- yl)-3-[tert-butyl(di:methyi )silyl]oxy-3-(5-f3uoro-3-pyridyl)propan-l-one (15.0 g, 40%) as light brown oil.
• Step 7 l-(3-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-l ⁇ ,4-triazoI-5-yl)-3-((tert- buty!dlmethylsihi)oxy)-3-(5-fluoropyridin-3-yl)propan-l-ol
• Step 8 -1 -(3-bromo-l -(tetrahydro-2H-pyran-2-yl)-lH-l ,2,4-triazol-5-yl)-3 ⁇ ((tert- butyldimethylsiIyl)oxy)-3-(5-fluoropyridin-3-yl)propyl pivalate
• Step 9 l-(3-bronio-lH-l,2,4-triazol-5-yI)-3-(5-fluoropyridin-3-yl)-3-hydroxypropyl pivalate
• Step 10 (trans)-2-bromo-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[l,2-b][l,2,4]triazol- 7-yl pivalate
• Step 11 Trans-2-bromo-5-(5-fluoropyridin-3-yl)-6,7-dihydro-5H-pyrrolo[l,2-b] [l,2,4]triazol-7- ol
• Step 12 (cis-2-bromo-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[l ,2- b] [ 1,2, 4] triazole
• Step 13 cyclopropyl-[(5R,7R)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7-dihydro-5H-pyrrolo[l,2- b] [l,2,4]triazol-2-yl]methanone and cyclopropyl-[(5S,7S)-7-fluoro-5-(5-fluoro-3-pyridyl)-6,7- dihydro-SH-pyrro!o [1 ,2-b] [ 1 ,2,4]triazol-2-yI] methanone
• the compounds of the present invention were tested for their capacity to inhibit RIP IK activity as described below.
• RIPK1 receptor interacting protein kinase
• ATP adenosine-5' -triphosphate
• Purified human RIP I kinase domain (2-375) (50 nM) derived from a baculovirus-infected insect cell expression sy stem is incubated with test compounds for 2 hours in 50 mM Hepes buffer (pH 7.5) containing 30 mM MgCL, 1 mM dithiothreitol, 50 mM ATP, 0.002% Bri j - 35, and 0.5% dimethyl sulfoxide (DMSO).
• Reactions are quenched by the addition of IX Beil Brooks Stop buffer B (20mM Hepes (ph7.5), 40mM ethylenediaminetetraacetic acid and 0.02% Brij-35) containing an additional 12 mM EOT A and 55 ug/mL ADP 2 antibody and 4 nM ADP-AlexaFluor® 633 tracer.
• the tracer bound to the antibody is displaced by the ADP generated during the RIP IK reaction, which causes a decrease in fluorescence polarization that is measured by laser excitation at 633 nm with a FP microplate reader M1000. Fractional activity was plotted against test article concentration.
• Exemplary compounds of the present invention are provided in Table 1 along with their physiochemical characterization and in vitro R1P1 kinase inhibitory activity data.“Method” in the first column of each table refers to the synthetic method(s) used to prepare each compound as shown in the Examples above.

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