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Definitions

• Phagocytes produce bactericidal reactive oxygen species (ROS) within the phagosome in an oxidative burst.
• ROS reactive oxygen species
• NOX2 a nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxygen reductase
• NETs Local tissue damage, inflammation, and autoantigens stemming from NETs exacerbate the pathology of chronic conditions such as atherosclerosis, psoriasis, gout, and lupus (Brinkmann, V., J. Innate Immun., 2018, 10, 414-421).
• Targeting the oxidative burst may have therapeutic potential, but there are safety concerns with inhibitors of NOX2 or enzymes of the pentose phosphate pathway including glucose-6-phosphate dehydrogenase (G6PDH).
• G6PDH glucose-6-phosphate dehydrogenase
• Barriers to their use include suppression of innate immunity and general toxicity (Diebold, B.A., et al., Antioxid.
• NETosis of neutrophils is crucial for the killing of extracellular bacteria (Brinkmann, V., et al., Science, 2004, 303, 1532-1535), but the underlying molecular mechanisms remain largely unknown.
• NOX2-dependent NETosis is described as a two phased process (Neubert, E., et al., J. Cell Sci. 133, 2020, jcs241075).
• active signaling cascades trigger a NOX2-induced oxidative burst and histone modifying enzymes such as neutrophil elastase (NE) and peptidyl- arginine deaminase 4 (PAD4) enter the nucleus.
• NE neutrophil elastase
• PAD4 peptidyl- arginine deaminase 4
• Phase 2 involves the entropic swelling of chromatin, rupture of the cell membrane, and dissemination of NETs composed of chromatin and granule proteins.
• Inhibitors of NETosis may control chronic neutrophil-driven diseases.
• GSDMD In neutrophils, caspase-4 cleaves GSDMD in response to cytosolic lipopolysaccharide (LPS), leading to the extrusion of NETs (Chen, K.W., et al., Sci. Immunol., 2018, 3, aar6676). GSDMD may also be cleaved by neutrophil-specific proteases such as NE and cathepsin G (Burgener, S.S., et al., Cell Rep., 2019, 27, 3646-3656; and Kambara, H., et al., Cell Rep., 2018, 22, 2924- 2936).
• LPS cytosolic lipopolysaccharide
• the invention provides a compound of the invention, which is a compound of formula (I): or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 is -NR a R b or a 5-10 membered heteroaryl that is optionally substituted with one or more groups R c ; R 2 is a 6-10 membered aryl that is optionally substituted with one or more groups R r ; or R 2 is a 5-10 membered heteroaryl that is that is optionally substituted with one or more groups R s ; or R 2 is a 3-10 membered heterocycle that is that is optionally substituted with one or more groups R z ; R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (
• E2-E81 of the first embodiment of the invention are described below.
• E2. The compound of E1, wherein R 1 is -NR a R b or a 5-10 membered heteroaryl that is optionally substituted with one or more groups R c ;
• R 2 is a phenyl that is optionally substituted with one or more groups R r ; or R 2 is a 5- 9 membered heteroaryl that is that is optionally substituted with one or more groups R s ; or R 2 is a 9-membered heterocycle that is that is optionally substituted with one or more groups R z ;
• R a is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkanoyl, (C 2 - C 6 )alkynylcarbonyl, 3-6 membered heterocycle, or a 5-membered heteroaryl
• R a is a 5-6 membered heteroaryl that is optionally substituted with one or more groups R f .
• R a is selected from the group consisting of:
• R 1 is a 5-membered heteroaryl that is optionally substituted with one or more groups independently selected from the group consisting of cyano, -NR d R e , and (C 1 -C 6 )alkyl, wherein each (C 1 -C 6 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, and cyano.
• R 1 is selected from the group consisting of: . E17.
• R 2 is a 5- 9 membered heteroaryl that is that is optionally substituted with one or more groups R s .
• E20 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, or E16, wherein R 2 is selected from the group consisting of:
• E21 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, or E16, wherein R 2 is a 5-6 membered heteroaryl that is that is optionally substituted with one or more groups R s .
• E24 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, or E16, wherein R 2 is a 3-10 membered heterocycle that is that is optionally substituted with one or more groups R z E25.
• E26 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, or E16, wherein R 2 is a 5-10 membered heterocycle that is that
• R 2 is a 6-12 membered aryl that is substituted with one or more groups R r ;
• R r is -NR t R u or (C 2 -C 6 )alkynyl that is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, and oxo;
• R t is H;
• E29 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, or E16, wherein R 2 is a phenyl that is substituted with one or more groups R r ; and R r (C 2 -C 6 )alkynyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and cyano.
• R 2 is a phenyl that is substituted with one or more groups R r ; and R r (C 2 -C 6 )alkynyl that is optionally substituted with one or more groups independently selected from the group consisting of hydroxy and cyano.
• E35 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, which is selected from the group consisting of: and prodrugs and pharmaceutically acceptable salts thereof.
• E36 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, which is selected from the group consisting of: and prodrugs and pharmaceutically acceptable salts thereof.
• E37 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, which is selected from the group consisting of: and prodrugs and pharmaceutically acceptable salts thereof.
• E38 The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, which is selected from the group consisting of: and prodrugs and pharmaceutically acceptable salts thereof.
• the prodrug of E1 which is a compound of formula (I) that comprises a hydroxy group that has been converted to a prodrug group that increases the aqueous solubility of the compound or a pharmaceutically acceptable salt thereof.
• E39. The prodrug or pharmaceutically acceptable salt thereof of E38, wherein the hydroxy group has been converted to a prodrug group selected from the group consisting of a phosphate, E40.
• E41. The compound or prodrug, or the pharmaceutically acceptable salt thereof of E1, E2, E3, E4, E5, E6, E12, E18, or E19, provided the compound is not: E42.
• a pharmaceutical composition comprising a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 and a pharmaceutically acceptable excipient.
• a method for treating or preventing a disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type in an animal comprising administering a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to the animal.
• a method for treating cancer in an animal comprising administering a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to the animal.
• E48 e.g., a mammal such as a human
• a method for treating diabetes in an animal comprising administering a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to the animal.
• E49 e.g., a mammal such as a human
• a method for treating a caspase-associated auto-inflammatory condition in an animal comprising administering a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to the animal.
• E50 E50.
• E51 A method for treating a disease or condition selected from the group consisting of pulmonary disease, a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer’s disease, psoriasis, and pulmonary fibrosis in an animal, comprising administering a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to the animal.
• a disease or condition selected from the group consisting of pulmonary disease, a systemic autoimmune disease, atherosclerosis, thro
• E52 The method of claim E51, wherein the pulmonary disease is acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis.
• E53 The method of E51, wherein the disease or condition is thrombosis.
• E54 The method of claim E51, wherein the pulmonary disease is acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis.
• a method for treating a disease or condition associated with the activity of a homologous PFK enzyme comprising administering a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to the animal.
• E55 E55.
• E54 The method of E54, wherein the disease or condition is associated with the activity of PFKM (muscle-type).
• E56. The method of E54, wherein the disease or condition is associated with the activity of PFKP (platelet type).
• E57. A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 for use in medical therapy.
• E58 A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 for the prophylactic or therapeutic treatment of a disease associated with the activity of glycolytic enzyme phosphofructokinase-1 liver type in an animal.
• E59 A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20,
• E60 A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E
• E61 A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E
• E62 A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36
• the compound, prodrug, or pharmaceutically acceptable salt of E61, wherein the caspase-associated auto-inflammatory condition is sepsis or septic shock.
• E63. A compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 for the prophylactic or therapeutic treatment of a disease or condition selected from the group consisting of pulmonary disease, a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer’s disease, psoriasis, and pulmonary fibros
• E64 The compound, prodrug, or pharmaceutically acceptable salt of claim E63, wherein the pulmonary disease is acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis.
• E65 The compound, prodrug, or pharmaceutically acceptable salt of E63, wherein the pulmonary disease is thrombosis.
• E66 The compound, prodrug, or pharmaceutically acceptable salt of claim E63, wherein the pulmonary disease is acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis.
• E67 E40, E41, E42, E43, or E44 for the prophylactic or therapeutic treatment of a disease or condition associated with the activity of a homologous PFK enzyme.
• E70 The use of a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to prepare a medicament for treating cancer in an animal (e.g. a mammal such as a human).
• an animal e.g. a mammal such as a human.
• E71 The use of a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to prepare a medicament for treating diabetes in an animal (e.g. a mammal such as a human).
• an animal e.g. a mammal such as a human.
• E72 wherein the caspase-associated auto-inflammatory condition is sepsis or septic shock in an animal (e.g. a mammal such as a human).
• E74 The use of a compound, a prodrug, or a pharmaceutically acceptable salt of E1, E2, E3, E4, E5, E6, E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22, E23, E24, E25, E36, E27, E28, E29, E30, E31, E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, E42, E43, or E44 to prepare a medicament for treating a disease or condition selected from the group consisting of pulmonary disease, a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer’s disease, psoriasis
• E74 a mammal such as a human.
• E75 The use of E74, wherein the pulmonary disease is acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis.
• E76 The use of E74, wherein the disease or condition is thrombosis.
• E77 The use of E74, wherein the disease or condition is thrombosis.
• E78 The use of E77, wherein the disease or condition is associated with the activity of PFKM (muscle-type).
• E79. The use of E77, wherein the disease or condition is associated with the activity of PFKP (platelet type).
• E80. The method of E47, the compound, prodrug, or pharmaceutically acceptable salt of E59, or the use of claim E70, wherein the cancer is selected from the group consisting of: brain, breast, lung, urinary bladder, cervical, skin, oral cavity, pharynx, colon, liver, cecum, stomach, pancreatic, prostate, oesophageal, hematologic, thyroid, uterine, and head and neck cancer.
• NT N-terminal fragment of GSDMD. Results representative of 3 independent experiments.
• D Coomassie blue staining of recombinant GSDMD. Results representative of 3 independent experiments.
• E TR-FRET assay measuring Europium-labeled biotin released from liposomes exposed to caspase-4 and GSDMD. Symbols indicate the mean ⁇ s.d. of 3 independent experiments.
• F-G Percentage of polymorphonuclear leukocytes (PMNs) undergoing NETosis induced by PMA (F) or the stimuli indicated (G). Data are the mean ⁇ s.d. of cells from 3 donors.
• H ROS production by PMNs. Bars show the mean ⁇ s.e.m.
• NOX2 activity can exacerbate inflammation, as in acute respiratory distress syndrome (ARDS).
• ARDS acute respiratory distress syndrome
• Two unbiased chemical proteomic strategies were utilized to show that small molecule LDC7559 and Example 6 inhibit the NOX2-dependent oxidative burst in neutrophils by activating the glycolytic enzyme phosphofructokinase-1 liver type (PFKL) and dampening flux through the pentose phosphate pathway. Accordingly, neutrophils treated with Example 6 exhibited defects in NOX2-dependent outputs, including neutrophil cell death (NETosis) and tissue damage.
• NETosis neutrophil cell death
• PFKL phosphofructokinase-1 platelet type
• PFKM muscle type
• Selective activation of different phosphofructokinase-1 isoforms could offer a new treatment paradigm for treating diseases such as ARDS, diabetes, and cancer.
• halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.
• alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C 1 -8 means one to eight carbons). Examples include (C 1 -C8)alkyl, (C 2 -C8)alkyl, C 1 -C 6 )alkyl, (C 2 -C 6 )alkyl and (C 3 -C 6 )alkyl.
• alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologs and isomers.
• alkenyl refers to an unsaturated alkyl radical having one or more double bonds.
• alkynyl refers to an unsaturated alkyl radical having one or more triple bonds. Examples of such unsaturated alkyl groups ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers.
• alkoxy refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy”).
• alkylthio refers to an alkyl groups attached to the remainder of the molecule via a thio group.
• cycloalkyl refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C 3 -C8)carbocycle).
• the term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).
• carbocycle includes multicyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms).
• 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.
• multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane, bicyclo[2.2.2]octane, etc).
• a spiro connection e.g., spiropentane, spiro[4,5]decane, etc
• a fused connection e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane
• a bridged connection e.g., norbornane, bicyclo[2.2.2]octane,
• Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.
• aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
• an 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 a phenyl radical.
• Aryl also includes multiple condensed carbon 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., cycloalkyl.
• 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 system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring.
• Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
• heterocycle refers to a single saturated or partially unsaturated 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; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below.
• the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
• 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.
• heterocycle also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form 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 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 heterocycle, aryl and carbocycle portion of the ring.
• heterocycle includes a 3-15 membered heterocycle.
• heterocycle includes a 3-10 membered heterocycle.
• heterocycle includes a 3-8 membered heterocycle.
• heterocycle includes a 3-7 membered heterocycle.
• heterocycle includes a 3-6 membered heterocycle.
• the term heterocycle includes a 4-6 membered heterocycle.
• heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms.
• 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- dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-1,1'- isoindolinyl]-3'-one, isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imid
• heteroaryl refers to a single 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 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, pyrimidinyl, oxazolyl or furyl.
• “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is 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, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl.
• heteroatom includes oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
• 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-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc).
• 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 carboxy group that blocks or protects the carboxy functionality.
• Common carboxy- protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 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.
• 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.
• the terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
• the terms “treat”, “treatment”, or “treating” also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer.
• 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.
• “treat”, “treatment”, or “treating” does not include preventing or prevention
• the phrase "therapeutically effective amount” or “effective amount” includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) 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.
• the term “mammal” as used herein refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human.
• patient refers to any animal including mammals.
• the patient is a mammalian patient.
• the patient is a human patient.
• the compounds disclosed herein can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. It is understood by one skilled in the art that this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D). As a non-limiting example, a -CH3 group may be substituted with -CD3.
• the pharmaceutical compositions of the invention can comprise one or more excipients.
• excipients refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition.
• excipients includes, but is not limited to: carriers, binders, disintegrating agents, lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes. Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.
• the compounds of the invention 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. Many organic compounds exist in optically active forms, 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 l 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.
• 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.
• racemic 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.
• racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
• the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
• optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
• the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
• Prodrugs In addition to salt forms, 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 formula (I).
• 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 formula (I) when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
• Prodrugs of the invention include compounds wherein 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 al., (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.
• More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C 1 -6)alkanoyloxymethyl, 1-((C 1 - 6)alkanoyloxy)ethyl, 1-methyl-1-((C 1 -6)alkanoyloxy)ethyl, (C 1 -6)alkoxycarbonyloxymethyl, N- (C 1 -6)alkoxycarbonylaminomethyl, succinoyl, (C 1 -6)alkanoyl, alpha-amino(C 1 -4)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha- aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2 , -P(O)(O(C 1 -6)alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the
• prodrug derivatives see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.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," by H. Bundgaard p.113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.
• a prodrug of a compound of formula (I) that comprises a hydroxy group can be prepared by converting the hydroxy group to a prodrug group that increases the aqueous solubility of the compound.
• a prodrug can undergo chemical changes under physiological conditions to provide the corresponding compound of formula (I) wherein R b is H.
• Non-limiting examples of a prodrug of a compound of formula (I) include the following compounds:
• Prodrugs of a compound of formula (I) and pharmaceutically acceptable salts thereof can be prepared from a corresponding compound of formula (I) using standard reagents and techniques. Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values may be combined. It is also to be understood that the values listed herein below (or subsets thereof) can be excluded.
• (C 1 -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl;
• (C 3 -C 6 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
• (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2- cyclopentylethyl, or 2-cyclohexylethyl;
• (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy
• the bromo compound can be coupled with the compound R 1 B(OH) 2 in a suitable polar solvent (e.g. DME or dioxane) in the presence of water using a suitable catalyst (e.g. Pd(dppf)Cl2).
• a suitable polar solvent e.g. DME or dioxane
• Pd(dppf)Cl2 e.g. Pd(dppf)Cl2
• a salt of a compound of formula (I) can be useful as an intermediate for isolating or purifying a compound of formula (I).
• administration of a compound of formula (I) as a pharmaceutically acceptable acid or base salt may be appropriate.
• pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ - ketoglutarate, and ⁇ -glycerophosphate.
• Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
• the compounds of formula (I) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
• a mammalian host such as a human patient
• the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
• the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
• the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
• the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
• a liquid carrier such as a vegetable oil or a polyethylene glycol.
• any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
• the active compound may be incorporated into sustained-release preparations and devices.
• the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
• solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
• the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
• the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
• the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
• the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
• Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
• the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
• a formulation suitable for intravenous administration comprising a compound of formula (I) or a prodrug thereof, or a salt of the compound of formula (I) or a salt of the prodrug is provided.
• the present compounds may be applied in pure form, i.e., when they are liquids.
• compositions or formulations in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
• a dermatologically acceptable carrier which may be a solid or a liquid.
• Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
• Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
• Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
• the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
• Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
• Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No.4,608,392), Geria (U.S. Pat.
• Useful dosages of the compounds of formula (I) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No.4,938,949.
• the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
• the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
• the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
• the ability of a compound of the invention to agonize the glycolytic enzyme phosphofructokinase-1 liver type may be determined using pharmacological models which are well known to the art, or using the assays described in the Examples below.
• a compound of the invention to treat cancer, diabetes, a caspase-associated auto-inflammatory condition (e.g., sepsis or septic shock), a pulmonary disease (e.g., acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis), a systemic autoimmune disease, atherosclerosis, thrombosis, multiple sclerosis, Alzheimer’s disease, psoriasis, pulmonary fibrosis, or a disease or condition associated with the activity of a homologous PFK enzyme can also be determined using pharmacological models which are well known to the art.
• a caspase-associated auto-inflammatory condition e.g., sepsis or septic shock
• a pulmonary disease e.g., acute respiratory distress syndrome ARDS, chronic obstructive pulmonary disease COPD, or bronchiectasis
• a systemic autoimmune disease atherosclerosis, thrombosis, multiple
• N-(2-Bromo-4H,10H-benzo[f]pyrazolo[5,1-c][1,4]oxazepin-7-yl)acetamide (NA-8)
• N-(2-Bromo-4H,10H-benzo[f]pyrazolo[5,1-c][1,4]oxazepin-7-yl)acetamide (NA-8)
• Et3N (2.89 g, 28.6 mmol, 3.98 mL)
• acetyl chloride (1.35 g, 17.14 mmol, 1.22 mL) were added and the mixture was stirred at 25°C for 25 minutes.
• N-(2-(3-Methoxyphenyl)-4H,10H-benzo[f]pyrazolo[5,1-c][1,4]oxazepin-7- yl)acetamide NA-8 200 mg, 621 ⁇ mol
• compound 6A 189 mg, 1.24 mmol
• Na 2 CO3 132 mg, 1.24 mmol
• Pd(dppf)Cl2 45.4 mg, 62.1 ⁇ mol
• N-(2-(4-Methoxyphenyl)-4H,10H-benzo[f]pyrazolo[5,1-c][1,4]oxazepin-7- yl)acetamide NA-8 200 mg, 621 ⁇ mol
• compound 7A 189 mg, 1.24 mmol
• Pd(dppf)Cl2 45.4 mg, 62.1 ⁇ mol
• Na 2 CO 3 132 mg, 1.24 mmol
• the intermediate compound 18 was prepared as follows. a. 5-(2-Bromophenyl)pent-4-yn-1-ol (17) A mixture of compound 16 (2.50 g, 8.84 mmol, 1.14 mL), CuI (100 mg, 530 ⁇ mol) and Pd(PPh3) 2 Cl2 (186 mg, 265 ⁇ mol) in Et3N (20.0 mL) was stirred under N2 at 25 °C for 30 minutes. Then compound 17A (892 mg, 10.6 mmol) was added and the mixture was stirred at 60 °C for 3 hours under Ar atmosphere.
• NA-4 2-(2-Methoxyphenyl)-4H,10H-benzo[f]pyrazolo[5,1-c][1,4]oxazepin-7-amine (NA-4)
• reaction mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 12 hours under N2 atmosphere.
• LCMS analysis showed compound 27 was consumed completely and one main peak of the desired product was detected.
• reaction mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 2 hours under N2 atmosphere.
• LCMS analysis showed the 4-bromo-3-(5-hydroxypent-1-yn-1-yl)phenol was consumed completely and one peak of the desired product was detected.
• the reaction mixture was diluted with H 2 O (70.0 mL) and extracted with ethyl acetate (25.0 mL x 3). The combined organic layers were washed with brine (20.0 mL x 2), dried over Na 2 SO 4 , filtered and concentrated under vacuum.
• 29 0.525 mmol, 1.50 eq
• Dioxane 3.0 mL
• K3PO 4 2.0 M, 350 ul
• Pd-118 0.018 mmol, 0.05 eq
• Condition A prep-HPLC under basic conditions
• Condition B prep-HPLC under formic acid
• Condition C prep-TLC.
• Example 67 N-(2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4H,10H-benzo[f]pyrazolo[5,1- c][1,4]oxazepin-7-yl)acetamide
• NA-8 0.120 mmol, 1.00 eq
• Compound 37 0.180 mmol, 1.50 eq
• Dioxane 1.0 mL
• PdCl2(dtbpf) 0.006 mmol, 0.05 eq
• Example 46 N-(2-(4-fluoro-2-(hydroxymethyl)phenyl)-4H,10H-benzo[f]pyrazolo[5,1- c][1,4]oxazepin-7-yl)acetamide
• NA-8 0.120 mmol, 1.00 eq
• Compound 38 (0.180 mmol, 1.50 eq) in Dioxane (1.0 mL) was added K3PO 4 (2 M, 120 uL) and Xphos Pd G3 (0.006 mmol, 0.05 eq).
• Example 46 (26.4 mg, 60%) as a white solid.
• Condition A prep-HPLC under basic conditions
• Condition B prep-HPLC under formic acid
• Condition C prep-TLC.
• Example 125 N-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4H,10H-benzo[f]pyrazolo[5,1- c][1,4]oxazepin-7-yl)acetamide
• NA-8 0.30 mmol, 1.00 eq
• Compound 39 (0.30 mmol, 1.0 eq) in Dioxane (0.15 M) and water (0.15 M) was added K3PO 4 (3 mmol, 10 eq) and Xphos Pd G3 (0.015 mmol, 0.05 eq).
• Example 125 (59.6 mg, 53%) as a white solid.
• LDC7559 did not alter GSDMD-dependent pyroptosis induced by nigericin, cytoplasmic LPS, or cytoplasmic poly(deoxyadenosine-deoxythymidine) [poly(dA- dT)] (Fig.1A).
• the GSDMD-dependent release of interleukin-1 ⁇ (IL-1 ⁇ ) from monocytes in response to nigericin or poly(dA-dT) also occurred normally in the presence of LDC7559 (Fig. 1B).
• Western blotting confirmed that LDC7559 did not prevent LPS-induced cleavage of GSDMD (Fig.1C).
• LDC7559 did not inhibit cleavage of recombinant GSDMD by caspase-4 (Fig.1D). Nor did it prevent the GSDMD pore-forming fragment from permeabilizing liposomes (Fig.1E). In contrast, inhibition of GSDMD with disulfiram (Hu et al., 2020) prevented liposome permeabilization (Fig.1E). It was determined that LDC7559 does not inhibit GSDMD.
• NETosis was classified in cells by measuring the DNA area in the fluorescence image and comparing with a select internal training set for each experiment. Unstimulated cells and PMA-stimulated, pyocyanin-inhibited cells served as negative controls. PMA-stimulated cells served as a positive control. NET-forming cells are presented as a percentage of total cells. Data for representative compounds of the invention is provided in the following Table.
• the activity of the compounds and salts can also be evaluated in biochemical assays measuring PFKL, PFKM and PFKP activity.
• Assay Example 3 ROS Detection Assay ROS were measured in neutrophils using the ROS-Glo bioluminescent assay (Promega) for the direct detection of H 2 Na. 2 C NOeu 3 trophils were isolated from fresh human blood using a biphasic Histopaque gradient as described here. Cells (100uL per well) were plated in 96-well plates at a density of 200,000 cells/mL in high glucose DMEM medium.
• DMSO vehicle or compounds (10-point dilution curve starting at 20uM with 3-fold serial dilution) for 30 min, and then stimulated with 50 nM PMA for 30 min.
• Luminescence after the addition of H 2 O 2 substrate solution for 20 min, and then ROS-Glo detection solution for 20 min, was recorded on a luminescence plate reader.
• the fifty percent inhibitory concentration (IC50) was determined with GraphPad Prism by plotting the assay output (RLU) versus the logarithm of the compound concentration using a non-linear sigmoid with variable slope algorithm with the default curve-fitting parameters in the Prism software.

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