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WO2019193541A1 - Dérivés de cycle aromatiques bicycliques de formule (i) utilisés en tant qu'inhibiteurs d'atf4 - Google Patents

Dérivés de cycle aromatiques bicycliques de formule (i) utilisés en tant qu'inhibiteurs d'atf4 Download PDF

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Publication number
WO2019193541A1
WO2019193541A1 PCT/IB2019/052776 IB2019052776W WO2019193541A1 WO 2019193541 A1 WO2019193541 A1 WO 2019193541A1 IB 2019052776 W IB2019052776 W IB 2019052776W WO 2019193541 A1 WO2019193541 A1 WO 2019193541A1
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Prior art keywords
substituted
disease
pharmaceutically acceptable
unsubstituted
cancer
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PCT/IB2019/052776
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English (en)
Inventor
Karen Anderson Evans
Mark A. Hilfiker
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Glaxosmithkline Intellectual Property Development Limited
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Publication of WO2019193541A1 publication Critical patent/WO2019193541A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides

Definitions

  • the present invention relates to substituted bicyclic aromatic derivatives that are inhibitors of the ATF4 pathway.
  • the present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of diseases/injuries associated with activated unfolded protein response pathways, such as cancer, pre-cancerous syndromes, Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
  • UPR unfolded protein response
  • the UPR is activated by unfolded or misfolded proteins that accumulate in the ER lumen because of an imbalance between protein folding load and protein folding capacity, a condition known as "ER stress".
  • the UPR is comprised of three signaling branches mediated by ER- localized transmembrane sensors, PERK, IRE1 , and ATF6.
  • PERK and IRE1 are homologous and likely activated in analogous ways by direct binding to unfolded peptides (12). This binding event leads to oligomerization and trans- autophosphorylation of their cytosolic kinase domains, and, for PERK, phosphorylation of its only known substrate, elF2a. In this way, PERK activation results in a quick reduction in the load of newly synthesized proteins that are translocated into the ER- lumen (13).
  • both the transcription factor XBP1 s produced as the consequence of a non-conventional mRNA splicing reaction initiated by IRE1
  • the transcription factor ATF6 produced by proteolysis and release from the ER membrane
  • ATF4 Upon ER stress, both the transcription factor XBP1 s, produced as the consequence of a non-conventional mRNA splicing reaction initiated by IRE1 , and the transcription factor ATF6, produced by proteolysis and release from the ER membrane, collaborate with ATF4 to induce the vast UPR transcriptional response.
  • Transcriptional targets of the UPR include the ER protein folding machinery, the ER-associated degradation machinery, and many other components functioning in the secretory pathway (14).
  • compositions that comprise a pharmaceutically acceptable excipient and compounds of Formula (I). It is also an object of the present invention to provide a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering novel inhibitors of the ATF4 pathway.
  • the invention is directed to substituted bicyclic aromatic derivatives. Specifically, the invention is directed to compounds according to Formula (I):
  • z 6 are as defined below; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • the present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of the ATF4 pathway.
  • the present invention also relates to the discovery that the compounds of Formula (I) prevent the translation of ATF4.
  • This invention also relates to a method of treating Alzheimer’s disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Parkinson’s disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating amyotrophic lateral sclerosis, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Huntington’s disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating C re utzfeldt- Jakob Disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating progressive supranuclear palsy (PSP), which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • PSP progressive supranuclear palsy
  • This invention also relates to a method of treating dementia, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating spinal cord injury, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating traumatic brain injury, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating ischemic stroke, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating diabetes, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating an integrated stress response-associated disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the patient.
  • This invention also relates to a method of improving long-term memory in a patient, the method including administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the patient.
  • This invention also relates to a method of increasing protein expression of a cell or in vitro expression system, the method including administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the cell or expression system.
  • This invention also relates to a method of treating an inflammatory disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.
  • This invention also relates to a method of using the compounds of Formula (I) in organ transplantation and in the transportation of organs for transplantation.
  • Also included in the present invention are methods of co-administering the presently invented compounds with further active ingredients.
  • Included in the present invention is a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease,
  • C re utzfeldt- Jakob Disease and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering the compounds of Formula (I).
  • CTE chronic traumatic encephalopathy
  • neurodegeneration dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering the compounds of Formula (I).
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer’s disease.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson’s disease syndromes.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of amyotrophic lateral sclerosis.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington’s disease.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of progressive supranuclear palsy (PSP).
  • PPS progressive supranuclear palsy
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of dementia.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of spinal cord injury.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of traumatic brain injury.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemic stroke.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes.
  • the invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from:
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an integrated stress response-associated disease.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease associated with phosphorylation of elF2a.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease selected from the group consisting of: cancer, a
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving long-term memory.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for increasing protein expression of a cell or in vitro expression system.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of inflammatory disease.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament in organ transplantation and in the transportation of organs for transplantation.
  • the invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease state selected from: neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
  • a disease state selected from: neurodegenerative diseases, cancer, and other diseases/inju
  • compositions that comprise a pharmaceutical excipient and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a pharmaceutical composition as defined above for use in therapy.
  • the invention also relates to a combination for use in therapy which comprises a therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (ii) further active ingreadients.
  • A is bicyclic aromatic optionally substituted by one to three substituents
  • C and D are independently phenyl or pyridyl; is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted Ci-6heteroalkylene, or l_2 is further taken together with R® to form heterocycloalkyl;
  • L® is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted C1 -6heteroalkylene, or L® is further taken together with to form heterocycloalkyl;
  • R 1 is selected from: hydrogen, Ci-6alkyl, substituted Ci -6alkyl, and heterocycloalkyl, or R ⁇ is taken together with L® to from heterocycloalkyl;
  • R® is selected from: hydrogen, Ci-6alkyl, substituted Ci -6alkyl, and heterocycloalkyl, or R® is taken together with l_2 to from heterocycloalkyl;
  • R® and R® are independently hydrogen, fluoro, chloro, bromo, iodo,
  • R2 and R ⁇ are independently NR®, O, CH2, or S;
  • R® is selected from: hydrogen, Ci-6alkyl and Ci-6alkyl substituted 1 to 6 times by fluoro;
  • z® and z® are independently an integer from 0 to 5; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I).
  • A is bicyclic aromatic optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -COOH, -CN, oxo, and fluoro;
  • C and D are independently phenyl or pyridyl
  • R 1 1 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and oxetanyl, or R 1 1 is taken together with
  • R 1 3 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and oxetanyl, or R 1 3 is taken together with
  • R ⁇ ® are independently hydrogen, methyl, or chloro
  • R12 and R ⁇ are O; are independently 0 or 1 ;
  • z15 and z ⁇ ® are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II).
  • A is bicyclic aromatic optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe,
  • C and D are independently phenyl or pyridyl l_22 is selected from: a bond, -NH-, -O-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted Ci-6heteroalkylene; l_23 taken together with R21 to form heterocycloalkyl; R23 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and heterocycloalkyl;
  • R25 and R26 are independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2, -N02, -C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH,
  • R22 and R24 are independently NR28, O, CH2, or S;
  • R28 is selected from: hydrogen, Ci-6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • z22 and z24 are independently 0 or 1 ;
  • z25 and z26 are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).
  • C and D are independently phenyl or pyridyl l_32 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,
  • R33 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and oxetanyl;
  • R32 and R ⁇ 4 are O;
  • ⁇ 32 and z ⁇ 4 are independently 0 or 1 ;
  • ⁇ 35 and z ⁇ 6 are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).
  • bicyclic aromatic optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -COOH, -CN, oxo and fluoro;
  • l_42 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted Ci-6heteroalkylene;
  • R41 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and
  • R45 and R46 are independently hydrogen, fluoro, chloro, bromo, iodo,
  • R48 is selected from: hydrogen, Ci-6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • z42 and z44 are independently 0 or 1 ;
  • z45 and z46 are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (V).
  • bicyclic aromatic optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe,
  • R55 and R56 are independently hydrogen, fluoro, chloro, bromo, iodo,
  • R52 and R®4 are independently NR®®, O, CH2, or S;
  • R®® is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • ⁇ ®2 and z®4 are independently 0 or 1 ; and ⁇ ®® and z®® are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VI).
  • A® is bicyclic aromatic optionally substituted by one or two substituents
  • C® and D® are independently phenyl or pyridyl
  • L® 2 and L®® are independently: -CH2-O-, -O-CH2-, -O-CH2-CH2-, and
  • R®® and R®® are independently hydrogen or chloro
  • R® 2 and R® 4 are O;
  • Z 62 and z 64 are independently 0 or 1 ; and Z®® and z®® are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VII).
  • A® is bicyclic aromatic optionally substituted by one or two substituents
  • C® and D® are independently phenyl or pyridyl
  • L® 2 and L®® are independently a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene or substituted or unsubstituted
  • Ci -6heteroalkylene R®® and R56 and are independently hydrogen, fluoro, chloro, bromo, iodo,
  • R52 and R®4 are independently NR®®, O, CH2, or S;
  • R58 is selected from: hydrogen, Ci-6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • ⁇ ®2 and z®4 are independently 0 or 1 ;
  • ⁇ ®® and z®® are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XVI).
  • A® is bicyclic aromatic optionally substituted by one or two substituents
  • C® and D® are independently phenyl or pyridyl
  • L® 2 and L®® are independently: -CH2-O-, -O-CH2-, -O-CH2-CH2-, and -CH2-CH2-O-;
  • R®® and R®® are independently hydrogen or chloro
  • R® 2 and R® 4 are O;
  • Z® 2 and z® 4 are independently 0 or 1 ;
  • Z®® and z®® are independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XVII).
  • the compounds of the inventiom are:
  • the adjacent“R*” and“L*” moieties form a ring, such as a heterocycloalkyl, for example a pyrrolidinyl, the“R*” and“L*” moieties do not have to be adjacent in the ring.
  • a * group is bicyclic aromatic, which is defined harein as a phenyl ring fused to another ring, such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a cycloalkyl ring.
  • the bicyclic aromatic group is attached to the rest of the molecule through the phenyl ring.
  • R 5 is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3,
  • R 5 is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -CH3, -OH, -CF3, -CN, -S(0)CH3, -NO2,
  • R 5 is— F.
  • R 5 is— Cl. In embodiments, R 5 is— Br. In embodiments, R 5 is— I. In embodiments, R 5 is substituted or unsubstituted Ci- 6 alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 5 is unsubstituted Ci- 6 alkylene, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 5 is -OCH3.
  • R 5 is -OCH2Ph.
  • R 5 is -
  • R 5 is -OH. In embodiments, R 5 is -CF3. In embodiments, R 5 is - CN. In embodiments, R 5 is -S(0)CH3. In embodiments, R 5 is -NO2. In embodiments, R 5 is -C(0)CH3. In embodiments, R 5 is -C(0)Ph. In embodiments, R 5 is -CH(CH3)2. In embodiments, R 5 is -CCH. In embodiments, R 5 is -CH2CCH. In embodiments, R 5 is - SO3H. In embodiments, R 5 is -SO2NH2. In embodiments, R 5 is— NHC(0)NH2. In embodiments, R 5 is -NHC(0)H. In embodiments, R 5 is -NHOH. In embodiments, R 5 is- OCH3. In embodiments, R is -OCF3. In embodiments, R 5 is -OCHF2.
  • R 6 is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3,
  • R 6 is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -CH3, -OH, -CF3, -CN, -S(0)CH3, -NO2, -C(0)CH3,
  • R 6 is— F. In embodiments, R 6 is— Cl.
  • R 6 is— Br. In embodiments, R 6 is— I. In embodiments, R 6 is substituted or unsubstituted Ci_ 6 alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 is unsubstituted Ci- 6 alkylene, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 6 is -OCH3.
  • R 6 is -OCH2Ph.
  • R 6 is -
  • R 6 is -OH. In embodiments, R 6 is -CF3. In embodiments, R 6 is - CN. In embodiments, R 6 is -S(0)CH3. In embodiments, R 6 is -NO2. In embodiments, R 6 is -C(0)CH3. In embodiments, R 6 is -C(0)Ph. In embodiments, R 6 is -CH(CH3)2. In embodiments, R 6 is -CCH. In embodiments, R 6 is -CH2CCH. In embodiments, R 6 is - SO3H. In embodiments, R 6 is -SO2NH2. In embodiments, R 6 is— NHC(0)NH2. In embodiments, R 6 is -NHC(0)H. In embodiments, R 6 is -NHOH. In embodiments, R 6 is - OCH3. In embodiments, R 6 is -OCF3. In embodiments, R 6 is -OCHF2.
  • R 2 is NR 8 .
  • R 2 is NH.
  • R 2 is O.
  • R 2 is S.
  • R 4 is NR 8 .
  • R 4 is NH.
  • R 4 is O.
  • R 4 is S.
  • R 2 and R 4 are NH.
  • R 2 and R 4 are O.
  • R 2 and R 4 are S.
  • R 2 and R 4 are NR 8 .
  • L 2 is a bond. In embodiments, L 2 is a substituted or unsubstituted Ci_ 6 alkylene. In embodiments, L 2 is a substituted or unsubstituted Ci- 6 heteroalkylene. In embodiments, L is L -L -L and L is bonded to the substituted or unsubstituted phenyl, which may be substituted with R . is a bond,— O-, -S-, -NH-, -S(O)-, or—
  • L is a bond or substituted or unsubstituted Ci- 6 alkylene. is a bond, -O-, or
  • L is a bond. In embodiments, L is— O-. In embodiments, L 2A is -S-. In embodiments, l_ 2A is -NH-. In embodiments, l_ 2A is -S(O)-. In
  • L is— S(0)2-. In embodiments, L is a bond. In embodiments, L is a substituted or unsubstituted Ci- 6 alkylene. In embodiments, L is an unsubstituted Ci_
  • L is a C1-C6 alkylene substituted with— CF3. In embodiments, L is a bond. In embodiments, L is -O-. In embodiments, L is— NH-.
  • L is a bond; L is unsubstituted methylene; and L is -O-.
  • L is a bond. In embodiments, L is— O-. In embodiments, L 3A is -S-. In embodiments, l_ 3A is -NH-. In embodiments, l_ 3A is -S(O)-. In
  • L is— S(0)2-. In embodiments, L is a bond. In embodiments, L is a substituted or unsubstituted Ci_ 6 alkylene. In embodiments, L is an unsubstituted Ci_ 6 alkylene. In embodiments, L 3B is a substituted or unsubstituted C1-C5 alkylene. In embodiments, L is an unsubstituted C1 -C5 alkylene. In embodiments, L is a substituted or unsubstituted Ci-C 4 alkylene. In embodiments, L is an unsubstituted Ci-
  • L is a substituted or unsubstituted Ci-C3alkylene. In embodiments, L is an unsubstituted C1 -C3 alkylene. In embodiments, L is a substituted C1-C5 alkylene. In embodiments, L is a substituted C1-C6 alkylene. In embodiments, L is a substituted C1-C5 alkylene. In embodiments, L is a substituted
  • L is a bond; L is unsubstituted methylene; and L is -0-.
  • L 3 is taken together with R 1 to form heterocycloalkyl.
  • the heterocycloalkyl is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyl is imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L 22 is taken together with R 23 to form heterocycloalkyl.
  • the heterocycloalkyl is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyl is imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L 23 is taken together with R 21 to form heterocycloalkyl.
  • the heterocycloalkyl is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyl is imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyl.
  • the heterocycloalkyl is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyl is imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L 42 is taken together with R 41 to form imidazolidinyl or pyrrolidinyl.
  • L 42 is taken together with R 41 to form imidazolidinyl.
  • L 42 is taken together with R 41 to form pyrrolidinyl.
  • L 43 is taken together with R 43 to form imidazolidinyl or pyrrolidinyl.
  • L 43 is taken together with R 43 to form imidazolidinyl.
  • L 43 is taken together with R 43 to form pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl.
  • L is taken together with R to form pyrrolidinyl.
  • L 62 is taken together with R 61 to form imidazolidinyl or pyrrolidinyl.
  • L 62 is taken together with R 61 to form imidazolidinyl.
  • L 62 is taken together with R 61 to form pyrrolidinyl.
  • L 63 is taken together with R 63 to form imidazolidinyl or pyrrolidinyl.
  • L 63 is taken together with R 63 to form imidazolidinyl.
  • L 63 is taken together with R 63 to form pyrrolidinyl.
  • the symbol z ⁇ is 0. In embodiments, the symbol z ⁇ is 1 . In embodiments, the symbol z 4 is 0. In embodiments, the symbol z 4 is 1 . In embodiments, the symbols z ⁇ and z 4 are 0. In embodiments, the symbols z ⁇ and z 4 are 1 . In embodiments, the symbol z® is 0. In embodiments, the symbol z® is 1 . In embodiments, the symbol z® is 2. In embodiments, the symbol z® is 3. In embodiments, the symbol z® is 4. In embodiments, the symbol z® is 0. In embodiments, the symbol z® is 1 . In embodiments, the symbol z® is 2. In embodiments, the symbol z® is 3. In embodiments, the symbol z® is 4.
  • any of A, A1 , A2, A3, A4, A5, or A6, is selected from: 2,3-dihydro-1 H- indene and isoindoline.
  • salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formula (I).
  • salts including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.
  • the salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulf
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS,
  • cyclohexylamine dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (/V-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t- butylamine, and zinc.
  • the compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof.
  • Chiral centers such as chiral carbon atoms, may be present in a substituent such as an alkyl group.
  • Isotopically-labelled compounds for example those into which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. , 3H, and carbon-14, i.e. , 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18F isotopes are particularly useful in PET (positron emission tomography), and 1251 isotopes are particularly useful in SPECT (single photon emission computerized tomography), both are useful in brain imaging.
  • Isotopically labelled compounds can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form.
  • the compounds of Formula (I) or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form.
  • the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water.
  • polymorphs may have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification.
  • Alkyl and alkylene include: methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.
  • Alkoxy refers to an -O-alkyl group wherein“alkyl” is as defined herein.
  • -C4alkoxy refers to an alkoxy group having from 1 to 4 member carbon atoms.
  • Representative branched alkoxy groups have one, two, or three branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy.
  • Aryl refers to an aromatic hydrocarbon ring.
  • aryl is phenyl.
  • Bicyclic aromatic refers to a phenyl ring fused to another ring, such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a cycloalkyl ring.
  • a heteroaryl ring such as a phenyl ring fused to another ring, such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a cycloalkyl ring.
  • bicyclic aromatic is 2,3- dihydro-1 /-/-indenyl or isoindolinyl.
  • Cycloalkyl refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member carbon atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitably cycolalkyl is cyclopropyl.
  • Halo refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to a monocyclic aromatic 5 or 6 member ring, containing 1 to 5 carbon atoms and containing 1 to 3 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms, or to such heteroaromatic ring fused to another ring, such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a cycloalkyl ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms.
  • Suitable examples of monocyclic heteroaryls for use herein includes but is not limited to: furanyl, pyrazolyl, imidazoly!, indolizinyl, naphthyridinyl, oxazolyl, oxadiazolyl, pyridyl, pyrrolyl, pyrimidyl, isothiazolyl, furazanyl, pyrimidinyl, tetrazinyl, isoxazolyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyridinyl, thiophenyl, thiadiazolyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
  • pyridinyl, thiophenyl, thiadiazolyl pyrazinyl, pyrimidinyl, or pyridazinyl.
  • bicyclic heteroaryls for use herein includes but is not limited to: 1 H- pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, oxothiadiazolyl, phthalazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl, quinoxalinyl, quin
  • naphthyridinyl isoquinolinyl; 2,3- dihydro-1 /-/-pyrrolo[3,4-c]pyridinyl; or 6,7-dihyd ro-5/-/-cyclopental[c]pyridinyl.
  • Heterocycloalkyl refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 1 1 are carbon atoms and from 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with an aryl ring having from 3 to 6 member atoms.
  • heterocycloalkyl includes: piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, oxetanyl, and pyrrolidinyl.
  • “heterocycloalkyl” is: imidazolidinyl or pyrrolidinyl.
  • Heteroatom refers to a nitrogen, sulphur or oxygen atom.
  • Heteroalkyl and“heteroalkylene” by itself or in combination with another term, means, unless otherwise stated, a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • Heteroalkyl being monovalent and heteroalkylene being bivalent.
  • the heteroalkyl and heteroalkylene groups may be taken together with another substituent to form a heterocycloalkyl group.
  • heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl or heteroalkylene group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to:
  • -CH CHN(CH3)2, -O-CH3, -O-CH2-CH3, -CN.
  • Examples include, but are not limited to: -CH3, -CH2-, -CH2-CH2-O-CH2-, CH2-CH2-NH-CH2-, -CH2-CH2-N(CH3)CH2-,
  • -CH CHN(CH3)CH2-, -O-CH2-, and -O-CH2-CH2-.
  • Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and— CH2-0-Si(CH3)3.
  • Substituted as used herein, unless otherwise defined, is meant that the subject chemical moiety has from one to nine substituents, suitably from one to five substituents, selected from the group consisting of: fluoro,
  • R x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,
  • R x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,
  • R x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,
  • R x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R x1 and R 5 2 are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6
  • R x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R x1 and R 5 2 are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6
  • R x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R x1 and R 5 2 are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6
  • R x is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R x is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R x is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R and R are each independently selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6
  • Substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,
  • Suitably“substituted” means the subject chemical moiety has from one to four substituents selected from the group consisting of:
  • R x is selected from Ci-4alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,
  • R x1 and R 5 2 are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro, guanidino,
  • R x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • Suitably“substituted” means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro,
  • R x is selected from Ci-4alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,
  • R x1 and R 5 2 are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,
  • R x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • R x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • R x1 and R 5 2 are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,
  • Suitably“substituted” means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro,
  • Ci-4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCH2CH3, and -CN,
  • R x is selected from Ci-4alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,
  • R x1 and R 5 2 are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,
  • R x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • R x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • R x1 and R 5 2 are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,
  • CSF cesium fluoride
  • ATP adenosine triphosphate
  • C18 refers to 18-carbon alkyl groups on silicon in HPLC stationary phase
  • DIPEA Hiinig’s base, A/-ethyl-A/-(1 -methylethyl)-2-propanamine
  • DMEDA (A/,A/-dimethylethylenediamine);
  • DPPA diphenyl phosphoryl azide
  • EDTA ethylenediaminetetraacetic acid
  • HEPES (4-(2-hydroxyethyl)-1 -piperazine ethane sulfonic acid);
  • HATU (0-(7-Azabenzotriazol-1-yl)-A/,A/,A/',A/'-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole);
  • HMDS hexamethyldisilazide
  • Hunig’s Base (A/,A/-Diisopropylethylamine);
  • IPA isopropyl alcohol
  • KHMDS potassium hexamethyldisilazide
  • LAH lithium aluminum hydride
  • LHMDS lithium hexamethyldisilazide
  • MTBE methyl tert-butyl ether
  • mCPBA m-chloroperbezoic acid
  • NaHMDS sodium hexamethyldisilazide
  • NBS (/V-bromosuccinimide
  • PE petroleum ether
  • TFA trifluoroacetic acid
  • the compounds according to Formula (I) are prepared using conventional organic synthetic methods. Suitable synthetic routes are depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art. The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P.
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • Substituted bicyclic aromatic compounds of general structure K were prepared from amines (B). Reaction of the diazonium salt of a suitable compound, such as 4- aminobenzenesulfonic acid, with the amine (B) provides the azo intermediate (C).
  • a suitable compound such as 4- aminobenzenesulfonic acid
  • Amine G can also be obtained from amines (A) using two general methods.
  • reaction of amine (A) with a suitable protecting group reagent, such as Boc 2 0, in the presence of a suitable base, such as DMAP and TEA, in a solvent, such as DCM provides the protected intermediate (D).
  • a suitable protecting group reagent such as Boc 2
  • a suitable base such as DMAP and TEA
  • a solvent such as DCM
  • D protected intermediate
  • Reaction with tert-butyl carbamate in the presence of a suitable catalyst, such as Pd(OAc) 2 , and a suitable ligand, sucha as XPhos, in the presence of a suitable base, such as cesium carbonate, in a suitable solvent, such as dioxane affords the protected amine (E ).
  • a suitable reagent such as HCI
  • a suitable reagent such as ammonium formate
  • a suitable catalyst such as palladium
  • a suitable solvent such as methanol
  • Amine (G) can then be coupled under three standard conditions.
  • Acid chloride (H) can be coupled to amine (G) using a suitable base, such as triethylamine, in a suitable solvent, such as DCM or DMF, to provide the general product (K), method A.
  • the final amide product (K) can be formed using method B: T3P and triethylamine in DCM, or method C: N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), using a suitable base, such as N-methylimidazole, in a suitable solvent, such as acetonitrile.
  • a suitable base such as N-methylimidazole
  • a suitable solvent such as acetonitrile
  • the compounds according to Formula (I) and pharmaceutically acceptable salts thereof are inhibitors of the ATF4 pathway.
  • Compounds which are inhibitors of the ATF4 pathway are readily identified by exhibiting activity in the ATF4 Cell Based Assay below. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to (but not limited to) modulation of the elF2alpha pathway, for example, neurodegenerative disorders, cancer, cardiovascular and metabolic diseases. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the Integrated Stress Response is a collection of cellular stress response pathways that converge in phosphorylation of the translation initiation factor elF2a resulting in a reduction in overall translation in cells.
  • Mammalian cells have four elF2a kinases that phosphorylate this initiation factor in the same residue (serine 51); PERK is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 is activated by amino acid starvation, PKR by viral infection and HRI by heme deficiency. Activation of these kinases decreases bulk protein synthesis but it also culminates in increased expression of specific mRNAs that contain uORFs.
  • An integrated stress response-associated disease is a disease characterized by increased activity in the integrated stress response (e.g. increased phosphorylation of elF2a by an elF2a kinase compared to a control such as a subject without the disease).
  • a disease associated with phosphorylation of elF2a is disease characterized by an increase in phosphorylation of elF2a relative to a control, such as a subject without the disease.
  • PERK Activation of PERK occurs upon ER stress and hypoxic conditions and its activation and effect on translation has been shown to be cytoprotective for tumor cells [17] Adaptation to hypoxia in the tumor microenvironment is critical for survival and metastatic potential. PERK has also been shown to promote cancer proliferation by limiting oxidative DNA damage and death [18, 19] Moreover, a newly identified PERK inhibitor has been shown to have antitumor activity in a human pancreatic tumor xenograft model [20] Compounds disclosed herein decrease the viability of cells that are subjected to ER-stress. Thus, pharmacological and acute inhibition of the PERK branch with the compounds disclosed herein results in reduced cellular fitness. During tumor growth, compounds disclosed herein, that block the cytoprotective effects of elF2a phosphorylation upon stress may prove to be potent anti-proliferative agents.
  • Prolonged ER stress leads to the accumulation of CHOP, a pro-apoptotic molecule.
  • CHOP a pro-apoptotic molecule.
  • overexpression of the phosphatase of elF2a increased survival of prion- infected mice whereas sustained elF2a phosphorylation decreased survival [22]
  • the restoration of protein translation rates during prion disease was shown to rescue synaptic deficits and neuronal loss.
  • the compounds disclosed herein th at make cells insensitive to elF2a phosphorylation sustain protein translation. Compounds disclosed herein could prove potent inhibitors of neuronal cell death in prion disease by blocking the deleterious effects of prolonged elF2a phosphorylation.
  • tissue-specific pathology that is linked to heightened elF2a phosphorylation is the fatal brain disorder, vanishing white matter disease (VWM) or childhood ataxia with CNS hypo-myelination (CACH).
  • VWM vanishing white matter disease
  • CACH CNS hypo-myelination
  • This disease has been linked to mutation in elF2B, the GTP exchange factor that is necessary for elF2 function in translation [23] elF2a phosphorylation inhibits the activity of elF2B and mutations in this exchange factor that reduce its exchange activity exacerbate the effects of elF2a phosphorylation.
  • the severe consequences of the CACH mutations point to the dangers of UPR hyper-activation, especially as it pertains to the myelin-producing oligodendrocyte.
  • Small molecules, such as compounds disclosed herein, that block signaling through elF2a phosphorylation may reduce the deleterious effects of its hyperactivation in VWM.
  • a method of improving long-term memory in a patient including administering a therapeutically effective amount of a compound of Fo rm u l a (I) to the patient.
  • the patient is human.
  • the patient is a mammal.
  • the compounds set forth herein are provided as pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient.
  • the compound, or a pharmaceutically acceptable salt thereof is co-adminstered with a second agent (e.g. therapeutic agent).
  • the compound, or a pharmaceutically acceptable salt thereof is co-adminstered with a second agent (e.g. therapeutic agent), which is administered in a therapeutically effective amount.
  • the second agent is an agent for improving memory.
  • Regulators of translation could serve as therapeutic agents that improve memory in human disorders associated with memory loss such as Alzheimer's disease and in other neurological disorders that activate the UPR in neurons and thus could have negative effects on memory consolidation such as Parkinson's disease, Amyotrophic lateral sclerosis and prion diseases.
  • elF2y that disrupts complex integrity linked intellectual disability (intellectual disability syndrome or ID) to impaired translation initiation in humans [27]
  • ID and VWM two diseases with impaired elF2 function, display distinct phenotypes but both affect mainly the brain and impair learning.
  • the compounds of Formula (I) are also useful in applications where increasing protein production output is desirable, such as in vitro cell free systems for protein production.
  • In vitro systems have basal levels of elF2a phosphorylation that reduce translational output [28, 29]
  • production of antibodies by hybridomas may also be improved by addition of compounds disclosed herein.
  • a method of increasing protein expression of a cell or in vitro expression system including administering an effective amount of a compound of Formula (I) to the cell or expression system.
  • the method is a method of increasing protein expression by a cell and includes administering an effective amount of a compound of Formula (I) to the cell.
  • the method is a method of increasing protein expression by an in vitro protein expression system and includes administering an effective amount of a compound of Formula (I) to the in vitro (e.g. cell free) protein expression system.
  • the compounds set forth herein are provided as pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient.
  • the compound, or a pharmaceutically acceptable salt thereof is co-adminstered with a second agent.
  • the compound, or a pharmaceutically acceptable salt thereof is co-adminstered with a second agent, which is administered in a therapeutically effective amount.
  • the second agent is an agent for improving protein expression.
  • the present invention relates to a method for treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.
  • the present invention relates to a method for treating or lessening the severity of colon cancer.
  • the present invention relates to a method for treating or lessening the severity of pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.
  • the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.
  • the present invention relates to a method for treating or lessening the severity of lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.
  • the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia,
  • the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the pre- cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.
  • the pre- cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) ne
  • the present invention relates to a method for treating or lessening the severity of neurodegenerative diseases/injury, such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
  • neurodegenerative diseases/injury such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases
  • the present invention relates to a method for preventing organ damage during and after organ transplantation and in the transportation of organs for transplantation.
  • the method of preventing organ damage during and after organ transplantation will comprise the in vivo administration of a compound of Formula (I).
  • the method of preventing organ damage during the transportation of organs for transplantation will comprise adding a compound of Formula (I) to the solution housing the organ during transportation.
  • the present invention relates to a method for treating or lessening the severity of ocular diseases/angiogenesis.
  • the method of treating or lessening the severity of ocular diseases/angiogenesis will comprise the in vivo administration of a compound of Formula (I).
  • the disorder of ocular diseases can be: edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma filtering blebs, conjunctival papilloma; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema, such as post surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, macular edema secondary to diabetes, and macular edema secondary to retinovascular occlusive disease (i.e.
  • retinal vascular disease such as rubeosis irides, neovascular glaucoma, pterygium,
  • retinal neovascularization due to diabetes such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eale's Disease; and genetic disorders, such as VonHippel-Lindau syndrome.
  • the neovascular age-related macular degeneration is wet age-related macular degeneration. In other embodiments, the neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized as being at increased risk of developing wet age-related macular degeneration.
  • the methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, thereof to a patient in need thereof.
  • the invention also provides a compound according to Formula (III) or a pharmaceutically-acceptable salt thereof for use in preventing organ damage during the transportation of organs for transplantation.
  • the invention is directed to the use of a compound according to Formula (III) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by activation of the UPR, such as cancer.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a mammal, suitably a human, in need thereof.
  • treating in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • treating and derivatives thereof refers to therapeutic therapy.
  • Therapeutic therapy is appropriate to alleviate symptions or to treat at early signs of disease or its progression.
  • Prophylactic therapy is appropriate when a subject has, for example, a strong family history of neurodegenerative diseases.
  • Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of formula (I), or a pharmaceutically acceptable salt thereof, means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of the compound will vary with the particular route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • patient refers to a human or other mammal, suitably a human.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration.
  • Systemic administration includes oral administration, and parenteral administration.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half- life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound.
  • esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.
  • anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and antifolate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.
  • anti-microtubule agents such as diterpen
  • the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of December 19, 2001 , International Publication Number W002/059110 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69.
  • a VEGFR inhibitor suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride
  • the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc. ), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti- VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.
  • immunostimulants e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.
  • monoclonal antibodies e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti- VE
  • radioimmunotherapy e.g., anti-CD20 monoclonal antibody conjugated to 1 11 1n, 90 Y, or 131 1 , etc.
  • the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as 47 Sc, 64 C 67 C, 89 Sr, 86 Y, 87 Y, and 212 Bi, optionally conjugated to antibodies directed against tumor antigens.
  • anti-neoplastic agent for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are anti-PD-L1 agents.
  • Anti-PD-L1 antibodies and methods of making the same are known in the art.
  • Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized.
  • PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer.
  • the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149.
  • the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent No. 8,217,149.
  • the anti-PD-L1 antibody is BMS-936559 (MDX-1 105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another embodiment, the anti-PD-L1 antibody is MEDI4736.
  • a further active ingredient or ingredients for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are PD-1 antagonist.
  • PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1 .
  • Alternative names or synonyms for PD-1 and its ligands include: PDCD1 , PD1 , CD279 and SLEB2 for PD-1 ; PDCD1 L1 , PDL1 , B7H1 , B7-4, CD274 and B7-H for PD-L1 ; and PDCD1 L2, PDL2, B7- DC, Btdc and CD273 for PD-L2.
  • the PD-1 antagonist blocks binding of human PD-L1 to human PD-1 , and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1 .
  • Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009.
  • Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515,
  • PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 , and preferably specifically binds to human PD-1 or human PD-L1 .
  • the mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region.
  • the human constant region is selected from the group consisting of lgG1 , lgG2, lgG3 and lgG4 constant regions, and in preferred embodiments, the human constant region is an lgG1 or lgG4 constant region.
  • the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.
  • Fab fragment-specific Fab
  • Fab'-SH fragment-specific Fab
  • F(ab')2 fragment-specific Fab
  • scFv fragment-specific Fab
  • Fv fragment-specific Fab fragment-specific Fab
  • mAbs that bind to human PD-1 are described in US7488802, US7521051 , US8008449, US8354509, US8168757, W02004/004771 ,
  • Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161 -162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No.
  • immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and
  • fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD- 1 .
  • Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C.
  • KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck.
  • the amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No. S.168,757.
  • Opdivo/nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity.
  • Nivolumab binds to and blocks the activation of PD-1 , an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens.
  • Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation.
  • Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in US Patent No. US
  • Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are immuno-modulators.
  • immuno-modulators refer to any substance including monoclonal antibodies that affects the immune system.
  • the ICOS binding proteins of the present invention can be considered immune-modulators.
  • Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer.
  • immune-modulators include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab).
  • Other immuno- modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41 BB antibodies and GITR antibodies.
  • Yervoy is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb.
  • the protein structure of ipilimumab and methods are using are described in US Patent Nos. 6,984,720 and 7,605,238.
  • the compounds of the invention are combined with an inhibitor of the activity of the protein kinase R (PKR)-like ER kinase, PERK.
  • PPKR protein kinase R
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of neurodegenerative diseases/injury.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of diabetes.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cardiovascular disease.
  • the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of ocular diseases.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers of secretory cells), neurodegenerative diseases, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, and/or intellectual disability syndromes (e.g. associated with impaired function of elF2 or components in a signal transduction pathway including elF2), or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • cancer e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers of secretory cells
  • neurodegenerative diseases e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers of secretory cells
  • neurodegenerative diseases e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers of secretory cells
  • neurodegenerative diseases
  • the compounds set forth herein are provided as pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient.
  • the compound, or a pharmaceutically acceptable salt thereof is co- adminstered with a second agent (e.g. therapeutic agent).
  • the compound, or a pharmaceutically acceptable salt thereof is co-adminstered with a second agent (e.g. therapeutic agent), which is administered in a therapeutically effective amount.
  • the second agent is an agent for treating cancer (e.g.
  • the second agent is an anti-cancer agent.
  • the second agent is a chemotherapeutic.
  • the second agent is an agent for improving memory.
  • the second agent is an agent for treating a neurodegenerative disease.
  • the second agent is an agent for treating vanishing white matter disease.
  • the second agent is an agent for treating childhood ataxia with CNS hypo- myelination. In embodiments, the second agent is an agent for treating an intellectual disability syndrome. In embodiments, the second agent is an agent for treating pancreatic cancer. In embodiments, the second agent is an agent for treating breast cancer. In embodiments, the second agent is an agent for treating multiple myeloma. In embodiments, the second agent is an agent for treating myeloma. In embodiments, the second agent is an agent for treating a cancer of a secretory cell. In embodiments, the second agent is an agent for reducing elF2a phosphorylation. In embodiments, the second agent is an agent for inhibiting a pathway activated by elF2a phosphorylation. In embodiments, the second agent is an agent for inhibiting the integrated stress response. In embodiments, the second agent is an anti-inflammatory agent.
  • elF2alpha refers to the protein "Eukaryotic translation initiation factor 2A".
  • elF2alpha refers to the human protein. Included in the term “elF2alpha” or “elF2a” are the wildtype and mutant forms of the protein.
  • elF2alpha refers to the protein associated with Entrez Gene 83939, OMIM 609234, UniProt Q9BY44, and/or RefSeq (protein) NP 114414.
  • the present invention relates to a method for treating an integrated stress response associated disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.
  • the integrated stress response-associated disease is cancer.
  • the integrated stress response-associated disease is a neurodegenerative disease.
  • the integrated stress response-associated disease is vanishing white matter disease.
  • the integrated stress response-associated disease is childhood ataxia with CNS hypo-myelination.
  • the integrated stress response-associated disease is an intellectual disability syndrome.
  • the present invention relates to a method for treating a disease associated with phosphorylation of elF2a in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.
  • the disease associated with phosphorylation of elF2 a is cancer.
  • the disease associated with phosphorylation of elF2 a is a neurodegenerative disease.
  • the disease associated with phosphorylation of elF2 a is vanishing white matter disease.
  • the disease associated with phosphorylation of elF2 a is childhood ataxia with CNS hypo-myelination.
  • the disease associated with phosphorylation of elF2 a is an intellectual disability syndrome.
  • the present invention relates to a method for treating a disease selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome.
  • the present invention relates to a method for treating an inflammatory disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.
  • the inflammatory disease is associated with neurological inflammation.
  • the inflammatory disease is postoperative cognitive dysfunction.
  • the inflammatory disease is traumatic brain injury or chronic traumatic encephalopathy (CTE).
  • the disease is selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, and an intellectual disability syndrome.
  • the disease is cancer.
  • the disease is a neurodegenerative disease.
  • the disease is vanishing white matter disease.
  • the disease is childhood ataxia with CNS hypo-myelination.
  • the method is an intellectual disability syndrome.
  • the disease is associated with phosphorylation of elF2a. In embodiments of the method of treating a disease, the disease is associated with an elF2a signaling pathway. In embodiments of the method of treating a disease, the disease is a cancer of a secretory cell type. In embodiments of the method of treating a disease, the disease is pancreatic cancer. In embodiments of the method of treating a disease, the disease is breast cancer. In embodiments of the method oftreating a disease, the disease is multiple myeloma. In embodiments of the method of treating a disease, the disease is lymphoma. In embodiments of the method of treating a disease, the disease is leukemia. In embodiments of the method of treating a disease, the disease is a hematopoietic cell cancer.
  • the disease is Alzheimer's disease. In embodiments of the method of treating a disease, the disease is Amyotrophic lateral sclerosis. In embodiments of the method of treating a disease, the disease is C re utzfeldt- Jakob disease. In embodiments of the method of treating a disease, the disease is frontotemporal dementia. In embodiments of the method of treating a disease, the disease is Gerstmann-Straussler-Scheinker syndrome. In embodiments of the method of treating a disease, the disease is Huntington's disease. In embodiments of the method of treating a disease, the disease is HIV-associated dementia. In embodiments of the method of treating a disease, the disease is kuru.
  • the disease is Lewy body dementia. In embodiments of the method of treating a disease, the disease is Multiple sclerosis. In embodiments of the method of treating a disease, the disease is Parkinson's disease. In embodiments of the method of treating a disease, the disease is a Prion disease.
  • the disease is an inflammatory disease.
  • the inflammatory disease is postoperative cognitive dysfunction.
  • the inflammatory disease is traumatic brain injury.
  • the inflammatory disease is arthritis.
  • the inflammatory disease is rheumatoid arthritis.
  • the inflammatory disease is psoriatic arthritis.
  • the inflammatory disease is juvenile idiopathic arthritis.
  • the inflammatory disease is multiple sclerosis.
  • the inflammatory disease is systemic lupus erythematosus (SLE).
  • the inflammatory disease is myasthenia gravis.
  • the inflammatory disease is juvenile onset diabetes.
  • the inflammatory disease is diabetes mellitus type 1 .
  • the inflammatory disease is Guillain-Barre syndrome.
  • the inflammatory disease is Hashimoto's encephalitis.
  • the inflammatory disease is Hashimoto's thyroiditis.
  • the inflammatory disease is ankylosing spondylitis.
  • the inflammatory disease is psoriasis.
  • the inflammatory disease is Sjogren's syndrome.
  • the inflammatory disease is vasculitis.
  • the inflammatory disease is glomerulonephritis.
  • the inflammatory disease is auto-immune thyroiditis.
  • the inflammatory disease is Behcet's disease.
  • the inflammatory disease is Crohn's disease. In embodiments, the inflammatory disease is ulcerative colitis. In embodiments, the inflammatory disease is bullous pemphigoid. In embodiments, the inflammatory disease is sarcoidosis. In embodiments, the inflammatory disease is ichthyosis. In embodiments, the inflammatory disease is Graves ophthalmopathy. In embodiments, the inflammatory disease is inflammatory bowel disease. In embodiments, the inflammatory disease is Addison's disease. In embodiments, the inflammatory disease is Vitiligo. In embodiments, the inflammatory disease is asthma. In embodiments, the inflammatory disease is allergic asthma. In embodiments, the inflammatory disease is acne vulgaris.
  • the inflammatory disease is celiac disease. In embodiments, the inflammatory disease is chronic prostatitis. In embodiments, the inflammatory disease is inflammatory bowel disease. In embodiments, the inflammatory disease is pelvic inflammatory disease. In embodiments, the inflammatory disease is reperfusion injury. In embodiments, the inflammatory disease is sarcoidosis. In embodiments, the inflammatory disease is transplant rejection. In embodiments, the inflammatory disease is interstitial cystitis. In embodiments, the inflammatory disease is atherosclerosis. In embodiments, the inflammatory disease is atopic dermatitis.
  • the method of treatment is a method of prevention.
  • a method of treating postsurgical cognitive dysfunction may include preventing postsurgical cognitive dysfunction or a symptom of postsurgical cognitive dysfunction or reducing the severity of a symptom of postsurgical cognitive dysfunction by administering a compound described herein prior to surgery.
  • this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome.
  • a disease selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome.
  • this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of an integrated stress response associated disease.
  • this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with phosphorylation of elF2a.
  • this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease selected from the group consisting of cancer, a
  • this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment an integrated stress response associated disease.
  • this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with phosphorylation of elF2a.
  • the pharmaceutically active compounds within the scope of this invention are useful as ATF4 pathway inhibitors in mammals, particularly humans, in need thereof.
  • the present invention therefore provides a method of treating cancer, neurodegeneration and other conditions requiring ATF4 pathway inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as ATF4 pathway inhibitors.
  • the drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular and parenteral.
  • a ATF4 pathway inhibitor may be delivered directly to the brain by intrathecal or intraventricular route, or implanted at an appropriate anatomical location within a device or pump that continuously releases the ATF4 pathway inhibiting drug.
  • Solid or liquid pharmaceutical carriers are employed.
  • Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • Liquid carriers include syrup, peanut oil, olive oil, saline, and water.
  • the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit.
  • the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.
  • compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular ATF4 pathway inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.
  • a compound of Formula (I) When administered to prevent organ damage in the transportation of organs for transplantation, a compound of Formula (I) is added to the solution housing the organ during transportation, suitably in a buffered solution.
  • the method of this invention of inducing ATF4 pathway inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective ATF4 pathway inhibiting amount of a pharmaceutically active compound of the present invention.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a ATF4 pathway inhibitor.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer, pre-cancerous syndromes, Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, C re utzfeldt- Jakob Disease, and related prion diseases, progressive
  • the invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in preventing organ damage during the transportation of organs for transplantation.
  • the invention also provides for a pharmaceutical composition for use as a ATF4 pathway inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a ATF4 pathway inhibitor.
  • the invention also provides novel processes and novel intermedites useful in preparing the presently invented compounds.
  • the invention also provides a pharmaceutical composition comprising from 0.5 to 1 ,000 mg of a compound of Formula (I) or pharmaceutically acceptable salt thereof and from 0.5 to 1 ,000 mg of a pharmaceutically acceptable excipient.
  • Step 1 tert-butyl 4-amino-7-((diphenylmethylene)amino)isoindoline-2-carboxylate
  • the sample was purified by column chromatography (Column size: 5 c 25 cm, column volume: 480 ml_, silica gel size: 100 ⁇ 200 mesh, quantity: 450 g) and eluted with ethyl acetate/petroleum ether. Collected fractions: ethyl acetate/petroleum ether(35/65) fractions were choosen as pure fractions. Those fractions were combined and concentrated under reduced pressure to afford the desired product. The desired product was isolated as a yellow solid, 900 mg; 92% pure; 37 % yield. LCMS MS (ESI, m/z): 414.2 [M+H] + ,
  • Step 2 tert-butyl 4.7-diaminoisoindoline-2-carboxylate
  • Step 3 tert-butyl 4.7-bis(2-(4-chlorophenoxy)acetamido)isoindoline-2-carboxylate
  • the sample was purified by column chromatography (Column size: 5 c 25 cm, column volume: 480 ml_, silica gel size: 100 ⁇ 200 mesh, quantity: 450 g) and eluted with ethyl acetate/petroleum ether. Collected fractions: ethyl acetate/petroleum ether(35/65) fractions were choosen as pure fractions. Those fractions were combined and concentrated under reduced pressure to afford the desired product as a yellow solid, 800 mg; 75% pure; 85% yield. LCMS MS (ESI, m/z): 486.1 [M-BOC+H] +
  • Step 4 N.N'-(isoindoline-4.7-diyl)bis(2-(4-chlorophenoxy)acetamide)
  • Step 5 N.N'-(2-methylisoindoline-4.7-divhbis(2-(4-chlorophenoxy)acetamide)
  • the product was extracted into dichloromethane (3 x 50 mL) and the organic layers were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product.
  • the crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column 30 x 150 mm, 5 mhi; Mobile Phase A:Water(10 mmol/L NH4HCO3 + 0.1 %NH 3 .H 2 O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 45 % B to 60 % B in 9 min; 220 nm; Rt: 7.70 min) to provide the desired product as a white solid, 10 mg; 99 % pure; 5 % yield.
  • Step 1 4-amino-7-bromo-3-hvdroxyisoindolin-1-one
  • Step 3 tert-butyl 4- ⁇ bisr(tert-butoxy)carbonyllaminoV7-bromo-1-oxo-2.3-dihvdro- 1 H-isoindole-2-carboxylate
  • the sample was purified by column chromatography (Column size 2.5 c 20 cm, column volume : 100 mL, silica gel size ( 100 ⁇ 200 mesh) quantity: 45 g) and eluted with petroleum ether/ethyl acetate. Collected fractions: 2 % - 4 % ethyl acetate/petroleum ether fractions were choosen as pure fractions. Those fractions were combined and concentrated under reduced pressure to afford the desired product as a brown oil ,900 mg, 75 % pure, 36.3 %yield.
  • Step 4 tert-butyl 4-(bis(tert-butoxycarbonyl)amino)-7-((tert-butoxycarbonyl)amino)-
  • tert-butyl 4- ⁇ bis[(tert-butoxy)carbonyl]amino ⁇ -7-bromo-1 -oxo-2,3-dihydro- 1 H-isoindole-2-carboxylate 870 mg, 1.65 mmol
  • tert-butyl carbamate 386 mg, 3.30 mmol
  • Pd(OAc) 2 37.0 mg, 0.165 mmol
  • dicyclohexyl(2',4',6'-triisopropyl-[1 ,T-biphenyl]-2-yl)phosphane (236 mg, 0.495 mmol) and Cs 2 C0 3 (1.61 g, 4.95 mmol).
  • the reaction mixture was stirred for 16 h at room temperature.
  • the reaction mixture was concentrated under reduced pressure to afford the crude product.
  • the crude product was diluted with dichloromethane (30 mL) and slurried with 100 ⁇ 200 silica gel mesh.
  • the sample was purified by column chromatography (Column size 2.5 c 20 cm, column volume: 100 mL, silicagel size (100 ⁇ 200 mesh) quantity: 40 g) and eluted with ethyl acetate/petroleum ether.
  • Step 6 N.N'-(1 -oxoisoindoline-4.7-diyl)bis(2-(4-chlorophenoxy)acetamide)
  • Step 1 4-nitro-2.3-dihvdro-1 H-indene-2-carboxylic acid
  • Nitric acid (8.27 ml_, 185 mmol) was added dropwise to a stirred solution of 2,3-dihydro- 1 H-indene-2-carboxylic acid (5.00 g, 30.8 mmol) inTrifluoroacetic acid (TFA) (50 mL) at 0 °C, and the solution stirred at 0 °C for 2.5 h.
  • the product was extracted into DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product.
  • the crude product was diluted with dichloromethane (30 mL) and slurried with 100 ⁇ 200 silica gel mesh (3 g).
  • the sample was purified by column chromatography (Column size 5 x 25 cm, column volume : 200 mL, silica gel size (300 ⁇ 400 mesh) quantity: 80 g) and eluted with EtOAc/petroleum ether (0-50 %). Pure fractions were combined and concentrated under reduced pressure to afford the product as a white solid, 5.7 g, 98.7 % pure, 88 %yield.
  • Step 3 (E)-4-amino-7-((4-sulfophenyl)diazenyl)-2.3-dihvdro-1 H-indene-2-carboxylic acid
  • Example 6 ATF4 Cell Based Assay
  • the ATF4 reporter assay measures the effect of Thapsigargin induced cellular stress on ATF4 expression.
  • a stable cell line was created by transfecting SH-SY5Y cells with a plasmid containing the NanoLuc® luciferase gene fused to the 5’-UTR of ATF4, under the control of the CMV promoter.
  • the ATF4 5’-UTR contains two open reading frames which mediate the cellular stress-dependent translation of the reporter gene. Clones stably expressing the reporter construct were isolated and selected based on the luminescence response to thapsigargin and inhibition of this signal by test compounds.
  • SH-SY5Y-ATF4-NanoLuc cells were challenged with Thapsigargin for 14-18 hours to determine the stress effect with or without test compounds.
  • Cells were propagated in growth media consisting of 90% DMEM F12 (InVitrogen
  • Cells were prepared for the assay by removing all media from cells, washing the plated cells with phosphate buffered saline, and detached by adding a solution comprised of 10% Tryple express solution (lnVitrogen12604-021) and 90% enzyme-free cell dissociation buffer HANKS base (Gibco 13150-016).
  • the trypsin was deactivated by adding assay media comprised of 90% phenol-red free DMEM F12 (InVitrogen, 11039), 10% Fetal Bovine Serum (Gibco # 10438-026), ( 5mM Glutamax (Gibco # 35050-061), 5mM Hepes, (Gibco # 15630-080), and 0.5mg/ml Geneticin (Gibco # 10131-027).
  • Assay plates were prepared by adding 250 nL of compound stock solution in 100% DMSO to each well, followed by dispensing 20 microliters/well cell suspension to deliver 15-20k cell/well. Cells were incubated for 1 hour at 37°C. Then, 5pL of 1 5pM or 1 pM of Thapsigargin (final concentration: 200-300nM) was added to each well of cells. Assay plates containing cells were incubated for 14-18 hours at 37°C.
  • luciferase produced by the ATF4 constructs was measured as follows. Aliquots of the Nano-Glo reagent (Nano-Glo® Luciferase Assay Substrate, Promega, N 113, Nano-Glo® Luciferase Assay Buffer, Promega, N112 (parts of Nano- Glo® Luciferase Assay System, N1150) were brought to room temperature, the substrate and buffer were mixed according to manufacturer’s instructions. The cell plates were equilibrated to room temperature. 25microliters/well of the mixed Nano-Glo reagent were dispensed into assay wells and pulse spun to settle contents and the plate was sealed with film. The plates were incubated at room temperature for 1 hour before detecting luminescence on an Envision plate reader.
  • An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table 2, below.
  • Example 8 Injectable Parenteral Composition
  • An injectable form for administering the present invention is produced by stirring 1 .7% by weight of N,N'-(1 -oxoisoindoline-4,7-diyl)bis(2-(4-chlorophenoxy)acetamide) (Compound of Example 2) in 10% by volume propylene glycol in water.
  • sucrose, calcium sulfate dihydrate and an ATF4 pathway inhibitor as shown in Table 3 below are mixed and granulated in the proportions shown with a 10% gelatin solution.
  • the wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.
  • indene-2-carboxylic acid (Compound of Example 3) calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg
  • Example 1 The compound of Example 1 was tested generally according to the above ATF4 cell based assay and in two experimental runs exhibited an ATF4 pathway inhibitory activity (IC50) of 250 nM.
  • Example 2 and 3 were tested generally according to the above ATF4 cell based assay and in two experimental runs exhibited an ATF4 pathway inhibitory activity (IC50) of between 1 and 10 mM.
  • Ron D Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007 Jul;8(7):519— 29.
  • PERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage.
  • Avivar-Valderas A Bobrovnikova-Marjon E, Diehl A, Nagi C, Debnath J, Aguirre- Guiso JA 201 1 .
  • PERK integrates autophagy and oxidative stress responses to promote survival during extracellular matrix detachment. Mol Cel Biol 31 :3616- 3629.

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Abstract

L'invention concerne des dérivés aromatiques bicycliques substitués. Plus particulièrement, l'invention concerne des composés de formule (I), dans laquelle A, C, D, L2, L3, R1, R2, R3, R4, R5, R6, z2, z4, z5 et z6 sont tels que définis dans la description ; ou des sels de ceux-ci. Les composés selon l'invention sont des inhibiteurs de la voie ATF4 et peuvent être utiles dans le traitement du cancer, de syndromes précancéreux et de maladies associées à des voies de réponse à des protéines dépliées (UPR) activées, telles que la maladie d'Alzheimer, les lésions de la moelle épinière, les lésions cérébrales traumatiques, les accidents ischémiques cérébraux, les accidents vasculaires cérébraux, le diabète, la maladie de Parkinson, la maladie de Huntington, la maladie de Creutzfeldt-Jakob et les maladies à prions apparentées, la paralysie supranucléaire progressive, la sclérose latérale amyotrophique, l'infarctus du myocarde, les maladies cardiovasculaires, l'inflammation, la fibrose, les maladies chroniques et aiguës du foie, les maladies chroniques et aiguës des poumons, les maladies chroniques et aiguës des reins, l'encéphalopathie traumatique chronique (ETC), la neurodégénérescence, la démence, la déficience cognitive, l'athérosclérose, les maladies oculaires, les arythmies, dans la transplantation d'organes et dans le transport d'organes en vue d'une transplantation. Par conséquent, l'invention concerne en outre des compositions pharmaceutiques comprenant un composé selon l'invention. L'invention concerne enfin des procédés d'inhibition de la voie ATF4 et de traitement de troubles associés à celle-ci à l'aide d'un composé selon l'invention ou d'une composition pharmaceutique comprenant un composé selon l'invention.
PCT/IB2019/052776 2018-04-06 2019-04-04 Dérivés de cycle aromatiques bicycliques de formule (i) utilisés en tant qu'inhibiteurs d'atf4 WO2019193541A1 (fr)

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