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EP3634952A1 - Composés chimiques utilisés comme inhibiteurs de la voie atf4 - Google Patents

Composés chimiques utilisés comme inhibiteurs de la voie atf4

Info

Publication number
EP3634952A1
EP3634952A1 EP18733953.6A EP18733953A EP3634952A1 EP 3634952 A1 EP3634952 A1 EP 3634952A1 EP 18733953 A EP18733953 A EP 18733953A EP 3634952 A1 EP3634952 A1 EP 3634952A1
Authority
EP
European Patent Office
Prior art keywords
azetidinyl
bicyclo
pentan
acetamide
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP18733953.6A
Other languages
German (de)
English (en)
Inventor
Jeffrey Michael Axten
Michael P. Demartino
Karen Anderson Evans
Jeffrey M Ralph
Biswajit Kalita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline Intellectual Property Development Ltd
Original Assignee
GlaxoSmithKline Intellectual Property Development Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GlaxoSmithKline Intellectual Property Development Ltd filed Critical GlaxoSmithKline Intellectual Property Development Ltd
Priority claimed from PCT/IN2018/050375 external-priority patent/WO2018225093A1/fr
Publication of EP3634952A1 publication Critical patent/EP3634952A1/fr
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
    • C07C235/22—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 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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Definitions

  • the present invention relates to substituted bridged cycloalkane 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, neurological disorders, pain, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
  • elF2a In metazoa, diverse stress signals converge at a single phosphorylation event at serine 51 of a common effector, the translation initiation factor elF2a.
  • This step is carried out by four elF2a kinases in mammalian cells: PERK, which responds to an accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 to amino acid starvation and UV light, PKR to viral infection, and HRI to heme deficiency.
  • ISR integrated stress response
  • elF2a phosphorylation results in an attenuation of translation with consequences that allow cells to cope with the varied stresses (1 ).
  • elF2 (which is comprised of three subunits, ⁇ , ⁇ , a n d ⁇ ) binds GTP and the initiator Met-tRNA to form the ternary complex (elF2-GTP-Met-tRNAi), which, in turn, associates with the 40S ribosomal subunit scanning the 5'UTR ofmRNAs to select the initiating AUG codon.
  • elF2 Upon phosphorylation of its a-subunit, elF2 becomes a competitive inhibitor of its GTP-exchange factor (GEF), elF2B (2).
  • GEF GTP-exchange factor
  • mRNAs that contain upstream open reading frames (uORFs) in their 5'UTR are translationally up-regulated (4,5).
  • uORFs upstream open reading frames
  • mRNAs that contain upstream open reading frames (uORFs) in their 5'UTR are translationally up-regulated (4,5).
  • ATF4 a cAMP element binding (CREB) transcription factor
  • CHOP a pro-apoptotic transcription factor
  • ATF4 regulates the expression of many genes involved in metabolism and nutrient uptake and additional transcription factors, such as CHOP, which is under both translational and transcriptional control (9).
  • Phosphorylation of elF2a thus leads to preferential translation of key regulatory molecules and directs diverse changes in the transcriptome of cells upon cellular stress.
  • 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 XBP 1 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 XBP 1 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, 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).
  • Small-molecule therapeutics that inhibit the UPR and/or the Integrated Stress Response could be used in cancer as a single agent or in combination with other chemotherapeutics ( 1 7 , 1 8 , 1 9 ) , for enhancement of long-term memory (24,25) , in neurodegenerative and prion associated diseases (20) , in white matter disease (VWM) (23) and in biotechnology applications that would benefit from increased protein translation.
  • chemotherapeutics 1 7 , 1 8 , 1 9
  • compositions that comprise a pharmaceutically acceptable excipient and compounds of Formula (IIIQ). 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, neurological disorders, pain, 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 bridged cycloalkane derivatives. Specifically, the invention is directed to compounds according to Formula I IIQ:
  • 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 HQ) are active as inhibitors of the ATF4 pathway.
  • the present invention also relates to the discovery that the compounds of Formula (I HQ) prevent the translation of ATF4.
  • This invention also relates to a method of treating Alzheimer's disease, which comprises administering to a human in need thereof an effective amount of a compound of Formula (II IQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Parkinson's disease, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating amyotrophic lateral sclerosis, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Huntington's disease, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating Creutzfeldt-Jakob Disease, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating progressive supranuclear palsy (PSP), which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) 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 human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating spinal cord injury, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating traumatic brain injury, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating ischemic stroke, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • This invention also relates to a method of treating diabetes, which comprises administering to a human in need thereof an effective amount of a compound of Formula (IIIQ) 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 human in need thereof an effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof.
  • a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias
  • This invention also relates to a method of treating an integrated stress response-associated disease in a patient in need of such treatment, which comprises administering a therapeutically effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof, to the patient.
  • This invention also relates to a method of treating a disease associated with phosphorylation of elF2a in a patient in need of such treatment, which comprises administering a therapeutically effective amount of a compound of Formula (IIIQ), or a pharmaceutically acceptable salt thereof, to the patient.
  • This invention also relates to a method of treating a disease in a patient in need of such treatment, which comprises administering a therapeutically effective amount of a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof, to the patient, wherein the disease is 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 is 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 also relates to a method of improving long-term memory in a patient, which comprises administering a therapeutically effective amount of a compound of Formula (IIIQ) 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, which comprises administering an effective amount of a compound of Formula (IIIQ) 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, which comprises administering a therapeutically effective amount of a compound of Formula (IIIQ), or a pharmaceutically acceptable salt thereof, to the patient.
  • This invention also relates to a method of using the compounds of Formula (IIIQ) 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, 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 the compounds of Formula (IIIQ).
  • Alzheimer's disease spinal cord injury
  • traumatic brain injury ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt- Jako
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in therapy.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease.
  • the invention also relates to a compound of Formula (IIIQ) 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 (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of amyotrophic lateral sclerosis.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington's disease.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of Creutzfeldt-Jakob Disease.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of progressive supranuclear palsy (PSP).
  • PSP progressive supranuclear palsy
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of dementia.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of spinal cord injury.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of traumatic brain injury.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemic stroke.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes.
  • the invention also relates to a compound of Formula (IIIQ) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from: myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.
  • the invention also relates to the use of a compound of Formula (IIIQ) 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 (IIIQ) 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 (IIIQ) 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 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.
  • the invention also relates to the use of a compound of Formula (IIIQ) 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 (IIIQ) 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 (IIIQ) 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 (IIIQ) 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 (IIIQ) 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, neurological disorders, pain, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.
  • a disease state selected from: neurodegenerative diseases, cancer,
  • compositions that comprise a pharmaceutical excipient and a compound of Formula (IIIQ) 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 (IIIQ) or a pharmaceutically acceptable salt thereof; and (ii) further active ingredients.
  • L 2 and l_3 are independently a bond, -NH-, -0-, -S-, -S(0)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene or substituted or unsubstituted C-
  • R5 and R 6 are each independently hydrogen, fluoro, chloro, bromo, iodo,
  • R 2 and R 4 are independently NR 8 , O, CH2, or S;
  • R 8 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridine
  • X is C-
  • Z 2 and z 4 are independently 0 or 1 ; and z5 and z 6 are independently an integer from 0 to 5; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (II):
  • L 1 2 and L 1 3 are independently: -CH2-O-, -O-CH2-, -O-CH2-CH2-, and
  • R " I 5 and R 1 6 are independently hydrogen or chloro
  • R 1 2 and R 1 4 are O; a 1 and b 1 are independently 0 or 1 ; C and D are independently phenyl or pyridine;
  • X 1 is selected from -CH2- and -CH2-CH2-; z 1 2 and z1 4 are independently 0 or 1 ; and z 1 5 and z 1 6 are independently an integer from 0 to 5; and salts thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (III):
  • L 2 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene or substituted or unsubstituted
  • Ci -6heteroalkylene, or L 2 is further taken together with R 3 to form heterocycloalkyi;
  • L 3 is selected from: a bond, -NH-, -0-, -S-, -S(0)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene or substituted or unsubstituted
  • R 1 is selected from: hydrogen, C-
  • R1 is taken together with L 3 to form heterocycloalkyi
  • R 3 is selected from: hydrogen, C-
  • R 3 is taken together with L 2 to form heterocycloalkyi
  • R5 and R 6 are each independently hydrogen, fluoro, chloro, bromo, iodo,
  • R 2 and R 4 are independently NR 8 , O, CH2, or S;
  • R 8 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl
  • X is C-
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III).
  • L 1 2 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,
  • L 1 2 is further taken together with R 1 1 to form imidazolidinyl;
  • L 1 3 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,
  • R 1 1 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, oxetanyl, or
  • R1 1 is taken together with
  • R 1 3 is selected from: hydrogen, C-
  • R ⁇ 3 is taken together with
  • R15 and R ⁇ are independently hydrogen, methyl, or chloro;
  • R 1 2 and R 1 4 are O;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl
  • X 1 is selected from -CH2- and -CH2-CH2-;
  • Z 1 2 and z 14 are independently 0 or 1 ;
  • Z 1 5 and z 1 6 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 (IV).
  • L 22 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene and substituted or unsubstituted
  • Ci -6heteroalkylene, or L 22 is taken together with R 28 to form heterocycloalkyi;
  • L 2 3 and R 21 are taken together to form heterocycloalkyi
  • R 2 3 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, heterocycloalkyi, or R 23 is taken together with L 22 to form heterocycloalkyi;
  • R 2 5 and R 26 are each independently hydrogen, fluoro, chloro, bromo, iodo,
  • R 22 and R 24 are independently NR 28 , O, CH2, or S;
  • R 28 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl
  • X is Ci -3alkylene or Ci -3alkylene substituted 1 to 3 times by fluoro; z 22 and z 24 are independently 0 or 1 ; and z 2 5 and z 26 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 (NIX).
  • L 32 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene and substituted or unsubstituted Ci -6heteroalkylene; l_33 taken together with R31 to form heterocycloalkyl;
  • R33 j S selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and heterocycloalkyl;
  • R35 and R ⁇ 6 are each independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH 2 Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH 3 , -OH, -NH 2 , -COOH, -CONH2, -NO2, -C(0)CH 3 , -CH(CH 3 )2, -C ⁇ CH, -CH 2 C ⁇ CH, -SO3H, -SO2NH2, -NHC(0)NH 2 , -NHC(0)H, -NHOH, -OCF3, -OCHF 2 , substituted or unsubstituted Ci -6alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroary
  • R 32 and R 34 are independently NR 38 , O, CH2, or S;
  • R 33 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C 3 and D 3 are independently phenyl or pyridyl
  • X 3 is C-
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IVX).
  • L 42 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,
  • L 43 is taken together with R 4 ⁇ to form imidazolidinyl or pyrrolidinyl;
  • R 41 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl, or
  • R 4 ⁇ is taken together with L 42 to form imidazolidinyl or pyrrolidinyl; R 4 5 and R 4 ⁇ are independently hydrogen, methyl, or chloro;
  • R 42 and R 44 are O;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl
  • X 4 is selected from -CH2- and -CH2-CH2-; Z42 and z 44 are independently 0 or 1 ; and Z 4 5 and z 46 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 (VX). Included in the compounds of the invention and used in the methods of the invention are com ounds of Formula (VIX):
  • L 52 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,
  • R5 1 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl; R55 and R 56 are independently hydrogen, methyl, or chloro; R 52 and R 54 are O;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl;
  • X 5 is selected from -CH2- and -CH2-CH2-;
  • Z ⁇ 2 and z54 are independently 0 or 1 ; and z55 and z ⁇ 6 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 (VIX). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VI IX):
  • L 62 is selected from : a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,
  • L 62 is taken together with R 61 to form imidazolidinyl or pyrrolidinyl; L.63 js taken together with R63 to form imidazolidinyl or pyrrolidinyl;
  • R 61 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl, or
  • R 61 is taken together with L ⁇ 2 to form imidazolidinyl or pyrrolidinyl; R65 and R66 are independently hydrogen, methyl, or chloro;
  • R 62 and R 64 are O;
  • C and D are independently phenyl or pyridyl
  • Z 62 and z 64 are independently 0 or 1 ;
  • ⁇ ⁇ 5 and z 66 are independently an integer from 0 to 3; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VIIX). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VI I IX) :
  • L 72 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, -O-CH2-CH2-, and -CH2-CH2-O-;
  • L 73 is taken together with R 7 ⁇ to form imidazolidinyl or pyrrolidinyl;
  • R 71 is selected from: hydrogen, C-
  • R75 and R 7 ⁇ are independently hydrogen, methyl, or chloro; R 72 and R 74 are O;
  • C 7 and D 7 are independently phenyl or pyridyl
  • Z 72 and z 74 are independently 0 or 1 ;
  • Z 7 5 and z 76 are independently an integer from 0 to 3; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VIIIX).
  • L 82 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl,
  • -O-cycloalkyl cycloalkyl-O-, -NH- cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, substituted or unsubstituted C-
  • Ci -6heteroalkylene, or L 82 is taken together with R 88 to form:
  • heterocycloalkyl heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyi, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-;
  • L 88 is selected from: cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L 88 and R 81 are taken together to form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyi, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-; R 81 is selected from: hydrogen, C-
  • R 88 j S selected from: hydrogen, C-
  • R 82 and R 84 are independently NR 88 , O, CH2, or S;
  • R 88 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl
  • X 6 is C-
  • Z 82 and z 84 are independently 0 or 1 ;
  • Z 8 5 and z 86 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 (IIIZ).
  • L 92 is selected from: a bond, -NH-, -0-, -S-, -S(0)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene and substituted or unsubstituted Ci -6heteroalkylene;
  • L.93 j S selected from: cycloalkyl, -O-cycloalkyl, and cycloalkyl-O-, azetidinyl,
  • heterocycloalkyi heterocycloalkyl-O-, oxoheterocycloalkyl
  • R 91 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and heterocycloalkyi, or R 91 is taken together with L 9 ⁇ to form: heterocycloalkyi, heterocycloalkyl-O-, oxoheterocycloalkyl, or oxoheterocycloalkyl-O-;
  • R 9 3 is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and heterocycloalkyi;
  • R95 and R 9 ⁇ are independently selected from: fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -C(0)Ph, -CF3, -CN, -S(0)CH3, -OH, -NH2,
  • Ci -6alkyl substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 92 and R 94 are independently NR 98 , O, or S;
  • R 98 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C 9 and D 9 are independently phenyl or pyridyl
  • X 7 is C-
  • Z 92 and z 94 are independently 0 or 1 ;
  • Z 9 5 and z 96 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 (IVZ).
  • L 1 02 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, cyclopropyl,
  • L 1 02 is taken together with Rl OI to form: imidazolidinyl, azetidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N
  • L 1 03 j S selected from: cyclopropyl, azetidinyl, -O-azetidinyl, azetidinyl-O-,
  • imidazolidinyl azetidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl, piperazinyl- ⁇ -, piperazinyl- ⁇ -, piperazinyl-CH2-,
  • oxopiperazinyl oxopiperazinyl, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-,
  • R 1 0 1 is selected from: hydrogen, C-
  • Ri d is taken together with
  • R 1 03 j S selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl, or R103 is taken together with
  • R 1 °2 and R 1 04 are O;
  • a and b are independently 0 or 1 ;
  • C ° and D ° are independently phenyl or pyridyl;
  • X 8 is selected from -CH2- and -CH2-CH2-;
  • ⁇ " ⁇ 5 and ⁇ " ⁇ 6 a re independently an integer from 0 to 5;
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VZ).
  • L 1 1 2 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, -O-CH2-CH2-, and -CH2-CH2-O-;
  • L 1 1 3 is selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl,
  • -O-azetidinyl, azetidinyl-O-, or iJ 13 is taken together with 13 to form: imidazolidinyl, azetidinyl, azetidinyl-O-, piperidinyl, piperidinyl-O-, piperazinyl, piperazinyl-O-, oxopiperazinyl, oxopiperazinyl-O-, pyrrolidinyl, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-;
  • R 1 1 3 j S selected from: hydrogen, C-
  • R 1 1 1 is selected from: hydrogen, C-
  • R 1 1 5 a nd R 1 1 6 are each independently selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3, -OCHF2, and -CF3;
  • R 1 1 2 and R 1 1 4 are O;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl;
  • X 9 is selected from -CH2- and -CH2-CH2-;
  • Z 1 1 2 and z 1 1 4 are independently 0 or 1 ;
  • Z 1 1 5 and z 1 1 6 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 (VIZ). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VI IZ):
  • W is selected from bicyclopentanyl and bicyclohexanyl
  • L 1 22 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, cyclopropyl,
  • L 1 22 is taken together with R121 to form: imidazolidinyl, azetidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl, oxopyrrolidinyl, oxopyrrolidinyl,
  • L 1 2 3 is selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-,
  • oxopiperazinyl oxopiperazinyl, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-,
  • R121 is taken together with
  • R123 j S hydrogen or R1 2 3 is taken together with iJ 2 3 to form:
  • R122 and R 124 are O;
  • C and D are independently phenyl or pyridyl
  • Z 1 22 and z 1 24 are independently 0 or 1 ;
  • Z 1 2 5 and z 1 26 are independently an integer from 0 to 3; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VIIZ).
  • W 1 is selected from bicyclopentanyl and bicyclohexanyl
  • L 1 32 is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, -O-CH2-CH2-, and -CH2-CH2-O-;
  • L 1 33 j S selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl, -O-azetidinyl, azetidinyl-O-, or j S taken together with R ⁇ S ⁇ 0 f 0 rm: imidazolidinyl, azetidinyl, azetidinyl-O-, piperidinyl, piperidinyl-O-, piperazinyl, piperazinyl- ⁇ -, oxopiperazinyl, oxopiperazinyl-O-, pyrrolidinyl, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-; R133 j S hydrogen or R ⁇ 33 j S taken together with
  • R 1 32 and R 1 34 are O;
  • C and D are each independently phenyl or pyridyl
  • Z 1 32 and z 1 34 are each independently 0 or 1 ;
  • Z 1 3 5 and z 1 36 are each independently an integer from 0 to 3; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VIIIZ).
  • L 82' is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, -O-cycloalkyl, cycloalkyl- ⁇ -, -NH-cycloalkyl, cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, substituted or unsubstituted C-
  • heterocycloalkyl heterocycloalkyl-O-, heterocycloalkyl-NH-,
  • L82' is taken together with an R85' substituent adjacent to the point of attachment of L ⁇ 2' to C 8 to form a cycloalkyl ring, a heterocycloalkyl ring, or
  • L.83' j S selected from: cycloalkyl, -O-cycloalkyl, cycloalkyl-O-, -NH-cycloalkyl,
  • cycloalkyl-NH-, azetidinyl, -O-azetidinyl, azetidinyl-O-, -N-azetidinyl, azetidinyl-N-, or L.33' and R& 1 ' are taken together to form: heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-,
  • R3 1 ' is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and heterocycloalkyl, or R 81 ' is taken together with L.33' to form:
  • heterocycloalkyl heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-;
  • R83 ' j S selected from: hydrogen, C-
  • heterocycloalkyl heterocycloalkyl, heterocycloalkyl-O-, heterocycloalkyl-NH-, heterocycloalkyl-CH2-, oxoheterocycloalkyl, oxoheterocycloalkyl-O-, oxoheterocycloalkyl-N-, or oxoheterocycloalkyl-CH2-;
  • R85 ' js selected from: fluoro, chloro, bromo, iodo,
  • heterocycloalkyl ring or heteroaryl ring fused to C ,
  • an R85 ' substituent adjacent to the point of attachment of L ⁇ 2' to C 8 can combine with L ⁇ 2' to form a cycloalkyi ring, a heterocycloalkyl ring, or
  • R86 ' js selected from: fluoro, chloro, bromo, iodo, -OCH3, -OCH 2 Ph, -C(0)Ph, -CF3, -CN, -S(0)CH 3 , -OH, -NH 2 , -COOH, -CONH2, -NO2, -C(0)CH 3 , -C ⁇ CH, -CH 2 CsCH, -SCH3, -SO3H, -SO2NH2, -NHC(0)NH 2 , -NHC(0)H, -NHOH, -OCF3, -OCHF 2 , substituted or unsubstituted C-
  • heterocycloalkyl ring or heteroaryl ring fused to D ,
  • an R 86 ' substituent adjacent to the point of attachment of L 88 ' to D 8 can combine with L 88 ' to form a cycloalkyi ring, a heterocycloalkyl ring, or
  • R 82 ' and R 84 ' are independently NR 88 ', O, CH2, or S;
  • R 88 ' is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;
  • a and b are independently 0 or 1 ;
  • C and D are independently phenyl or pyridyl
  • X 6 is C-
  • Z 82 ' and z 84 ' are independently 0 or 1 ;
  • Z 8 5' and z 86 ' 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 (IIIQ).
  • L 92' is selected from: a bond, -NH-, -0-, -S-, -S(0)-, -S(0)2-, substituted or unsubstituted Ci -6alkylene and substituted or unsubstituted Ci -6heteroalkylene;
  • L.93' j S selected from: cycloalkyi, -O-cycloalkyI, and cycloalkyl-O-, azetidinyl,
  • R9 1 ' is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and heterocycloalkyl, or R91 ' is taken together with L.93' to form: heterocycloalkyl, heterocycloalkyl-O-, oxoheterocycloalkyl,
  • R93' j S selected from: hydrogen, C-
  • R95' js selected from: fluoro, chloro, bromo, iodo,
  • R96' js selected from: fluoro, chloro, bromo, iodo,
  • heterocycloalkyl ring or heteroaryl ring fused to D ,
  • R9 6 ' substituent adjacent to the point of attachment of L.93' to D 9 can combine with to form a cycloalkyi ring, a heterocycloalkyl ring, or heteroaryl ring fused to D ,9 ' ;
  • R 92 ' and R 94 ' are independently NR 98 ', O, or S;
  • R 98 ' is selected from: hydrogen, C-
  • a and b are independently 0 or 1 ;
  • C 9 ' and D 9 ' are independently phenyl or pyridyl
  • X 7 ' is Ci -3alkylene or Ci -3alkylene substituted 1 to 3 times by fluoro;
  • Z 92' and z 94 ' are independently 0 or 1 ; and Z 9 5' and z 96 ' 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 (IVQ).
  • L 1 02 ' is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, cyclopropyl,
  • O-CH2-CH2-, and -CH2-CH2-O-, or L 1 02 ' is taken together with R101 ' to form: imidazolidinyl, azetidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2-, piperazinyl, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2- pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-,
  • L 1 0 2' is taken together with an R 1 05 ' substituent adjacent to the point of attachment of
  • R 1 0 1 ' is selected from: hydrogen, C-
  • R 1 03 ' j S selected from: hydrogen, C-
  • R 1 05 ' j S selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3,
  • an R 1 05 ' substituent adjacent to the point of attachment of iJ O 2' to C 10 can combine with
  • R 1 06 ' is selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3, -OCHF2, and -CF3, or, an R 1 06 ' substituent adjacent to the point of attachment of
  • R 1 °2 ' and R 1 04' are O;
  • a and b are independently 0 or 1 ;
  • C 0 and D 1 0 are independently phenyl or pyridyl;
  • X 8' is selected from -CH2- and -CH2-CH2-;
  • Z 1 02' and z 1 04' are independently 0 or 1 ;
  • Z 1 05 ' an( j z 106 ' 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 (VQ).
  • iJ 12' j S selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, -O-CH2-CH2-, and -CH2-CH2-O-;
  • L 1 1 3' j S selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl,
  • -O-azetidinyl, azetidinyl-O-, or iJ 13' is taken together with 13' to form: imidazolidinyl, azetidinyl, azetidinyl-O-, piperidinyl, piperidinyl-O-, piperazinyl, piperazinyl-O-, oxopiperazinyl, oxopiperazinyl-O-, pyrrolidinyl, pyrrolidinyl-O-, oxopyrrolidinyl, or oxopyrrolidinyl-O-,
  • L 1 1 3' is taken together with an R 1 1 6 ' substituent adjacent to the point of attachment of L 1 1 3' to form a heterocycloalkyl ring;
  • R 1 1 3' is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl or
  • R 1 1 1 ' is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl;
  • R 1 1 5' j S selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3, -OCHF2, and -CF3;
  • R 1 1 6 ' is selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3,
  • an R 1 1 6 ' substituent adjacent to the point of attachment of L 1 1 3' to D 1 1 can combine with iJ 13' to form a heterocycloalkyl ring fused to D 1 1 ;
  • R 1 1 2 ' and R 1 1 4 ' are O;
  • Z 1 1 2 ' and z 1 1 4 ' are independently 0 or 1 ;
  • Z 1 1 5' and z 1 1 6 ' 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 (VIQ).
  • W is selected from bicyclopentanyl and bicyclohexanyl
  • L 1 22 ' is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, cyclopropyl,
  • L 1 22 ' is taken together with R ' ' 2 ' ' ' to form: imidazolidinyl, azetidinyl, azetidinyl-O-, azetidinyl-N-, azetidinyl-CH2-, piperidinyl, piperidinyl-O-, piperidinyl-N-, piperidinyl-CH2- piperazinyl, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl, oxopiperazinyl- ⁇ -, oxopiperazinyl- ⁇ -, oxopiperazinyl-CH2-, pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-,
  • L 1 22' is taken together with an R 1 2 5 ' substituent adjacent to the point of attachment of L 1 22' to form a cyclohexyl ring, a cyclobutyl ring, or a tetrahydro-pyran ring;
  • L 1 2 3 ' is selected from: cyclopropyl, azetidinyl, -O-azetidinyl, azetidinyl-O-,
  • L 1 2 3 ' is taken together with an R 1 26 ' substituent adjacent to the point of attachment of
  • R 1 21 ' is selected from: hydrogen, Ci -6alkyl, substituted Ci -6alkyl, and oxetanyl, or
  • R1 2 1 is taken together with iJ 22' to form: imidazolidinyl, azetidinyl, azetidinyl-O-, azetidinyl- ⁇ -, azetidinyl-CH2-, piperidinyl, piperidinyl-O-, piperidinyl- ⁇ -, piperidinyl-CH2-, piperazinyl, piperazinyl-O-, piperazinyl-N-, piperazinyl-CH2-, oxopiperazinyl, oxopiperazinyl-O-, oxopiperazinyl-N-, oxopiperazinyl-CH2-, pyrrolidinyl, pyrrolidinyl-O-, pyrrolidinyl-N-, pyrrolidinyl-CH2-, oxopyrrolidinyl, oxopyrrolidinyl-O-, oxo
  • R 1 2 5' is selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3,
  • an R 1 2 5' substituent adjacent to the point of attachment of L 1 22' to C 12 can combine with
  • R 1 26 ' is selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3,
  • an R 1 26 ' substituent adjacent to the point of attachment of L 1 23 ' to D 12 can combine with
  • R 1 22 ' and R 1 24 ' are O;
  • C and D are independently phenyl or pyridyl
  • Z 1 22 ' and z 1 24 ' are independently 0 or 1 ;
  • Z 1 2 5' and z 1 26 ' are independently an integer from 0 to 3; or a salt thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VIIQ).
  • W 1 is selected from bicyclopentanyl and bicyclohexanyl
  • L 1 32 ' is selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-, -O-CH2-CH2-, and -CH2-CH2-O-;
  • J 33' j S selected from: cyclopropyl, -O-cyclopropyl, cyclopropyl-O-, azetidinyl,
  • J 33' t 0 form a cyclohexyl ring, a cyclobutyl ring, or a tetrahydro-pyran ring;
  • R133' j S hydrogen or R1 33' j S taken together with
  • R 1 35' j S selected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3, -OCHF2, and -CF3;
  • R 1 36' j S gelected from: methyl, cyclopropyl, -OCF3, fluoro, chloro, -SCH3, -OCH3,
  • J 33' t 0 D 13 can combine with
  • R 1 32' and R 1 3 4' are O;
  • C and D are each independently phenyl or pyridyl
  • Z 1 32' and z 1 34' a re each independently 0 or 1 ;
  • Z 1 35' and z 1 36' a re each independently an integer from 0 to 3; t thereof including a pharmaceutically acceptable salt thereof.
  • This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VIIIQ).
  • each can be a
  • one R can be F and the other R can be CI.
  • R is independently fluoro, chloro, bromo, iodo, -OCH3, -OCH 2 Ph, -C(0)Ph, -CF 3 , -CN, -S(0)CH 3 , -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -C(0)CH 3 , -C ⁇ CH, -CH 2 C ⁇ CH, -SO3H, -SO2NH2, -NHC(0)NH 2 ,
  • R is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH 2 Ph, -CH 3 , -OH, -CF 3 , -CN, -S(0)CH 3 , -N0 2 , -C(0)CH3, -C(0)Ph, -CH(CH3)2, or -C ⁇ CH.
  • R 5 is -F.
  • R is -CI. In embodiments, R is -Br. In embodiments, R is -I. In embodiments, R is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocycloalkyi, substituted or
  • R is unsubstituted C 1-6 alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyi, unsubstituted
  • R is -
  • R is -OCH2Ph. In embodiments, R is -CH3. In embodiments,
  • R is -OH. In embodiments, R is -CF3. In embodiments, R is -CN. In embodiments, R is -S(0)CH3. In embodiments, R 5 is -NO2. In embodiments, R 5 is -C(0)CH3. In
  • R is -C(0)Ph. In embodiments, R is -CH(CH3)2. In embodiments, R is -
  • R is -CH2C ⁇ CH. In embodiments, R is -SO3H. In
  • R is -SO2NH2. In embodiments, R is -NHC(0)NH2. In embodiments, R is -NHC(0)H. In embodiments, R 5 is -NHOH. In embodiments, R 5 1S-OCH3. In
  • R is -OCF3. In embodiments, R is -OCHF2.
  • R is independently fluoro, chloro, bromo, iodo, -OCH3, -OCH 2 Ph, -C(0)Ph, -CF3, -CN, -S(0)CH 3 , -OH, -NH 2 , -COOH, -CONH 2 , -NO2,
  • R 6 is independently hydrogen, fluoro, chloro, bromo, iodo, - OCH3, -OCH 2 Ph, -CH3, -OH, -CF3, -CN, -S(0)CH 3 , -NO2, -C(0)CH 3 , -C(0)Ph, -CH(CH3)2, or -C ⁇ CH.
  • R 6 is -F.
  • R 6 is -CI.
  • R 6 is -Br.
  • R 6 is -I.
  • R 6 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocycloalkyi, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 6 is unsubstituted C 1-6 alkyl, unsubstituted heteroalkyi, unsubstituted cycloalkyi, unsubstituted heterocycloalkyi, unsubstituted aryl, or unsubstituted heteroaryl.
  • R 6 is - OCH3.
  • R 6 is -OCH2Ph. In embodiments, R 6 is -CH3. In embodiments, 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 -N02- 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 - C ⁇ CH. In embodiments, R 6 is -CH2C ⁇ CH. In embodiments, R 6 is -SO3H. In embodiments, R 6 is -SO2NH2.
  • 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 is NR . In embodiments, R is NH. In embodiments, R is O. In
  • R is S. In embodiments, R is CH2. In embodiments, R is NR . In
  • R is NH. In embodiments, R is O. In embodiments, R is S. In
  • R is CH2. In embodiments, R and R are NH. In embodiments, R and
  • R are O. In embodiments, R and R are S. In embodiments, R and R are NR .
  • L is a bond. In embodiments, L is a substituted or unsubstituted Ci-
  • L is a substituted or unsubstituted Ci- 6 heteroalkylene.
  • L is L -L -L and L is bonded to the substituted or unsubstituted
  • L is a bond, -0-, -S-, -NH-, -S(O)-, or -S(0)2-.
  • L is a bond, -0-, or -NH-.
  • L is a bond. In embodiments, L is -0-. In embodiments, L is -S-. In
  • L is -NH-. In embodiments, L is -S(0)-. In embodiments, L is -S(0)2-
  • L is a bond. In embodiments, L is a substituted or unsubstituted Ci-
  • L is an unsubstituted Ci-ealkylene. In embodiments, L is a 2B
  • L is an unsubstituted C-
  • L is a substituted or unsubstituted C1 -C4 alkylene.
  • L is an unsubstituted C-1 -C4 alkylene. In embodiments, L is a
  • L is an unsubstituted C-
  • L is a substituted C1 -C5 alkylene. In embodiments, L is
  • L is a substituted C1 -C5 alkylene.
  • L is a substituted C-1 -C4 alkylene. In embodiments, L is a C-1 -C6
  • L is a bond. In embodiments, L is -
  • L is -NH-. In embodiments, L is a bond; L is unsubstituted
  • L is a bond. In embodiments, L is a substituted or unsubstituted Ci-
  • L is a substituted or unsubstituted Ci-eheteroalkylene.
  • L is L -L -L and L is bonded to the substituted or unsubstituted
  • L is a bond, -0-, -S-, -NH-, -S(0)-, or -S(0)2-.
  • L is a bond or substituted or unsubstituted d- 6 alkylene.
  • L is a bond, -0-, or -NH-.
  • L is a bond. In embodiments, L is -0-. In embodiments, L is -S-. In
  • L is -NH-. In embodiments, L is -S(0)-. In embodiments, L is -S(0)2-
  • L is a bond. In embodiments, L is a substituted or unsubstituted Ci-
  • L is an unsubstituted d- 6 alkylene. In embodiments, L is a
  • L is an unsubstituted C-
  • L is a substituted or unsubstituted C1 -C4 alkylene.
  • L is an unsubstituted C1 -C4 alkylene. In embodiments, L is a
  • L is an unsubstituted C-
  • L is a substituted C1 -C5 alkylene. In embodiments, L is
  • L is a substituted C1 -C5 alkylene.
  • L is a substituted C1 -C4 alkylene. In embodiments, L is a C-
  • L is a bond. In embodiments, L is -
  • L is -NH-. In embodiments, L is a bond; L is unsubstituted 3C
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is imidazolidinyl.
  • the heterocycloalkyi is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is imidazolidinyl.
  • the heterocycloalkyi is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is imidazolidinyl.
  • the heterocycloalkyi is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is imidazolidinyl.
  • the heterocycloalkyi is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is imidazolidinyl.
  • the heterocycloalkyi is pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl.
  • L is taken together with R 61 to form pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl.
  • L is taken together with R 63 to form pyrrolidinyl.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is
  • heterocycloalkyi is pyrrolidinyl.
  • L is taken
  • the oxoheterocycloalkyi is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyi is oxopyrrolidinyl.
  • heterocycloalkyl- O- is azetidinyl-O- or pyrrolidinyl-O-.
  • heterocycloalkyl-O- is pyrrolidinyl-O-.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is imidazolidinyl.
  • the heterocycloalkyi is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is 93 imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is 93 imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L is taken together with R to form heterocycloalkyi.
  • the heterocycloalkyi is imidazolidinyl or pyrrolidinyl.
  • the heterocycloalkyi is 93 imidazolidinyl.
  • the heterocycloalkyl is pyrrolidinyl.
  • L is taken together with R to form heterocyclo
  • oxoheterocycloalkyl is 2-
  • oxoimidazolidinyl is oxopyrrolidinyl.
  • L is oxopyrrolidinyl.
  • heterocycloalkyl-O- is taken together with R to form heterocycloalkyl-O-.
  • the heterocycloalkyl-O- is azetidinyl-O- or pyrrolidinyl-O-.
  • the heterocycloalkyl-O- is pyrrolidinyl-O-.
  • L 1 02 is taken together with R 101 to form imidazolidinyl or pyrrolidinyl.
  • L 1 02 is taken together with R 1 01 to form imidazolidinyl.
  • L 1 02 is taken together with R 1 01 to form pyrrolidinyl.
  • L 1 02 is taken together with R 1 01 to form oxoheterocycloalkyl.
  • the oxoheterocycloalkyl is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyl is oxopyrrolidinyl.
  • L is taken together with
  • R 1 01 to form heterocycloalkyl-O- is azetidinyl-O- or pyrrolidinyl-O-.
  • the heterocycloalkyl-O- is pyrrolidinyl-O-.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • oxoheterocycloalkyl is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyl is oxopyrrolidinyl.
  • L is taken together with
  • heterocycloalkyl-O- is azetidinyl-O- or pyrrolidinyl-O-.
  • heterocycloalkyl-O- is pyrrolidinyl-O-.
  • L is taken together with R to form imidazolidinyl, pyrrolidinyl or
  • L is taken together with R to form imidazolidinyl.
  • L is taken together with R to form pyrrolidinyl.
  • L is taken together with R to form pyrrolidinyl.
  • oxoheterocycloalkyl is taken together with R to form oxoheterocycloalkyl.
  • oxoheterocycloalkyl is
  • 2-oxoimidazolidinyl is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyl is oxopyrrolidinyl.
  • heterocycloalkyl-O- is taken together with R to form heterocycloalkyl-O-.
  • heterocycloalkyl- O- is azetidinyl-O- or pyrrolidinyl-O-.
  • heterocycloalkyl-O- is pyrrolidinyl-O-.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • oxoheterocycloalkyi is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyi is oxopyrrolidinyl.
  • L is taken together with
  • heterocycloalkyl-O- is azetidinyl-O- or pyrrolidinyl-O-.
  • heterocycloalkyl-O- is pyrrolidinyl-O-.
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • oxoheterocycloalkyi is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyi is oxopyrrolidinyl.
  • L is taken together with
  • heterocycloalkyl-O- is azetidinyl-O- or pyrrolidinyl-O-.
  • heterocycloalkyl-O- is pyrrolidinyl-O-
  • L is taken together with R to form imidazolidinyl or pyrrolidinyl.
  • oxoheterocycloalkyi is 2-oxoimidazolidinyl.
  • the oxoheterocycloalkyi is oxopyrrolidinyl.
  • L is taken together with
  • heterocycloalkyl-O- is azetidinyl-O- or pyrrolidinyl-O-.
  • heterocycloalkyl-O- is pyrrolidinyl-O-.
  • the symbol ⁇ is 0. In embodiments, the symbol ⁇ is 1 . In embodiments, the symbol z ⁇ is 0. In embodiments, the symbol z ⁇ is 1 . In embodiments, the symbols z 2 and z ⁇ are 0. In embodiments, the symbols z 2 and z ⁇ are 1 . In embodiments, the symbol z ⁇ is 0. 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.
  • salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I I IQ) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I IIQ) 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 I IQ).
  • 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 sulfate), ethane-1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate
  • Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS, tromethamine), arginine, benethamine (A/-benzylphenethylamine), benzathine ( ⁇ , ⁇ '- dibenzylethylenediamine), jfc>/ ' s-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl-2-pyrrolildine-1 '-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (A/-methylglu
  • the compounds according to Formula (IIIQ) 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.
  • compounds according to Formula (IIIQ) containing one or more chiral centers may be used as racemic mixtures, enantiomerically or diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers.
  • the compounds according to Formula (IIIQ) and pharmaceutically acceptable salts thereof may contain isotopically-labelled compounds, which are identical to those recited in Formula (IIIQ) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251.
  • 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. 1 1 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 (IIIQ) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (IIIQ), 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 (IIIQ) whether such tautomers exist in equilibrium or predominately in one form.
  • the compounds of Formula (IIIQ) 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.
  • polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • Alkyl and alkylene refer to a hydrocarbon chain having the specified number of "member atoms”. Alkyl being monovalent and alkylene being bivalent. For example, C-
  • 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 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 groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl.
  • aryl is phenyl.
  • 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 atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitably cycolalkyl is selected from: cyclopropyl, cyclobutyl and cyclohexyl. Suitably cycolalkyl is cyclopropyl.
  • Halo refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to a monocyclic aromatic 4 to 8 member ring containing 1 to 7 carbon atoms and containing 1 to 4 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms, or to such aromatic ring is fused one or more rings, such as heteroaryl rings, aryl rings, heterocyclic rings, or cycloalkyl rings. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms.
  • Heteroaryl includes but is not limited to: benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1 ,4]dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, pyrazolyl, imidazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl, pyrimidyl, isothiazolyl, furazanyl, pyrimidinyl, te
  • heteroaryl is selected from: pyrazolyl, imidazolyl, oxazolyl and thienyl.
  • heteroaryl is a pyridyl group or an imidazolyl group.
  • heteroaryl is a pyridyl.
  • 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 or to a heteroaryl ring having from 3 to 6 member atoms.
  • Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 1 ,3oxazolidin-2-one, hexahydro-1 H-azepin, 4,5,6,7,tetrahydro
  • heterocycloalkyl includes: piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, oxetanyl, and pyrrolidinyl.
  • heterocycloalkyl is selected from: imidazolidinyl, tetrahydropyranyl and pyrrolidinyl.
  • Heteroatom refers to a nitrogen, sulfur 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 up to the number specified) 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.
  • -6heteroalkyl(ene) contains at least one and up to 6 carbon atoms, in addition to at least one heteroatom.
  • Heteroalkyl being monovalent and heteroalkylene being bivalent.
  • heteroalkyl and heteroalkylene groups may be taken together with another substituent to form a heterocycloalkyl group.
  • the 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.
  • Heteroalkyl examples include, but are not limited to:
  • Heteroalkylene examples include, but are not limited to:
  • -O-CH2-CH2- Up to two or three heteroatoms may be consecutive, such as, for example, CH 2 -NH-OCH 3 and -CH 2 -0-Si(CH 3 ) 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,
  • -OCi -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, mercapto,
  • R is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH,
  • R is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH,
  • R 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, oxo,
  • R is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R and R are each independently selected from C-
  • R is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R and R are each independently selected from C-
  • R is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R and R are each independently selected from C-
  • R is selected from Ci -6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents
  • R and R are each independently selected from C-
  • Substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN, nitro, and
  • substituted means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro,
  • -OCi -4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH,
  • R is selected from Ci ⁇ alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,
  • R and R are each independently selected from Ci -4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • R and R are each independently selected from Ci -4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • substituted means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro, chloro, bromo, iodo,
  • Ci -4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH 2 , -NHCi -3alkyl, -N(Ci -3alkyl) 2 , -OCi -4alkyl and -CN, -OCi -4alkyl,
  • R is selected from C-i ⁇ alkyl, and C-i ⁇ alkyl substituted one to 4 times by fluoro
  • R and R are each independently selected from Ci -4alkyl, and Ci -4alkyl substituted one to four 20 times by fluoro,
  • R and R are each independently selected from Ci -4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • 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,
  • -OCi -4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH,
  • R is selected from Ci ⁇ alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,
  • R and R are each independently selected from Ci -4alkyl, and Ci -4alkyl substituted one to four times by fluoro,
  • R is selected from Ci -4alkyl, and Ci -4alkyl substituted one to four times by fluoro, -C(0)NR X1 R X2
  • R and R are each independently selected from C-
  • substituted means the subject chemical moiety has from one to three substituents selected from the group consisting of: fluoro,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Furan Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Pyrane Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

L'invention concerne des dérivés de cycloalcanes pontés substitués. L'invention concerne particulièrement des composés de formule (IIIQ) : dans laquelle X6', a, b, C8', D8', L82', L83', R81', R82', R83', R84', R85', R86', z82', z84', z85' et z86' sont tels que définis dans la description ; ou leurs sels. Les composés selon l'invention sont des inhibiteurs de la voie ATF4. Par conséquent, l'invention concerne également des compositions pharmaceutiques comprenant un composé selon l'invention. L'invention concerne enfin des procédés d'inhibition de la voie ATF4 et le traitement de troubles associés, au moyen d'un composé de l'invention ou d'une composition pharmaceutique comprenant un composé de l'invention.
EP18733953.6A 2017-06-07 2018-06-07 Composés chimiques utilisés comme inhibiteurs de la voie atf4 Withdrawn EP3634952A1 (fr)

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