WO2015095449A1 - Methods for modulating the amount rna transcripts - Google Patents

Methods for modulating the amount rna transcripts Download PDF

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Publication number
WO2015095449A1
WO2015095449A1 PCT/US2014/071032 US2014071032W WO2015095449A1 WO 2015095449 A1 WO2015095449 A1 WO 2015095449A1 US 2014071032 W US2014071032 W US 2014071032W WO 2015095449 A1 WO2015095449 A1 WO 2015095449A1
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chromen
pyrazin
amino
pyridin
alkyl
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PCT/US2014/071032
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French (fr)
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Nikolai Naryshkin
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Ptc Therapeutics, Inc.
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Publication of WO2015095449A1 publication Critical patent/WO2015095449A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • Described herein are methods for modulating the amount of a gene product and compounds for use in such methods. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product as the result of gene expression and compounds for use in such methods.
  • RNA transcripts e.g., an RNA transcript or protein
  • the resulting aberrant amounts of RNA transcripts may lead to disease due to corresponding changes in protein expression.
  • Changes in the amount of a particular RNA transcript may be the result of several factors.
  • changes in the amount of RNA transcripts may be due to an aberrant level of transcription of a particular gene, such as by the perturbation of a transcription factor or a portion of the transcription process, resulting in a change in the expression level of a particular RNA transcript.
  • changes in the splicing of particular RNA transcripts can change the levels of a particular RNA transcript.
  • Changes to the stability of a particular RNA transcript or to components that maintain RNA transcript stability, such as the process of poly-A tail incorporation or an effect on certain factors or proteins that bind to and stabilize RNA transcripts may lead to changes in the levels of a particular RNA transcript.
  • the level of translation of particular RNA transcripts can affect the amount of those transcripts, affecting or upregulating RNA transcript decay processes.
  • RNA transport or RNA sequestration may also lead to changes in functional levels of RNA transcripts, and may have an effect on the stability, further processing, or translation of the RNA transcripts.
  • diseases associated with changes to RNA transcript amount are treated with a focus on the aberrant protein expression.
  • the processes responsible for the aberrant changes in RNA levels such as components of the splicing process or associated transcription factors or associated stability factors, could be targeted by treatment with a small molecule, it would be possible to restore protein expression levels such that the unwanted effects of the expression of aberrant levels of RNA transcripts or associated proteins. Therefore, there is a need for methods of modulating the amount of RNA transcripts encoded by certain genes as a way to prevent or treat diseases associated with aberrant expression of the RNA transcripts or associated proteins.
  • RNA transcripts e.g., rRNA, tRNA, miRNA, siRNA, IncRNA, pre-mRNA, or mRNA transcripts
  • methods for modulating the amount of one or more RNA transcripts comprising contacting a cell with a compound of Formula (I)
  • provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 1, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • methods for modulating one, two, three or more RNA transcripts of one, two, three or more genes by way of nonlimiting example, disclosed in Table 1, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • RNA transcripts of a gene comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • methods for modulating one, two, three or more RNA transcripts of one, two, three or more genes comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • the cell is contacted with the compound of Formula (I) or a form thereof in a cell culture.
  • the cell is contacted with the compound of Formula (I) or a form thereof in a subject ⁇ e.g., a non- human animal subject or a human subject).
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcripts of a gene comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcripts of a gene by way of nonlimiting example, disclosed in Table 1, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcripts of one, two, three or more genes disclosed in Table 1, infra comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcripts of a gene by way of nonlimiting example, disclosed in Table 2, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcripts of one, two, three or more genes disclosed in Table 2, infra comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • kits for preventing and/or treating a disease associated with the aberrant expression of a gene product comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript or protein a gene product ⁇ e.g., an RNA transcript or protein
  • a gene product e.g., an RNA transcript or protein
  • Table 1 infra
  • administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA transcript or protein a gene product ⁇ e.g., an RNA transcript or protein
  • a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA isoforms encoded by a gene are beneficial to the prevention and/or treatment of the disease, comprising
  • RNA isoforms encoded by gene by way of nonlimiting example, disclosed in Table 1 , infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • RNA isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • kits for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • provided herein are methods for preventing and/or treating a disease in which the increase in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a disease in which the decrease in the expression one, two, three or more protein isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • kits for preventing and/or treating a disease in which the increase in the expression one, two, three or more protein isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a disease in which the decrease in the expression one, two, three or more protein isoforms encoded by a gene by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcripts of one or more of genes comprising contacting a cell with a compound of Formula (I) or a form thereof.
  • a compound of Formula (I) or a form thereof modulates the amount of one or more of the RNA transcripts of one or more of the genes, by way of nonlimiting example, in Table 1, infra.
  • a compound of Formula (I) or a form thereof modulates the amount of one or more of the RNA transcripts of one or more of the genes, by way of nonlimiting example, in Table 2, infra.
  • RNA transcripts of a gene(s) comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more of the RNA transcripts of one, two, three or more of the genes, by way of nonlimiting example, in Table 1, infra.
  • a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more of the RNA transcripts of one, two, three or more of the genes, by way of nonlimiting example, in Table 2, infra.
  • a disease associated with the aberrant expression of a gene comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • the disease is associated with the aberrant expression of a gene, by way of nonlimiting example, in Table 1, infra.
  • the disease is associated with the aberrant expression of a gene, by way of nonlimiting example, in Table 2, infra.
  • the disease is not associated with the aberrant expression of the SMN2 gene.
  • RNA isoforms of a gene(s) are beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • an increase in the level of expression of one, two, three or more RNA isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 1, infra is beneficial to prevent and/or treat a disease.
  • a decrease in the level of expression of one, two, three or more RNA isoforms of one, two or more genes, by way of nonlimiting example, in Table 1, infra is beneficial to prevent and/or treat a disease.
  • an increase in the level of expression of one, two, three or more RNA isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 2, infra is beneficial to prevent and/or treat a disease.
  • a decrease in the level of expression of one, two, three or more RNA isoforms of one, two or more genes, by way of nonlimiting example, in Table 2, infra is beneficial to prevent and/or treat a disease.
  • kits for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more protein isoforms of a gene(s) is beneficial to the prevention and/or treatment of the disease comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
  • an increase in the level of expression of one, two, three or more protein isoforms of one, two, three or more genes is beneficial to prevent and/or treat a disease.
  • a decrease in the level of expression of one, two, three or more protein isoforms of one, two or more genes, by way of nonlimiting example, in Table 1, infra, is beneficial to prevent and/or treat a disease.
  • an increase in the level of expression of one, two, three or more protein isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 2, infra is beneficial to prevent and/or treat a disease.
  • a decrease in the level of expression of one, two, three or more protein isoforms of one, two or more genes, by way of nonlimiting example, in Table 2, infra is beneficial to prevent and/or treat a disease.
  • wi and w 2 are C-Ri or C-R 2 ; wherein, one of wi and w 2 is C-Ri and the other is C-R 2 , provided that, when wi is C-Ri, then w 2 is C-R 2 ; or, when wi is C-R 2 , then w 2 is C-Ri;
  • Ri is Ci_ 8 alkyl, amino, Ci_ 8 alkyl-amino, (Ci_ 8 alkyl) 2 -amino,
  • Ci_8alkoxy-Ci_8alkyl-amino Ci_8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl) 2 -amino,
  • Ci_8alkyl-amino-C i.salkyl-amino (C i.galkyl-amino-C i_8alkyl) 2 -amino,
  • Ci_ 8 alkyl-amino-C 2 - 8 alkynyl Ci_ 8 alkyl-amino-C 2 - 8 alkynyl, (Ci_ 8 alkyl) 2 -amino-C 2 - 8 alkynyl,
  • heterocyclyl-Ci_salkyl heterocyclyl-Ci_ 8 alkoxy, heterocyclyl-amino,
  • heterocyclyl (Ci_8alkyl)amino
  • heterocyclyl-amino-Ci_8alkyl heterocyclyl-Ci_8alkyl-amino
  • heterocyclyl-Ci_8alkyl 2 -amino
  • heterocyclyl-Ci_8alkyl (heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heterocyclyl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl,
  • heterocyclyl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl) 2 -amino,
  • aryl-Ci_ 8 alkyl 2 -amino-Ci_ 8 alkyl, (aryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl) 2 -amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl or
  • each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R 3 substituents and one additional, optional R 4 substituent;
  • each instance of heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R 3 substituents;
  • R 2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or
  • each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three 3 ⁇ 4 substituents and one additional, optional R 7 substituent;
  • R a is, in each instance, independently selected from hydrogen, halogen, Ci_ 8 alkyl or deuterium;
  • R b is hydrogen, halogen, Ci_salkyl, Ci_ 8 alkoxy or deuterium;
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo,
  • Ci_ 8 alkoxy-Ci_ 8 alkyl-amino Ci_ 8 alkyl-carbonyl-amino, Ci_ 8 alkoxy-carbonyl-amino,
  • R4 is C 3 _i 4 cycloalkyl, C 3 -i 4 cycloalkyl-Ci_galkyl, C 3 _i 4 cycloalkyl-amino, aryl-Ci_salkyl, aryl-Ci.galkoxy-carbonyl, aryl-sulfonyloxy-Ci_galkyl, heterocyclyl or heterocyclyl-Ci_galkyl; wherein, each instance of C 3 _i 4 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5 substituents;
  • R 5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_ 8 alkyl, halo-Ci_ 8 alkyl, Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy, amino, Ci_ 8 alkyl-amino,
  • Ci_ 8 alkyl 2 -amino or Ci_ 8 alkyl-thio
  • Re is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_salkyl, C 2 -galkenyl, halo-Ci_salkyl, hydroxy-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl) 2 -amino or Ci_galkyl-thio; and,
  • R 7 is C 3 _i 4 cycloalkyl, C 3 _i 4 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • Ri is Ci_ 8 alkyl, amino, Ci.galkyl-amino, (Ci_galkyl) 2 -amino, Ci_galkoxy-Ci_galkyl-amino, (Ci_galkoxy-Ci_galkyl) 2 -amino, (Ci_galkoxy-Ci_galkyl)(Ci_galkyl)amino, amino-Ci_galkyl, Ci_galkyl-amino-Ci_galkyl,
  • Ci_galkyl 2 -amino-Ci_galkyl
  • Ci_galkyl-amino-C 2 -galkynyl Ci_galkyl-amino-C 2 -galkynyl, (Ci_galkyl) 2 -amino-C 2 -galkynyl,
  • halo-Ci_galkyl-amino (halo-Ci_galkyl) 2 -amino, (halo-Ci_galkyl)(Ci_galkyl)amino, hydroxy-Ci-galkyl, hydroxy-Ci-galkoxy-Ci.galkyl, hydroxy-Ci.galkyl-amino,
  • heterocyclyl-Ci.galkyl heterocyclyl-Ci_galkoxy, heterocyclyl-amino
  • heterocyclyl (Ci_galkyl)amino
  • heterocyclyl-amino-Ci_galkyl heterocyclyl-Ci_galkyl-amino
  • heterocyclyl-Ci_ 8 alkyl 2 -amino
  • heterocyclyl-Ci_ 8 alkyl (heterocyclyl-Ci_ 8 alkyl)(Ci_galkyl)amino,
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heterocyclyl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl,
  • heterocyclyl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl) 2 -amino,
  • aryl-Ci_ 8 alkyl 2 -amino-Ci_ 8 alkyl, (aryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl) 2 -amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl or
  • heteroaryl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl; wherein, each instance of heterocyclyl and heteroaryl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Ci_8alkoxy-Ci_8alkyl-amino Ci_8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl) 2 -amino,
  • Ci_ 8 alkyl-amino-C 2 - 8 alkynyl Ci_ 8 alkyl-amino-C 2 - 8 alkynyl, (Ci_ 8 alkyl) 2 -amino-C 2 - 8 alkynyl,
  • halo-Ci_ 8 alkyl-amino (halo-Ci_ 8 alkyl) 2 -amino, hydroxy-Ci_ 8 alkyl, hydroxy-Ci_ 8 alkoxy-Ci_ 8 alkyl, hydroxy-C i_ 8 alkyl-amino, (hydroxy-Ci_ 8 alkyl) 2 -amino, (hydroxy-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino, hydroxy-Ci_ 8 alkyl-amino-Ci_ 8 alkyl, (hydroxy-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl,
  • heterocyclyl (Ci_ 8 alkyl)amino
  • heterocyclyl-amino-Ci.salkyl heterocyclyl-Ci_ 8 alkyl-amino
  • heterocyclyl-Ci_ 8 alkyl-amino heterocyclyl-Ci_ 8 alkyl 2 -amino
  • heterocyclyl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heterocyclyl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl,
  • heterocyclyl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_ 8 alkyl-amino, (aryl-Ci_ 8 alkyl) 2 -amino,
  • aryl-Ci_ 8 alkyl 2 -amino-Ci_ 8 alkyl, (aryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heteroaryl, heteroaryl-Ci_ 8 alkyl, heteroaryl-Ci_ 8 alkoxy, heteroaryl-amino, heteroaryl-Ci_ 8 alkyl-amino, (heteroaryl-Ci_ 8 alkyl) 2 -amino, (heteroaryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl or
  • Ri is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1 ,4-diazepanyl, 1 ,2,5,6-tetrahydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-3 ⁇ 4]pyrrol-(lH)-yl, (3a5',6a5)-hexahydropyrrolo[3,4-3 ⁇ 4]pyrrol-(lH)-yl,
  • Ri is heterocyclyl selected from azetidin-l-yl, tetrahydrofuran-3-yl, pyrrolidin-l-yl, piperidin-l-yl, piperidin-4-yl, piperazin- 1 -yl, 1 ,4-diazepan- 1 -yl, 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 ,2,3 ,6-tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-£]pyrrol-l(2H)-yl, (3a5',6a5)-hexahydropyrrolo[3,4-3 ⁇ 4]pyrrol-l(2H)-yl, (3 aS ⁇ a ⁇ -hexahydropyrrolo [3 ,4-3 ⁇ 4]pyrrol-5 ( lH)-yl,
  • Ri is substituted heterocyclyl selected from (3a5',6a5)-l-methylhexahydropyrrolo[3,4-3 ⁇ 4]pyrrol-5(lH)-yl,
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-Ci_ 8 alkyl wherein heterocyclyl is selected from morpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-Ci_galkyl selected from morpholin-4-yl-methyl, morpholin-4-yl-ethyl,
  • morpholin-4-yl-propyl piperidin-l-yl-methyl, piperazin-l-yl-methyl, piperazin-l-yl-ethyl, piperazin-l-yl-propyl, piperazin-l-yl-butyl, imidazol-l-yl-methyl, imidazol-l-yl-ethyl, imidazol-l-yl-propyl, imidazol-l-yl-butyl, pyrrolidin-l-yl-methyl, pyrrolidin-l-yl-ethyl, pyrrolidin-l-yl-propyl or pyrrolidin-l-yl-butyl; wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-Ci.galkoxy wherein heterocyclyl is selected from pyrrolidinyl, piperidinyl or morpholinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-Ci_8alkoxy selected from pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-ethoxy, pyrrolidin-l-yl-methoxy, pyrrolidin-l-yl-ethoxy, piperidin-l-yl-methoxy, piperidin-l-yl-ethoxy, morpholin-4-yl-methoxy or morpholin-4-yl-ethoxy; wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-amino wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or (li?,55)-9-azabicyclo[3.3.1]nonyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is heterocyclyl-amino selected from azetidin-3-yl-amino, pyrrolidin-3-yl-amino, piperidin-4-yl-amino,
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl (Ci_8alkyl)amino, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-amino-Ci_ 8 alkyl wherein heterocyclyl is selected from tetrahydrofuranyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-amino-Ci.galkyl selected from 3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl wherein heterocyclyl is selected from tetrahydrofuranyl, thienyl or pyridinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl selected from 3-[(tetrahydrofuran-2- ylmethyl)amino]propyl, 3 - [(thiophenyl-3 -ylmethyl)amino]propyl, 3 - [(pyridin-2- ylmethyl)amino]propyl or 3-[(pyridin-4-ylmethyl)amino]propyl; wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is heterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is heterocyclyl-oxy selected from pyrrolidin-3-yl-oxy or piperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionally substituted. [0052] In one embodiment of the use of a compound of Formula (I), Ri is
  • heterocyclyl-carbonyl wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-carbonyl selected from piperazin-l-yl-carbonyl; wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-carbonyl-oxy wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heterocyclyl-carbonyl-oxy selected from piperazin-l-yl-carbonyl-oxy; wherein, each instance of heterocyclyl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • aryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl wherein aryl is selected from phenyl; wherein, each instance of aryl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • aryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl selected from 3-(benzylamino)propyl; wherein, each instance of aryl is optionally substituted.
  • Ri is heteroaryl, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted.
  • Ri is heteroaryl selected from pyridin-4-yl; wherein, each instance of heteroaryl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heteroaryl-Ci_ 8 alkyl wherein heteroaryl is selected from lH-imidazolyl; and, wherein, each instance of heteroaryl is optionally substituted.
  • Ri is heteroaryl-Ci_salkyl selected from lH-imidazol-l-yl-methyl; wherein, each instance of heteroaryl is optionally substituted.
  • Ri is
  • heteroaryl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heteroaryl-Ci_8alkyl (Ci_8alkyl)amino selected from (pyridin-3-yl-methyl)(methyl)amino; wherein, each instance of heteroaryl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl wherein heteroaryl is selected from thienyl or pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted.
  • Ri is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 3 is selected from cyano, halogen, hydroxy, oxo, Ci_salkyl, halo-Ci_salkyl, Ci_galkyl-carbonyl, Ci_galkoxy, halo-Ci_ 8 alkoxy, Ci_ 8 alkoxy-Ci_ 8 alkyl, Ci_ 8 alkoxy-carbonyl, amino, Ci_ 8 alkyl-amino,
  • Ci_ 8 alkoxy-Ci_ 8 alkyl-amino Ci_galkyl-carbonyl-amino, Ci_galkoxy-carbonyl-amino,
  • R 3 is selected from cyano, halogen, hydroxy, oxo, Ci_ 8 alkyl, halo-Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxy-Ci_galkyl,
  • Ci_galkoxy-carbonyl amino, Ci_galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci_galkyl,
  • Ci_galkoxy-Ci_galkyl-amino Ci_galkoxy-carbonyl-amino, hydroxy-C i_galkyl,
  • R 3 is Ci_galkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl. [0069] In one embodiment of the use of a compound of Formula (I), R 3 is Ci.galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
  • R 3 is halo-Ci_galkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
  • R 3 is halo-Ci_ 8 alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl,
  • halo is selected from fluoro, chloro, bromo or iodo.
  • R 3 is hydroxy-Ci_ 8 alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • R 3 is hydroxy-Ci_galkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • R 3 is Ci_ 8 alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
  • R 3 is halo-Ci_8alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.
  • R 3 is
  • Ci_8alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.
  • R a is, in each instance, independently selected from hydrogen, halogen, Ci.galkyl.
  • R a is, in each instance, optionally and independently deuterium.
  • R b is hydrogen, halogen, Ci_8alkyl, Ci_8alkoxy.
  • R b is deuterium.
  • R4 is C 3 _i 4 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C3-i 4 cycloalkyl is optionally substituted.
  • R4 is C3- 8 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C 3 _ 8 cycloalkyl is optionally substituted.
  • R4 is
  • C 3 -i 4 cycloalkyl-Ci_ 8 alkyl wherein C 3 _i 4 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C 3 _i 4 cycloalkyl is optionally substituted.
  • R4 is
  • C 3 _ 8 Cycloalkyl-Ci_ 8 alkyl, wherein C 3 _gcycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C 3 _gcycloalkyl is optionally substituted.
  • R4 is
  • C 3 _i 4 cycloalkyl-amino wherein C 3 _i 4 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C 3 _i 4 cycloalkyl is optionally substituted.
  • R4 is
  • C 3 _8Cycloalkyl-amino wherein C 3 _gcycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C 3 _gcycloalkyl is optionally substituted.
  • R4 is aryl-Ci_ 8 alkyl, aryl-Ci_ 8 alkoxy-carbonyl or aryl-sulfonyloxy-Ci_ 8 alkyl, wherein each instance of aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted.
  • R4 is aryl-Ci_ 8 alkyl or aryl-Ci_ 8 alkoxy-carbonyl, wherein each instance of aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted.
  • R4 is heterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxanyl or morpholinyl; wherein, each instance of heterocyclyl is optionally substituted.
  • R 4 is heterocyclyl selected from oxetan-3-yl, pyrrolidin-l-yl, piperidin-l-yl, piperazin-l-yl, l,3-dioxan-5-yl or morpholin-4-yl; wherein, each instance of heterocyclyl is optionally substituted.
  • R 4 is
  • heterocyclyl-Ci_ 8 alkyl wherein each instance of heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
  • R 4 is
  • heterocyclyl-Ci.galkyl selected from pyrrolidin-l-yl-Ci_galkyl or piperidin-l-yl-Ci_galkyl;
  • each instance of heterocyclyl is optionally substituted.
  • R 5 is selected from halogen, hydroxy, cyano, nitro, halo-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino,
  • Ci_galkyl-amino (Ci_galkyl)2-amino or Ci_galkyl-thio.
  • R5 is hydroxy
  • R 5 is Ci_ 8 alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
  • R 5 is Ci_galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
  • R 5 is halo-Ci_ 8 alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
  • R 5 is Ci_galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
  • R 5 is halo-Ci_galkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.
  • R 2 is aryl selected from phenyl; wherein, each instance of aryl is optionally substituted.
  • R 2 is aryl-amino, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted.
  • R 2 is aryl-amino selected from phenyl-amino; wherein, each instance of aryl is optionally substituted.
  • R 2 is
  • aryl-amino-carbonyl wherein aryl is selected from phenyl; wherein, each instance of aryl is optionally substituted.
  • R 2 is
  • aryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, each instance of aryl is optionally substituted.
  • R 2 is heterocyclyl selected from 1,2,3,6-tetrahydropyridinyl, 1,3-benzodioxolyl,
  • R 2 is heterocyclyl selected from l,2,3,6-tetrahydropyridin-4-yl, l,3-benzodioxol-5-yl or
  • R 2 is heteroaryl selected from thienyl, IH-pyrazolyl, IH-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, indolyl, lH-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, lH-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzooxazolyl, 9H-purinyl, furo[3,2-3 ⁇ 4]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, lH
  • R 2 is heteroaryl selected from thien-2-yl, thien-3-yl, lH-pyrazol-3-yl, lH-pyrazol-4-yl, lH-pyrazol-5-yl,
  • R 2 is substituted heteroaryl selected from 4-methylthiophen-2-yl, l-methyl-lH-pyrazol-3-yl, 4-methyl-lH- pyrazol-3-yl, 1 -phenyl- lH-pyrazol-3-yl, 1 -phenyl- lH-imidazol-4-yl, 2-methyl-l-(pyridin-2-yl)- lH-imidazol-4-yl, 4-methyl-l,3-thiazol-2-yl, 4-(trifluoromethyl)-l,3-thiazol-2-yl, 4-phenyl-l,3- thiazol-2-yl, 5-phenyl-l,2,4-oxadiazol-3-yl, 3-fluoropyridin-4-yl, 6-fluoropyridin-2-yl, 2- chloropyridin-4-yl, 4-chloropyridin-3-yl
  • 6-cyanoimidazo[l,2-a]pyridin-2-yl also referred to as 2-imidazo[l,2-a]pyridine-6-carbonitrile
  • R 2 is heteroaryl-amino, wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and, wherein, each instance of heteroaryl is optionally substituted.
  • R 2 is
  • heteroaryl-amino selected from pyridin-2-yl-amino, pyridin-3-yl-amino or pyrimidin-2-yl-amino; wherein, each instance of heteroaryl is optionally substituted.
  • a compound of Formula (I) is selected from halogen, hydroxy, cyano, nitro, Ci_galkyl, halo-Ci_galkyl, hydroxy-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, (Ci_galkyl) 2 -amino or Ci_galkyl-thio
  • 3 ⁇ 4 is Ci_ 8 alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.
  • Ci_galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
  • 3 ⁇ 4 is C 2 _ 8 alkenyl selected from ethenyl, allyl or buta-l,3-dienyl.
  • a compound of Formula (I) is C 2 _galkenyl selected from ethenyl or allyl.
  • halo-Ci_galkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
  • a compound of Formula (I) is hydroxy-Ci_galkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • a compound of Formula (I) is hydroxy-Ci_galkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • Ci_galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
  • R ⁇ is halo-Ci_ 8 alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.
  • R 7 is C 3 _i 4 cycloalkyl, C 3 _i 4 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl; wherein C 3 -i 4 cycloalkyl is selected from cyclopropyl or cyclobutoxy; wherein aryl is selected from phenyl; wherein heterocyclyl is selected from pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl; and, wherein heteroaryl is selected from thienyl or pyridinyl.
  • R 7 is C 3 _i 4 cycloalkyl or C 3 _i 4 cycloalkyl-oxy, wherein each instance of C 3 _i 4 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • R 7 is C 3 _ 8 cycloalkyl or C 3 _ 8 cycloalkyl-oxy, wherein each instance of C 3 -scycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • R 7 is aryl selected from phenyl.
  • R 7 is heterocyclyl selected from pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.
  • R 7 is heterocyclyl selected from pyrrolidin-l-yl or l,2,3,6-tetrahydropyridin-4-yl.
  • R 7 is heteroaryl selected from thienyl or pyridinyl.
  • R 7 is heteroaryl selected from pyridinyl.
  • R 7 is heteroaryl selected from thien-2-yl or pyridin-2-yl.
  • R 7 is heteroaryl selected from pyridin-2-yl.
  • the compound is selected from Formula (la) or Formula (lb):
  • w 2 is C-R 2 and Ri is selected from (methyl) 2 -amino and R 2 is benzothiazol-2-yl optionally substituted with one R 6 substituent, then R ⁇ is other than chloro.
  • R 2 is benzothiazol-2-yl substituted with one, two or three R 6 substituents and one additional, optional R 7 substituent.
  • w 2 is C-R 2 and Ri is piperazin-l-yl substituted with one R 3 substituent selected from methyl, 2-fluoro- ethyl, 2-hydroxy-ethyl or 3 -hydroxy-propyl; or, one R4 substituent selected from
  • R 2 is benzothiazol-2-yl substituted with one, two or three R6 substituents and one additional, optional R 7 substituent.
  • w 2 is C-R 2 and Ri is piperazin-l-yl substituted with one R 3 substituent selected from 2-fluoro-ethyl and R 2 is imidazo[l ,2-a]pyridin-2-yl optionally substituted with one R 6 substituent, then 5 is other than chloro.
  • R 2 is benzooxazol-2-yl substituted with one, two or three 3 ⁇ 4 substituents and one additional, optional R 7 substituent.
  • w 2 is C-R 2 and Ri is selected from (methyl) 2 -amino and R 2 is benzooxazol-2-yl optionally substituted with one R 6 substituent, then R ⁇ is other than chloro.
  • R 2 is lH-benzoimidazol-2-yl substituted with one, two or three 3 ⁇ 4 substituents and one additional, optional R 7 substituent.
  • w 2 is C-R 2 and Ri is selected from (methyl) 2 -amino and R 2 is lH-benzoimidazol-2-yl substituted with one substituent, then R 6 is other than methyl.
  • the compound of Formula (I) is other than:
  • wi and w 2 are C-Ri or C-R 2 ; wherein, one of wi and w 2 is C-Ri and the other is C-R 2 , provided that, when wi is C-Ri, then w 2 is C-R 2 ; or, when wi is C-R 2 , then w 2 is C-Ri;
  • Ri is amino, Ci.galkoxy-Ci.galkyl-amino, (Ci_ 8 alkoxy-Ci_ 8 alkyl) 2 -amino,
  • Ci_8alkyl-amino-C i.salkyl-amino (C i_8alkyl-amino-C i_8alkyl) 2 -amino,
  • Ci_ 8 alkyl-amino-C 2 - 8 alkynyl Ci_ 8 alkyl-amino-C 2 - 8 alkynyl, (Ci_ 8 alkyl) 2 -amino-C 2 - 8 alkynyl,
  • halo-Ci_ 8 alkyl-amino (halo-Ci_ 8 alkyl) 2 -amino, hydroxy-Ci_salkyl, hydroxy-Ci.galkoxy-Ci.galkyl, hydroxy-Ci-galkyl-amino, (hydroxy-Ci_8alkyl) 2 -amino, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino, hydroxy-Ci-galkyl-amino-Ci-galkyl, (hydroxy-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl,
  • heterocyclyl-Ci_salkyl heterocyclyl-Ci_salkoxy, heterocyclyl-amino
  • heterocyclyl (Ci_8alkyl)amino
  • heterocyclyl-amino-Ci_8alkyl heterocyclyl-Ci_8alkyl-amino
  • heterocyclyl-Ci_8alkyl 2 -amino
  • heterocyclyl-Ci_8alkyl (heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heterocyclyl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl,
  • heterocyclyl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl) 2 -amino,
  • aryl-Ci_ 8 alkyl 2 -amino-Ci_ 8 alkyl, (aryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-Ci_galkoxy, heteroaryl-amino, heteroaryl-Ci.galkyl-amino, (heteroaryl-Ci_8alkyl) 2 -amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl (heteroaryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl or
  • each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R 3 substituents and one additional, optional R 4 substituent;
  • each instance of heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R 3 substituents;
  • R 2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;
  • each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three 3 ⁇ 4 substituents and one additional, optional R 7 substituent;
  • Ra is, in each instance, independently selected from hydrogen, halogen, Ci_ 8 alkyl or deuterium;
  • R b is hydrogen, halogen, Ci_ 8 alkyl, Ci_ 8 alkoxy or deuterium;
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci.galkyl, halo-Ci_galkyl, Ci_galkyl-carbonyl, Ci_galkoxy, halo-Ci_galkoxy, Ci_galkoxy-Ci_galkyl, Ci_galkoxy-carbonyl, amino, Ci_galkyl-amino, (Ci_galkyl) 2 -amino, amino-Ci_galkyl,
  • Ci_galkoxy-Ci_galkyl-amino Ci_galkyl-carbonyl-amino, Ci_galkoxy-carbonyl-amino,
  • R4 is C 3 -i 4 cycloalkyl, C 3 _i 4 cycloalkyl-Ci_ 8 alkyl, C 3 _i 4 cycloalkyl-amino, aryl-Ci_ 8 alkyl, aryl-Ci_ 8 alkoxy-carbonyl, heterocyclyl or heterocyclyl-Ci_ 8 alkyl; wherein, each instance of C 3 _i 4 cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R 5 substituents;
  • R 5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_ 8 alkyl, halo-Ci_ 8 alkyl, Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy, amino, Ci_ 8 alkyl-amino,
  • Ci_ 8 alkyl 2 -amino or Ci_ 8 alkyl-thio
  • Re is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_ 8 alkyl, halo-Ci_ 8 alkyl, hydroxy-Ci_ 8 alkyl, Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy, amino,
  • Ci_ 8 alkyl-amino (Ci_ 8 alkyl) 2 -amino or Ci_ 8 alkyl-thio;
  • R 7 is C 3 _i 4 cycloalkyl, C 3 _i 4 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • R 3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci_ 8 alkyl-carbonyl, Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy, Ci_ 8 alkoxy-Ci_ 8 alkyl, Ci_ 8 alkoxy-carbonyl, amino, Ci_ 8 alkyl-amino,
  • a compound of Formula (I) is, in each instance, independently selected from hydroxy, cyano, nitro, halo-Ci_ 8 alkyl, hydroxy-Ci_ 8 alkyl,
  • R 7 is C 3 _i 4 cycloalkyl, C 3 _i 4 Cycloalkyl-oxy, aryl or heterocyclyl.
  • the compound of Formula (I) used in a method disclosed herein is a com ound from the group consisting of:
  • the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of:

Abstract

Described herein are methods for modulating the amount of a gene product and compounds for use in such methods. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product as the result of gene expression and compounds for use in such methods.

Description

METHODS FOR MODULATING THE AMOUNT OF RNA TRANSCRIPTS
CROSS-REFERENCE
[0001] This application claims the benefit of priority to United States Provisional Application Serial No. 61/918,600, filed December 19, 2013, which is incorporated herein by reference in its entirety and for all purposes.
INTRODUCTION
[0002] Described herein are methods for modulating the amount of a gene product and compounds for use in such methods. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product as the result of gene expression and compounds for use in such methods.
BACKGROUND
[0003] A number of diseases are associated with aberrant expression of a gene product (e.g., an RNA transcript or protein) of a gene. The resulting aberrant amounts of RNA transcripts may lead to disease due to corresponding changes in protein expression. Changes in the amount of a particular RNA transcript may be the result of several factors. First, changes in the amount of RNA transcripts may be due to an aberrant level of transcription of a particular gene, such as by the perturbation of a transcription factor or a portion of the transcription process, resulting in a change in the expression level of a particular RNA transcript. Secondly, changes in the splicing of particular RNA transcripts, such as by perturbation of a particular splicing process or mutations in the gene that lead to modified splicing can change the levels of a particular RNA transcript. Changes to the stability of a particular RNA transcript or to components that maintain RNA transcript stability, such as the process of poly-A tail incorporation or an effect on certain factors or proteins that bind to and stabilize RNA transcripts, may lead to changes in the levels of a particular RNA transcript. Also, the level of translation of particular RNA transcripts can affect the amount of those transcripts, affecting or upregulating RNA transcript decay processes. Finally, aberrant RNA transport or RNA sequestration may also lead to changes in functional levels of RNA transcripts, and may have an effect on the stability, further processing, or translation of the RNA transcripts. [0004] Often, diseases associated with changes to RNA transcript amount are treated with a focus on the aberrant protein expression. However, if the processes responsible for the aberrant changes in RNA levels, such as components of the splicing process or associated transcription factors or associated stability factors, could be targeted by treatment with a small molecule, it would be possible to restore protein expression levels such that the unwanted effects of the expression of aberrant levels of RNA transcripts or associated proteins. Therefore, there is a need for methods of modulating the amount of RNA transcripts encoded by certain genes as a way to prevent or treat diseases associated with aberrant expression of the RNA transcripts or associated proteins.
SUMMARY
[0005] In one aspect, provided herein are methods for modulating the amount of one or more RNA transcripts (e.g., rRNA, tRNA, miRNA, siRNA, IncRNA, pre-mRNA, or mRNA transcripts) or proteins thereof expressed as the product of one or more of genes, comprising contacting a cell with a compound of Formula (I)
Figure imgf000003_0001
(I)
or a form thereof, wherein Ra, Rb, wi and w2 are as defined herein. In one embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 1, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof. In another embodiment, provided herein are methods for modulating one, two, three or more RNA transcripts of one, two, three or more genes, by way of nonlimiting example, disclosed in Table 1, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 2, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof. In another embodiment, provided herein are methods for modulating one, two, three or more RNA transcripts of one, two, three or more genes, by way of nonlimiting example, disclosed in Table 2, infra, comprising contacting a cell with a compound of Formula (I) or a form thereof. In certain embodiments, the cell is contacted with the compound of Formula (I) or a form thereof in a cell culture. In other embodiments, the cell is contacted with the compound of Formula (I) or a form thereof in a subject {e.g., a non- human animal subject or a human subject). In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0006] In another aspect, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In one embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 1, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of one, two, three or more genes disclosed in Table 1, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof, and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0007] In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of a gene, by way of nonlimiting example, disclosed in Table 2, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for modulating the amount of one, two, three or more RNA transcripts of one, two, three or more genes disclosed in Table 2, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof, and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0008] In another aspect, provided herein are methods for preventing and/or treating a disease associated with the aberrant expression of a gene product, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In one embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a gene product {e.g., an RNA transcript or protein) a gene, by way of nonlimiting example, disclosed in Table 1, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease associated with aberrant expression of a gene product {e.g., an RNA transcript or protein) a gene, by way of nonlimiting example, disclosed in Table 2, infra, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0009] In another aspect, provided herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more RNA isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, comprising
administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In one embodiment, provided herein are methods for preventing and/or treating a disease in which the increase in the expression one, two, three or more RNA isoforms encoded by gene, by way of nonlimiting example, disclosed in Table 1 , infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the decrease in the expression one, two, three or more RNA isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0010] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the increase in the expression one, two, three or more RNA isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the decrease in the expression one, two, three or more RNA isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0011] In another aspect, provided herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more protein isoforms encoded by a gene is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In one embodiment, provided herein are methods for preventing and/or treating a disease in which the increase in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the decrease in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 1, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
[0012] In another embodiment, provided herein are methods for preventing and/or treating a disease in which the increase in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein are methods for preventing and/or treating a disease in which the decrease in the expression one, two, three or more protein isoforms encoded by a gene, by way of nonlimiting example, disclosed in Table 2, infra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) is a compound of Formula (la) or Formula (lb) described infra. In some embodiments, a compound of Formula (I) is a compound selected from a compound described herein.
DETAILED DESCRIPTION
[0013] In one aspect, provided herein are methods for modulating the amount of one or more RNA transcripts of one or more of genes, comprising contacting a cell with a compound of Formula (I) or a form thereof. In certain embodiments, a compound of Formula (I) or a form thereof modulates the amount of one or more of the RNA transcripts of one or more of the genes, by way of nonlimiting example, in Table 1, infra. In other embodiments, a compound of Formula (I) or a form thereof modulates the amount of one or more of the RNA transcripts of one or more of the genes, by way of nonlimiting example, in Table 2, infra.
[0014] In another aspect, provided herein are methods for modulating an aberrant amount of RNA transcripts of a gene(s) comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more of the RNA transcripts of one, two, three or more of the genes, by way of nonlimiting example, in Table 1, infra. In other embodiments, a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more of the RNA transcripts of one, two, three or more of the genes, by way of nonlimiting example, in Table 2, infra.
[0015] In another aspect, provided herein are methods for preventing and/or treating a disease associated with the aberrant expression of a gene, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, the disease is associated with the aberrant expression of a gene, by way of nonlimiting example, in Table 1, infra. In other embodiments, the disease is associated with the aberrant expression of a gene, by way of nonlimiting example, in Table 2, infra. In certain embodiments, the disease is not associated with the aberrant expression of the SMN2 gene.
[0016] In another aspect, provided herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more RNA isoforms of a gene(s) is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, an increase in the level of expression of one, two, three or more RNA isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 1, infra, is beneficial to prevent and/or treat a disease. In other embodiments, a decrease in the level of expression of one, two, three or more RNA isoforms of one, two or more genes, by way of nonlimiting example, in Table 1, infra, is beneficial to prevent and/or treat a disease. In some embodiments, an increase in the level of expression of one, two, three or more RNA isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 2, infra, is beneficial to prevent and/or treat a disease. In other embodiments, a decrease in the level of expression of one, two, three or more RNA isoforms of one, two or more genes, by way of nonlimiting example, in Table 2, infra, is beneficial to prevent and/or treat a disease.
[0017] In another aspect, provided herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more protein isoforms of a gene(s) is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In certain embodiments, an increase in the level of expression of one, two, three or more protein isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 1, infra, is beneficial to prevent and/or treat a disease. In other embodiments, a decrease in the level of expression of one, two, three or more protein isoforms of one, two or more genes, by way of nonlimiting example, in Table 1, infra, is beneficial to prevent and/or treat a disease. In some embodiments, an increase in the level of expression of one, two, three or more protein isoforms of one, two, three or more genes, by way of nonlimiting example, in Table 2, infra, is beneficial to prevent and/or treat a disease. In other embodiments, a decrease in the level of expression of one, two, three or more protein isoforms of one, two or more genes, by way of nonlimiting example, in Table 2, infra, is beneficial to prevent and/or treat a disease. COMPOUNDS
[0018] Provided herein are compounds of Formula (I) for use in the methods described herein:
Figure imgf000010_0001
(I)
[0019] or a form thereof, wherein:
[0020] wi and w2 are C-Ri or C-R2; wherein, one of wi and w2 is C-Ri and the other is C-R2, provided that, when wi is C-Ri, then w2 is C-R2; or, when wi is C-R2, then w2 is C-Ri;
[0021] Ri is Ci_8alkyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino,
Ci_8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl)2-amino,
(Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl,
(Ci_8alkyl)2-amino-Ci_8alkyl, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl,
(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, amino-Ci_8alkyl-amino, (amino-Ci_8alkyl)2-amino, (amino-Ci_8alkyl)(Ci_8alkyl)amino,
Ci_8alkyl-amino-C i.salkyl-amino, (C i.galkyl-amino-C i_8alkyl)2-amino,
(Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino,
[(Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino, amino-Ci_8alkoxy, Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkyl)2-amino-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkoxy,
(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, amino-C2-8alkenyl, Ci_8alkyl-amino-C2-8alkenyl, (Ci_8alkyl)2-amino-C2-8alkenyl,
amino-C2-8alkynyl, Ci_8alkyl-amino-C2-8alkynyl, (Ci_8alkyl)2-amino-C2-8alkynyl,
halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, (halo-Ci_8alkyl)(Ci_8alkyl)amino,
hydroxy-Ci_salkyl, hydroxy-Ci_8alkoxy-Ci_salkyl, hydroxy-Ci-salkyl-amino,
(hydroxy-Ci_8alkyl)2-amino, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino,
hydroxy-Ci_8alkyl-amino-Ci_8alkyl, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, hydroxy-Ci_8alkyl-amino-Ci_8alkoxy,
(hydroxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino, (hydroxy-Ci_8alkyl-amino-Ci_8alkyl)2-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino,
(hydroxy-C i_8alkyl)2-amino-C i_8alkyl-amino,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino,
[(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino,
[(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl](Ci_8alkyl)amino, heterocyclyl,
heterocyclyl-Ci_salkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-amino,
(heterocyclyl)(Ci_8alkyl)amino, heterocyclyl-amino-Ci_8alkyl, heterocyclyl-Ci_8alkyl-amino, (heterocyclyl-Ci_8alkyl)2-amino, (heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino,
heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, (heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl)2-amino,
(aryl-Ci_8alkyl)(Ci_8alkyl)amino, aryl-Ci_8alkyl-amino-Ci_8alkyl,
(aryl-Ci_8alkyl)2-amino-Ci_8alkyl, (aryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl)2-amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl)2-amino-Ci_8alkyl or
(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl;
[0022] wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R3 substituents and one additional, optional R4 substituent; and,
[0023] wherein, alternatively, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
[0024] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or
heteroaryl-amino;
[0025] wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three ¾ substituents and one additional, optional R7 substituent;
[0026] Ra is, in each instance, independently selected from hydrogen, halogen, Ci_8alkyl or deuterium;
[0027] Rb is hydrogen, halogen, Ci_salkyl, Ci_8alkoxy or deuterium;
[0028] R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo,
Ci_8alkyl, halo-Ci_8alkyl, Ci_8alkyl-carbonyl, Ci_8alkoxy, halo-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl, Ci_8alkoxy-carbonyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl, amino-Ci_8alkyl-amino,
Ci_8alkyl-amino-Ci_8alkyl-amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino,
Ci_8alkoxy-Ci_8alkyl-amino, Ci_8alkyl-carbonyl-amino, Ci_8alkoxy-carbonyl-amino,
hydroxy-Ci_8alkyl, hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-Ci_galkyl-amino,
(hydroxy-Ci_8alkyl)2-amino or (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino;
[0029] R4 is C3_i4cycloalkyl, C3-i4cycloalkyl-Ci_galkyl, C3_i4cycloalkyl-amino, aryl-Ci_salkyl, aryl-Ci.galkoxy-carbonyl, aryl-sulfonyloxy-Ci_galkyl, heterocyclyl or heterocyclyl-Ci_galkyl; wherein, each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
[0030] R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_8alkyl, halo-Ci_8alkyl, Ci_8alkoxy, halo-Ci_8alkoxy, amino, Ci_8alkyl-amino,
(Ci_8alkyl)2-amino or Ci_8alkyl-thio;
[0031] Re is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_salkyl, C2-galkenyl, halo-Ci_salkyl, hydroxy-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino or Ci_galkyl-thio; and,
[0032] R7 is C3_i4cycloalkyl, C3_i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
[0033] In one embodiment of the use of a compound of Formula (I), Ri is Ci_8alkyl, amino, Ci.galkyl-amino, (Ci_galkyl)2-amino, Ci_galkoxy-Ci_galkyl-amino, (Ci_galkoxy-Ci_galkyl)2-amino, (Ci_galkoxy-Ci_galkyl)(Ci_galkyl)amino, amino-Ci_galkyl, Ci_galkyl-amino-Ci_galkyl,
(Ci_galkyl)2-amino-Ci_galkyl, Ci_galkoxy-Ci_galkyl-amino-Ci_galkyl,
(Ci_galkoxy-Ci_galkyl)2-amino-Ci_galkyl, (Ci_galkoxy-Ci_galkyl)(Ci_galkyl)amino-Ci_galkyl, amino-Ci_galkyl-amino, (amino-Ci_galkyl)2-amino, (amino-Ci_galkyl)(Ci_galkyl)amino,
Ci_galkyl-amino-C i_galkyl-amino, (C i_galkyl-amino-C i_galkyl)2-amino,
(Ci_galkyl-amino-Ci_galkyl)(Ci_galkyl)amino, (Ci_galkyl)2-amino-Ci_galkyl-amino,
[(Ci_galkyl)2-amino-Ci_galkyl](Ci_galkyl)amino, amino-Ci_galkoxy, Ci_galkyl-amino-Ci_galkoxy, (Ci_galkyl)2-amino-Ci_galkoxy, Ci_galkoxy-Ci_galkyl-amino-Ci_galkoxy,
(Ci_galkoxy-Ci_galkyl)2-amino-Ci_galkoxy, (Ci_galkoxy-Ci_galkyl)(Ci_galkyl)amino-Ci_galkoxy, amino-C2-galkenyl, Ci_galkyl-amino-C2-galkenyl, (Ci_galkyl)2-amino-C2-galkenyl,
amino-C2-galkynyl, Ci_galkyl-amino-C2-galkynyl, (Ci_galkyl)2-amino-C2-galkynyl,
halo-Ci_galkyl-amino, (halo-Ci_galkyl)2-amino, (halo-Ci_galkyl)(Ci_galkyl)amino, hydroxy-Ci-galkyl, hydroxy-Ci-galkoxy-Ci.galkyl, hydroxy-Ci.galkyl-amino,
(hydroxy-Ci_galkyl)2-amino, (hydroxy-Ci_8alkyl)(Ci_galkyl)amino,
hydroxy-Ci-galkyl-amino-Ci-galkyl, (hydroxy-Ci_galkyl)2-amino-Ci_galkyl,
(hydroxy-Ci_galkyl)(Ci_galkyl)amino-Ci_galkyl, hydroxy-Ci_galkyl-amino-Ci_galkoxy, (hydroxy-Ci_galkyl)2-amino-Ci_galkoxy, (hydroxy-Ci_galkyl)(Ci_galkyl)amino-Ci_galkoxy, hydroxy-Ci_galkyl-amino-Ci_galkyl-amino, (hydroxy-Ci_galkyl-amino-Ci_galkyl)2-amino, (hydroxy-Ci_galkyl-amino-Ci_galkyl)(Ci_galkyl)amino,
(hydroxy-C i_galkyl)2-amino-C i_galkyl-amino,
(hydroxy-Ci_galkyl)(Ci_galkyl)amino-Ci_galkyl-amino,
[(hydroxy-Ci_galkyl)2-amino-Ci_galkyl](Ci_galkyl)amino,
[(hydroxy-Ci_galkyl)(Ci_galkyl)amino-Ci_galkyl](Ci_galkyl)amino, heterocyclyl,
heterocyclyl-Ci.galkyl, heterocyclyl-Ci_galkoxy, heterocyclyl-amino,
(heterocyclyl)(Ci_galkyl)amino, heterocyclyl-amino-Ci_galkyl, heterocyclyl-Ci_galkyl-amino, (heterocyclyl-Ci_8alkyl)2-amino, (heterocyclyl-Ci_8alkyl)(Ci_galkyl)amino,
heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, (heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl)2-amino,
(aryl-Ci_8alkyl)(Ci_8alkyl)amino, aryl-Ci_8alkyl-amino-Ci_8alkyl,
(aryl-Ci_8alkyl)2-amino-Ci_8alkyl, (aryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl)2-amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl)2-amino-Ci_8alkyl or
(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl; wherein, each instance of heterocyclyl and heteroaryl is optionally substituted.
[0034] In one embodiment of the use of a compound of Formula (I), Ri is
Ci_8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl)2-amino,
(Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl,
(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, amino-Ci_8alkyl-amino, (amino-Ci_8alkyl)2-amino, (amino-Ci_8alkyl)(Ci_8alkyl)amino, Ci_8alkyl-amino-C i.galkyl-amino, (C i_8alkyl-amino-C i_8alkyl)2-amino, (Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino, amino-Ci_8alkoxy, Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkyl)2-amino-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkoxy,
(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, amino-C2-8alkenyl, Ci_8alkyl-amino-C2-8alkenyl, (Ci_8alkyl)2-amino-C2-8alkenyl,
amino-C2-8alkynyl, Ci_8alkyl-amino-C2-8alkynyl, (Ci_8alkyl)2-amino-C2-8alkynyl,
halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, hydroxy-Ci_8alkyl, hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-C i_8alkyl-amino, (hydroxy-Ci_8alkyl)2-amino, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino, hydroxy-Ci_8alkyl-amino-Ci_8alkyl, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, hydroxy-Ci_8alkyl-amino-Ci_8alkoxy,
(hydroxy-C i_8alkyl)2-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino, (hydroxy-Ci_8alkyl-amino-Ci_8alkyl)2-amino, (hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino,
(hydroxy-C i_8alkyl)2-amino-C i_8alkyl-amino,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino,
[(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino,
[(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl](Ci_8alkyl)amino, heterocyclyl,
heterocyclyl-Ci_8alkyl, heterocyclyl-Ci_8alkoxy, heterocyclyl-amino,
(heterocyclyl)(Ci_8alkyl)amino, heterocyclyl-amino-Ci.salkyl, heterocyclyl-Ci_8alkyl-amino, (heterocyclyl-Ci_8alkyl)2-amino, (heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino,
heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, (heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl)2-amino,
(aryl-Ci_8alkyl)(Ci_8alkyl)amino, aryl-Ci_8alkyl-amino-Ci_8alkyl,
(aryl-Ci_8alkyl)2-amino-Ci_8alkyl, (aryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino, (heteroaryl-Ci_8alkyl)2-amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl)2-amino-Ci_8alkyl or
(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl; wherein, each instance of heterocyclyl and heteroaryl is optionally substituted. [0035] In another embodiment of the use of a compound of Formula (I), Ri is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1 ,4-diazepanyl, 1 ,2,5,6-tetrahydropyridinyl, 1 ,2,3,6-tetrahydropyridinyl, hexahydropyrrolo[3,4-¾]pyrrol-(lH)-yl, (3a5',6a5)-hexahydropyrrolo[3,4-¾]pyrrol-(lH)-yl,
(3ai?,6ai?)-hexahydropyrrolo[3,4-¾]pyrrol-(lH)-yl, hexahydropyrrolo[3,4-¾]pyrrol-(2H)-yl, (3a5',6a5)-hexahydropyrrolo[3,4-¾]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, (3ai?,6a5)-hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-£]pyridinyl, (4ai?,7ai?)-octahydro-6H-pyrrolo[3,4-£]pyridinyl, (4a5',7a5)-octahydro-6H-pyrrolo[3,4-¾]pyridinyl, hexahydropyrrolo[l ,2-a]pyrazin-(lH)-yl, (7i?,8a5)-hexahydropyrrolo[ 1 ,2-a]pyrazin-(lH)-yl,
(8a5)-hexahydropyrrolo[ 1 ,2-a]pyrazin-(lH)-yl, (8ai?)-hexahydropyrrolo[ 1 ,2-a]pyrazin-(lH)-yl, (8a5)-octahydropyrrolo[l ,2-a]pyrazin-(lH)-yl, (8ai?)-octahydropyrrolo[l ,2-a]pyrazin-(lH)-yl, hexahydropyrrolo[ 1 ,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[ 1 ,2-a]pyrazinyl,
3-azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,
(li?,55)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,
( li?,5iS)-8-azabicyclo[3.2.1 ]oct-2-enyl, 9-azabicyclo[3.3.1 ]nonyl,
(li?,55)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl,
(lS^S^^-diazabicycloP^. lJheptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (li?,55)-3,8-diazabicyclo[3.2.1]octyl, l ,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl,
2.6- diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl,
2.7- diazaspiro[4.4]nonyl or 6,9-diazaspiro[4.5]decyl; wherein, each instance of heterocyclyl is optionally substituted.
[0036] In another embodiment of the use of a compound of Formula (I), Ri is heterocyclyl selected from azetidin-l-yl, tetrahydrofuran-3-yl, pyrrolidin-l-yl, piperidin-l-yl, piperidin-4-yl, piperazin- 1 -yl, 1 ,4-diazepan- 1 -yl, 1 ,2,5 ,6-tetrahydropyridin-3-yl, 1 ,2,3 ,6-tetrahydropyridin-4-yl, hexahydropyrrolo[3,4-£]pyrrol-l(2H)-yl, (3a5',6a5)-hexahydropyrrolo[3,4-¾]pyrrol-l(2H)-yl, (3 aS^a^-hexahydropyrrolo [3 ,4-¾]pyrrol-5 ( lH)-yl,
(3ai?,6ai?)-hexahydropyrrolo[3,4-¾]pyrrol-5(lH)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, (3ai?,6a5)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl, (4ai?,7ai?)-octahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl, (4a5',7a5)-octahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl, hexahydropyrrolo[l ,2-a]pyrazin-2(lH)-yl, hexahydropyrrolo[l,2-a]pyrazin-6(2H)-one, (7i?,8a5)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, (8a5)-hexahydropyrrolo[ 1 ,2-a]pyrazin-2(lH)-yl,
(8ai?)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl,
(8a5)-octahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, (8ai?)-octahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl, 3-azabicyclo[3.1.0]hex-3-yl,
8-azabicyclo[3.2.1]oct-3-yl, (lR,5S)-8-azabicyclo[3.2.1]oct-3-yl,
8- azabicyclo[3.2.1]oct-2-en-3-yl, (li?,55)-8-azabicyclo[3.2.1]oct-2-en-3-yl,
9- azabicyclo[3.3.1]non-3-yl, (li?,55)-9-azabicyclo[3.3.1]non-3-yl,
2,5-diazabicyclo[2.2. l]hept-2-yl, (15',45)-2,5-diazabicyclo[2.2. l]hept-2-yl,
2.5- diazabicyclo[2.2.2]oct-2-yl, 3,8-diazabicyclo[3.2.1]oct-3-yl,
(li?,55)-3,8-diazabicyclo[3.2.1]oct-3-yl, l,4-diazabicyclo[3.2.2]non-4-yl, azaspiro[3.3]hept-2-yl,
2.6- diazaspiro[3.3]hept-2-yl, 2,7-diazaspiro[3.5]non-7-yl, 5,8-diazaspiro[3.5]non-8-yl, 2,7- diazaspiro[4.4]non-2-yl or 6,9-diazaspiro[4.5]dec-9-yl; wherein, each instance of heterocyclyl is optionally substituted.
[0037] In another embodiment of the use of a compound of Formula (I), Ri is substituted heterocyclyl selected from (3a5',6a5)-l-methylhexahydropyrrolo[3,4-¾]pyrrol-5(lH)-yl,
(3 aS,6aS)-5 -methylhexahydropyrrolo [3 ,4-¾]pyrrol- 1 (2H)-yl,
(3ai?,6ai?)-l-methylhexahydropyrrolo[3,4-¾]pyrrol-5(lH)-yl,
(3 aR,6aS)-5 -methylhexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl,
(3ai?,6a5)-5-(2-hydroxyethyl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl,
(3ai?,6a5)-5-(propan-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl,
(3 aR,6aS)-5 -ethylhexahydropyrrolo [3 ,4-c]pyrrol-2( lH)-yl,
(4ai?,7ai?)-l-methyloctahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl,
(4ai?,7ai?)-l-ethyloctahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl,
(4ai?,7ai?)-l-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl,
(4a5',7a5)-l-methyloctahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl,
(4a5',7a5)-l-(2-hydroxyethyl)octahydro-6H-pyrrolo[3,4-¾]pyridin-6-yl,
(7R, 8a5)-7-hydroxyhexahydropyrrolo [ 1 ,2-a]pyrazin-2( 1 H)-yl,
(8a5)-8a-methyloctahydropyrrolo[ 1 ,2-a]pyrazin-2(lH)-yl,
(8ai?)-8a-methyloctahydropyrrolo[l,2-a]pyrazin-2(lH)-yl,
(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl, (li?,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl, 9-methyl-9-azabicyclo[3.3.1]non-3-yl, (3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl, (li?,5S)-9-methyl-9-azabicyclo[3.3.1]non-3-yl, ( 15*,45)-5-methyl-2,5 -diazabicyclo [2.2.1 ]hept-2-yl or
( 1 S,4S)-5 -ethyl-2,5 -diazabicyclo [2.2.1 ]hept-2-yl.
[0038] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-Ci_8alkyl, wherein heterocyclyl is selected from morpholinyl, piperidinyl, piperazinyl, imidazolyl or pyrrolidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0039] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-Ci_galkyl selected from morpholin-4-yl-methyl, morpholin-4-yl-ethyl,
morpholin-4-yl-propyl, piperidin-l-yl-methyl, piperazin-l-yl-methyl, piperazin-l-yl-ethyl, piperazin-l-yl-propyl, piperazin-l-yl-butyl, imidazol-l-yl-methyl, imidazol-l-yl-ethyl, imidazol-l-yl-propyl, imidazol-l-yl-butyl, pyrrolidin-l-yl-methyl, pyrrolidin-l-yl-ethyl, pyrrolidin-l-yl-propyl or pyrrolidin-l-yl-butyl; wherein, each instance of heterocyclyl is optionally substituted.
[0040] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-Ci.galkoxy, wherein heterocyclyl is selected from pyrrolidinyl, piperidinyl or morpholinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0041] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-Ci_8alkoxy selected from pyrrolidin-2-yl-methoxy, pyrrolidin-2-yl-ethoxy, pyrrolidin-l-yl-methoxy, pyrrolidin-l-yl-ethoxy, piperidin-l-yl-methoxy, piperidin-l-yl-ethoxy, morpholin-4-yl-methoxy or morpholin-4-yl-ethoxy; wherein, each instance of heterocyclyl is optionally substituted.
[0042] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, 9-azabicyclo[3.3.1]nonyl or (li?,55)-9-azabicyclo[3.3.1]nonyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0043] In one embodiment of the use of a compound of Formula (I), Ri is heterocyclyl-amino selected from azetidin-3-yl-amino, pyrrolidin-3-yl-amino, piperidin-4-yl-amino,
9-azabicyclo[3.3. l]non-3-yl-amino, (li?,5S)-9-azabicyclo[3.3. l]non-3-yl-amino,
9-methyl-9-azabicyclo[3.3.1 ]non-3-yl-amino, (3-exo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl-amino or (li?,55)-9-methyl-9- azabicyclo[3.3.1]non-3-yl-amino; wherein, each instance of heterocyclyl is optionally
substituted.
[0044] In one embodiment of the use of a compound of Formula (I), Ri is
(heterocyclyl)(Ci_8alkyl)amino, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0045] In one embodiment of the use of a compound of Formula (I), Ri is
(heterocyclyl)(Ci_8alkyl)amino selected from (pyrrolidin-3-yl)(methyl)amino or
(piperidin-4-yl)(methyl)amino; wherein, each instance of heterocyclyl is optionally substituted.
[0046] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-amino-Ci_8alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0047] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-amino-Ci.galkyl, selected from 3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance of heterocyclyl is optionally substituted.
[0048] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl, thienyl or pyridinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0049] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, selected from 3-[(tetrahydrofuran-2- ylmethyl)amino]propyl, 3 - [(thiophenyl-3 -ylmethyl)amino]propyl, 3 - [(pyridin-2- ylmethyl)amino]propyl or 3-[(pyridin-4-ylmethyl)amino]propyl; wherein, each instance of heterocyclyl is optionally substituted.
[0050] In one embodiment of the use of a compound of Formula (I), Ri is heterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0051] In one embodiment of the use of a compound of Formula (I), Ri is heterocyclyl-oxy selected from pyrrolidin-3-yl-oxy or piperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionally substituted. [0052] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-carbonyl, wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0053] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-carbonyl selected from piperazin-l-yl-carbonyl; wherein, each instance of heterocyclyl is optionally substituted.
[0054] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-carbonyl-oxy, wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0055] In one embodiment of the use of a compound of Formula (I), Ri is
heterocyclyl-carbonyl-oxy selected from piperazin-l-yl-carbonyl-oxy; wherein, each instance of heterocyclyl is optionally substituted.
[0056] In one embodiment of the use of a compound of Formula (I), Ri is
aryl-Ci_8alkyl-amino-Ci_8alkyl, wherein aryl is selected from phenyl; wherein, each instance of aryl is optionally substituted.
[0057] In one embodiment of the use of a compound of Formula (I), Ri is
aryl-Ci_8alkyl-amino-Ci_8alkyl selected from 3-(benzylamino)propyl; wherein, each instance of aryl is optionally substituted.
[0058] In one embodiment of the use of a compound of Formula (I), Ri is heteroaryl, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted.
[0059] In one embodiment of the use of a compound of Formula (I), Ri is heteroaryl selected from pyridin-4-yl; wherein, each instance of heteroaryl is optionally substituted.
[0060] In one embodiment of the use of a compound of Formula (I), Ri is
heteroaryl-Ci_8alkyl, wherein heteroaryl is selected from lH-imidazolyl; and, wherein, each instance of heteroaryl is optionally substituted.
[0061] In one embodiment of the use of a compound of Formula (I), Ri is heteroaryl-Ci_salkyl selected from lH-imidazol-l-yl-methyl; wherein, each instance of heteroaryl is optionally substituted. [0062] In one embodiment of the use of a compound of Formula (I), Ri is
(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted.
[0063] In one embodiment of the use of a compound of Formula (I), Ri is
(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino selected from (pyridin-3-yl-methyl)(methyl)amino; wherein, each instance of heteroaryl is optionally substituted.
[0064] In one embodiment of the use of a compound of Formula (I), Ri is
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, wherein heteroaryl is selected from thienyl or pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted.
[0065] In one embodiment of the use of a compound of Formula (I), Ri is
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl selected from thien-3-yl-methyl-amino-propyl, pyridin-2- yl-methyl-amino-propyl, pyridin-3-yl-methyl-amino-propyl or pyridin-4- yl-methyl-amino-propyl; wherein, each instance of heteroaryl is optionally substituted.
[0066] In one embodiment of the use of a compound of Formula (I), R3 is selected from cyano, halogen, hydroxy, oxo, Ci_salkyl, halo-Ci_salkyl, Ci_galkyl-carbonyl, Ci_galkoxy, halo-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl, Ci_8alkoxy-carbonyl, amino, Ci_8alkyl-amino,
(Ci_8alkyl)2-amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl, amino-Ci_8alkyl-amino, Ci_8alkyl-amino-Ci_8alkyl-amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino,
Ci_8alkoxy-Ci_8alkyl-amino, Ci_galkyl-carbonyl-amino, Ci_galkoxy-carbonyl-amino,
hydroxy-C i_galkyl, hydroxy-Ci_galkoxy-Ci_galkyl, hydroxy-Ci_galkyl-amino,
(hydroxy-C i_galkyl)(C i_galkyl)amino or (hydroxy-C i_galkyl)2-amino .
[0067] In one embodiment of the use of a compound of Formula (I), R3 is selected from cyano, halogen, hydroxy, oxo, Ci_8alkyl, halo-Ci_8alkyl, Ci_8alkoxy, Ci_8alkoxy-Ci_galkyl,
Ci_galkoxy-carbonyl, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino, amino-Ci_galkyl,
Ci_galkyl-amino-Ci_galkyl, (Ci_galkyl)2-amino-Ci_galkyl, Ci_galkyl-amino-Ci_galkyl-amino,
Ci_galkoxy-Ci_galkyl-amino, Ci_galkoxy-carbonyl-amino, hydroxy-C i_galkyl,
hydroxy-C i_galkoxy-Ci_galkyl, hydroxy-Ci_galkyl-amino, (hydroxy-Ci_galkyl)(Ci_galkyl)amino or
(hydroxy-C i_galkyl)2-amino .
[0068] In one embodiment of the use of a compound of Formula (I), R3 is Ci_galkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl. [0069] In one embodiment of the use of a compound of Formula (I), R3 is Ci.galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
[0070] In one embodiment of the use of a compound of Formula (I), R3 is halo-Ci_galkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[0071] In one embodiment of the use of a compound of Formula (I), R3 is halo-Ci_8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl,
trihalo-propyl or dihalo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[0072] In one embodiment of a compound of Formula (I), R3 is hydroxy-Ci_8alkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
[0073] In one embodiment of the use of a compound of Formula (I), R3 is hydroxy-Ci_galkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
[0074] In one embodiment of a compound of Formula (I), R3 is Ci_8alkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
[0075] In one embodiment of the use of a compound of Formula (I), R3 is halo-Ci_8alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[0076] In one embodiment of the use of a compound of Formula (I), R3 is
Ci_8alkoxy-carbonyl-amino selected from methoxy-carbonyl-amino, ethoxy-carbonyl-amino, propoxy-carbonyl-amino, isopropoxy-carbonyl-amino, tert-butoxy-carbonyl-amino.
[0077] In one embodiment of the use of a compound of Formula (I), Ra is, in each instance, independently selected from hydrogen, halogen, Ci.galkyl.
[0078] In one embodiment of the use of a compound of Formula (I), Ra is, in each instance, optionally and independently deuterium.
[0079] In one embodiment of the use of a compound of Formula (I), Rb is hydrogen, halogen, Ci_8alkyl, Ci_8alkoxy.
[0080] In one embodiment of the use of a compound of Formula (I), Rb is deuterium. [0081] In one embodiment of the use of a compound of Formula (I), R4 is C3_i4cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C3-i4cycloalkyl is optionally substituted.
[0082] In one embodiment of the use of a compound of Formula (I), R4 is C3-8cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C3_8cycloalkyl is optionally substituted.
[0083] In one embodiment of the use of a compound of Formula (I), R4 is
C3-i4cycloalkyl-Ci_8alkyl, wherein C3_i4cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C3_i4cycloalkyl is optionally substituted.
[0084] In one embodiment of the use of a compound of Formula (I), R4 is
C3_8Cycloalkyl-Ci_8alkyl, wherein C3_gcycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C3_gcycloalkyl is optionally substituted.
[0085] In one embodiment of the use of a compound of Formula (I), R4 is
C3_i4cycloalkyl-amino, wherein C3_i4cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C3_i4cycloalkyl is optionally substituted.
[0086] In one embodiment of the use of a compound of Formula (I), R4 is
C3_8Cycloalkyl-amino, wherein C3_gcycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C3_gcycloalkyl is optionally substituted.
[0087] In one embodiment of the use of a compound of Formula (I), R4 is aryl-Ci_8alkyl, aryl-Ci_8alkoxy-carbonyl or aryl-sulfonyloxy-Ci_8alkyl, wherein each instance of aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted.
[0088] In one embodiment of the use of a compound of Formula (I), R4 is aryl-Ci_8alkyl or aryl-Ci_8alkoxy-carbonyl, wherein each instance of aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted.
[0089] In one embodiment of the use of a compound of Formula (I), R4 is heterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxanyl or morpholinyl; wherein, each instance of heterocyclyl is optionally substituted. [0090] In one embodiment of the use of a compound of Formula (I), R4 is heterocyclyl selected from oxetan-3-yl, pyrrolidin-l-yl, piperidin-l-yl, piperazin-l-yl, l,3-dioxan-5-yl or morpholin-4-yl; wherein, each instance of heterocyclyl is optionally substituted.
[0091] In one embodiment of the use of a compound of Formula (I), R4 is
heterocyclyl-Ci_8alkyl, wherein each instance of heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted.
[0092] In one embodiment of the use of a compound of Formula (I), R4 is
heterocyclyl-Ci.galkyl selected from pyrrolidin-l-yl-Ci_galkyl or piperidin-l-yl-Ci_galkyl;
wherein, each instance of heterocyclyl is optionally substituted.
[0093] In one embodiment of the use of a compound of Formula (I), R5 is selected from halogen, hydroxy, cyano, nitro, halo-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino,
Ci_galkyl-amino, (Ci_galkyl)2-amino or Ci_galkyl-thio.
[0094] In one embodiment of the use of a compound of Formula (I), R5 is hydroxy.
[0095] In one embodiment of a compound of Formula (I), R5 is Ci_8alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
[0096] In one embodiment of the use of a compound of Formula (I), R5 is Ci_galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
[0097] In one embodiment of the use of a compound of Formula (I), R5 is halo-Ci_8alkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[0098] In one embodiment of the use of a compound of Formula (I), R5 is Ci_galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
[0099] In one embodiment of the use of a compound of Formula (I), R5 is halo-Ci_galkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[00100] In one embodiment of the use of a compound of Formula (I), R2 is aryl selected from phenyl; wherein, each instance of aryl is optionally substituted. [00101] In one embodiment of the use of a compound of Formula (I), R2 is aryl-amino, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted.
[00102] In one embodiment of the use of a compound of Formula (I), R2 is aryl-amino selected from phenyl-amino; wherein, each instance of aryl is optionally substituted.
[00103] In one embodiment of the use of a compound of Formula (I), R2 is
aryl-amino-carbonyl, wherein aryl is selected from phenyl; wherein, each instance of aryl is optionally substituted.
[00104] In one embodiment of the use of a compound of Formula (I), R2 is
aryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, each instance of aryl is optionally substituted.
[00105] In one embodiment of the use of a compound of Formula (I), R2 is heterocyclyl selected from 1,2,3,6-tetrahydropyridinyl, 1,3-benzodioxolyl,
3a,7a-dihydrooxazolo[4,5-£]pyridinyl or 2,3-dihydro-l,4-benzodioxinyl; wherein, each instance of heterocyclyl is optionally substituted.
[00106] In another embodiment of the use of a compound of Formula (I), R2 is heterocyclyl selected from l,2,3,6-tetrahydropyridin-4-yl, l,3-benzodioxol-5-yl or
2,3-dihydro-l,4-benzodioxin-6-yl; wherein, each instance of heterocyclyl is optionally substituted.
[00107] In one embodiment of the use of a compound of Formula (I), R2 is heteroaryl selected from thienyl, IH-pyrazolyl, IH-imidazolyl, 1,3-thiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, pyridinyl, pyrimidinyl, indolyl, lH-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, lH-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzooxazolyl, 9H-purinyl, furo[3,2-¾]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, lH-pyrrolo[2,3-£]pyridinyl, lH-pyrrolo[2,3-c]pyridinyl,
pyrrolo[ 1 ,2-a]pyrimidinyl, pyrrolo[l ,2-a]pyrazinyl, pyrrolo[ 1 ,2-£]pyridazinyl,
pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5-a]pyrazinyl, imidazo[l,2-a]pyridinyl, [l,3]oxazolo[4,5- £]pyridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-c]pyrimidinyl, imidazo[l,2-£]pyridazinyl, imidazo[l,2-a]pyrazinyl, imidazo[2,l-¾][l,3]thiazolyl, imidazo[2,l-¾][l,3,4]thiadiazolyl or quinoxalinyl; wherein, each instance of heteroaryl is optionally substituted. [00108] In another embodiment of the use of a compound of Formula (I), R2 is heteroaryl selected from thien-2-yl, thien-3-yl, lH-pyrazol-3-yl, lH-pyrazol-4-yl, lH-pyrazol-5-yl,
IH-imidazol-l-yl, lH-imidazol-4-yl, l,3-thiazol-2-yl, l,2,4-oxadiazol-3-yl, l,3,4-oxadiazol-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-4-yl, lH-indol-3-yl, lH-indol-4-yl, indol-5-yl, indol-6-yl, lH-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzothien-2-yl, benzothien-3-yl, lH-benzimidazol-2-yl, lH-benzimidazol-6-yl, l,3-benzoxazol-2-yl,
l,3-benzoxazol-5-yl, l,3-benzoxazol-6-yl, l,3-benzothiazol-2-yl, l,3-benzothiazol-5-yl, l,3-benzothiazol-6-yl, 9H-purin-8-yl, furo[3,2-£]pyridin-2-yl, furo[3,2-c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl,
lH-pyrrolo[2,3-£]pyridin-5-yl, lH-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[l ,2-a]pyrimidin-7-yl, pyrrolo[ 1 ,2-a]pyrazin-7-yl, pyrrolo[ 1 ,2-£]pyridazin-2-yl, pyrrolo[l ,2-£]pyridazin-6-yl, pyrazolo[ 1 ,5-a]pyridin-2-yl, pyrazolo[ 1 ,5-a]pyrazin-2-yl, imidazo[2, 1 -b][ 1 ,3]thiazol-6-yl, imidazo[2,l-£][l,3,4]thiadiazol-6-yl, [l,3]oxazolo[4,5-£]pyridin-2-yl imidazo[l,2-a]pyridin-2-yl, imidazo[ 1 ,2-a]pyridin-6-yl, imidazo[ 1 ,2-a]pyrimidin-2-yl, imidazo[l ,2-a]pyrimidin-6-yl, imidazo[l,2-c]pyrimidin-2-yl, imidazo[l,2-¾]pyridazin-2-yl, imidazo[l,2-a]pyrazin-2-yl or quinoxalin-2-yl; wherein, each instance of heteroaryl is optionally substituted.
[00109] In another embodiment of the use of a compound of Formula (I), R2 is substituted heteroaryl selected from 4-methylthiophen-2-yl, l-methyl-lH-pyrazol-3-yl, 4-methyl-lH- pyrazol-3-yl, 1 -phenyl- lH-pyrazol-3-yl, 1 -phenyl- lH-imidazol-4-yl, 2-methyl-l-(pyridin-2-yl)- lH-imidazol-4-yl, 4-methyl-l,3-thiazol-2-yl, 4-(trifluoromethyl)-l,3-thiazol-2-yl, 4-phenyl-l,3- thiazol-2-yl, 5-phenyl-l,2,4-oxadiazol-3-yl, 3-fluoropyridin-4-yl, 6-fluoropyridin-2-yl, 2- chloropyridin-4-yl, 4-chloropyridin-3-yl, 5-chloropyridin-2-yl, 6-methylpyridin-3-yl, 2- (trifluoromethyl)pyridin-3-yl, 4-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-2-yl, 2- methoxypyridin-4-yl, 4-methoxypyridin-3-yl, 6-methoxypyridin-2-yl, 2-ethoxypyridin-3-yl, 6- ethoxypyridin-2-yl, 6-(propan-2-yloxy)pyridin-2-yl, 6-(dimethylamino)pyridin-3 -yl,
6-(methylsulfanyl)pyridin-2-yl, 6-(cyclobutyloxy)pyridin-2-yl, 6-(pyrrolidin- 1 -yl)pyridin-2-yl, 2- methylpyrimidin-4-yl, 2-(propan-2-yl)pyrimidin-4-yl, 2-cyclopropylpyrimidin-4-yl, 1-methyl- lH-indol-3-yl, 2-methyl-2H-indazol-5-yl, 1 -methyl- lH-benzimidazol-2-yl, 4-methyl-lH- benzimidazol-2-yl 5-fluoro-lH-benzimidazol-2-yl, 4-fluoro-l,3-benzoxazol-2-yl, 5-fluoro-l,3- benzoxazol-2-yl, 4-chloro- 1 ,3-benzoxazol-2-yl, 4-iodo-l ,3-benzoxazol-2-yl,
2-methyl- 1 ,3-benzoxazol-6-yl, 4-methyl- 1 ,3-benzoxazol-2-yl, 4-(trifluoromethyl)-l ,3- benzoxazol-2-yl, 7-(trifluoromethyl)-l,3-benzoxazol-2-yl, 4-chloro-l,3-benzothiazol-2-yl, 7- chloro-1 ,3-benzothiazol-2-yl, 2-methyl- 1 ,3-benzothiazol-2-yl, 4-(trifluoromethyl)- 1 ,3- benzothiazol-2-yl, 5-methylfuro[3,2-£]pyridin-2-yl, 4,6-dimethylfuro[3,2-c]pyridin-2-yl,
5.7- dimethylfuro[2,3-c]pyridin-2-yl, 4,6-dimethylthieno[3,2-c]pyridin-2-yl,
2,4-dimethylthieno[2,3-(i]pyrimidin-6-yl, l-methylpyrrolo[l,2-a]pyrazin-7-yl,
3-methylpyrrolo[l ,2-a]pyrazin-7-yl, 1 ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl,
2-methylpyrrolo[l ,2-¾]pyridazin-6-yl, 5-methylpyrazolo[l ,5-a]pyridin-2-yl,
4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl, 2-chloroimidazo[2,l-£][l,3]thiazol-6-yl,
2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl, 3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl, 2- ethylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl, 2-methylimidazo[2, 1 -b] [ 1 ,3 ,4]thiadiazol-6-yl,
6-cyanoimidazo[l,2-a]pyridin-2-yl (also referred to as 2-imidazo[l,2-a]pyridine-6-carbonitrile),
6- fluoroimidazo[l,2-a]pyridin-2-yl, 8-fluoroimidazo[l,2-a]pyridin-2-yl,
6.8- difluoroimidazo[ 1 ,2-a]pyridin-2-yl, 7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl,
8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl, 6-chloroimidazo[ 1 ,2-a]pyridin-2-yl,
7- chloroimidazo[l,2-a]pyridin-2-yl, 8-chloroimidazo[l,2-a]pyridin-2-yl,
8- bromoimidazo[l,2-a]pyridin-2-yl, 2-methylimidazo[l,2-a]pyridin-2-yl,
5- methylimidazo[l,2-a]pyridin-2-yl, 6-methylimidazo[l,2-a]pyridin-2-yl,
7-methylimidazo[l,2-a]pyridin-2-yl, 8-methylimidazo[l,2-a]pyridin-2-yl,
7-ethylimidazo[l,2-a]pyridin-2-yl, 8-ethylimidazo[l,2-a]pyridin-2-yl,
6,8-dimethylimidazo[l,2-a]pyridin-2-yl, 8-ethyl-6-methylimidazo[l,2-a]pyridin-2-yl,
7- methoxyimidazo [ 1 ,2-a]pyridin-2-yl, 8-methoxyimidazo [ 1 ,2-a]pyridin-2-yl,
6- fluoro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl, 8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl,
8- chloro-6-methylimidazo[l,2-a]pyridin-2-yl, 6-methyl-8-nitroimidazo[l,2-a]pyridin-2-yl, 8-cyclopropylimidazo[ 1 ,2-a]pyridin-2-yl, 2-methylimidazo[ 1 ,2-a]pyridin-6-yl,
2-ethylimidazo[l,2-a]pyridin-6-yl, 2,3-dimethylimidazo[l,2-a]pyridin-6-yl,
2,8-dimethylimidazo[l,2-a]pyridin-6-yl, 2-(trifluoromethyl)imidazo[l,2-a]pyridin-6-yl, 8-chloro-2-methylimidazo[l,2-a]pyridin-6-yl, 8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl, 6-fluoroimidazo[l ,2-a]pyrimidin-2-yl, 6-chloroimidazo[l ,2-a]pyrimidin-2-yl,
6-methylimidazo[l,2-a]pyrimidin-2-yl, 7-methylimidazo[l,2-a]pyrimidin-2-yl,
2-methylimidazo[l,2-a]pyrimidin-6-yl, 6-methylimidazo[l,2-¾]pyridazin-2-yl,
2-methyl-3-(l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2-¾]pyridazin-6-yl, 6-methylimidazo[l,2-a]pyrazin-2-yl, 8-methylimidazo[l,2-a]pyrazin-2-yl,
6,8-dimethylimidazo[l ,2-a]pyrazin-2-yl, 6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl,
6-methyl-8-(trifluoromethyl)imidazo[ 1 ,2-a]pyrazin-2-yl or
8-(methylsulfanyl)imidazo[ 1 ,2-a]pyrazin-2-yl.
[00110] In one embodiment of the use of a compound of Formula (I), R2 is heteroaryl-amino, wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and, wherein, each instance of heteroaryl is optionally substituted.
[00111] In another embodiment of the use of a compound of Formula (I), R2 is
heteroaryl-amino selected from pyridin-2-yl-amino, pyridin-3-yl-amino or pyrimidin-2-yl-amino; wherein, each instance of heteroaryl is optionally substituted.
[00112] In one embodiment of the use of a compound of Formula (I), is selected from halogen, hydroxy, cyano, nitro, Ci_galkyl, halo-Ci_galkyl, hydroxy-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, (Ci_galkyl)2-amino or Ci_galkyl-thio
[00113] In one embodiment of the use of a compound of Formula (I), ¾ is Ci_8alkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.
[00114] In one embodiment of the use of a compound of Formula (I), is Ci_galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
[00115] In one embodiment of the use of a compound of Formula (I), ¾ is C2_8alkenyl selected from ethenyl, allyl or buta-l,3-dienyl.
[00116] In one embodiment of the use of a compound of Formula (I), is C2_galkenyl selected from ethenyl or allyl.
[00117] In one embodiment of the use of a compound of Formula (I), is halo-Ci_galkyl selected from trihalo-methyl, dihalo-methyl, halo-methyl, trihalo-ethyl, dihalo-ethyl, halo-ethyl, trihalo-propyl, dihalo-propyl or halo-propyl; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[00118] In one embodiment of the use of a compound of Formula (I), is hydroxy-Ci_galkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
[00119] In one embodiment of the use of a compound of Formula (I), is hydroxy-Ci_galkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl. [00120] In one embodiment of a compound of Formula (I), 5 is Ci_galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
[00121] In one embodiment of the use of a compound of Formula (I), R^ is halo-Ci_8alkoxy selected from trihalo-methoxy, dihalo-methoxy, halo-methoxy, trihalo-ethoxy, dihalo-ethoxy, halo-ethoxy, trihalo-propoxy, dihalo-propoxy or halo-propoxy; wherein, halo is selected from fluoro, chloro, bromo or iodo.
[00122] In one embodiment of the use of a compound of Formula (I), R7 is C3_i4cycloalkyl, C3_i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl; wherein C3-i4cycloalkyl is selected from cyclopropyl or cyclobutoxy; wherein aryl is selected from phenyl; wherein heterocyclyl is selected from pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl; and, wherein heteroaryl is selected from thienyl or pyridinyl.
[00123] In one embodiment of the use of a compound of Formula (I), R7 is C3_i4cycloalkyl or C3_i4cycloalkyl-oxy, wherein each instance of C3_i4cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
[00124] In one embodiment of the use of a compound of Formula (I), R7 is C3_8cycloalkyl or C3_8cycloalkyl-oxy, wherein each instance of C3-scycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
[00125] In one embodiment of the use of a compound of Formula (I), R7 is aryl selected from phenyl.
[00126] In one embodiment of the use of a compound of Formula (I), R7 is heterocyclyl selected from pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.
[00127] In one embodiment of the use of a compound of Formula (I), R7 is heterocyclyl selected from pyrrolidin-l-yl or l,2,3,6-tetrahydropyridin-4-yl.
[00128] In one embodiment of the use of a compound of Formula (I), R7 is heteroaryl selected from thienyl or pyridinyl.
[00129] In one embodiment of the use of a compound of Formula (I), R7 is heteroaryl selected from pyridinyl.
[00130] In one embodiment of the use of a compound of Formula (I), R7 is heteroaryl selected from thien-2-yl or pyridin-2-yl.
[00131] In one embodiment of the use of a compound of Formula (I), R7 is heteroaryl selected from pyridin-2-yl. [00132] In one embodiment of the use of a compound of Formula (I), the compound is selected from Formula (la) or Formula (lb):
Figure imgf000029_0001
(la), and (ib);
[00133] or a form thereof, wherein all variables are as previously defined.
[00134] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is selected from (methyl)2-amino and R2 is benzothiazol-2-yl optionally substituted with one R6 substituent, then R^ is other than chloro.
[00135] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is selected from (methyl)2-amino or (2-fluoro-ethyl)(methyl)amino, then R2 is benzothiazol-2-yl substituted with one, two or three R6 substituents and one additional, optional R7 substituent.
[00136] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is piperazin-l-yl substituted with one R3 substituent selected from methyl, 2-fluoro- ethyl, 2-hydroxy-ethyl or 3 -hydroxy-propyl; or, one R4 substituent selected from
3-(4-methyl-phenyl-sulfonyloxy)-propyl, then R2 is benzothiazol-2-yl substituted with one, two or three R6 substituents and one additional, optional R7 substituent.
[00137] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is piperazin-l-yl substituted with one R3 substituent selected from 2-fluoro-ethyl and R2 is imidazo[l ,2-a]pyridin-2-yl optionally substituted with one R6 substituent, then 5 is other than chloro.
[00138] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is (2-fluoro-ethyl)(methyl)amino and R2 is [l ,3,4]oxadiazol-2-yl optionally substituted with one R7 substituent, then R7 is other than thien-2-yl.
[00139] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is piperazin-l-yl substituted with one R3 substituent selected from 3-fluoro-propyl and R2 is thiazol-2-yl optionally substituted with two R6 substituents, then R6 is not simultaneously methyl and buta-l ,3-dienyl.
[00140] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is selected from methyl-amino or (methyl)2-amino, then R2 is benzooxazol-2-yl substituted with one, two or three ¾ substituents and one additional, optional R7 substituent.
[00141] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is selected from (methyl)2-amino and R2 is benzooxazol-2-yl optionally substituted with one R6 substituent, then R^ is other than chloro.
[00142] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is piperazin-l-yl substituted with one R3 substituent selected from methyl, then R2 is benzooxazol-2-yl substituted with one, two or three R6 substituents and one additional, optional R7 substituent.
[00143] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is selected from (methyl)2-amino, then R2 is lH-benzoimidazol-2-yl substituted with one, two or three ¾ substituents and one additional, optional R7 substituent.
[00144] In one embodiment of the use of a compound of Formula (I), when wi is C-Ri, w2 is C-R2 and Ri is selected from (methyl)2-amino and R2 is lH-benzoimidazol-2-yl substituted with one substituent, then R6 is other than methyl.
[00145] In certain embodiments of the use of a compound of Formula (I), the compound of Formula (I) is other than:
3-benzothiazol-2-yl-7-[4-(2-fluoro-ethyl)-piperazin-l -yl]-chromen-2-one,
3-benzothiazol-2-yl-7-[4-(2-hydroxy-ethyl)-piperazin-l-yl]-chromen-2-one,
3-(6-chloro-imidazo[l ,2-a]pyridin-2-yl)-7-[4-(2-fluoro-ethyl)-piperazin-l-yl]-chromen-2-one,
3-benzothiazol-2-yl-7-(4-methyl-piperazin-l-yl)-chromen-2-one,
3-benzothiazol-2-yl-7-[(2-fluoro-ethyl)-methyl-amino]-chromen-2-one,
7-[(2-fluoro-ethyl)-methyl-amino]-3-(5-thiophene-2-yl-[l ,3,4]oxadiazol-2-yl)-chromen-2-one,
3-(4-buta-l ,3-dienyl-5-methyl-thiazol-2-yl)-7-[4-(3-fluoro-propyl)-piperazin-l-yl]-chromen-2- one,
toluene-4-sulfonic acid 3-[4-(3-benzothiazol-2-yl-2-oxo-2H-chromen-7-yl)-piperazin-l-yl]- propyl ester,
3-benzothiazol-2-yl-7-[4-(3-hydroxy-propyl)-piperazin-l-yl]-chromen-2-one,
3-benzooxazol-2-yl-7-(4-methyl-piperazin- 1 -yl)-chromen-2-one, 7-dimethylamino-3-(l -methyl- lH-benzoimidazol-2-yl)-chromen-2-one,
3-(lH-benzoimidazol-2-yl)-7-dimethylamino-chromen-2-one,
3-(6-chloro-benzothiazol-2-yl)-7-dimethylamino-chromen-2-one,
3-benzothiazol-2-yl-7-dimethylamino-chromen-2-one,
3-benzooxazol-2-yl-7-dimethylamino-chromen-2-one,
3-benzooxazol-2-yl-7-methylamino-chromen-2-one, and
3-(5-chloro-benzooxazol-2-yl)-7-dimethylamino-chromen-2-one.
[00146] Further provided herein are uses of a compound of Formula (I):
Figure imgf000031_0001
(I)
[00147] or a form thereof, wherein:
[00148] wi and w2 are C-Ri or C-R2; wherein, one of wi and w2 is C-Ri and the other is C-R2, provided that, when wi is C-Ri, then w2 is C-R2; or, when wi is C-R2, then w2 is C-Ri;
[00149] Ri is amino, Ci.galkoxy-Ci.galkyl-amino, (Ci_8alkoxy-Ci_8alkyl)2-amino,
(Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl,
(Ci_8alkyl)2-amino-Ci_8alkyl, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl,
(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, amino-Ci_8alkyl-amino, (amino-Ci_8alkyl)2-amino, (amino-Ci_8alkyl)(Ci_8alkyl)amino,
Ci_8alkyl-amino-C i.salkyl-amino, (C i_8alkyl-amino-C i_8alkyl)2-amino,
(Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino,
[(Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino, amino-Ci_8alkoxy, Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkyl)2-amino-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkoxy,
(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, amino-C2-8alkenyl, Ci_8alkyl-amino-C2-8alkenyl, (Ci_8alkyl)2-amino-C2-8alkenyl,
amino-C2-8alkynyl, Ci_8alkyl-amino-C2-8alkynyl, (Ci_8alkyl)2-amino-C2-8alkynyl,
halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, hydroxy-Ci_salkyl, hydroxy-Ci.galkoxy-Ci.galkyl, hydroxy-Ci-galkyl-amino, (hydroxy-Ci_8alkyl)2-amino, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino, hydroxy-Ci-galkyl-amino-Ci-galkyl, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, hydroxy-Ci_8alkyl-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkoxy, hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)2-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino,
(hydroxy-C i_8alkyl)2-amino-C i_8alkyl-amino,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino,
[(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino,
[(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl](Ci_8alkyl)amino, heterocyclyl,
heterocyclyl-Ci_salkyl, heterocyclyl-Ci_salkoxy, heterocyclyl-amino,
(heterocyclyl)(Ci_8alkyl)amino, heterocyclyl-amino-Ci_8alkyl, heterocyclyl-Ci_8alkyl-amino, (heterocyclyl-Ci_8alkyl)2-amino, (heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino,
heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, (heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl-oxy, heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino, (aryl-Ci_8alkyl)2-amino,
(aryl-Ci_8alkyl)(Ci_8alkyl)amino, aryl-Ci_8alkyl-amino-Ci_8alkyl,
(aryl-Ci_8alkyl)2-amino-Ci_8alkyl, (aryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heteroaryl, heteroaryl-Ci_salkyl, heteroaryl-Ci_galkoxy, heteroaryl-amino, heteroaryl-Ci.galkyl-amino, (heteroaryl-Ci_8alkyl)2-amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, (heteroaryl-Ci_8alkyl)2-amino-Ci_8alkyl or
(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl;
[00150] wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R3 substituents and one additional, optional R4 substituent; and,
[00151] wherein, alternatively, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two, three or four R3 substituents;
[00152] R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino;
[00153] wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three ¾ substituents and one additional, optional R7 substituent; [00154] Ra is, in each instance, independently selected from hydrogen, halogen, Ci_8alkyl or deuterium;
[00155] Rb is hydrogen, halogen, Ci_8alkyl, Ci_8alkoxy or deuterium;
[00156] R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci.galkyl, halo-Ci_galkyl, Ci_galkyl-carbonyl, Ci_galkoxy, halo-Ci_galkoxy, Ci_galkoxy-Ci_galkyl, Ci_galkoxy-carbonyl, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino, amino-Ci_galkyl,
Ci_galkyl-amino-Ci_galkyl, (Ci_galkyl)2-amino-Ci_galkyl, amino-Ci_galkyl-amino,
Ci_galkyl-amino-Ci_galkyl-amino, (Ci_galkyl)2-amino-Ci_galkyl-amino,
Ci_galkoxy-Ci_galkyl-amino, Ci_galkyl-carbonyl-amino, Ci_galkoxy-carbonyl-amino,
hydroxy-Ci_8alkyl, hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-Ci_8alkyl-amino,
(hydroxy-Ci_8alkyl)2-amino or (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino;
[00157] R4 is C3-i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-amino, aryl-Ci_8alkyl, aryl-Ci_8alkoxy-carbonyl, heterocyclyl or heterocyclyl-Ci_8alkyl; wherein, each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
[00158] R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_8alkyl, halo-Ci_8alkyl, Ci_8alkoxy, halo-Ci_8alkoxy, amino, Ci_8alkyl-amino,
(Ci_8alkyl)2-amino or Ci_8alkyl-thio;
[00159] Re is, in each instance, independently selected from halogen, hydroxy, cyano, nitro, Ci_8alkyl, halo-Ci_8alkyl, hydroxy-Ci_8alkyl, Ci_8alkoxy, halo-Ci_8alkoxy, amino,
Ci_8alkyl-amino, (Ci_8alkyl)2-amino or Ci_8alkyl-thio; and,
[00160] R7 is C3_i4cycloalkyl, C3_i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
[00161] In one embodiment of the use of a compound of Formula (I), R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci_8alkyl-carbonyl, Ci_8alkoxy, halo-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl, Ci_8alkoxy-carbonyl, amino, Ci_8alkyl-amino,
(Ci_8alkyl)2-amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl, amino-Ci_8alkyl-amino, Ci_8alkyl-amino-Ci_8alkyl-amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, Ci_8alkoxy-Ci_8alkyl-amino, Ci_8alkyl-carbonyl-amino, Ci_8alkoxy-carbonyl-amino,
hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-Ci_8alkyl-amino, (hydroxy-Ci_8alkyl)2-amino or (hydroxy-C i_8alkyl)(C i_8alkyl)amino . [00162] In one embodiment of the use of a compound of Formula (I), is, in each instance, independently selected from hydroxy, cyano, nitro, halo-Ci_8alkyl, hydroxy-Ci_8alkyl,
Ci_8alkoxy, halo-Ci_8alkoxy, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino or Ci_8alkyl-thio.
[00163] In one embodiment of the use of a compound of Formula (I), R7 is C3_i4cycloalkyl, C3_i4Cycloalkyl-oxy, aryl or heterocyclyl.
[00164] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a com ound from the group consisting of:
Figure imgf000034_0001
10 11
Figure imgf000035_0001
-34-
Figure imgf000036_0001
Figure imgf000037_0001
-36-
Figure imgf000038_0001
-37-
Figure imgf000039_0001
Figure imgf000040_0001
-39-
Figure imgf000041_0001
Figure imgf000042_0001
-41 -
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
-44-
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
-62-
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
-71 -
Figure imgf000073_0001
Figure imgf000074_0001
-73 -
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
-86-
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
-90-
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
985 986
[00165] or a form thereof.
[00166] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of:
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-benzoxazol-2-yl]-2H-chromen-2-one 7-(piperazin- 1 -yl)-3-[7-(trifluoromethyl)- 1 ,3-benzoxazol-2-yl]-2H-chromen-2-one
2- oxo-N-phenyl-7-(piperazin- 1 -yl)-2H-chromene-3-carboxamide
3- (l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(7-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-ylmethyl)-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one
7- [(propan-2-ylamino)methyl] -3 - [4-(trifluoromethyl)- 1 ,3 -benzothiazol-2-yl]-2H-chromen-
2- one
3- (4-chloro-l,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one 7-(4-methylpiperazin- 1 -yl)-3 - [3 -(trifluoromethyl)phenyl] -2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyridin-3-yl)-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-o
3-(l,3-benzothiazol-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(5-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
3-(4-methyl-l,3-benzoxazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-methyl-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2- one
3-(3-fluorophenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyridin-4-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(4-methylpiperazin-l-yl)carbonyl]-2H-chromen-2- one
7-(piperazin-l-yl)-3-(lH-pyrazol-5-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2-oxo-N-phenyl-2H-chromene-3-carboxamide
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(4-methyl-l,3-benzoxazol-2-yl)-2H-chromen-2- one
7-(piperazin- 1 -yl)-3-(pyridin-2-ylamino)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyrimidin-2-ylamino)-2H-chromen-2-one
3-(imidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[2-(propan-2-ylamino)ethyl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[3-(propan-2-ylamino)propyl]-2H-chromen-2-one
3-(4-methyl-l,3-thiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(1 -methyl- lH-pyrazol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(4-fluoro-l,3-benzoxazol-2-yl)-2H-chromen-2- one
3-(4-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-2-oxo-2H-chromen-7-yl piperazine- 1 -carboxylate
3-(4-chloro-l,3-benzothiazol-2-yl)-2-oxo-2H-chromen-7-yl piperazine- 1 -carboxylate benzyl 4- [3 -( 1 -methyl- 1 H-benzimidazol-2-yl)-2-oxo-2H-chromen-7-yl]piperazine- 1 - carboxylate
3-(8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-(4-phenyl-l,3-thiazol-2-yl)-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
3-(l ,3-benzoxazol-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(l ,3-benzoxazol-2-yl)-7-[3-(dimethylamino)pyrrolidin- 1 -yl]-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-{[2-(dimethylamino)ethyl](methyl)amino}-2H-chromen-2-one
3-(5-phenyl-l,2,4-oxadiazol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(3S)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7- [(3R)-pyrrolidin-3 -yloxy] -2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(2S)-pyrrolidin-2-ylmethoxy]-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7- [(diethylamino)methyl] -2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(diethylamino)methyl]-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7-(piperidin- 1 -ylmethyl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperidin-l-ylmethyl)-2H-chromen-2-one
3 - [(3 -methylpyridin-2-yl)amino]-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-[(4-methylpyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
3 - [(5 -methylpyridin-2-yl)amino]-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-[(6-methylpyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
3 - [(5 -chloropyridin-2-yl)amino] -7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyridin-3-ylamino)-2H-chromen-2-one
3-(4-iodo-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzoxazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2- one
3-(4-chloro-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-( 1 -methyl- 1 H-pyrazol-3-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-( 1 -phenyl- 1 H-pyrazol-3-yl)-2H-chromen-2-one
3-(phenylamino)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3 -[4-(trifluoromethyl)pyridin-2-yl] -2H-chromen-2-one 3-(3-methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7-[(methylamino)methyl] -2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-{[(2-hydroxyethyl)(methyl)amino]methyl}-2H-chrom
3-(4-methyl-lH-pyrazol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen^
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chrom one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-(2,5-dimethylpiperazin-l-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(piperazin-l -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin-l-yl)-3-[6-(trifluoromethyl)pyridin-2-yl]-2H-chromen-2-one
3-(l H-indazol-5-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(2R,5S)-2,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2- one
3-(3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7- { [( 1 ,3 -dihydroxypropan-2-yl)amino]methyl} -2H-chromen-2- one
7-(4-ethylpiperazin- 1 -yl)-3-(8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
7-[4-(2-hydroxyethyl)piperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(6-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H-chromen-
2- one
3- (6-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
tert-butyl {(3S)-l-[3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-2-oxo-2H-chromen-7- yl]pyrrolidin-3-yl} carbamate 7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(im
one
7-(4-ethylpiperazin-l-yl)-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-propylpiperazin- 1 -yl)-2H-chromen-2-one
3-([ 1 ,3]oxazolo[4,5-b]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-([l,3]oxazolo[4,5-b]pyridin-2-yl)-2H-chromen-2-one 3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-4-methyl-7-(piperazin-l-yl)-2H-chromen-2-one 3-(5-chloropyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[7-(M
2H-chromen-2-one
3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H-chromen-
2- one
3- (8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-2H- chromen-2-one
3-(7-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
7-(piperazin- 1 -yl)-3 -[2-(trifluoromethyl)pyridin-3 -yl] -2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3 - [2-(trifluoromethyl)pyridin-3 -yl]-2H-chromen-2-one
3-(3-fluoropyridin-4-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7- {[(3R)- 1 -ethylpyrrolidin-3-yl]oxy} -2H-chromen-2-one
3-(imidazo[l,2-b]pyridazin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(lS,4S)-2,5-diazabicyclo[2.2 ]hept-2-yl]-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H- chromen-2-one
7- { [2-(dimethylamino)ethyl] (methyl)amino } -3 -(imidazo [ 1 ,2-a]pyrimidin-2-yl)-2H- chromen-2-one
3-(7-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(5-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one 3-(5-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chrom
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-fluoroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-o
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-^^
3-(imidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-2H-chrome one
3-(3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(l ,3-benzothiazol-2-yl)-7-[ 1 -(dimethylamino)ethyl]-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7-[ 1 -(propan-2-ylamino)ethyl]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7- { [2-(dimethylamino)ethy 1] (methyl)amino } -2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-4-methyl-7-(piperazin-l-yl)-2H-chromen-2-one
7- { [(2-hydroxy ethyl)(methyl)amino]methyl} -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-(2-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H- chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-
2- one
7- [3-(dimethylamino)pyrrolidin- 1 -yl]-3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H- chromen-2-one
8- fluoro-7-(piperazin- 1 -yl)-3-(pyridin-2-yl)-2H-chromen-2-one
8-fluoro-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3- (l ,3-benzothiazol-2-yl)-6-fluoro-7-(piperazin- 1 -yl)-2H-chromen-2-one
6- fluoro-3 -(6-methylimidazo [l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one 3-(l,3-benzoxazol-2-yl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-5-fluoro-7-(piperazin- 1 -yl)-2H-chromen-2-one
5-fluoro-7-(piperazin- 1 -yl)-3-(pyridin-2-yl)-2H-chromen-2-one
5 -fluoro-3 -(6-methylimidazo [l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one 3-(6-methylpyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7- (4-methylpiperazin-l-yl)-3-(6-methylpyridin-3-yl)-2H-chromen-2-one 3 -(2-methoxypyridin-4-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(2R,5S)-2,5-dimethylpiperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[2,l-b][l ,3]thiazol-6-yl)-2H-chrom
2- one
3- [7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-7-[(3R,5S)-3,4,5-trimethylpi^ yl]-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-on^
7- [( 1 S ,4S)-2,5 -diazabicyclo [2.2.1 ]hept-2-yl]-3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7- { [2-(dimethy lamino)ethyl] (methyl)amino } -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(l,4-diazepan-l-yl)-3 -(6-methylimidazo [l,2-a]pyridin-2-yl)-2H-chromen-2-one tert-butyl {(3S)-l-[3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2-oxo-2H-chromen-7- yl]pyrrolidin-3-yl} carbamate
7-(4-ethylpiperazin- 1 -yl)-3-(3-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(3-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-
2- one
3- (2-chloropyridin-4-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[methyl(l -methylpyrrolidin-3-yl)amino]-2H-chromen-
2- one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-(3-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H- chromen-2-one
3- (8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyrazolo[ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -3 -(pyrazolo [ 1 ,5 -a]pyridin-2-yl)-2H-chromen-2-one
7-[4-(2-hydroxyethyl)piperazin-l-yl]-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3 -(pyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one 7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(pyrazolo[ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one 7-(4-ethylpiperazin-l-yl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-propylpiperazin- 1 -yl)-3-(pyrazolo[ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
7-[4-(propan-2-yl)piperazin- 1 -yl]-3-(pyrazolo[ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one 3-(imidazo[l,2-a]pyrimidin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
7-[(dimethylamino)methyl]-3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-2-one 3-(imidazo[2,l-b][l,3]thiazol-6-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one
7-[3-(dimethylamino)piperidin-l-yl]-3-(6^
2- one
7-(4-ethylpiperazin- 1 -yl)-3-(imidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
7-{[2-(dimethylamino)ethyl](methyl)amino}-3-(imidazo[2,l-b][l,3]thiazol-6-yl)-2H- chromen-2-one
3- (imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(4-methyl- 1 ,4-diazepan-l -yl)-2H-chromen-2-one 3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one 3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one 7-(l ,4-diazepan- 1 -yl)-3-(imidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
2- [7-(4-methylpiperazin- 1 -yl)-2-oxo-2H-chromen-3-yl]imidazo[ 1 ,2-a]pyridine-6- carbonitrile
7-(piperazin- 1 -yl)-3-[8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-[8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[8-(trifluoromethyl)imidazo[l,2-a]pyridin^ 2H-chromen-2-one
3- (8-chloroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7-(3,3-dimethylpiperazin-l-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(6-methoxypyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-aminopiperidin-l-yl)-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one 3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-7-[methyl(pyridin-3 -ylmethyl)amino] -2H- chromen-2-one
7-(3,3-dimethylpiperazin- 1 -yl)-3-(6-m
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chrom
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-m
chromen-2-one
7- { [2-(dimethy lamino)ethyl] (methyl)amino } -3 -(7-methylimidazo [ 1 ,2-a]pyrimidin-2-yl)- 2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3 -(7-methylimidazo [l,2-a]pyrimidin-2-yl)-2H-chromen-2- one
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
3- (7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7-(l,4-diazepan-l-yl)-3 -(7-methylimidazo [l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
3-(2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-
2- one
3- (2-methylimidazo[2,l-b][l,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
7-(l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3- (4-methoxypyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4-chloropyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2- one
7-[(3R)-3-methylpiperazin-l-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2- one
3 -(6-methylimidazo [l,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(6-methylimidazo [l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-2H- chromen-2-one
3-(8-cyclopropylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2- one
3-(8-bromoimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one 7-(4-methyl-l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H-chrom one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(3,3-dimethylpiperazin-l-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(6-methylimid^
one
7-{[(l-hydroxypropan-2-yl)amino]methyl}-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7- [(4-hydroxypiperidin- 1 -yl)methyl] -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H-chromen-
2- one
7- [(3 -hydroxypyrrolidin- 1 -yl)methyl] -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
5-fluoro-7-(piperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one
3 - (6-methylimidazo [l,2-a]pyridin-2 -yl)-7-(octahydro-6H-pyrrolo [3, 4-b]pyridin-6-yl)-2H- chromen-2-one
3-(2-ethoxypyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-methoxypyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3 -(1 -methyl- lH-indol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(1 -methyl- lH-indol-3-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
3- (6-chloro-8-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]- 2H-chromen-2-one
7-[(lS,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H- chromen-2-one
7-[(3R)-3-methylpiperazin- 1 -yl]-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-[7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-2H- chromen-2-one
7-(3 ,3 -dimethylpiperazin- 1 -yl)-3 - [7-(trifluoromethyl)imidazo [ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one 3-(4-chloro-l,3-benzothiazol-2-yl)-7-{[(l-hydroxypropan-2-yl)amino]methyl}-2H- chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-{[(2-hydroxyethyl)(methyl)amino]methyl}-2H- chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(3-hydroxypyrrolidin-l-yl)methyl]-2H-chromen-2 one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(4-hydroxypiperidin-l-yl)methyl]-2H-chromen-2- one
3-(2-methylpyrimidin-4-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-[7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-2H-chromen-2- one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(2R,5S)-2,5-dimethylpiperazin-l-yl]-3-[7-(M
2H-chromen-2-one
3-(2-cyclopropylpyrimidin-4-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(piperazin-l-yl)-3-[2-(propan-2-yl)pyrimidin-4-yl]-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-7- [methyl( 1 -methylpiperidin-4-yl)amino]-2H- chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(4-methyl-l,3-thiazol-2-yl)-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(4-methyl-l ,3-thiazol-2-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(4-methyl- 1 ,3-thiazol-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(4-methyl-l,3-thiazol-2-yl)-2H-chromen-2-one
3-(7-ethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(7-ethylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-ethylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(3,5-difluorophenyl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,5-difluorophenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
5-fluoro-3-(4-fluoro-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-[8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
3-(6-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2H-chromen- 2-one 7-(4-methylpiperazin- 1 -yl)-3 -(2-methylpyrimidin-4-yl)-2H-chromen-2-one
3 -(2-cyclopropylpyrimidin-4-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(2S,5R)-2,5-dimethylpiperazin- 1 -yl]-3-(4-methyl- 1 ,3-thiazol-2-yl)-2H-chromen-2-one
7-[(3R)-3-methylpiperazin-l-yl]-3-(4-methyl-l,3-thiazol-2-yl)-2H-chromen-2-one
7-(3,3-dimethylpiperazin-l-yl)-3-(4-methyl-l,3-thiazol-2-yl)-2H-chromen-2-one
3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H- chromen-2-one
7-(3,3-dimethylpiperazin-l-yl)-3-(5-methylpyrazolo[l ,5-a]pyridin-2-yl)-2H-chromen-2- one
7- [(3R)-3 -methylpiperazin- 1 -yl]-3 -(5 -methylpyrazolo [ 1 ,5 -a]pyridin-2-yl)-2H-chromen-2- one
7-(4-ethylpiperazin- 1 -yl)-3 -(5 -methylpyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2- one
5-fluoro-3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 5-fluoro-3-(imidazo[l,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(9H-purin-8-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methoxypyridin-2-yl)-2H-chromen-2-o
3-(3,4-dimethoxyphenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-methylthiophen-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(thiophen-3-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-(thiophen-3-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chrom
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-on^
3 -(imidazo [2, 1 -b] [ 1 ,3 ]thiazol-6-yl)-7- [(3R)-pyrrolidin-3 -yloxy] -2H-chromen-2-one
3-(2-methylimidazo[2,l-b][l,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chrom one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one 3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-^ 3-(6-fluoro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 3-(6-fluoro-8-methylimidazo[ 1 ,2-a]pyrid^
2- one
3- (6-fluoro-8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-fl^^
2H-chromen-2-one
3-(8-ethyl-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H- chromen-2-one
3-(7-ethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-ethyl-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
5-fluoro-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-(l,4-diazepan-l-yl)-5-fluoro-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
3-(6-chloroimidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methyl- 1 ,4-diazepan- l-yl)-2H-chromen-2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H-chromen-
2- one
3- (8-ethyl-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-
2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-ethyl-6-methylimidazo[l,2-a]pyridin-2-yl)- 2H-chromen-2-one
3- (8-chloro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]- 2H-chromen-2-one
3-(8-chloro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
3- (8-chloro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan-l -yl)-2H- chromen-2-one
7- {[(2-hydroxyethyl)(methyl)amino]methyl} -3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H- chromen-2-one
7-[(4-hydroxypiperidin- 1 -yl)methyl]-3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H-chromen-2- one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H- chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one 5-fluoro-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-5-fluoro-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-ch^
2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-^ 2H-chromen-2-one
3- (8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H- chromen-2-one
3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(8-ethylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-methoxypyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin-l-yl)-3-(6-methoxypyridin-2-yl)-2H-chromen-2-one
3 -(6-methoxypyridin-2-yl)-7- [(3R)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3 -(6-methoxypyridin-2-yl)-7- [(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(thiophen-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(thiophen-2-yl)-2H-chromen-2-one
3-(3,5-difluorophenyl)-5-fluoro-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
5-fluoro-3-(4-fluoro-l,3-benzoxazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-5-fluoro-3-(4-fluoro-l,3-benzoxazol-2-yl)-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-5-fluoro-3-(4-fluoro- 1 ,3-benzoxazol-2-yl)-2H-chromen-2-one
5-fluoro-3-(4-fluoro-l ,3-benzoxazol-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
3-(lH-benzimidazol-2-yl)-5-fluoro-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-5-fluoro-2H-chromen-2- one
5-fluoro-3-(imidazo[2,l-b][l,3]thiazol-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2- one
5-fluoro-3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-
2- one
3- (lH-benzimidazol-2-yl)-7-(l,4-diazepan-l-yl)-5-fluoro-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7- [( 1 -benzylpyrrolidin-3 -yl)(methyl)amino]-3 -(7-methylimidazo [ 1 ,2-a]pyrimidin-2-yl)- 2H-chromen-2-one 7-(l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chrom
2- one
3- (6-fluoropyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-ethoxypyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
7-(piperazin-l-yl)-3-[6-(propan-2-yloxy)pyridin-2-yl]-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[6-(pyrrolidin- 1 -yl)pyridin-2-yl]-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(3,5-dimethoxyphenyl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3
2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-
2- one
3- (8-chloroimidazo[l,2-a]pyridin-2-yl)-5-fluoro-7-[(3R)-3-methylpiperazin-l-yl]-2H- chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -5 -fluoro-3 - [7-(trifluoromethyl)imidazo [ 1 ,2- a]pyridin-2-yl]-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-5-fluoro-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3 -(4-methyl- 1 H-benzimidazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(5-fluoro- lH-benzimidazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one
5-fluoro-7-(hydroxymethyl)-3-(imidazo[2,l-b][l,3]thiazol-6-yl)-2H-chromen-2-one
3-[8-(methylsulfanyl)imidazo[ 1 ,2-a]pyrazin-2-yl]-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-[8-(methylsulfanyl)imidazo[ 1 ,2-a]pyrazin-2-yl]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[8-(methylsulfanyl)imidazo[l,2-a]pyrazin-2-yl]- 2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-[8-(methylsulfanyl)imidazo[l,2-a]pyrazin-2-yl]-2H- chromen-2-one
3-(8-methoxyimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-methoxyimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(3 ,4-dimethoxyphenyl)-5 -fluoro-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-5-fluoro-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one 3-(l -benzothiophen-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l-benzothiophen-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(l -benzothiophen-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one
3-(l-benzothiophen-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,5-dimethoxyphenyl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3-(3,5-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3 -(3 ,5 -dimethoxyphenyl)-7-[(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-[6-(cyclobutyloxy)pyridin-2-yl]-7-(piperazin-l-yl)-2H-chromen-2-one
3 - [6-(cyclobutyloxy)pyridin-2-yl] -7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-5-fluoro-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-methoxyimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-methoxyimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2- one
3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H- chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
5-fluoro-3-(imidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
5-fluoro-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen^
2- one
5-fluoro-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
7-(3,3-dimethylpiperazin-l-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3- (2-ethylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-(2-ethylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(2-ethylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3-(2-ethylimidazo[2,l-b][l,3]thiazol-6-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-[ 1 -(pyridin-2-yl)- lH-imidazol-4-yl]-2H- chromen-2-one 3-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chrom one
3-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(7-methoxyimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-[(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(imidazo[2,l- b][l,3]thiazol-6-yl)-2H-chromen-2-one
7-( 1 ,4-diazabicyclo [3.2.2]non-4-yl)-3 -(imidazo [2, 1 -b] [ 1 ,3 ]thiazol-6-yl)-2H-chromen-2-one
7-[(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(imidazo[l,2- a]pyrimidin-2-yl)-2H-chromen-2-one
7-(l ,4-diazabicyclo [3.2.2]non-4-yl)-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-2H-chromen-2-one 3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-
2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)- 2H-chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(pyridin-2-yl)-2H-chromen-2-one
3 - [6-(methylsulfany l)pyridin-2-yl] -7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(lS,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(3,4-dimethoxyphenyl)-5-fluoro-2H- chromen-2-one
3- (4-methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b][ 1 ,3,4]thiadiazol-6-yl)-2H-chromen-2-one
7-(4-methyl- 1 ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [ 1 ,3 ,4]thiadiazol-6-yl)-2H- chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -3 -( 1 -phenyl- 1 H-imidazol-4-yl)-2H-chromen-2-one
7-(4-methyl- 1 ,4-diazepan- 1 -yl)-3 -[2-methyl- 1 -(pyridin-2-yl)- 1 H-imidazol-4-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3 -(imidazo [ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
3 -(imidazo [ 1 ,2-a]pyrazin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2-one
3 -(imidazo [ 1 ,2-a]pyrazin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -(imidazo [ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3 -(imidazo [l,2-c]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[l,2-c]pyrimidin-2-yl)-2H-chromen-2- one
3 -(imidazo [ 1 ,2-c]pyrimidin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one 7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(quinoxalin-2-yl)-2H-chromen-2-one 3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- one
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-ch^
2- one
3- (3,4-dimethoxyphenyl)-5-fluoro-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one 3-(2,4-dimethoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -(2,4-dimethoxyphenyl)-7- [(3R)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
5-fluoro-3-(6-methoxypyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
5-fluoro-3-(6-methoxypyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7- { [2-(dimethylamino)ethyl] amino } -3 -(7-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H-chromen-
2- one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3- (3,4-dimethoxyphenyl)-7-[(2S)-2-methylpiperazin-l-yl]-2H-chromen-2-one
3-(2-chloroimidazo[2,l-b][l,3]thiazol-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(l-methylpiperidin-4-yl)amino]-2H-ch^ one
7- { [3 -(dimethylamino)propyl]amino } -3 -(7-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(2-chloroimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(2-chloroimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(4-methyl- 1 ,4-diazepan-l -yl)-2H-chromen-
2- one
3- (6-fluoroimidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-fluoroimidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(3-chloro-4-fluorophenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3-chloro-4-fluorophenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(l ,3-benzodioxol-5-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l,3-benzodioxol-5-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one 3-(l,3-benzodioxol-5-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
- I l l - 3 -( 1 ,3 -benzodioxol-5 -yl)-7- [(3 S)-3 -methylpiperazin- 1 -yl]-2H-chromen-2-one
7- [(3 S)-3 -methylpiperazin- 1 -yl] -3 - [3 -(trifluoromethyl)phenyl]-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-fluoroimidazo[l,2-a]pyrimidin-2-yl)-2H chromen-2-one
3-(6-fluoroimidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chrom one
7-(4-methyl-l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(2-chloroimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-(piperidin-4-ylamino)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H-chromen-2-^
3-(6-cyclopropyl-8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l- yl]-2H-chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H- chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2- one
7-(l ,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(6-fluoroimidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H- chromen-2-one
7-(l,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-
2- one
7-(3,8-diazabicyclo[3.2 ]oct-3-yl)-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
7-(3,3-dimethylpiperazin-l-yl)-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one 7-(3,3-dimethylpiperazin-l-yl)-3-(6-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one 3 -(3 -chlorophenyl)-7- [(3 S)-3 -methylpiperazin- 1 -yl]-2H-chromen-2-one
3- (2-chloro-4-fluorophenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3-methylphenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(3 -methylphenyl)-7- [(3 S)-3 -methylpiperazin- l-yl]-2H-chromen-2-one
3-(2,3-dihydro-l,4-benzodioxin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(2,3-dihydro-l,4-benzodioxin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one 3-(6,8-dimethylimidazo[l ,2-a]pyrazin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chrom
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-
2- one
3- (6,8-difluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-(l,4-diazabicyclo[3 ]non-4-yl)-3-(7-methylimidazo[l ,2-a]pyridin-2-yl)-2H-chromen-
2 - one
3- (6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
3- (8-fluoroimidazo[l ,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(3,8-diazabicyclo[3 ]oct-3-yl)-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(2,5-diazabicyclo[2 .2]oct-2-yl)-2H-chromen-2- one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-2H-chromen-2-one
3-(indolizin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-2H-chromen-2-one
3-(6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(8aS)-hexahydropyrrolo[l ,2-a]pyrazin-2(lH)-yl]-3-(7-methylimidazo[l ,2-a]pyridin-2- yl)-2H-chromen-2-one
7-[(lR,5S)-8-methyl-3,8-diazabicyclo[3.2 ]oct-3-yl]-3-(7-methylimidazo[l,2-a]pyridin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen- 2-one 3-(3,5-difluoro-2-methoxyphenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,5-difluoro-2-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,5-difluoro-2-methoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chrome one
3 -(4-methoxy-3 -methylphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -(4-methoxy-3 -methylphenyl)-7-[(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -3 -(4-methoxy-3 -methylphenyl)-2H-chromen-2-one
3 -(3 -fluoro-4-methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3 -(2,3 -difluorophenyl)-7- [(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-[6-(dimethylamino)pyridin-3-yl]-7-(piperazin-l-yl)-2H-chromen-2-one
3-[6-(dimethylamino)pyridin-3-yl]-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(pyridin-4-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-5-fluoro-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(indolizin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(l -methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(l-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-( 1 -methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
7-(l,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-ylamino)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chromen^ one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin^
one
3 -(indolizin-2-yl)-7- [(3 S)-3 -methylpiperazin- l-yl]-2H-chromen-2-one 7-[(3S)-3-methylpiperazin-l-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3 -(3 -methoxy-4-methylphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(3-methoxy-4-methylphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3 -(4-fluoro-3 -methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(piperazin-l-yl)-3-(pyrrolo[l,2-a]pyrimidin-7-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(pyrrolo[l,2-a]pyrimidin-7-yl)-2H-chromen-2- one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chrom
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H- chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(8-fl
2- one
7-[(3R)-3-methylpiperazin-l-yl]-3-(l-methylpyrrolo[l ,2-a]pyrazin-7-yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(l -methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3- (3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
5-fluoro-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one 5-fluoro-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
5-fluoro-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
7-(5,8-diazaspiro[3.5]non-8-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
7-(6,9-diazaspiro[4.5]dec-9-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-
2- one
7-(5,8-diazaspiro[3.5]non-8-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(6,9-diazaspiro[4.5]dec-9-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2- one
3-(l -benzofuran-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l-benzofuran-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(l-benzofuran-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl^ chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-[6-methyl-8-(trifluoromethyl)imidazo[ 1 ,2-a]pyrazin-2-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-5-fluoro-2H-chromen-2- one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(8aR)-hexahydropyrrolo[l,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(octahydro-2H-pyrido[l,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(8-methyl-3,8-diazabicyclo[3.2.1 ]oct-3- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-5-fluoro-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H- chromen-2-one 3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-[methyl( 1 -methylpyrrolidin-3 -yl)amino] - 2H-chromen-2-one
7- [( 1 -benzylpyrrolidin-3 -yl)(methyl)amino] -3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-b]pyridazin-2-yl)-2H- chromen-2-one
7-(4-ethyl-l,4-diazepan-l-yl)-3 -(6-methylimidazo [l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-(azetidin-3-ylamino)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{methyl[(3S)-pyrrolidin-3-yl]amino}-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3 -(6-methylimidazo [ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
7- [( 1 S ,4S)-2, 5 -diazabicyclo [2.2.1 ]hept-2-yl] -3 -(6-methylimidazo [ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
3 -(6-methylimidazo [l,2-b]pyridazin-2-yl)-7- [(3 S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-2H- chromen-2-one
7- [(3 S)-4-ethyl-3-methylpiperazin-l-yl] -3 -(6-methylimidazo [l,2-a]pyrazin-2 -yl)-2H- chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-
2- one
7-[(3S)-3-methylpiperazin-l-yl]-3-(thieno[3,2-c]pyridin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(thieno[3,2-c]pyridin-2-yl)-2H-chromen-2-one 7-(l,4-diazepan-l-yl)-3 -(6-methylimidazo [l,2-b]pyridazin-2-yl)-2H-chromen-2-one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3 -(6-methylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-(octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7- yl)-2H-chromen-2-one
7-[(3R)-3-methylpiperazin-l-yl]-3-(3-methylpyrrolo[l ,2-a]pyrazin-7-yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one 7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(2-methylpyrrolo[l,2-b]pyridazin-6-yl)-2H- chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3-(2-methylpyrrolo[l,2-b]pyridazin-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7- yl)-2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7- yl)-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2- one
7-[(lS,4S)-2,5-diazabicyclo[2.2 ]hept-2-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(2-methylimidazo[l,2-a]pyrimidm^
6- yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyrimidm^
2- one
7- [(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(2-methylimidazo[l,2-a]pyridin-6- yl)-2H-chromen-2-one
3- (2-methylimidazo[l,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chrom one
7-(4-methyl-l,4-diazepan-l-yl)-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{methyl[(3S)-l-methylpyrrolidin-3- yl] amino } -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3S)- 1 -methylpyrro lidin-3-yl] amino } -2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-methyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-fluoro-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one 7-[(3R)-3,4-dimethylpiperazin- 1 -yl]^
chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-ch^
2- one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[ 1 ,2-a]pyrimidin-6-yl)-2H-chromen-2- one
7-( 1 ,4-diazepan- 1 -yl)-3-(2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-2H-chromen-2-one
3- (2-methylimidazo[l ,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l ,2-a]pyrazin-2-yl)-7-(3-ethylpiperazin-l-yl)-2H-chromen-2-one
7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-(4-ethyl- 1 ,4-diazepan- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one 3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
3- (l ,3-dimethylpyiTolo[l ,2-a]pyrazin-7-yl)-7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin- 2( 1 H)-yl]-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(4-ethyl-l ,4-diazepan- 1 -yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2( 1 H)-yl]-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[l ,2-a]pyrazin-7-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2-one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(2-methylimidazo[l ,2-a]pyridin-6-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(3-ethyl-4-methylpiperazin- 1 -yl)-2H- chromen-2-one
3-(2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-( 1 ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3S)-3-methylpiperazin-l -yl]-2H-chromen-
2 - one
3- (l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one 7- [4-(2-hydroxyethyl)piperazin- 1 -yl] -3 -(3 -methylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-2H-chromen-
2- one
3- (l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol- 1 (2H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4 c]pyrrol-2(lH)-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-5-methylhexahydropyrrolo[3,4- b]pyrrol- 1 (2H)-yl]-2H-chromen-2-one
7-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl]-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7- [(3 S)-3 -(dimethylamino)pyrrolidin- 1 -yl] -3 -(6,8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one
3 -(3 -methylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin- 1 -yl]-2H-chromen-2- one
7-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(2-methyl-l,3-benzoxazol-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one
7- [(3 S)-3 -(dimethylamino)pyrrolidin- 1 -yl] -3 -( 1 ,3 -dimethylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(5-methylmro[3,2-b]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {methyl[(3R)-pyrrolidin-3-yl]amino} -2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methyl-8-nitroimidazo[l,2-a]pyridm^ 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3-exo)-9-methyl-9-azabicyclo[3.3.1 ]non- 3-yl]amino} -2H-chromen-2-one
3-(6-methyl-8-nitroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aR)-l-methylhexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl]-2H-chromen-2-one 3-(2,4-dimethylthieno[2,3-d]pyrimidin-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-l-methylhexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- (methyl[(3R)- 1 -methylpyrrolidin-3- yl] amino } -2H-chromen-2-one
7-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-
2- one
3- (6-chloro-8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[ 1 ,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2- a] pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H- chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
7-(4-aminopiperidin-l-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-[4-(dimethylamino)piperidin-l-yl]-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-[4-(dimethylamino)piperidin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chrom 2-one
7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H chromen-2-one
7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl]-3-(6-methylimidazo[l ,2-a]pyrazin-
2- yl)-2H-chromen-2-one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4- b] pyridin-6-yl]-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)-2H-chromen-
2- one
7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)- 2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)- 2H-chromen-2-one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
tert-butyl {(3S)- 1 -[3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2-oxo-2H-chromen-7- yl]pyrrolidin-3-yl} carbamate
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-l-yl]- 2H-chromen-2-one 3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyraz
chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-{[(lR,5S)-9-methyl-9-azabicyclo[3.3.1]non- 3-yl]amino} -2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3aS,6aS)- 1 -methylhexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl]-2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7- { [(3 R)- 1 -methy lpyrrolidin-3 -yljamino } -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -ethylpyrrolidin-3-yl]amino} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(2-hydroxyethyl)pyrrolidin-3- yl] amino } -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(propan-2-yl)pyrrolidin-3- yl] amino } -2H-chromen-2-one
7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2- a]pyrazin-7-yl)-2H-chromen-2-one
7-[3-(diethylamino)pyrrolidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(3,3-dimethylpiperazin-l-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(3,3,4-trimethylpiperazin-l-yl)-2H- chromen-2-one
7- [(3 S ,4S)-3 -(dimethylamino)-4-hydroxypyrrolidin- 1 -yl] -3 -(6, 8-dimethylimidazo [ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-[(3 ' S ,4 ' S)-4 ' -hydroxy- 1,3' -bipyrrolidin- 1 ' - yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l,2,3,6-tetrahydropyridin-4-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-(2- hydroxyethyl)hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-(propan-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl]-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-
2- one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-2H-chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin- 1 -yl)-5-fluoro-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-methylpiperidin-4-yl)-2H-ch^
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-ethylpiperidin-4-yl)-2H-chrom
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(2-hydroxyethyl)piperidin-4-yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[l ,2-a]pyrazin-7-yl)-7-[(3 'R,4'R)-4'-hydroxy-l ,3 '-bipyrrolidin-1 '- yl]-2H-chromen-2-one
7-(4-cyclopropylpiperazin-l-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-
2- one
3- (3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)- 1 ,4-diazepan- 1 -yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)- 1 ,4-diazepan- 1 -yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3aR,6aR)- 1 -methylhexahydropyrrolo[3,4- b] pyrrol-5(lH)-yl]-2H-chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4- c] pyrrol-2(lH)-yl]-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[3-(morpholin-4-yl)pyrrolidin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(7R,8aS)-7-hydroxyhexahydropyrrolo[ 1 ,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-methoxy-6-methylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-hydroxy-6-methylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(6,8- dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-(4-cyclopropylpiperazin- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chrome
2- one
3- (6-chloro-8-methylimidazo[ 1 ,2-a]py
yl]-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2- one 3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(7R,8aS)-7-hydroxyhexahydropyrrolo[ 1 ,2- a] pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin- 1 - yl]-2H-chromen-2-one
3-(2-methyl-l,3-benzothiazol-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(2-methyl-l,3-benzothiazol-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(2-methyl-l,3-benzothiazol-6-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin- 1 -yl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(propan-2-yl)piperidin-4-yl]-2H- chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H- chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2- one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(2 -methyl- l,3-benzothiazol-6-yl)-2H-chromen-2- one
7-[(3S)-4-ethyl-3-methylpiperazin-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-ethyl-4-methylpiperazin-l-yl]-2H- chromen-2-one
7-[(3S)-3,4-diethylpiperazin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-2,5-diazabicyclo[2.2.1]hept-
2- yl]-2H-chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4- b] pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-methyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-[4-(aminomethyl)piperidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-(2-hydroxyethyl)octahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-ethyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-methyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl]-2H-chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2-one 3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen^ one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7- {4-[(propan-2-ylamino)methyl]piperidin- 1 - yl} -2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-ethyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-ethyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-l-methyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(4aS,7aS)- 1 -(2-hydroxyethyl)octahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
7-[(3R,5S)-4-ethyl-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-(4-cyclopropylpiperazin-l-yl)-3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-methoxyethyl)piperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl) 2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(2-hydroxyethyl)-l, 2,3,6- tetrahydropyridin-4-yl]-2H-chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(propan-2-yl)-l,2,3,6-tetrahydropyridin-
4- yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-l-ethyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H-chromen^
2- one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2H-chromen^
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-(propan-2-yl)piperazin-l-yl]-2H- chromen-2-one 3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-methyl-3-(propan-2-yl)piperazin-l- yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-(propan-2-yl)piperazin-l- yl]-2H-chromen-2-one
7-(4-cyclopropylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2- one
7-(4-tert-butylpiperazin-l-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen^ one
3 -( 1 ,3 -dimethylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-7- [(3R)-3 -methyl-4-(propan-2-yl)piperazin- 1 - yl]-2H-chromen-2-one
7-(4-cyclobutylpiperazin-l-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
7-[4-(cyclopropylmethyl)piperazin-l-yl]-3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-2H- chromen-2-one
3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-3-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-[4-(2-methoxyethyl)piperazin-l-yl]-2H- chromen-2-one
7-(l-cyclobutylpiperidin-4-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
7-(4-cyclobutylpiperazin- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin- 1 -yl]-2H- chromen-2-one
3-(8-ethyl-6-methylimidazo[l,2-a]pyrazin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-(l-methylpiperidin-4-yl)-2H-chromen-2-one
7-(l-ethylpiperidin-4-yl)-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-[l-(oxetan-3-yl)piperidin-4-yl]-2H-chromen-2- one
7-[l-(2-hydroxyethyl)piperidin-4-yl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen^
2- one
3- (8-ethyl-6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
3- (4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one 3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2- one
3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-7-(l-methylpiperidin-4-yl)-2H-chrom
7-(l-ethylpiperidin-4-yl)-3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-2H-chrom
7-[4-(2-hydroxyethyl)piperazin- 1 -yl]-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(4-cyclobutylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-l-yl]-2H-chromen-2- one
3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)^
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-propylpiperidin-4-yl)-2H-chromen-2-on^
7-[l-(2-hydroxyethyl)piperidin-4-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(l-ethylpiperidin-4-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-[2-methyl-3-(l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2-b]pyridazin-6-yl]-7-(l,2,3,6- tetrahydropyridin-4-yl)-2H-chromen-2-one
7-[(dimethylamino)methyl]-3-(6,8-dimet^^
one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-l-ylmethyl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperazin-l-ylmethyl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(4-methylpiperazin- 1 -yl)methyl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen^ one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(lH-imidazol-l-ylmethyl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-ethyl-3-methylpiperazin- 1 -yl)-2H- chromen-2-one
3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-7-(l-ethylpiperidin-4-yl)-2H-chromen-2-one
7-(l-cyclopropylpiperidin-4-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(oxetan-3-yl)piperidin-4-yl]-2H- chromen-2-one
3-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
7-[3-(dimethylamino)propyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazm^
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[3-(piperazin- 1 -yl)propyl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[3-(4-methylpiperazin- 1 -yl)propyl]-2H- chromen-2-one
7-[l-(2-hydroxyethyl)piperidin-4-yl]-3-(2-methyl-2H-indazol-5-yl)-2H-chromen-2-one
3-(2-methyl-2H-indazol-5-yl)-7-(l-methylpiperidin-4-yl)-2H-chromen-2-one
7-(l-ethylpiperidin-4-yl)-3-(2-methyl-2H-indazol-5-yl)-2H-chromen-2-one
7-[2-(dimethylamino)ethyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chrom one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(propan-2-ylamino)ethyl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[2-(piperazin- 1 -yl)ethyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(l -methylpiperidin-4-yl)oxy]-2H-chromen-
2- one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
7-(l-cyclobutylpiperidin-4-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxyethyl)amino]ethyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxyethyl)(methyl)amino]ethyl} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(l -hydroxypropan-2-yl)amino]ethyl} - 2H-chromen-2-one
7- {2-[(l ,3-dihydroxypropan-2-yl)amino]ethyl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2R)-2-(hydroxymethyl)pyrrolidin- 1 - yl]ethyl} -2H-chromen-2-one
7- {2-[bis(2-hydroxyethyl)amino]ethyl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[2-(dimethylamino)ethoxy]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(propan-2-ylamino)ethoxy]-2H-chromen-
2- one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(oxetan-3-yl)piperidin-4-yl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2-hydroxyethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2- hydroxyethyl)(methyl)amino]propyl}-2H-chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(l -hydroxypropan-2-yl)amino]propyl} - 2H-chromen-2-one
7- {3-[(l ,3-dihydroxypropan-2-yl)amino]propyl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2R)-2-(hydroxymethyl)pyrrolidin- 1 - yl]propyl} -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(morpholin-4-yl)propyl]-2H-chrom one
7-{3-[bis(2-hydroxyethyl)amino]propyl}-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(morpholin-4-yl)ethyl]-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(l -propylpiperidin-4-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3 S)-4-(2-hydroxyethyl)-3- methylpiperazin- 1 -yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -methylpyrrolidin-3-yl]oxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -ethylpyrrolidin-3-yl]oxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(propan-2-yl)pyrrolidin-3-yl]oxy} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(2-hydroxyethyl)pyrrolidin-3- yl]oxy } -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(1 -hydroxypropan-2-yl)pyrrolidin- 3-yl]oxy} -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-(2-fluoroethyl)-3-methylpiperazin-l- yl]-2H-chromen-2-one
7-[2-(diethylamino)ethoxy]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
7- {2-[bis(2-hydroxyethyl)amino]ethoxy} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(l-ethylpiperidin-4-yl)oxy]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{[l-(2-hydroxyethyl)piperidin-4-yl]oxy}- 2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-(3-fluoropropyl)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{[l-(propan-2-yl)piperidin-4-yl]oxy}-2H- chromen-2-one 7-[4-(dimethylamino)butyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chrom one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {4-[(2-hydroxyethyl)(methyl)amino]butyl} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {4-[(2R)-2-(hydroxymethyl)pyrrolidin- 1 - yl]butyl} -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(piperazin- 1 -yl)butyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(3-fluoropropyl)piperidin-4-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-(3-hydroxypropyl)-3- methylpiperazin- 1 -yl] -2H-chromen-2-one
7-[3-(dimethylamino)propyl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-2-one
7-[3-(dimethylamino)propyl]-3-(8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one
7-[3-(dimethylamino)propyl]-3-(8-ethyl-2-methylimidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(methylamino)ethyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(methylamino)propyl]-2H-chromen-2- one
3 -(8-fluoro-2-methylimidazo [ 1 ,2-a]pyridin-6-yl)-7- [3 -(methylamino)propyl] -2H-chromen-
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(2-methylpropyl)piperidin-4-yl]-2H- chromen-2-one
7-{[l-(l,3-dihydroxypropan-2-yl)piperidin-4-yl]oxy}-3-(6,8-dimethylimidazo[l,2- a]pyrazin-2-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(2-methylpropyl)piperidin-4-yl]-2H- chromen-2-one
7-[l-(3-fluoropropyl)piperidin-4-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen^
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[2-(pyrrolidin- 1 -yl)ethoxy]-2H-chromen-2- one
7-(4-aminopiperidin-l-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-on^
7-(4-amino-4-methylpiperidin- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[4-(dimethylamino)piperidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H chromen-2-one
7-[4-(diethylamino)piperidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(propan-2-ylamino)piperidin- 1 -yl]-2H- chromen-2-one 7-[4-(cyclobutylamino)piperidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2 chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{4-[(l-hydroxypropan-2-yl)amino]piperidin- 1 -yl} -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(ethylamino)propyl]-2H-chromen-2-one
7-(3-aminopropyl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7- {4-[bis(2-hydroxyethyl)amino]piperidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2- yl)-2H-chromen-2-one
7- {4-[(l ,3-dihydroxypropan-2-yl)amino]piperidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin^
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2-methoxyethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(tetrahydrofuran-2- ylmethyl)amino]propyl}-2H-chromen-2-one
7-[3-(benzylamino)propyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(thiophen-3-ylmethyl)amino]propyl} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(pyridin-2-ylmethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(pyridin-4-ylmethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[ethyl(methyl)amino]ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[ethyl(2-hydroxyethyl)amino]ethoxy } - 2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-[3 -(tetrahydrofuran-3 -ylamino)propyl] -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(3R)-3-hydroxypyrrolidin- 1 -yljethoxy} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[3-(2-methylpiperidin- 1 -yl)azetidin- 1 -yl]- 2H-chromen-2-one
7-[3-(dimethylamino)azetidin- 1 -yl]-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[3-(diethylamino)azetidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(2,7-diazaspiro[4^]non-2-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(2-{[(2R)-l-hydroxypropan-2- yl] amino } ethoxy)-2H-chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(2- {[(2S)- 1 -hydroxypropan-2- yl] amino } ethoxy)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(2R)-pyrrolidin-2-ylmethoxy]-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-l, 2,3,6- tetrahydropyridin-4-yl)-2H-chromen-2-one
7-[(3R)-3-(aminomethyl)pyrrolidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(piperidin-l-yl)azetidin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(methylamino)butyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(piperidin-l-yl)ethoxy]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{2-[(3S)-3-hydroxypyrrolidin-l-yl]ethoxy}- 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(l -hydroxy-2-methylpropan-2- yl)amino] ethoxy } -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(morpholin-4-yl)ethoxy]-2H-chromen^ one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(4-hydroxypiperidin-l-yl)ethoxy]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-ethyl-4-fluoropiperidin-4-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxyethyl)amino]ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-methoxyethyl)amino]ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2- [(2-hydroxypropyl)amino] ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(2-hydroxy-2-methylpropyl)piperazin-l- yl]-2H-chromen-2-one
7-[3-(aminomethyl)azetidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(3S)-3-(aminomethyl)pyrrolidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H chromen-2-one
7- {(3R)-3-[(dimethylamino)methyl]pyrrolidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
7- {3-[(dimethylamino)methyl]azetidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one 7- {(3S)-3-[(dimethylamino)methyl]pyrrolidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
7-[2-(diethylamino)ethyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chrom
7-[3-(diethylamino)propyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chrom one
7-[4-(diethylamino)butyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-(2,6-diazaspiro[3.3]hept-2-yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2H- chromen-2-one
2- [3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7- yl]hexahydropyrrolo[l,2-a]pyrazin-6(2H)-one
1- [3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7-yl]piperidine-4- carbonitrile
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(4-hydroxypiperidin-l-yl)-2H-chromen-2- one
7-(2,7-diazaspiro[3.5]non-7-yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-
2- one
7-(6-amino-2-azaspiro[3.3]hept-2-yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
3- (imidazo[l,2-a]pyridin-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(imidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one
3-(imidazo[l,2-a]pyridin-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chrom
2- one
3- (8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3-(8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
7-(2,6-diazaspiro[33]hept-2-yl)-3-(8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one, and
3-(8-fluoro-2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one;
[00167] or a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
[00168] In another embodiment, the compound of Formula (I) used in a method disclosed herein is a compound selected from the group consisting of: 7-(piperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one
trifluoroacetate
7-(piperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one hydrochloride
7-(piperazin-l-yl)-3-[7-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one
trifluoroacetate
7-(piperazin-l-yl)-3-[7-(trifiuoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one hydrochloride
2- oxo-N-phenyl-7-(piperazin- 1 -yl)-2H-chromene-3-carboxamide trifluoroacetate
3- (l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(7-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(4-chloro- 1 ,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one hydrochloride
3-(5-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
3-(4-methyl- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
3-(4-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one trifluoroacetate
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one hydrochloride
7-(4-methylpiperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2-one trifluoroacetate
3-(4-iodo-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(4-chloro-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-([ 1 ,3]oxazolo[4,5-b]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
7-[(lS,4S)-2,5-diazabicyclo[2.2 ]hept-2-yl]-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2- one hydrochloride (1 :3)
3-(3-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
hydrochloride (1 :3)
7-(l,4-diazepan-l-yl)-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one hydrochloride
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one hydrochloride
3-(2-methylpyrimidin-4-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(2-cyclopropylpyrimidin-4-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
7-(piperazin- 1 -yl)-3-[2-(propan-2-yl)pyrimidin-4-yl]-2H-chromen-2-one hydrochloride
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3 -(imidazo [2, 1 -b] [ 1 ,3 ]thiazol-6-yl)-7- [(3R)-pyrrolidin-3 -yloxy] -2H-chromen-2-one
hydrochloride (1 :2) 3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
7-[(l-benzylpyrrolidin-3-yl)(methyl)a
chromen-2-one acetate
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-methoxy-6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one acetate (1 :2)
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-hydroxy-6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one acetate
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(2 -methyl- l,3-benzothiazol-6-yl)-2H-chromen-2-one acetate (2: 1)
7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-3-(2 -methyl- l,3-benzothiazol-6-yl)-2H-chromen-2-one acetate
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-ethyl-4-methylpiperazin-l-yl]-2H- chromen-2-one acetate, and
7-[(3S)-3,4-diethylpiperazin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one acetate (1 :2);
[00169] or a free base, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
[00170] Compounds of Formula (I) can be prepared using reagents and methods known in the art, including the methods provided in International Application No. PCT/US2012/0071899, filed on December 28, 2012, and published as International Publication No. WO 2013/101974 on July 4, 2013, the entire contents which are incorporated herein by reference (see in particular,
General Synthetic Methods, Schemes A-N, at paragraphs [00540] to [00569]; and Specific
Synthetic Examples, at paragraphs [00570] to [001118] and Table 1).
TERMINOLOGY
[00171] The chemical terms used above and throughout the description herein, unless
specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.
[00172] As used herein, the term "Ci.galkyl" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl, n-pentyl (also referred to as pentyl or pentanyl), n-hexyl (also referred to as hexyl or hexanyl), n-heptyl (also referred to as heptyl or heptanyl), n-octyl and the like. In some embodiments, Ci.galkyl includes, but is not limited to, Ci_6alkyl, Ci_4alkyl and the like. A Ci_8alkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
[00173] As used herein, the term "C2_8alkenyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl and the like. In some embodiments,
C2_galkenyl includes, but is not limited to, C2_6alkenyl, C2_4alkenyl and the like. A C2_galkenyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
[00174] As used herein, the term "C2_8alkynyl" generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl, propynyl, butynyl and the like. In some embodiments, C2-8alkynyl includes, but is not limited to, C2_6alkynyl, C2_4alkynyl and the like. A C2_8alkynyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
[00175] As used herein, the term "Ci_8alkoxy" generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -O- Ci.galkyl, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like. In some embodiments, Cl-8alkoxy includes, but is not limited to, Ci_6alkoxy, Ci_4alkoxy and the like. A Ci.galkoxy radical is optionally substituted with substituent species as described herein where allowed by available valences.
[00176] As used herein, the term "C3_i4cycloalkyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, lH-indanyl, indenyl, tetrahydro-naphthalenyl and the like. In some embodiments,
C3-i4cycloalkyl includes, but is not limited to, C3-scycloalkyl, Cs-scycloalkyl, C3_iocycloalkyl and the like. A C3_i4cycloalkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
[00177] As used herein, the term "aryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical is optionally substituted with substituent species as described herein where allowed by available valences.
[00178] As used herein, the term "heteroaryl" generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more
heteroatoms, such as an O, S or N atom, including, but not limited to, furanyl (also referred to as furyl), thienyl (also referred to as thiophenyl), pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, lH-pyrazolyl, imidazolyl, lH-imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl (such as lH-l,2,3-triazolyl and the like), oxadiazolyl (such as 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like), thiadiazolyl, tetrazolyl (such as lH-tetrazolyl, 2H-tetrazolyl and the like), pyridinyl (also referred to as pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, lH-indolyl, indazolyl, lH-indazolyl, 2H-indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl (also referred to as benzothiophenyl), benzoimidazolyl, lH-benzoimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl (also referred to as 1,3-benzooxazolyl), purinyl,
9H-purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1 ,2-diazinyl, 1 ,2-diazolyl, 1 ,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo [2,3 -c]pyridinyl, 6H-thieno [2,3 -b]pyrrolyl, thieno [3 ,2-c]pyridinyl, thieno [2,3 -d]pyrimidinyl, lH-pyrrolo[2,3-b]pyridinyl, lH-pyrrolo[2,3-c]pyridinyl, lH-pyrrolo[3,2-b]pyridinyl,
pyrrolo[ 1 ,2-a]pyrazinyl, pyrrolo[l ,2-b]pyridazinyl, pyrazolo[ 1 ,5-a]pyridinyl,
pyrazolo[ 1 ,5-a]pyrazinyl, imidazo[ 1 ,2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,
imidazo[ 1 ,2-a]pyrimidinyl, imidazo[ 1 ,2-c]pyrimidinyl, imidazo[ 1 ,2-b]pyridazinyl,
imidazo[ 1 ,2-a]pyrazinyl, imidazo[2, 1 -b] [ 1 ,3]thiazolyl, imidazo[2, 1 -b][ 1 ,3,4]thiadiazolyl,
[l,2,4]triazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl and the like. A heteroaryl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.
[00179] As used herein, the term "heterocyclyl" generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1 ,4-diazepanyl, 1,3-benzodioxolyl (also referred to as benzo[d][l,3]dioxolyl), 1 ,4-benzodioxanyl, 2,3-dihydro-l,4-benzodioxinyl (also referred to as 2,3-dihydrobenzo[b][l,4]dioxinyl), hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl,
(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl,
(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(lH)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl,
(3 aR,6aR)-hexahydropyrrolo [3 ,4-b]pyrrol-(2H)-yl, hexahydropyrrolo [3 ,4-c]pyrrol-( 1 H)-yl, (3 aR,6aS)-hexahydropyrrolo [3 ,4-c]pyrrol-( 1 H)-yl,
(3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(lH)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[l,2-a]pyrazin-(lH)-yl, (7R,8aS)-hexahydropyrrolo[l,2-a]pyrazin-(lH)-yl,
(8aS)-hexahydropyrrolo[l,2-a]pyrazin-(lH)-yl, (8aR)-hexahydropyrrolo[l,2-a]pyrazin-(lH)-yl, (8aS)-octahydropyrrolo[l,2-a]pyrazin-(lH)-yl, (8aR)-octahydropyrrolo[l,2-a]pyrazin-(lH)-yl, hexahydropyrrolo [ 1 ,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[ 1 ,2-a]pyrazinyl,
3-azabicyclo[3.1.0]hexyl, (lR,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl,
(lR,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl,
( 1 R,5 S)-8-azabicyclo[3.2.1 ]oct-2-enyl, 9-azabicyclo[3.3.1 ]nonyl,
( 1 R,5 S)-9-azabicyclo [3.3.1 ]nonyl, 2,5 -diazabicyclo [2.2.1 Jheptyl,
(lS,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl,
3,8-diazabicyclo[3.2.1]octyl, (lR,5S)-3,8-diazabicyclo[3.2.1]octyl, l,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,7-diazaspiro[3.5]nonyl,
5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl and the like. A heterocyclyl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.
[00180] As used herein, the term "Ci_8alkoxy-Ci_8alkyl" refers to a radical of the
formula: -Ci_8alkyl-0-Ci_8alkyl.
[00181] As used herein, the term "Ci_8alkoxy-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-0-Ci_8alkyl.
[00182] As used herein, the term "(Ci_8alkoxy-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-0-Ci_8alkyl)2.
[00183] As used herein, the term "Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci.8alkyl- H-Ci.8alkyl-0-Ci.8alkyl.
[00184] As used herein, the term "(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-N(Ci_8alkyl-0-Ci_8alkyl)2.
[00185] As used herein, the term "(Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-0-Ci_8alkyl).
[00186] As used herein, the term "Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-0-Ci_8alkyl.
[00187] As used herein, the term "(Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-0-Ci_8alkyl)2.
[00188] As used herein, the term "(Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-0-Ci_8alkyl).
[00189] As used herein, the term "Ci_8alkoxy-carbonyl" refers to a radical of the
formula: -C(0)-0-Ci_8alkyl.
[00190] As used herein, the term "Ci_8alkoxy-carbonyl-C2_8alkenyl" refers to a radical of the formula: -C2_8alkenyl-C(0)-0-Ci_8alkyl.
[00191] As used herein, the term "Ci_8alkoxy-carbonyl-amino" refers to a radical of the formula: -NH-C(0)-0-Ci_8alkyl.
[00192] As used herein, the term "Ci.salkyl-amino" refers to a radical of the
formula: -NH-Ci_8alkyl.
[00193] As used herein, the term "(Ci_8alkyl)2-amino" refers to a radical of the
formula: -N(Ci_8alkyl)2. [00194] As used herein, the term "Ci_8alkyl-amino-C2-8alkenyl" refers to a radical of the formula: -C2_8alkenyl-NH-Ci_8alkyl.
[00195] As used herein, the term "(Ci_8alkyl)2-amino-C2-8alkenyl" refers to a radical of the formula: -C2-8alkenyl-N(Ci_8alkyl)2.
[00196] As used herein, the term "Ci_8alkyl-amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-NH-Ci_8alkyl.
[00197] As used herein, the term "(Ci_8alkyl)2-amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-N(Ci_8alkyl)2.
[00198] As used herein, the term "Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl.
[00199] As used herein, the term "(Ci_8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)2.
[00200] As used herein, the term "Ci_8alkyl-amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-C i_8alkyl-NH-C i_8alkyl.
[00201] As used herein, the term "(Ci_8alkyl)2-amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-N(Ci_8alkyl)2.
[00202] As used herein, the term "(Ci_8alkyl-amino-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-NH-Ci_8alkyl)2.
[00203] As used herein, the term "[(Ci_8alkyl)2-amino-Ci_8alkyl]2-amino" refers to a radical of the formula: -N[Ci_8alkyl-N(Ci_8alkyl)2]2.
[00204] As used herein, the term "(Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-NH-Ci_8alkyl).
[00205] As used herein, the term "[(Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)[Ci_8alkyl-N(Ci_8alkyl)2].
[00206] As used herein, the term "Ci_8alkyl-amino-C2-8alkynyl" refers to a radical of the formula: -C2-8alkynyl-NH-Ci_8alkyl.
[00207] As used herein, the term "(Ci_8alkyl)2-amino-C2-8alkynyl" refers to a radical of the formula: -C2-8alkynyl-N(Ci_8alkyl)2.
[00208] As used herein, the term "Ci_8alkyl-carbonyl" refers to a radical of the
formula: -C(0)-Ci_8alkyl. [00209] As used herein, the term "Ci_8alkyl-carbonyl-amino" refers to a radical of the formula: -NH-C(0)-Ci_8alkyl.
[00210] As used herein, the term "Ci_8alkyl-thio" refers to a radical of the
formula: -S-Ci_8alkyl.
[00211] As used herein, the term "amino-C2-8alkenyl" refers to a radical of the
formula: -C2_8alkenyl-NH2.
[00212] As used herein, the term "amino-Ci_8alkoxy" refers to a radical of the
formula: -0-Ci_8alkyl-NH2.
[00213] As used herein, the term "amino-Ci_8alkyl" refers to a radical of the
formula: -Ci_8alkyl-NH2.
[00214] As used herein, the term "amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-NH2.
[00215] As used herein, the term "(amino-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-NH2)2.
[00216] As used herein, the term "(amino-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-NH2).
[00217] As used herein, the term "amino-C2-8alkynyl" refers to a radical of the
formula: -C2_8alkynyl-NH2.
[00218] As used herein, the term "aryl-Ci_8alkoxy-carbonyl" refers to a radical of the formula: -C(0)-0-Ci_8alkyl-aryl.
[00219] As used herein, the term "aryl-Ci_8alkyl" refers to a radical of the
formula: -Ci_8alkyl-aryl.
[00220] As used herein, the term "aryl-Ci_8alkyl-amino" refers to a radical of the
formula: -NH-Ci_8alkyl-aryl.
[00221] As used herein, the term "(aryl-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-aryl)2.
[00222] As used herein, the term "(aryl-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-aryl).
[00223] As used herein, the term "aryl-Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-aryl. [00224] As used herein, the term "(aryl-Ci_8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-aryl)2.
[00225] As used herein, the term "(aryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-aryl).
[00226] As used herein, the term "aryl-amino" refers to a radical of the formula: -NH-aryl.
[00227] As used herein, the term "aryl-amino-carbonyl" refers to a radical of the
formula: -C(0)-NH-aryl.
[00228] As used herein, the term "aryl-sulfonyloxy-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-0-S02-aryl.
[00229] As used herein, the term "benzoxy-carbonyl" refers to a radical of the
formula: -C(0)0-CH2-phenyl.
[00230] As used herein, the term "C3_i4Cycloalkyl-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-C3_i4Cycloalkyl.
[00231] As used herein, the term "C3_i4cycloalkyl-amino" refers to a radical of the formula: -NH-C3_i4Cycloalkyl.
[00232] As used herein, the term "C3_i4Cycloalkyl-oxy" refers to a radical of the
formula: -0-C3_i4Cycloalkyl.
[00233] As used herein, the term "halo" or "halogen" generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
[00234] As used herein, the term "halo-Ci_8alkoxy" refers to a radical of the
formula: -O-Ci-salkyl-halo, wherein Ci_salkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.
[00235] As used herein, the term "halo-Ci.galkyl" refers to a radical of the
formula: -Ci_8alkyl-halo, wherein Ci_8alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.
[00236] As used herein, the term "halo-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_salkyl-halo.
[00237] As used herein, the term "(halo-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-halo).
[00238] As used herein, the term "(halo-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_salkyl-halo)2. [00239] As used herein, the term "heteroaryl-Ci_8alkoxy" refers to a radical of the formula: -O-Ci.galkyl-heteroaryl.
[00240] As used herein, the term "heteroaryl-Ci_8alkyl" refers to a radical of the
formula: -Ci_8alkyl-heteroaryl.
[00241] As used herein, the term "heteroaryl-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-heteroaryl.
[00242] As used herein, the term "(heteroaryl-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-heteroaryl)2.
[00243] As used herein, the term "(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-heteroaryl).
[00244] As used herein, the term "heteroaryl-Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-heteroaryl.
[00245] As used herein, the term "(heteroaryl-Ci_8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-heteroaryl)2.
[00246] As used herein, the term "(heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-heteroaryl).
[00247] As used herein, the term "heteroaryl-amino" refers to a radical of the
formula: -NH-heteroaryl.
[00248] As used herein, the term "heterocyclyl-Ci.salkoxy" refers to a radical of the formula: -0-Ci_8alkyl-heterocyclyl.
[00249] As used herein, the term "heterocyclyl-Ci_8alkyl" refers to a radical of the
formula: -Ci_8alkyl-heterocyclyl.
[00250] As used herein, the term "heterocyclyl-Ci.salkyl-amino" refers to a radical of the formula: -NH-C i_8alkyl-heterocyclyl.
[00251] As used herein, the term "(heterocyclyl-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-heterocyclyl)2.
[00252] As used herein, the term "(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-heterocyclyl).
[00253] As used herein, the term "heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-heterocyclyl. [00254] As used herein, the term "(heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-heterocyclyl)2.
[00255] As used herein, the term "(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-heterocyclyl).
[00256] As used herein, the term "heterocyclyl-amino" refers to a radical of the
formula: -NH-heterocyclyl.
[00257] As used herein, the term "(heterocyclyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(heterocyclyl).
[00258] As used herein, the term "heterocyclyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-heterocyclyl.
[00259] As used herein, the term "heterocyclyl-carbonyl" refers to a radical of the
formula: -C(0)-heterocyclyl.
[00260] As used herein, the term "heterocyclyl-carbonyl-oxy" refers to a radical of the formula: -0-C(0)-heterocyclyl.
[00261] As used herein, the term "heterocyclyl-oxy" refers to a radical of the
formula: -O-heterocyclyl.
[00262] As used herein, the term "hydroxy" refers to a radical of the formula: -OH.
[00263] As used herein, the term "hydroxy-Ci.galkoxy-Ci.galkyl" refers to a radical of the formula: -Ci_8alkyl-0-Ci_8alkyl-OH.
[00264] As used herein, the term "hydroxy-Ci_8alkyl" refers to a radical of the
formula: -Ci_8alkyl-OH, whereinCi-salkyl is partially or completely substituted with one or more hydroxy radicals where allowed by available valences.
[00265] As used herein, the term "hydroxy-Ci.galkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-OH.
[00266] As used herein, the term "(hydroxy-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-OH)2.
[00267] As used herein, the term "(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-OH).
[00268] As used herein, the term "hydroxy-Ci_8alkyl-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-OH. [00269] As used herein, the term "(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-OH)2.
[00270] As used herein, the term "(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl" refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-OH).
[00271] As used herein, the term "hydroxy-Ci_8alkyl-amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-NH-Ci_8alkyl-OH.
[00272] As used herein, the term "(hydroxy-Ci_8alkyl)2-amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-N(Ci_8alkyl-OH)2.
[00273] As used herein, the term "(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy" refers to a radical of the formula: -0-Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-OH).
[00274] As used herein, the term "hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-NH-Ci_8alkyl-OH.
[00275] As used herein, the term "(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)2-amino" refers to a radical of the formula: -N(Ci_8alkyl-NH-Ci_8alkyl-OH)2.
[00276] As used herein, the term "(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-N(Ci_8alkyl-OH)2.
[00277] As used herein, the term "(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)(Ci_8alkyl-NH-Ci_8alkyl-OH).
[00278] As used herein, the term "[(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)[Ci_8alkyl-N(Ci_8alkyl-OH)2].
[00279] As used herein, the term "(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino" refers to a radical of the formula: -NH-Ci_8alkyl-N(Ci_8alkyl,Ci_8alkyl-OH).
[00280] As used herein, the term
[(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl](Ci_8alkyl)amino" refers to a radical of the formula: -N(Ci_8alkyl)[Ci_8alkyl -N(Ci_8alkyl)(Ci_8alkyl -OH)].
[00281] As used herein, the term "substituent" means positional variables on the atoms of a core molecule that are attached at a designated atom position, replacing one or more hydrogen atoms on the designated atom, provided that the atom of attachment does not exceed the available valence or shared valences, such that the substitution results in a stable compound. Accordingly, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. It should also be noted that any carbon as well as heteroatom with a valence level that appears to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown.
[00282] For the purposes of this description, where one or more substituent variables for a compound of Formula (I) encompass functionalities incorporated into a compound of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.
[00283] As used herein, the terms "independently selected," or "each selected" refer to functional variables in a substituent list that may be attached more than once on the structure of a core molecule, where the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent on a core structure for a compound provided herein is understood to include the replacement of the generic substituent with specie substituents that are included within the particular genus, e.g., aryl may be independently replaced with phenyl or naphthalenyl (also referred to as naphthyl) and the like, such that the resulting compound is intended to be included within the scope of the compounds described herein.
[00284] As used herein, the term "each instance of when used in a phrase such as "...aryl, aryl-Cl-8alkyl, heterocyclyl and heterocyclyl-Cl-8alkyl, wherein each instance of aryl and heterocyclyl is optionally substituted with one or two substituents..." is intended to include optional, independent substitution on each of the aryl and heterocyclyl rings and on the aryl and heterocyclyl portions of aryl-Cl-8alkyl and heterocyclyl-Cl-8alkyl.
[00285] As used herein, the term "optionally substituted" means that the specified substituent variables, groups, radicals or moieties represent the scope of the genus and may be independently chosen as needed to replace one or more hydrogen atoms on the designated atom of attachment of a core molecule.
[00286] As used herein, the terms "stable compound' or "stable structure" mean a compound that is sufficiently robust to be isolated to a useful degree of purity from a reaction mixture and formulations thereof into an efficacious therapeutic agent.
[00287] Compound names provided herein were obtained using ACD Labs Index Name software provided by ACD Labs and/or ChemDraw Ultra software provided by
CambridgeSoft®. When the compound name disclosed herein conflicts with the structure depicted, the structure shown will supercede the use of the name to define the compound intended. Nomenclature for substituent radicals defined herein may differ slightly from the chemical name from which they are derived; one skilled in the art will recognize that the definition of the substituent radical is intended to include the radical as found in the chemical name.
[00288] As used herein the term "aberrant" refers to a deviation from the norm of, e.g., the average healthy subject or a cell(s) or tissue sample from a healthy subject. The term "aberrant expression," as used herein, refers to abnormal expression (up-regulated or down-regulated resulting in an excessive or deficient amount thereof) of a gene product (e.g., RNA transcript or protein) by a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. In a specific embodiment, the "aberrant expression" refers to an altered level of a gene product (e.g., RNA transcript or protein) in a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. The term "aberrant amount" as used herein refers to an altered level of a gene product (e.g., RNA, protein, polypeptide, or peptide) in a cell, tissue sample, or subject relative to a corresponding normal, healthy cell, tissue sample or subject. In specific embodiments, the amount of a gene product (e.g., RNA, protein, polypeptide, or peptide) in a cell, tissue sample, or subject relative to a corresponding cell or tissue sample from a healthy subject or a healthy subject, is considered aberrant if it is 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6-fold or more above or below the amount of the gene product in the corresponding cell or tissue sample from a healthy subject or healthy subject.
[00289] As used herein, the term "substantial change" in the context of the amount of one or more RNA transcripts (e.g., rRNA, tRNA, miRNA, siRNA, IncRNA, pre-mRNA or mRNA transcripts), an alternative splice variant thereof or an isoform thereof, or one or more proteins thereof, each expressed as the product of one or more of genes, means that the amount of such products changes by a statistically significant amount such as, in a nonlimiting example, a p value less than a value selected from 0.1, 0.01, 0.001, or 0.0001.
[00290] As used herein, the terms "subject" and "patient" are used interchangeably to refer to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Non-limiting examples include members of the human, equine, porcine, bovine, rattus, murine, canine and feline species. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In certain embodiments, the subject is a non-human animal. In specific embodiments, the subject is a human.
COMPOUND FORMS
[00291] As used herein, the terms "a compound of Formula (la)" and "a compound of Formula (lb)" refer to sub-genuses of the compound of Formula (I) or a form thereof and are defined herein. Rather than repeat embodiments for a compound of Formula (la) or a compound of Formula (lb), in certain embodiments, the term "a compound(s) of Formula (I) or a form thereof is used to refer to either a compound of Formula (la) or a form thereof, a compound of Formula (lb) or a form thereof, or both. Thus, embodiments and references to "a compound of Formula (I)" are intended to include compounds of Formula (la) and Formula (lb).
[00292] Rather than repeat embodiments for the various subgenera of the compound of Formula (I), in certain embodiments, the term "a compound of Formula (I) or a form thereof is used to inclusively to refer to a compound of Formula (la) or a form thereof or a compound of Formula (lb) or a form thereof, either separately or together.
[00293] Thus, embodiments and references to "a compound of Formula (I)" are intended to be inclusive of compounds of Formula (la) and Formula (lb).
[00294] As used herein, the term "form" means a compound of Formula (I) selected from a free acid, free base, salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer, or tautomer thereof.
[00295] In certain embodiments described herein, the form of the compound of Formula (I) is a selected from a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
[00296] In certain embodiments described herein, the form of the compound of Formula (I) is a selected from a free acid, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
[00297] In certain embodiments described herein, the form of the compound of Formula (I) is a selected from a free base, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
[00298] In certain embodiments described herein, the form of the compound of Formula (I) is a free acid, free base or salt thereof. [00299] In certain embodiments described herein, the form of the compound of Formula (I) is an isotopologue thereof.
[00300] In certain embodiments described herein, the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
[00301] In certain embodiments described herein, the form of the compound of Formula (I) is a tautomer thereof.
[00302] In certain embodiments described herein, the form of the compound of Formula (I) is a pharmaceutically acceptable form.
[00303] In certain embodiments described herein, the compound of Formula (I) or a form thereof is isolated for use.
[00304] As used herein, the term "isolated" means the physical state of a compound of Formula (I) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
[00305] As used herein, the term "protected" means that a functional group on a compound of Formula (I) is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.
[00306] Prodrugs of a compound of Formula (I) or a form thereof are also contemplated herein.
[00307] As used herein, the term "prodrug" means that a functional group on a compound of Formula (I) is in a form (e.g., acting as an active or inactive drug precursor) that is transformed in vivo to yield an active or more active compound of Formula (I) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by V.J.. Stella, et. al., "Biotechnology: Pharmaceutical Aspects, Prodrugs: Challenges and Rewards,"American Association of Pharmaceutical Scientists and Springer Press, 2007. [00308] In one example, when a compound of Formula (I) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or a form thereof contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a functional group such as alkyl or substituted carbonyl and the like. In another example, when a compound of Formula (I) or a form thereof contains an amine functional group, a prodrug can be formed by the replacement of one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. In another example, when a compound of Formula (I) or a form thereof contains a hydrogen substituent, a prodrug can be formed by the replacement of one or more hydrogen atoms with an alkyl substituent.
[00309] Pharmaceutically acceptable prodrugs of compounds of Formula (I) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters phosphonate esters, mono-, di- or triphosphate esters or alkyl substituents where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or a form thereof for use as a prodrug.
[00310] The compounds of Formula (I) can form salts which are intended to be included within the scope of this description. Reference to a compound of Formula (I) herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein.
[00311] The term "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of Formula (I) may be formed, for example, by reacting a compound of Formula (I) with an amount of acid or base, such as an equivalent or stoichiometric amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
[00312] Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Embodiments of acid addition salts include, and are not limited to, acetate, acid phosphate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, hydrobromide, hydrochloride, dihydrochloride, hydroiodide, isonicotinate, lactate, maleate, methanesulfonate,
naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. One or more embodiments of acid addition salts include a chloride, hydrochloride, dihydrochloride, trihydrochloride, hydrobromide, acetate, diacetate or trifluoroacetate salt. More particular embodiments include a chloride, hydrochloride, dihydrochloride, hydrobromide or trifluoroacetate salt.
[00313] Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (see, website for Food & Drug Administration, Washington, D.C.). These disclosures are incorporated herein by reference thereto.
[00314] Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. Certain compounds described herein can also form pharmaceutically acceptable salts with organic bases (for example, organic amines) such as, but not limited to, dicyclohexylamines, tert-butyl amines and the like, and with various amino acids such as, but not limited to, arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. [00315] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the description herein and all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for the purposes described herein.
[00316] Compounds of Formula I and forms thereof may further exist in a tautomeric form. All such tautomeric forms are contemplated herein as part of the present description.
[00317] The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, may exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures.
[00318] The compounds of Formula (I) described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R/S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one embodiment, the compounds of Formula (I) described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another embodiment, the compounds of Formula (I) described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds of Formula (I) described herein may also include portions described as an (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.
[00319] As used herein, the term "substantially pure" refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.
[00320] In one aspect, a compound of Formula (I) is a substantially pure (S) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
[00321] In one aspect, a compound of Formula (I) is a substantially pure (R) enantiomer present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.
[00322] As used herein, a "racemate" is any mixture of isometric forms that are not
"enantiomerically pure", including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, about 80/20, about 85/15 or about 90/10.
[00323] In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description herein.
[00324] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art.
[00325] Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure
enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered part of this description.
[00326] All stereoisomer forms (for example, geometric isomers, optical isomers, positional isomers and the like) of the present compounds (including salts, solvates, esters and prodrugs and transformed prodrugs thereof) which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, diastereomeric forms and regioisomeric forms are contemplated within the scope of the description herein. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures thereof, are embraced within the scope of the description herein. Also, for example, all keto-enol and imine-enamine tautomeric forms of the compounds are included in the description herein. Individual stereoisomers of the compounds of Formula (I) described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra. [00327] The use of the terms "salt," "prodrug" and "transformed prodrug" are intended to equally apply to the salts, prodrugs and transformed prodrugs of all contemplated isotopologues, stereoisomers, racemates or tautomers of the instant compounds.
[00328] The term "isotopologue" refers to isotopically-enriched compounds which are identical to those recited herein, 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. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as H2, H3, C13, C14, N15, 018, 017, P31, P32, S35, F18, C135 and C136, respectively, each of which is also within the scope of this description.
[00329] Certain isotopically-enriched compounds described herein (e.g., those labeled with H3 and C14) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H3) and carbon-14 (i.e., C14) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., "deuterium enriched") may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically-enriched compounds of Formula (I) can generally be prepared using procedures known to persons of ordinary skill in the art by substituting an appropriate isotopically-enriched reagent for a non-isotopically-enriched reagent.
[00330] When the compounds are enriched with deuterium, the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium-to- hydrogen ratio.
[00331] An embodiment described herein may include an isotopologue form of the compound of Formula (I), wherein the isotopologue is substituted on one or more atom members of the compound of Formula (I) with one or more deuterium atoms in place of one or more hydrogen atoms.
[00332] An embodiment described herein may include a compound of Formula (I) and forms thereof, wherein a carbon atom may have from 1 to 3 hydrogen atoms optionally replaced with deuterium. [00333] One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.
[00334] As used herein, the term "solvate" means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, "solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
[00335] One or more compounds described herein may optionally be converted to a solvate. Preparation of solvates is generally known. A typical, non-limiting process involves dissolving a compound in a desired amount of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example infrared spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
[00336] As used herein, the term "hydrate" means a solvate wherein the solvent molecule is water.
[00337] Polymorphic crystalline and amorphous forms of the compounds of Formula (I), and of the salts, solvates, esters and prodrugs of the compounds of Formula (I), are further intended to be included in the scope of the compounds described herein.
METHODS FOR DETERMINING WHICH COMPOUNDS OF FORMULA (I)
MODULATE THE EXPRESSION OF CERTAIN GENES
[00338] Provided herein are methods for determining whether a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one, two, three or more genes. In certain embodiments, the gene is not the SMN2 gene. In certain embodiments, provided herein are methods for determining whether a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one, two, three or more of the genes in, by way of nonlimiting example, Table 1 , infra. In other embodiments, provided herein are methods for determining whether a compound of Formula (I) or a form thereof modulates the amount of one, two, three or more RNA transcripts (e.g., pre -mRNA or mRNA transcripts or isoforms thereof) of one, two, three or more of the genes in, by way of nonlimiting example, Table 1, infra.
[00339] In one embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript, comprising: (a) contacting a cell(s) with a compound of Formula (I) or a form thereof, and (b) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell(s) with a compound of Formula (I) or a form thereof, (b) contacting a second cell(s) with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first cell(s) and the second cell(s); and (d) comparing the amount of the RNA transcript produced by the first cell(s) to the amount of the RNA transcript expressed by the second cell(s), wherein an alteration in the amount of the RNA transcript produced by the first cell(s) relative to the amount of the RNA transcript produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain embodiments, the contacting of the cell(s) with the compound occurs in cell culture. In other embodiments, the contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject. In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1 or Table 2, infra, is measured. In some embodiments, the amount of 1, 2, 3 or more splice variants of an RNA transcript encoded by a gene in Table 1 or Table 2, infra, is measured. In other embodiments, the amount of 1, 2, 3 or more splice variants of RNA transcripts encoded by 1, 2, 3, 4 or more genes in Table 1 or Table 2, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00340] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; and (b) determining the amount of the two or more RNA transcript splice variants produced by the cell(s), wherein an alteration in the amount of the two or more RNA transcript in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript.
[00341] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) isolating two or more RNA transcript splice variants from the cell(s) after a certain period of time; and (c) determining the amount of the two or more RNA transcript splice variants produced by the cell(s), wherein an alteration in the amount of the two or more RNA transcript in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising (a) culturing a first cell(s) in the presence of a compound of Formula (I) or a form thereof; (b) culturing a second cell(s) in the presence of a negative control (e.g., a vehicle control, such as PBS or DMSO); (c) isolating two or more RNA transcript splice variants produced by the first cell(s) and isolating two or more RNA transcript splice variants produced by the second cell(s); (d) determining the amount of the two or more RNA transcript splice variants produced by the first cell(s) and the second cell(s); and (e) comparing the amount of the two or more RNA transcript splice variants produced by the first cell(s) to the amount of the two or more RNA transcript splice variants produced by the second cell(s), wherein an alteration in the amount of the two or more RNA transcript splice variants produced by the first cell(s) relative to the amount of the two or more RNA transcript splice variants produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the aplicing of the RNA transcript. In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 , Table 2, or Table 4 infra. In certain embodiments, the splicing of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1, Table 2, or Table 4, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00342] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell-free system with a compound of Formula (I) or a form thereof, and (b) determining the amount of the RNA transcript produced by the cell- free system, wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell-free system with a compound of Formula (I) or a form thereof, (b) contacting a second cell-free system with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first cell-free system and the second cell- free system; and (d) comparing the amount of the RNA transcript produced by the first cell-free system to the amount of the RNA transcript expressed by the second cell-free system, wherein an alteration in the amount of the RNA transcript produced by the first cell- free system relative to the amount of the RNA transcript produced by the second cell-free system indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain embodiments, the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises purely synthetic RNA and nuclear extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract. In other embodiments, the cell-free system comprises purely synthetic RNA and whole cell extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract. In certain
embodiments, the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs). In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1 or Table 2, infra, is measured. In some embodiments, the amount of 1, 2, 3 or more splice variants of an RNA transcript encoded by a gene in Table 1 or Table 2, infra, is measured. In other
embodiments, the amount of 1, 2, 3 or more splice variants of RNA transcripts encoded by 1, 2, 3, 4 or more genes in Table 1 or Table 2, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00343] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a cell-free system with a compound of Formula (I) or a form thereof; and (b) determinging the amount of two or more RNA transcript splice variants produced by the cell-free system, wherein an alteration in the amount of the two or more RNA transcript splice variants in the presence of the compound relative to the amount of the two or more RNA transcript splice variants in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first cell-free system with a compound of Formula (I) or a form thereof; (b) contacting a second cell-free system with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of two or more RNA transcript splice variants produced by the first cell-free system and the second cell-free system; and (d) comparing the amount of the two or more RNA transcript splice variants produced by the first cell-free system to the amount of the RNA transcript expressed by the second cell-free system, wherein an alteration in the amount of the two or more RNA transcript splice variants produced by the first cell-free system relative to the amount of the two or more RNA transcript splice variants produced by the second cell-free system indicates that the compound of Formula (I) or a form thereof modulates the aplicing of the RNA transcript. In certain embodiments, the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors. In other embodiments, the cell-free system comprises purely synthetic RNA and nuclear extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract. In other embodiments, the cell-free system comprises purely synthetic RNA and whole cell extract. In other embodiments, the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract. In certain
embodiments, the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs). In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene Table 1, Table 2, or Table 4, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1, Table 2, or Table 4, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00344] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) isolating the RNA transcript from the cell(s) after a certain period of time; and (c) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising (a) culturing a first cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) culturing a second cell(s) in the presence of a negative control (e.g., a vehicle control, such as PBS or DMSO); (c) isolating the RNA transcript produced by the first cell(s) and isolating the RNA transcript produced by the second cell(s); (d) determining the amount of the RNA transcript produced by the first cell(s) and the second cell(s); and (e) comparing the amount of the RNA transcript produced by the first cell(s) to the amount of the RNA transcript produced by the second cell(s), wherein an alteration in the amount of the RNA transcript produced by the first cell(s) relative to the amount of the RNA transcript produced by the second cell(s) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1 or Table 2, infra, is measured. In some embodiments, the amount of 1, 2, 3 or more splice variants of an RNA transcript encoded by a gene in Table 1 or Table 2, infra, is measured. In other
embodiments, the amount of 1, 2, 3 or more splice variants of RNA transcripts encoded by 1, 2, 3, 4 or more genes in Table 1 or Table 2, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00345] In certain embodiments, the method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript) is described in Example 1 , infra.
[00346] In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease. In specific embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease associated with an aberrant amount of an RNA transcript(s) for a particular gene(s), e.g., a gene in Table 1 or Table 2, infra. In some specific embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject with a disease associated with an aberrant amount of an isoform(s) of a particular gene(s), e.g., a gene in Table 1 or Table 2, infra. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a fibroblast (e.g., GM03813 fibroblasts), an immune cell (e.g., a T cell, B cell, natural killer cell, macrophage), or a muscle cell. In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell.
[00347] In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cell line derived from a subject with a disease. In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line known to have aberrant RNA transcript levels for a particular gene(s), e.g., a gene in Table 1 or Table 2, infra. In specific embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line derived from a subject with a disease known to have aberrant RNA transcript levels for a particular gene(s), e.g., a gene in Table 1 or Table 2, infra. In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell line. In some specific embodiments, the cell(s) contacted or culured with the compound of Formula (I) or a form thereof is from a cell line derived from a subject with a disease known to have an aberrant amount of an RNA isoform(s) and/or protein isoform(s) of a particular gene(s), e.g., a gene in Table 1 or Table 2, infra. Non-limiting examples of cell lines include 293, 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR- L23, COS, COV-434, CML Tl, CMT, CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL- 60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KGl, KYOl, LNCap, Ma-Mel, MC-38, MCF-7, MCF-IOA, MDA-MB-231, MDA-MB- 468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-IA, NCI-H69, NIH-3T3, NALM-1, NS0, NW-145, OPCN, OPCT,, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN- 5F, RMA, Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vera, VERY, W138, WM39, WT-49, X63, YAC-1, or YAR cells. In one embodiment, the cells are from a patient.
[00348] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a tissue sample with a compound of Formula (I) or a form thereof; and (b) determining the amount of the RNA transcript produced by the tissue sample, wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) contacting a first tissue sample with a compound of Formula (I) or a form thereof, (b) contacting a second tissue sample with a negative control (e.g., a vehicle control, such as PBS or DMSO); and (c) determining the amount of the RNA transcript produced by the first tissue sample and the second tissue sample; and (d) comparing the amount of the RNA transcript produced by the first tissue sample to the amount of the RNA transcript produced by the second tissue sample, wherein an alteration in the amount of the RNA transcript produced by the first tissue sample relative to the amount of the RNA transcript produced by the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. Any tissue sample containing cells may be used in the accordance with these methods. In certain embodiments, the tissue sample is a blood sample, a skin sample, a muscle sample, or a tumor sample. Techniques known to one skilled in the art may be used to obtain a tissue sample from a subject. In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1 or Table 2, infra, is measured. In some embodiments, the amount of 1, 2, 3 or more splice variants of an RNA transcript encoded by a gene in Table 1 or Table 2, infra, is measured. In other embodiments, the amount of 1, 2, 3 or more splice variants of RNA transcripts encoded by 1, 2, 3, 4 or more genes in Table 1 or Table 2, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00349] In some embodiments, a dose-response assay is performed. In one embodiment, the dose response assay comprises: (a) contacting a cell(s) with a concentration of a compound of Formula (I) or a form thereof; (b) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript; (c) repeating steps (a) and (b), wherein the only experimental variable changed is the concentration of the compound or a form thereof; and (d) comparing the amount of the RNA transcript produced at the different concentrations of the compound or a form thereof. In another embodiment, the dose response assay comprises: (a) culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof, (b) isolating the RNA transcript from the cell(s) after a certain period of time; (c) determining the amount of the RNA transcript produced by the cell(s), wherein an alteration in the amount of the RNA transcript in the presence of the compound relative to the amount of the RNA transcript in the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO) indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript; (d) repeating steps (a), (b), and (c), wherein the only experimental variable changed is the concentration of the compound or a form thereof; and (e) comparing the amount of the RNA transcript produced at the different concentrations of the compound or a form thereof. In another embodiments, the dose-response assay comprises: (a) contacting each well of a microtiter plate containing cells with a different concentration of a compound of Formula (I) or a form thereof; (b) determining the amount of an RNA transcript produced by cells in each well; and (c) assessing the change of the amount of the RNA transcript at the different concentrations of the compound or form thereof.
[00350] In one embodiment, the dose response assay comprises: (a) contacting a cell(s) with a concentration of a compound of Formula (I) or a form thereof, wherein the cells are within the wells of a tissue culture container (e.g., a 96-well plate) at about the same density within each well, and wherein the cells are contacted with different concentrations of compound in different wells; (b) isolating the RNA from said cells in each well; (c) determining the amount of the RNA transcript produced by the cell(s) in each well; and (d) assessing change in the amount of the RNA transcript in the presence of one or more concentrations of compound relative to the amount of the RNA transcript in the presence of a different concentration of the compound or the absence of the compound or the presence of a negative control (e.g., a vehicle control such as PBS or DMSO).
[00351] In certain embodiments, the contacting of the cell(s) with the compound occurs in cell culture. In other embodiments, the contacting of the cell(s) with the compound occurs in a subject, such as a non-human animal subject. In specific embodiments, the RNA transcript is an R A transcript encoded by a gene in Table 1 or Table 2, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1 or Table 2, infra, is measured. In some embodiments, the amount of 1, 2, 3 or more splice variants of an RNA transcript encoded by a gene in Table 1 or Table 2, infra, is measured. In other embodiments, the amount of 1, 2, 3 or more splice variants of RNA transcripts encoded by 1, 2, 3, 4 or more genes in Table 1 or Table 2, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
[00352] In certain embodiments, a dose-response assay is performed as described in Example 2, infra.
[00353] In certain embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a compound of Formula (I) or a form thereof, or a negative control for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In other embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a compound of Formula (I) or a form thereof, or a negative control for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.
[00354] In certain embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.01 μΜ, 0.05 μΜ, 1 μΜ, 2 μΜ, 5 μΜ, 10 μΜ, 15 μΜ, 20 μΜ, 25 μΜ, 50 μΜ, 75 μΜ, 100 μΜ, or 150 μΜ. In other embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 175 μΜ, 200 μΜ, 250 μΜ, 275 μΜ, 300 μΜ, 350 μΜ, 400 μΜ, 450 μΜ, 500 μΜ, 550 μΜ 600 μΜ, 650 μΜ, 700 μΜ, 750 μΜ, 800 μΜ, 850 μΜ, 900 μΜ, 950 μΜ or 1 mM. In some embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, or a tissue sample is contacted with a certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is between 0.01 μΜ to 0.1 μΜ, 0.1 μΜ to 1 μΜ, 1 μΜ to 50 μΜ, 50 μΜ to 100 μΜ, 100 μΜ to 500 μΜ, 500 μΜ to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM.
[00355] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an R A transcript (e.g., an mR A transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a subject (in certain embodiments, a non-human animal); and (b) determining the amount of the RNA transcript in a sample obtained from the subject, wherein an alteration in the amount of the RNA transcript measured in the sample from the subject administered the compound or form thereof relative to the amount of the RNA transcript in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a first subject (in certain embodiments, a non-human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in certain embodiments, a non-human animal) of the same species as the first subject; and (c) determining the amount of the RNA transcript in a first tissue sample from the first subject and the amount of the RNA transcript in the second tissue sample from the second subject; and (d) comparing the amount of the RNA transcript in the first tissue sample to the amount of the RNA transcript in the second tissue sample, wherein an alteration in the amount of the RNA transcript in the first tissue sample relative to the amount of the RNA transcript in the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the amount of the RNA transcript. In certain embodiments, a compound of Formula (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In some embodiments, a single dose of a compound of Formula (I) or a form thereof is administered to a subject in accordance with the methods described herein. In other embodiments, 2, 3, 4 , 5 or more doses of a compound of Formula (I) is administered to a subject in accordance with the methods described herein. In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1 or Table 2, infra, is measured. In some embodiments, the amount of 1, 2, 3 or more splice variants of an RNA transcript encoded by a gene in Table 1 or Table 2, infra, is measured. In other embodiments, the amount of 1, 2, 3 or more splice variants of RNA transcripts encoded by 1, 2, 3, 4 or more genes in Table 1 or Table 2, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured. In specific embodiments, the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.
[00356] In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a subject (in certain embodiments, a non-human animal); and (b) determining the amount of two or more RNA transcript splice variants in a sample obtained from the subject, wherein an alteration in the amount of the two or more RNA transcript splice variants measured in the sample from the subject administered the compound or form thereof relative to the amount of the two or more RNA transcript splice variants in a sample from the subject prior to administration of the compound or form thereof or a sample from a different subject from the same species not administered the compound or form thereof indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In another embodiment, provided herein is a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript (e.g., an mRNA transcript), comprising: (a) administering a compound of Formula (I) or a form thereof to a first subject (in certain embodiments, a non- human animal); (b) administering a negative control (e.g., a pharmaceutical carrier) to a second subject (in certain embodiments, a non-human animal) of the same species as the first subject; and (c) determining the amount of two or more RNA transcript splice variants in a first tissue sample from the first subject and the amount of two or more RNA transcript splice variants in the second tissue sample from the second subject; and (d) comparing the amount of the two or more RNA transcript splice variants in the first tissue sample to the amount of the two or more RNA transcript splice variants in the second tissue sample, wherein an alteration in the amount of the two or more RNA transcript splice variants in the first tissue sample relative to the amount of the two or more RNA transcript splice variants in the second tissue sample indicates that the compound of Formula (I) or a form thereof modulates the splicing of the RNA transcript. In certain embodiments, a compound of Formula (I) or form thereof is administered to a subject at a dose of about 0.001 mg/kg/day to about 500 mg/kg/day. In some embodiments, a single dose of a compound of Formula (I) or a form thereof is administered to a subject in accordance with the methods described herein. In other embodiments, 2, 3, 4 , 5 or more doses of a compound of Formula (I) is administered to a subject in accordance with the methods described herein. In specific embodiments, the RNA transcript is an RNA transcript encoded by a gene in Table 1 , Table 2, or Table 3, infra. In certain embodiments, the amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more RNA transcripts encoded by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 or more of the genes listed in Table 1, Table 2, or Table 3, infra, is measured. In certain embodiments, the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured. In specific embodiments, the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.
[00357] In some embodiments, the compound of Formula (I) or a form thereof that is contacted or cultured with a cell(s) or a tissue sample, or administered to a subject is a compound of Formula (la) and Formula (lb). In some embodiments, the compound of Formula (I) or a form thereof that is contacted or cultured with a cell(s) or a tissue sample, or administered to a subject is a compound described herein.
[00358] Techniques known to one skilled in the art may be used to determine the amount of an RNA transcript(s). In some embodiments, the amount of one, two, three or more RNA transcripts is measured using deep sequencing, such as ILLUMINA® RNASeq, ILLUMINA® next generation sequencing (NGS), ION TORRENTTM RNA next generation sequencing, 454TM pyrosequencing, or Sequencing by Oligo Ligation Detection (SOLIDTM). In other embodiments, the amount of multiple RNA transcripts is measured using an exon array, such as the GENECHIP® human exon array. In certain embodiments, the amount of one, two, three or more RNA transcripts is determined by RT-PCR. In other embodiments, the amount of one, two, three or more RNA transcripts is measured by RT-qPCR. Techniques for conducting these assays are known to one skilled in the art.
[00359] In some embodiments, a statistical analysis or other analysis is performed on data from the assay utilized to measure an RNA transcript. In certain embodiments, a student t-test statistical analysis is performed on data from the assay utilized to measure an RNA transcript to determined those RNA transcripts that have an alternation in amount in the presence of the compound relative to the amount in the absence of the compound or presence of a negative control. In specific embodiments, the student t-test value of those RNA transcripts with the alternation is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%. In some specific embodiments, p value of those RNA transcripts with the alternation is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%. In certain specific embodiments, the student t-test and p values of those RNA transcripts with the alteration are 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1% and 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%), respectively.
[00360] In certain embodiments, a further analysis is performed to determine how the compound of Formula (I) or a form thereof is changing the amount of an RNA transcript(s). In specific embodiments, a further analysis is performed to determine if an alternation in the amount of an RNA transcript(s) in the presence of a compound of Formula (I) or a form thereof relative the amount of the RNA transcript(s) in the absence of the compound or a form thereof, or the presence of a negative control is due to changes in transcription, splicing, and/or stability of the RNA transcript(s). Techniques known to one skilled in the art may be used to determine whether a compound of Formula (I) or a form thereof changes, e.g., the transcription, splicing and/or stability of an R A transcript(s).
[00361] In certain embodiments, the stability of one or more RNA transcripts is determined by serial analysis of gene expression (SAGE), differential display analysis (DD), RNA arbitrarily primer (RAP)-PCR, restriction endonuclease-lytic analysis of differentially expressed sequences (READS), amplified restriction fragment-length polymorphism (ALFP), total gene expression analysis (TOGA), RT-PCR, RT-qPCR, high-density cDNA filter hybridization analysis
(HDFCA), suppression subtractive hybridization (SSH), differential screening (DS), cDNA arrays, oligonucleotide chips, or tissue microarrays. In other embodiments, the stability of one or more RNA transcripts is determined by Northern blots, RNase protection, or slot blots.
[00362] In some embodiments, the transcription in a cell(s) or tissue sample is inhibited before (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours before) or after (e.g., 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or 72 hours after) the cell or the tissue sample is contacted or cultured with an inhibitor of transcription, such as a-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D. In other embodiments, the transcription in a cell(s) or tissue sample is inhibited with an inhibitor of transcription, such as a-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D, while the cell(s) or tissue sample is contacted or cultured with a compound of Formula (I) or a form thereof.
[00363] In certain embodiments, the level of transcription of one or more RNA transcripts is determined by nuclear run-on assay or an in vitro transcription initiation and elongation assay. In some embodiments, the detection of transcription is based on measuring radioactivity or fluorescence. In some embodiments, a PCR-based amplification step is used.
[00364] In certain embodiments, the amount of alternatively spliced forms of the RNA transcripts of a particular gene, e.g., a gene in Table 1 or Table 2, infra, are measured to see if there is an alteration in the amount of one, two or more alternatively spliced forms of the RNA transcripts of the gene. In some embodiments, the amount of an isoform(s) encoded by a particular gene, e.g., a gene in Table 1 or Table 2, infra, are measured to see if there is an alteration in the amount of the isoform(s). In certain embodiments, the levels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, or northern blotting. In other embodiments, sequence-specific techniques may be used to detect the levels of an individual spliceoform. In certain embodiments, splicing is measured in vitro using nuclear extracts. In some embodiments, detection is based on measuring radioactivity or fluorescence. Techniques known to one skilled in the art may be used to measure alterations in the amount of alternatively spliced forms of an R A transcript of a gene and alterations in the amount of an isoform encoded by a gene.
PHARMACEUTICAL COMPOSITIONS AND MODES OF ADMINISTRATION
[00365] When administered to a patient, a compound of Formula (I) or a form thereof is preferably administered as a component of a composition that optionally comprises a
pharmaceutically acceptable carrier, excipient or diluent. The composition can be administered orally, or by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa) and may be administered together with another biologically active agent.
Administration can be systemic or local. Various delivery systems are known, e.g.,
encapsulation in liposomes, microparticles, microcapsules, capsules, and can be used to administer the compound.
[00366] Methods of administration include, but are not limited to, parenteral, intradermal, intramuscular, intraocular, intratumoral, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, ocularly, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. The mode of
administration is left to the discretion of the practitioner. In most instances, administration will result in the release of a compound into the bloodstream, tissue or cell(s). In a specific embodiment, a compound is administered orally.
[00367] The amount of a compound of Formula (I) or a form thereof that will be effective in the treatment of a disease resulting from an aberrant amount of mRNA transcripts depends, e.g., on the route of administration, the disease being treated, the general health of the subject, ethnicity, age, weight, and gender of the subject, diet, time, and the severity of disease progress, and should be decided according to the judgment of the practitioner and each patient's or subject's circumstances.
[00368] In specific embodiments, an "effective amount" in the context of the administration of a compound of Formula (I) or a form thereof, or composition or medicament thereof refers to an amount of a compound of Formula (I) or a form thereof to a patient which has a therapeutic effect and/or beneficial effect. In certain specific embodiments, an "effective amount" in the context of the administration of a compound of Formula (I) or a form thereof, or composition or medicament thereof to a patient results in one, two or more of the following effects: (i) reduces or ameliorates the severity of a disease; (ii) delays onset of a disease; (iii) inhibits the progression of a disease; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life of a subject; (viii) reduces the number of symptoms associated with a disease; (ix) reduces or ameliorates the severity of a symptom(s) associated with a disease; (x) reduces the duration of a symptom associated with a disease associated; (xi) prevents the recurrence of a symptom associated with a disease; (xii) inhibits the development or onset of a symptom of a disease; and/or (xiii) inhibits of the progression of a symptom associated with a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to restore the amount of a R A transcript of a gene (e.g., a gene in Table 1 or Table 2, infra) to the amount of the RNA transcript detectable in healthy patients or cells from healthy patients. In other embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to restore the amount an RNA isoform and/or protein isoform of gene (e.g., a gene in Table 1 or Table 2, infra) to the amount of the RNA isoform and/or protein isoform detectable in healthy patients or cells from healthy patients.
[00369] In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to decrease the aberrant amount of an RNA transcript of a gene (e.g., a gene in Table 1 or Table 2, infra) which associated with a disease. In certain
embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to decrease the amount of the aberrant expression of an isoform of a gene (e.g., a gene in Table 1 or Table 2, infra). In some embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to result in a substantial change in the amount of an RNA transcript (e.g., mRNA transcript), alternative splice variant or isoform.
[00370] In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an RNA transcript (e.g., an mRNA transcript) of gene (e.g., a gene in Table 1 or Table 2, infra) which is beneficial for the prevention and/or treatment of a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an alternative splice variant of an R A transcript of gene (e.g., a gene in Table 1 or Table 2, infra) which is beneficial for the prevention and/or treatment of a disease. In certain embodiments, an effective amount of a compound of Formula (I) or a form thereof is an amount effective to increase or decrease the amount of an isoform of gene (e.g., a gene in Table 1 or Table 2, infra) which is beneficial for the prevention and/or treatment of a disease. Non-limiting examples of effective amounts of a compound of Formula (I) or a form thereof are described herein.
[00371] For example, the effective amount may be the amount required to prevent and/or treat a disease associated with the aberrant amount of an mRNA transcript of gene (e.g., a gene in Table 1 or Table 2, infra) in a human subject.
[00372] In general, the effective amount will be in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day for a patient having a weight in a range of between about 1 kg to about 200 kg. The typical adult subject is expected to have a median weight in a range of between about 70 and about 100 kg.
[00373] Within the scope of the present description, the "effective amount" of a compound of Formula (I) or a form thereof for use in the manufacture of a medicament, the preparation of a pharmaceutical kit or in a method for preventing and/or treating a disease in a human subject in need thereof, is intended to include an amount in a range of from about 0.001 mg to about 35,000 mg.
[00374] The compositions described herein are formulated for administration to the subject via any drug delivery route known in the art. Non-limiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.
[00375] Embodiments described herein include the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition. In a specific embodiment, described herein is the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition for preventing and/or treating a disease in a human subject in need thereof comprising administering an effective amount of a compound of Formula (I) or a form thereof in admixture with a pharmaceutically acceptable carrier, excipient or diluent. In a specific embodiment, the human subject is a patient with a disease associated with the aberrant amount of an mRNA transcript(s). [00376] A compound of Formula (I) or a form thereof may optionally be in the form of a composition comprising the compound or a form thereof and an optional carrier, excipient or diluent. Other embodiments provided herein include pharmaceutical compositions comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In a specific embodiment, the pharmaceutical compositions are suitable for veterinary and/or human administration. The pharmaceutical compositions provided herein can be in any form that allows for the composition to be administered to a subject.
[00377] In a specific embodiment and in this context, the term "pharmaceutically acceptable carrier, excipient or diluent" means a carrier, excipient or diluent approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term
"carrier" refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a specific carrier for intravenously administered pharmaceutical compositions. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
[00378] Typical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and non limiting examples of suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient and the specific active ingredients in the dosage form. Further provided herein are anhydrous pharmaceutical compositions and dosage forms comprising one or more compounds of Formula (I) or a form thereof as described herein. The compositions and single unit dosage forms can take the form of solutions or syrups (optionally with a flavoring agent), suspensions (optionally with a flavoring agent), emulsions, tablets (e.g., chewable tablets), pills, capsules, granules, powder (optionally for reconstitution), taste-masked or sustained-release formulations and the like.
[00379] Pharmaceutical compositions provided herein that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets, caplets, capsules, granules, powder, and liquids. Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.
[00380] Examples of excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
METHODS OF MODULATING THE AMOUNT OF RNA TRANSCRIPTS ENCODED BY CERTAIN GENES
[00381] In one aspect, provided herein is a method for modulating the amount of one or more RNA transcripts (e.g. , pre-mRNA or mRNA transcripts or isoforms thereof) of one or more genes, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one
embodiment, provided herein is a method for modulating the amount of one, two or more RNA transcripts (e.g. , pre -mRNA or mRNA transcripts or isoforms thereof) of one, two or more genes in Table 1 or Table 2, infra, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In another embodiment, provided herein is a method for modulating the amount of one, two or more alternatively spliced variants of a gene in Table 1 or Table 2, infra, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In certain embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture. In other embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in a subject, such as a non-human animal or a human.
[00382] In another aspect, provided herein is a method for modulating the amount of one or more RNA isoforms encoded by one or more genes, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In some embodiments, the RNA isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for modulating the amount of one or more RNA isoforms of one or more genes in Table 1 or Table 2, infra, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In certain embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture. In other embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in a subject, such as a non-human animal or a human.
[00383] In another aspect, provided herein is a method for modulating the amount of one or more protein isoforms encoded by one or more genes, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In some embodiments, the protein isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for modulating the amount of one or more protein isoforms of one or more genes in Table 1 or Table 2, infra, comprising contacting a compound of Formula (I) or a form thereof with a cell(s). In certain embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture. In other embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in a subject, such as a non-human animal or a human.
[00384] In another aspect, provided herein is a method for modulating the amount of one or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one or more genes, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a methods for modulating the amount of one, two or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one, two or more genes in Table 1 or Table 2, infra, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In another embodiment, provided herein is a method for modulating the amount of one, two or more alternatively spliced variants of a gene in Table 1 or Table 2, infra, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. .
[00385] In another aspect, provided herein is a method for modulating the amount of one or more RNA isoforms encoded by one or more genes, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In some embodiments, the RNA isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for modulating the amount of one or more RNA isoforms of one or more genes in Table 1 or Table 2, infra, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In certain embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture. In other embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in a subject, such as a non-human animal or a human. [00386] In another aspect, provided herein is a method for modulating the splicing of one or more RNA transcripts encoded by one or more genes, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for modulating the amount of one or more RNA transcript splice variants of one or more genes in Table 1, Table 2, or Table 3, infra, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In certain embodiments, the compound upregulates one, two, or more splice variants encoded by the genes identified in Table 3 as upregulated. In certain embodiments, the compound down-regulates one, two, or more splice variants encoded by the genes identified in Table 3 as down-regulated. In specific embodiments, the compound upregulates one or more splice variants encoded by a gene(s) in Table 1, Table 2, or Table 3 and down-regulates a corresponding alternative splice variant(s).
[00387] In certain embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture. In other embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in a subject, such as a non-human animal or a human.
[00388]
[00389] In another specific embodiment, provided herein is a method for down- regulating the splicing of one or more RNA transcripts (e.g., the genes in Table 1, Table 2, or Table 3) encoded by one or more genes comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In certain embodiments, the compound down-regulates one, two, or more of the genes identified in Table 3 as down-regulated.
[00390] In another aspect, provided herein is a method for modulating the amount of one or more protein isoforms encoded by one or more genes, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In some embodiments, the protein isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a methods for modulating the amount of one or more protein isoforms of one or more genes in Table 1 or Table 2, infra, comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof. In certain embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture. In other embodiments, the cell(s) is contacted with a compound of Formula (I) or a form thereof in a subject, such as a non-human animal or a human. [00391] In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is primary cell(s) or cell(s) from a cell line. In some embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a fibroblast(s), an immune cell(s), or a muscle cell(s). In certain embodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is associated with aberrant expression of a gene, e.g., a gene in Table 1 or Table 2. In some enbodiments, the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell. Non- limiting examples of cell lines include 293, 3T3, 4T1, 721, 9L, A2780, A172, A20, A253, A431, A-549, ALC, B16, B35, BCP-1, BEAS-2B, bEnd.3, BHK, BR 293, BT20, BT483, BxPC3, C2C12, C3H-10T1/2, C6/36, C6, Cal-27, CHO, COR-L23, COS, COV-434, CML Tl, CMT, CRL7030, CT26, D17, DH82, DU145, DuCaP, EL4, EM2, EM3, EMT6, FM3, H1299, H69, HB54, HB55, HCA2, HEK-293, HeLa, Hepalclc7, HL-60, HMEC, Hs578T, HsS78Bst, HT-29, HTB2, HUVEC, Jurkat, J558L, JY, K562, Ku812, KCL22, KG1, KYOl, LNCap, Ma-Mel, MC-38, MCF-7, MCF-IOA, MDA- MB-231, MDA-MB-468, MDA-MB-435, MDCK, MG63, MOR/0.2R, MONO-MAC 6, MRC5, MTD-1A, NCI-H69, NIH-3T3, NALM-1, NSO, NW-145, OPCN, OPCT,, PNT-1A, PNT-2, Raji, RBL, RenCa, RIN-5F, RMA, Saos-2, Sf21, Sf9, SiHa, SKBR3, SKOV-3, T2, T-47D, T84, THP1, U373, U87, U937, VCaP, Vera, VERY, W138, WM39, WT-49, X63, YAC-1, or YAR cells. In one embodiment, the cells are from a patient.
[00392] In certain embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof with a compound of Formula (I) or a form thereof for a period of 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 12 hours, 18 hours, 24 hours, 48 hours, 72 hours or more. In other embodiments described herein, the cell(s) is contacted or cultured with a compound of Formula (I) or a form thereof with a compound of Formula (I) or a form thereof for a period of 15 minutes to 1 hour, 1 to 2 hours, 2 to 4 hours, 6 to 12 hours, 12 to 18 hours, 12 to 24 hours, 28 to 24 hours, 24 to 48 hours, 48 to 72 hours.
[00393] In certain embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 0.01 μΜ, 0.05 μΜ, 1 μΜ, 2 μΜ, 5 μΜ, 10 μΜ, 15 μΜ, 20 μΜ, 25 μΜ, 50 μΜ, 75 μΜ, 100 μΜ, or 150 μΜ. In other embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 175 μΜ, 200 μΜ, 250 μΜ, 275 μΜ, 300 μΜ, 350 μΜ, 400 μΜ, 450 μΜ, 500 μΜ, 550 μΜ 600 μΜ, 650 μΜ, 700 μΜ, 750 μΜ, 800 μΜ, 850 μΜ, 900 μΜ, 950 μΜ or 1 mM. In some embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is 5 nM, 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, 100 nM, 150 nM, 200 nM, 250 nM, 300 nM, 350 nM, 400 nM, 450 nM, 500 nM, 550 nM, 600 nM, 650 nM, 700 nM, 750 nM, 800 nM, 850 nM, 900 nM, or 950 nM. In certain embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof, wherein the certain concentration is between 0.01 μΜ to 0.1 μΜ, 0.1 μΜ to 1 μΜ, 1 μΜ to 50 μΜ, 50 μΜ to 100 μΜ, 100 μΜ to 500 μΜ, 500 μΜ to 1 nM, 1 nM to 10 nM, 10 nM to 50 nM, 50 nM to 100 nM, 100 nM to 500 nM, 500 nM to 1000 nM. In certain embodiments described herein, the cell(s) is contacted or cultured with certain concentration of a compound of Formula (I) or a form thereof that results in a substantial change in the amount of an RNA transcript (e.g., an mRNA transcript), an alternatively spliced variant, or an isoform of a gene in Table 1 or Table 2, infra.
[00394] In another aspect, provided herein is a method for modulating the amount of one or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one or more genes, comprising administering to a subject (e.g., a non-human animal or a human) a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one
embodiment, provided herein is a methods for modulating the amount of one, two or more RNA transcripts (e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of one, two or more genes in Table 1 or Table 2, infra, comprising administering to a subject (e.g., a non-human animal or a human) an effective amount compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In another embodiment, provided herein is a method for modulating the amount of one, two or more alternatively spliced variants of a gene in Table 1 or Table 2, infra, comprising administering to a subject (e.g., a non-human animal or a human) an effective amount compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
[00395] In another aspect, provided herein is a method for modulating the amount of one or more RNA isoforms encoded by one or more genes, comprising administering to a subject (e.g., a non-human animal or a human) a compound of Formula (I) or a form thereof, or a
pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the RNA isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for modulating the amount of one, two or more RNA isoforms of one, two or more genes in Table 1 or Table 2, infra, comprising administering to a subject (e.g., a non-human animal or a human) an effective amount compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
[00396] In another aspect, provided herein is a method for modulating the splicing of one or more RNA transcripts encoded by one or more genes, comprising administering to a subject (e.g., a non-human animal or a human) a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for modulating the splicing of one, two or more RNA transcripts of one, two or more genes in Table 1, Table 2, or Table 3, infra, comprising administering to a subject (e.g., a non-human animal or a human) an effective amount compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In certain embodiments, the compound upregulates one, two, or more splice variants encoded by the genes identified in Table 3 as upregulated. In certain embodiments, the compound down-regulates one, two, or more splice variants encoded by the genes identified in Table 3 as down-regulated. In specific embodiments, the compound upregulates one or more splice variants encoded by a gene(s) in Table 1, Table 2, or Table 3 and down-regulates a corresponding alternative splice variant(s). [00397] In another aspect, provided herein is a method for modulating the amount of one or more protein isoforms encoded by one or more genes, comprising administering to a subject (e.g., a non-human animal or a human) a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the protein isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a methods for modulating the amount of one, two or more protein isoforms of one, two or more genes in Table 1 or Table 2, infra, comprising administering to a subject (e.g., a non-human animal or a human) an effective amount compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
[00398] In certain embodiments, a compound of Formula (I) or a form thereof contacted or cultured with a cell(s), or administered to a subject is a compound of Formula (la) and Formula (lb). In some embodiments, a compound of Formula (I) or a form thereof contacted or cultured with a cell(s), or administered to a subject is a compound described herein.
[00399] In certain embodiments, a compound of Formula (I) or a form thereof modulates the transcription of one, two, three or more genes in Table 1 or Table 2, infra. In some
embodiments, a compound of Formula (I) or a form thereof modulates the stability of an RNA transcript (e.g., mR A transcript) of one, two, three or more genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript of one, two, three or more genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof modulates the transport of an RNA transcript of one, two, three or more genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof modulates the sequestration of an RNA transcript of one, two, three or more genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof modulates the decay of an RNA transcript of one, two, three or more genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof modulates the translation of an RNA transcript of one, two, three or more genes in Table 1 or Table 2, infra.
[00400] In certain embodiments, a compound of Formula (I) or a form thereof may perturb the transcription process for a particular gene or multiple genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof may perturb the activity of a particular transcription factor that regulates transcription of a gene or multiple genes in Table 1 or Table 2, infra. In other embodiments, a compound of Formula (I) or a form thereof may perturb a component of the pre-mRNA splicing process. In other embodiments, a compound of Formula (I) or a form thereof may perturb interaction(s) between RNA transcript(s) of a gene(s) in Table 1 or Table 2, infra, and a protein(s) that stabilizes the transcript(s). ). In certain embodiments, a compound of Formula (I) or a form thereof may perturb a protein(s) that stabilizes an mRNA transcript(s) of a gene in Table 1 or Table 2, infra.
Table 1
Gene GenelD Example of Associated Function
ABI1 10006 cytoskeletal protein binding
ACKR3 57007 C-X-C chemokine receptor activity
ADAM9 8754 metalloendopeptidase activity
ALDH4A1 8659 aldehyde dehydrogenase activity
AMT 275 aminomethyltransferase activity
ANKMY1 5 1281 metal ion binding
ANKRD28 23243 protein binding
ANKZF1 55 139 protein binding
APAF1 317 cysteine -type endopeptidase activator activity involved in apoptotic process
APLP2 334 Possible regulation of hemostasis with inhibitory properties towards coagulation factors
ARHGAP8 23779 Rho GTPase activator activity
ARHGAP12 94134 GTPase activator activity
ARHGEF1 9138 Rho guanyl-nucleotide exchange factor activity
ARMC10 83787 regulation of growth
ATP1B3 483 sodium:potassium-exchanging ATPase activity
ATXN10 25814 identical protein binding
B3GNT8 374907 galactosyltransferase activity
B3GNTL1 146712 transferase activity, transferring glycosyl groups
BAIAP2 10458 cytoskeletal adaptor activity
BCAP31 10134 receptor binding
BCL6B 255877 negative regulation of transcription from RNA polymerase II promoter Gene GenelD Example of Associated Function
BCLAF1 9774 DNA binding
BPHL 670 hydrolase activity
BZW2 28969 nervous system development
C3orfl7 25871 integral to membrane
C5orf38 153571 extracellular region
Cl lorf73 5 1501 protein transporter activity, Hsp70 protein binding; specific nuclear import carrier for HSP70 proteins following heat-shock stress
CACNA1C 775 voltage-gated calcium channel activity
CAND1 55832 TBP-class protein binding
CAST 83 1 endopeptidase inhibitor activity
CBFA2T2 9139 sequence-specific DNA binding transcription factor activity
CD3EAP 10849 DNA-directed RNA polymerase activity
CD46 4179 complement binding
CECR1 5 1816 adenosine deaminase activity
CLK4 57396 protein serine/threonine/tyrosine kinase activity
CNOT1 23019 poly(A)-specific ribonuclease activity
COL5A2 1290 extracellular matrix structural constituent
COL6A2 1292 extracellular matrix structural constituent
CORIN 10699 serine-type endopeptidase activity
CPT1B 1375 carnitine O-palmitoyltransferase activity
CPT1C 126129 carnitine O-palmitoyltransferase activity
CREG2 200407 oxidoreductase activity
CREM 1390 sequence-specific DNA binding transcription factor activity
CRNKL1 5 1340 RNA binding
CRYZLl 9946 NADPH:quinone reductase activity
CUL4A 845 1 ubiquitin protein ligase binding
CYP3A5 1577 monooxygenase activity
DIAPH3 81624 Actin binding, Rho GTPase binding
DBNDD2 55861 protein binding
DCAF5 8816 protein ubiquitination
DCAF6 55827 ligand-dependent nuclear receptor transcription coactivator activity
DCST2 127579 integral to membrane Gene GenelD Example of Associated Function
DENND5A 23258 Guanine nucleotide exchange factor (GEF), possibly activates RAB6A and RAB39A and/or RAB39B, promotes exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into active GTP-bound form
DK 3 27122 Wnt receptor signaling pathway
DLAT 1737 dihydrolipoyllysine-residue acetyltransferase activity
DNAJC17 55 192 RNA binding
DNAJC7 7266 heat shock protein binding
DRD4 ;1815 dopamine neurotransmitter receptor activity
DTNBP1 84062 positive regulation of neurotransmitter secretion
DYNLRB2 83657 microtubule motor activity
ECI2 10455 dodecenoyl-CoA delta-isomerase activity
ENTPD6 955 guanosine-5'-triphosphate,3' -diphosphate diphosphatase activity
EPB41 2035 structural constituent of cytoskeleton
ERBB2IP 55914 ErbB-2 class receptor binding
ERC2 26059 protein binding
EYA3 2140 protein tyrosine/serine/threonine phosphatase activity
RAM 120 A 23196 RNA binding
FCGR2A 2212 IgG binding
FEZ1 9638 gamma-tubulin binding
FLNB 2317 actin binding
FN1 2335 extracellular matrix structural constituent
FOXM1 2305 sequence-specific DNA binding transcription factor activity
FOXP1 27086 sequence-specific DNA binding
FOXRED1 55572 oxidoreductase activity
GAL3ST2 64090 galactosylceramide sulfotransferase activity
GAL3ST3 189792 galactosylceramide sulfotransferase activity
GALC 2581 hydrolyzes galactose ester bonds of galactosylceramide,
galactosylsphingosine, lactosylceramide, and
monogalactosyldiglyceride
GGCT 79017 gamma-glutamylcyclotransferase activity
GIGYF2 26058 spinal cord motor neuron differentiation
GJB2 2706 gap junction channel activity
GNPDA1 10007 glucosamine-6-phosphate deaminase activity
GPI 2821 glucose-6-phosphate isomerase activity Gene GenelD Example of Associated Function
GPR88 541 12 G-protein coupled receptor activity
GPS2 2874 transcription corepressor activity
GRB10 2887 insulin receptor binding
GTF2I 2969 sequence-specific DNA binding transcription factor activity
HAGHL 84264 hydroxyacylglutathione hydrolase activity
HAUS4 154930 spindle assembly
HLA-A 3105 peptide antigen binding
HLA-B 3106 peptide antigen binding
HLA-C 3107 peptide antigen binding
HLTF 6596 helicase and E3 ubiquitin ligase activities, intrinsic ATP-dependent nucleosome-remodeling activity
HMBS 3145 hydroxymethylbilane synthase activity
HMGA1 3159 sequence-specific DNA binding transcription factor activity
HMHA1 23526 GTPase activator activity
HNRNPD 3184 RNA binding
HNR PK 3190 RNA polymerase II core promoter proximal region sequence-specific
DNA binding
HNR PUL1 1 1 100 RNA binding
HOGA1 1 12817 4-hydroxy-2-oxoglutarate aldolase activity
HVCN1 84329 voltage-gated cation channel activity
IL15RA 3601 cytokine receptor activity
INSL6 1 1 172 hormone activity
INTS3 165123 DNA repair
ITSN1 6453 guanyl-nucleotide exchange factor activity
KCNG2 26251 delayed rectifier potassium channel activity
KIAA1462 57608 cell adhesion
KRT18 3875 scaffold protein binding
LARP7 5 1574 RNA binding
LRBA 987 cytoplasmic membrane -bounded vesicle
LPJF1 55791 retinoic acid receptor binding
LYRM2 57226 mitochondrion
LZTS1 1 1 178 sequence-specific DNA binding transcription factor activity
MAP2K4 6416 protein kinase activity
MATR3 9782 RNA binding Gene GenelD Example of Associated Function
MBTD1 54799 transcription, DNA-dependent
MCL1 4170 protein channel activity
MECR 5 1 102 trans-2-enoyl-CoA reductase (NADPH) activity
MGR 1 23295 ubiquitin-protein ligase activity
MICB 4277 natural killer cell lectin-like receptor binding
MPI 435 1 mannose-6-phosphate isomerase activity
MY01B 4430 microfilament motor activity
NADK 165220 NAD+ kinase activity
NAV2 89797 helicase activity
NEURL4 84461 centriole
NFATC3 4775 sequence-specific DNA binding transcription factor activity
NFATC4 4776 sequence-specific DNA binding RNA polymerase II transcription factor activity
NR3C1 2908 glucocorticoid receptor activity
NREP 93 15 regulation of transforming growth factor beta receptor signaling pathway
NUMB 8650 Notch signaling pathway
OR1Q1 15813 1 olfactory receptor activity
OR2C1 4993 olfactory receptor activity
P2RX5 5026 purinergic nucleotide receptor activity
PALD1 27143 protein binding
PAPD4 167153 polynucleotide adenylltransferase activity; cytoplasmic poly(A) RNA polymerase adds successive AMP monomers to the 3 '-end of specific RNA transcripts
PDDC1 347862 extracellular region
PDXDC2P 283970 PDXDC1 pseudogene
PDXDC1 23042 Carboxy-lyase activity, pyridoxal phosphate binding
PELI3 246330 Toll signaling pathway
PHF16 9767 histone acetyltransferase complex
PHTF2 57157 transcription, DNA-dependent
PICALM 8301 1-phosphatidylinositol binding
PITPNB 23760 lipid binding protein, catalyzing transfer of Ptdlns and
phosphatidylcholine between membranes
PLEKHH1 57475 phospholipid binding
PP2D1 15 1649 catalytic activity Gene GenelD Example of Associated Function
PPHLN1 5 1535 keratinization
PREPL 95 S I serine-type endopeptidase activity
PSG8 440533 extracellular region
PSMD1 5707 enzyme regulator activity
PUS 10 150962 RNA binding
PYCR1 583 1 pyrroline-5-carboxylate reductase activity
RAB34 «3871 GTP binding
RBFOX3 146713 regulation of alternative mRNA splicing, via spliceosome
RBM33 155435 RNA binding
RCC1 1 104 Guanine-nucleotide releasing factor, promoting exchange of Ran- bound GDP by GTP, regulating onset of chromosome condensation in the S phase and nucleo-cytoplasmic transport, mitosis and the nuclear- envelope
RGS3 5998 GTPase activator activity
RIF1 55 183 telomere maintenance
RIPK1 8737 protein serine/threonine kinase activity
RPL3 6122 structural constituent of ribosome
RPN2 6185 dolichyl-diphosphooligosaccharide -protein glycotransferase activity
RTK 6242 GTPase inhibitor activity
RUSC1 23623 actin binding
SARNP 84324 transcription, DNA-dependent
SC5D 6309 C-5 sterol desaturase activity
SCRN1 9805 dipeptidase activity
SEC31A 22872 calcium-dependent protein binding
SGMS2 166929 sphingomyelin synthase activity
SIRPA 140885 SH3 domain binding
SLC22A1 6580 acetylcholine transmembrane transporter activity
SLC24A3 57419 calcium, potassium:sodium antiporter activity
SLC25A17 10478 ATP transmembrane transporter activity
SLC35E2B 728661 integral to membrane
SLC37A3 84255 transporter activity
SLC39A13 91252 zinc ion transmembrane transporter activity
SLC39A3 29985 zinc ion transmembrane transporter activity
SLIT1 6585 calcium ion binding
SLIT3 6586 calcium ion binding Gene GenelD Example of Associated Function
SLPI 6590 endopeptidase inhibitor activity
SMARCA4 6597 RNA polymerase II regulatory region sequence-specific DNA binding
SMARCE1 6605 transcription coactivator activity
SMN2 6607 spliceosomal complex, spliceosomal complex assembly, spliceosomal snRNP assembly
SNX14 5723 1 phosphatidylinositol binding
SPATS2L 26010 nucleolus
SPI1 6688 RNA polymerase II distal enhancer sequence-specific DNA binding
SRD5A2 6716 3-0X0-5 -alpha- steroid 4-dehydrogenase activity
SSFA2 6744 actin binding
STAT6 6778 RNA polymerase II core promoter sequence-specific DNA binding
STRN3 29966 sequence-specific DNA binding transcription factor activity, binding calmodulin in a calcium dependent manner, also possibly functioning as a scaffolding or signaling protein
SV2C 22987 transmembrane transporter activity
SYTL2 154843 phosphatidylserine binding
TARS 6897 threonine -tRNA ligase activity
TBC1D25 4943 Rab GTPase activator activity
TEX21P 441687 testis-expressed 21 pseudogene with assumed/tentative functions
TGFA 7039 epidermal growth factor receptor binding
TMEM150A 129303 catabolic process
TMEM254 80195 integral to membrane
TOP3B 8940 DNA topoisomerase activity
TRIM6 1 17854 zinc ion binding
TSC22D3 183 1 sequence-specific DNA binding transcription factor activity
TUSC3 7991 dolichyl-diphosphooligosaccharide -protein glycotransferase activity
TXLNG 55787 syntaxin binding
UBE3B 89910 ubiquitin-protein ligase activity
VPS29 5 1699 a component of the retromer complex, retrieving lysosomal enzyme receptors (IGF2R and M6PR) from endosomes to the trans-Golgi network and regulating transcytosis of the polymeric immunoglobulin receptor (plgR-pIgA)
WDR5 1 1091 histone methyltransferase activity (H3-K4 specific)
WRAP53 55 135 telomere formation via telomerase
WWTR1 25937 transcription coactivator activity Gene GenelD Example of Associated Function
ZKSCAN8 7745 sequence-specific DNA binding transcription factor activity
ZMYND11 10771 negative regulation of transcription from RNA polymerase II promoter
ZNF185 17739 zinc ion binding
ZNF512 84450 transcription, DNA-dependent
ZNF540 163255 j translation repressor activity, nucleic acid binding
ZNF542 147947 j transcription, DNA-dependent
ZNF619 285267 j transcription, DNA-dependent
Table 2
Gene GenelD Example(s) of Associated Disease or Disorder
ABI1 10006 Leukemia, Acute Myeloid Leukemia, Myeloid Leukemia, Acute
Leukemia, Colon Cancer, Gastric Cancer, Macular Degeneration, Acute Monocytic Leukemia, Monocytic Leukemia, Breast Cancer, Cblc, Hepatocellular Carcinoma, Noma
ADAM9 8754 Cone-rod Dystrophy 9, Alveolar Soft Part Sarcoma, Myeloma, Cone- rod Dystrophy, Skin Melanoma, Prostatitis, Pancreatitis, Pancreatic Cancer, Colon Cancer, Retinitis, Adenocarcinoma, Adenoiditis, Adenoid Cystic Carcinoma, Cataract, Retinal Degeneration,
Gastrointestinal Stromal Tumor, Wegener's Granulomatosis, Sarcoma, Melanoma, Myopathy, Prostate Adenocarcinoma, Alzheimer's Disease
ALDH4A1 8659 Hyperprolinemia Type 2, Hyperprolinemia, Acne, Tuberculosis,
Succinic Semialdehyde Dehydrogenase Deficiency, Gastric Cancer, Esophagitis, Adenocarcinoma, Mental Retardation, Esophageal Adenocarcinoma
AMT 275 Amt-related Glycine Encephalopathy, Glycine Encephalopathy,
Crohn's Disease, Spina Bifida, Tuberculosis, Autosomal Recessive Disease, Schizophrenia, Leukemia, Neural Tube Defects, Lung Cancer, Atypical Glycine Encephalopathy, Neonatal Glycine Encephalopathy, Infantile Glycine Encephalopathy
ANKRD28 23243 Leukemia, Myelodysplasia Syndromes
Gene GenelD Example(s) of Associated Disease or Disorder
APAF1 317 Leukemia, Amyotrophic Lateral Sclerosis, Neuronitis, Lateral
Sclerosis, Germ Cell Tumors, Parkinson's Disease, Pancreatic Cancer, Pancreatitis, Talipes Equinovarus, Dystrophinopathies,
Nonseminomatous Germ Cell Tumor, Acute Myeloid Leukemia, Hodgkin's Lymphoma, Ovarian Cancer, Myeloid Leukemia, Non- hodgkin Lymphoma, Multiple Myeloma, Chronic Myeloid Leukemia, Colon Cancer, Ischemia, Acute Lymphoblastic Leukemia, Gastric Cancer, Renal Cell Carcinoma, Transitional Cell Carcinoma,
Colorectal Cancer, Chronic Lymphocytic Leukemia, Anaplastic Large Cell Lymphoma, Myeloma, Lymphoblastic Leukemia, Acute
Leukemia, Kidney Cancer, Cerebritis, Non-small Cell Lung
Carcinoma, Cervicitis, Autism Spectrum Disorder, Oral Cancer, Brain Ischemia, Clubfoot, Clear Cell Renal Cell Carcinoma, Melanoma, Lung Cancer, Fibrosarcoma
j APLP2 334 : Alzheimer's disease, thrombosis, cerebritis, dementia, lissencephaly,
i amyloidosis, neuronitis, infertility, brain disease, neuroblastoma, breast i cancer, pancreatitis, endotheliitis, ataxia, spinocerebellar ataxia
1 ARHGAP8 23779 i Breast Cancer, Cervical Cancer, Cleft Lip, Cleft Palate, Cervicitis j ARHGAP12 94134 : Bladder-related disorders, for example, attenuated expression of
: mRNA associated with urothelial integrity in bladder pain syndrome, i Alzheimer's Disease
j ARHGEF1 9138 : Pancreatitis, Pancreatic Cancer, Spasticity, Lipoma, Scleroderma,
: Gitelman Syndrome, Poliomyelitis, Paralysis, Aagenaes Syndrome, i Skin Lipoma, Oculomotor Nerve Paralysis
j ARMC10 83787 : Nervous system related disorders; high expression in developing adult
: nervous system, hepatocellular carcinoma, otosclerosis, Meniere's : disease, Menieres disease, cloacogenic carcinoma
1 C3orfl7 25871 : Cancer, Fanconi's anemia, anemia
j C5or08 153571 : Hypertension
j (Ί l or 173 51501 i Glomerulonephritis, crescentic glomerulonephritis
1 CD46 4179 : Ear disorders, for example, splicing isoforms related to genetic
\ predisposition to otosclerosis, hematologic cancers (hematologic i malignancies), solid tissue cancers (solid tumors)
j CECRl 51816 : Heart diseases, for example, overexpression associated with cat eye
\ syndrome and related heart, kidney, and eye defects
1 CNOT1 23019 : Cancer, for example, depletion associated with breast cancer,
: cholangiocarcinoma, myocardial stunning
1 DIAPH3 81624 : Neuropathy, auditory neuropathy, benign epilepsy with centrotemporal
: spikes, prostate cancer, pancreatitis, prostatitis, sensorineural hearing : loss Gene GenelD Example(s) of Associated Disease or Disorder
DENND5A 23258 Stomatitis
FEZ1 9638 Nervous system disorders; for example, critical regulator of
dopaminergic neuron differentiation and release of dopamine, associated with regulation of neuronal microenvironment in
Parkinson's disease
FLNB 2317 Cancer, for example, hepatocelluar carcinoma biomarker
FN1 2335 Cancer, for example, associated with regulation of cell migration in ovarian cancer
FOXM1 2305 Pancreatitis, thyroiditis, gastric cancer, acute myeloid leukemia,
pancreatic cancer, ovarian cancer, leukemia, myeloid leukemia, meduUoblastoma, basal cell carcinoma, maturity-onset diabetes of the young, papilloma, colorectal cancer, non-small cell lung carcinoma, adenocarcinoma, diabetes mellitus, astrocytoma, insulinoma, achondroplasia, hemangioma, hyperglycemia, metabolic disorders, protein C deficiency, sclerosing hemangioma, pulmonary sclerosing hemangioma, central pontine myelinolysis, breast cancer, squamous cell carcinoma, endotheliitis, lung cancer, obesity, hepatocellular carcinoma, prostatitis, melanoma, B-cell lymphomas, hypoxia, esophagitis, neuroblastoma, diffuse large B-cell lymphoma, papillary thyroid carcinoma, pancreatic ductal adenocarcinoma, hepatitis, glioblastoma, retinitis, hepatitis B, laryngeal squamous cell carcinoma, neuronitis, laryngitis, anaplastic astrocytoma, asphyxiating thoracic dystrophy
GALC 2581 Krabbe disease, leukodystrophy, metachromatic leukodystrophy, lipid storage disease, infantile krabbe disease, chron's disease, neuropathy, neuronitis, motor neuron disease, hereditary spastic paraplegia, cerebritis, peripheral neuropathy, paraplegia, spasticity, Gaucher 's disease, blindness, lysosomal storage disease, gangliosidosis, farber lipogranulomatosis, lipogranulomatosis, open-angle glaucoma, primary open angle glaucoma, glaucoma, multiple sclerosis, hepatitis, squamous cell carcinoma, hematopoietic stem cell transplantation, late- infantile or juvenile krabbe disease, adult krabbe disease
GGCT 79017 Meningioma, osteosarcoma, tuberculosis, gestational diabetes,
leukemia, eczema, eczema herpeticum, myoblastoma
GPS2 2874 Metabolic disorders, for example, reduced expression associated with adipocyte inflammation linked to obesity
HAUS4 54930 Cancer Gene GenelD Example(s) of Associated Disease or Disorder
Ι Ι Ι .ΊΊ·" 6596 : Colon cancer, adenocarcinoma, colorectal cancer, adenoma, gastric
i cancer, squamous cell carcinoma, cervical squamous cell carcinoma, : cervical adenocarcinoma, endometrial adenocarcinoma, cervicitis, : gastric cardia adenocarcinoma, cervical cancer, esophagitis, laryngeal : squamous cell carcinoma, laryngitis, esophageal squamous cell : carcinoma
j HNRNPD 3184 : Developmental disorders, for example, microdeletion 4q21 syndrome j HNRNPUL1 11100 i Cancer
j IL15RA 3601 : Musculoskeletal disorders, for example, polymorphism associated with
i susceptibility to ossification of the posterior longitudinal ligament j (OPLL)
j MATR3 9782 : Musculoskeletal disorders, for example, component of nuclear matrix
i crucial for normal skeletal muscle structure and associated with distal i myopathy
MPI 4351 : Congenital disorders, for example, disorders of glycosylation with
i symptoms including liver fibrosis
j NEURL4 84461 : Autism spectrum disorders, for example, forms part of complex with
i E6AP, associated with Angelman syndrome
j NR3C1 2908 : Hypothalamic-pituatary-adrenal axis related disorders, for example
: genetic variant associated with neuroticism and hypothalamic- i pituatary-adrenal axis related disorders
j PAPD4 167153 : Sleeping sickness
PDXDC2P 283970 : PDXDC1 pseudogene
j PDXDC1 23042 : Carboxy-lyase activity, pyridoxal phosphate binding
j PHTF2 57157 : Cancer
j PITPNB 23760 i Obesity
PPHLN1 51535 : Nervous system disorders, for example, interacts with synphilin-1,
i mutations of which are implicated in Parkinson's disease, gastric : cancer, ichthyosis
j RAB34 83871 i Cancer, for example, a tumor-associated protein
j Rcci 1104 : Retinoblastoma, attention deficit hyperactivity disorder, vaccinia,
: lateral sclerosis, retinitis pigmentosa, retinitis, herpes simplex, raynaud i disease, anemia, Fanconi's anemia, retinitis pigmentosa 3
1 RGS3 5998 : Cancer, for example, high expression associated with blastic crisis of
: chronic myelogenous leukemia
j RPL3 6122 : Cancer
I RTKN 6242 : Nervous system disorders; for example, associated with regulation of
i neurite outgrowth and differentiation Gene GenelD Example(s) of Associated Disease or Disorder
SLC35E2B 728661 Cancer
SLC37A3 84255 Metabolic disorders, for example, associated with regulation of insulin secretion and congenital hyperinsulinism
SMN2 6607 Neuronitis, spinal muscular atrophy, muscular atrophy, adult spinal muscular atrophy, motor neuron disease, multifocal motor neuropathy, proximal spinal muscular atrophy, amyotrophic lateral sclerosis, lateral sclerosis, neuropathy, neuromuscular disease, Werdnig-Hoffman disease, spinal cord disease, autosomal recessive disease, prostate cancer, prostatitis, juvenile spinal muscular atrophy, spinal muscular atrophy 1
j SPATS2L 26010 i Nervous system disorders, for example, restless leg syndrome
j STAT6 6778 : Lung diseases, for example polymorphism associated with asthma j STRN3 29966 : Cerebritis, cerebral cavernous malformation, cavernous malformation,
: cerebral cavernous malformations 3, neuronitis
j TBC1D25 4943 : Cancer, mood disorders
j TEX21P 441687 \ pseudogene
1 VPS29 51699 : Down syndrome, paraplegia
j WRAP53 55135 i Cancer, for example breast cancer
j ZNF619 285267 i Cancer
Table 3. Examples of RNA transcripts encoded by genes who splicing may be modulated.
down spl j gene up spl j gene
PDXDC2P* STRN3
PDXDC1 APLP2
GGCT TEX21P*
SMN2 RCC1
PAPD4 FOXM1
Cl lorf73 VPS29
DIAPH3
DENND5A
HLTF
PPHLN1
GALC
PITPNB METHODS OF PREVENTING AND/OR TREATING DISEASES
[00401] In one aspect, presented herein are methods for preventing and/or treating a disease by modulating the amount of one or more RNA transcripts of one or more genes (e.g., a gene(s) in Table 1 or Table 2, supra), comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for preventing and/or treating a disease by modulating the amount of one or more RNA transcripts of a gene(s) in Table 1 or Table 2, supra, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
[00402] In another aspect, presented herein are methods for preventing and/or treating a disease in which there is aberrant expression of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra), comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, presented herein is a method for preventing and/or treating a disease in which there is aberrant expression of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof.
[00403] In another aspect, presented herein are methods for preventing and/or treating a disease which is associated with aberrant amount of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra), comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, presented herein is a method for preventing and/or treating a disease which is associated with an aberrant amount of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra), comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof.
[00404] In another aspect, presented herein are methods for preventing and/or treating a disease which is associated with a change in the amount of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra) is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the RNA transcript(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for preventing and/or treating a disease which is associated with an increase in the amount of an RNA transcript (e.g., an mRNA transcript) of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein is a method for preventing and/or treating a disease in which an decrease in the amount of an RNA transcript (e.g., an mRNA transcript) of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
[00405] In another aspect, presented herein are methods for preventing and/or treating a disease in which a change in the amount of a splice variant of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra) is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the splice variant(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for preventing and/or treating a disease in which an increase in the amount of a splice variant of an RNA transcript (e.g., an mRNA transcript) of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein is a method for preventing and/or treating a disease in which an decrease in the amount of a splice variant of an RNA transcript (e.g., an mRNA transcript) of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
[00406] In another aspect, presented herein are methods for preventing and/or treating a disease in which a change in the amount of an alternative splice variant of an RNA transcript (e.g., an mRNA transcript) of a gene(s) (e.g., a gene in Table 1 or Table 2, supra) is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the splice variant(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for preventing and/or treating a disease in which an increase in the amount of an alternative splice variant of an RNA transcript (e.g., an mRNA transcript) of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein is a method for preventing and/or treating a disease in which an decrease in the amount of an alternative splice variant of an RNA transcript (e.g., an mRNA transcript) of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a
pharmaceutically acceptable carrier, excipient or diluent.
[00407] In another aspect, presented herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more RNA isoforms of a gene(s) (e.g., a gene in Table 1 or Table 2, supra), is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the RNA isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for preventing and/or treating a disease in which an increase in the level of expression of one, two, three or more RNA isoforms of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein is a method for preventing and/or treating a disease in which an decrease in the level of expression of one, two, three or more R A isoforms of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
[00408] In another aspect, presented herein are methods for preventing and/or treating a disease in which a change in the level of expression of one, two, three or more protein isoforms of a gene(s) (e.g., a gene in Table 1 or Table 2, supra), is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof a compound of Formula (I) or a form thereof. In some embodiments, the protein isoform(s) is not encoded by the SMN2 gene. In one embodiment, provided herein is a method for preventing and/or treating a disease in which an increase in the level of expression of one, two, three or more protein isoforms of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent. In another embodiment, provided herein is a method for preventing and/or treating a disease in which an decrease in the level of expression of one, two, three or more protein isoforms of a gene(s) in Table 1 or Table 2, supra, is beneficial to the prevention and/or treatment of the disease, comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) or a form thereof, or a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient or diluent.
[00409] In some embodiments, the compound of Formula (I) or a form thereof that is administered to a subject is a compound of Formula (la) or Formula (lb). In some embodiments, the compound of Formula (I) or a form thereof that is administered to a subject is a compound described herein. [00410] In certain embodiments, a compound of Formula (I) or a form thereof modulates the transcription of one, two, three or more genes in Table 1 or Table 2, infra. In some
embodiments, a compound of Formula (I) or a form thereof modulates the stability of an RNA transcript (e.g., mR A transcript) of one, two, three or more genes in Table 1 or Table 2, infra. In certain embodiments, a compound of Formula (I) or a form thereof modulates the splicing of an RNA transcript of one, two, three or more genes in Table 1 or Table 2, infra.
[00411] In a specific embodiment, the methods for preventing a disease described herein prevent the onset or development of one or symptoms of the disease. In another embodiment, the methods for preventing a disease described herein prevent the recurrence of the disease or delays the recurrence of the disease. In another embodiment, the methods for treating a disease described herein has one, two or more of the effects: (i) reduce or ameliorates the severity of the disease; (ii) inhibit the progression of the disease; (iii) reduce hospitalization of a subject; (iv) reduce hospitalization length for a subject; (v) increase the survival of a subject; (vi) improve the quality of life of a subject; (vii) reduce the number of symptoms associated with the disease; (viii) reduce or ameliorates the severity of a symptom(s) associated with the disease; (ix) reduce the duration of a symptom(s) associated with the disease; (x) prevent the recurrence of a symptom associated with the disease; (xi) inhibit the development or onset of a symptom of the disease; and/or (xii) inhibit of the progression of a symptom associated with the disease.
[00412] In certain embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is a disease or disorder listed in Table 2. In certain
embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is a disease or disorder associated with a gene listed in Table 1. In specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is leukemia, acute myeloid leukemia, colon cancer, gastric cancer, macular degeneration, acute monocytic leukemia, breast cancer, combined methylmalonic aciduria and homocystinuria, cblC type, hepatocellular carcinoma, cone-rod dystrophy, alveolar soft part sarcoma, myeloma, skin melanoma, prostatitis, pancreatitis, pancreatic cancer, retinitis, adenocarcinoma, adenoiditis, adenoid cystic carcinoma, cataract, retinal degeneration, gastrointestinal stromal tumor, Wegener's granulomatosis, sarcoma, myopathy, prostate adenocarcinoma, Alzheimer's disease, hyperprolinemia, acne, tuberculosis, succinic
semialdehyde dehydrogenase deficiency, esophagitis, mental retardation, esophageal adenocarcinoma, glycine encephalopathy, Crohn's disease, spina bifida, tuberculosis, autosomal recessive disease, schizophrenia, neural tube defects, lung cancer, myelodysplasia syndromes, amyotropic lateral sclerosis, neuronitis, germ cell tumors, Parkinson's disease, talipes
equinovarus, dystrophinopathies, Hodgkin's lymphoma, ovarian cancer, non-Hodgkin's lymphoma, multiple myeloma, chronic myeloid leukemia, ischemia, acute lymphoblastic leukemia, renal cell carcinoma, transitional cell carcinoma, colorectal cancer, chronic
lymphocytic leukemia, anaplastic large cell lymphoma, kidney cancer, cerebritis, bladder related disorders, breast cancer, cervical cancer, cleft lip, cleft palate, cervicitis, spasticity, lipoma, scleroderma, Gitelman syndrome, poliomyelitis, paralysis, Aagenaes syndrome, or oculomotor nerve paralysis. In specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is basal cell carcinoma, goblet cell metaplasia, or a malignant glioma. In other specific embodiments, the disease or disorder prevented and/or treated in accordance with a method described herein is a cancer of the liver, breast, lung, prostate, cervix, uterus, colon, pancreas, kidney, stomach, bladder, ovary, or brain.
[00413] In certain embodiments, the disease prevented and/or treated in accordance with a method described herein is cancer amenable to treatment by upregulation or downregulation of a gene or isoform thereof as described herein. In specific embodiments, cancers that can be prevented and/or treated in accordance with a method described herein include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, esophagus, chest, bone, lung, kidney, colon, rectum or other gastrointestinal tract organs, stomach, spleen, skeletal muscle, subcutaneous tissue, prostate, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.
[00414] Specific examples of cancers that can be prevented and/or treated in accordance with the methods provided herein include, but are not limited to, the following: renal cancer, kidney cancer, glioblastoma multiforme, metastatic breast cancer; breast carcinoma; breast sarcoma; neurofibroma; neurofibromatosis; pediatric tumors; neuroblastoma; malignant melanoma;
carcinomas of the epidermis; leukemias such as but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia leukemias and myclodysplastic syndrome, chronic leukemias such as but not limited to, chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia; polycythemia vera; lymphomas such as but not limited to Hodgkin's disease, non-Hodgkin's disease; multiple myelomas such as but not limited to smoldering multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma and extramedullary plasmacytoma; Waldenstrom's
macroglobulinemia; monoclonal gammopathy of undetermined significance; benign monoclonal gammopathy; heavy chain disease; bone cancer and connective tissue sarcomas such as but not limited to bone sarcoma, myeloma bone disease, multiple myeloma, cholesteatoma-induced bone osteosarcoma, Paget' s disease of bone, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma; brain tumors such as but not limited to, glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglial tumor, acoustic neurinoma, craniopharyngioma, medulloblastoma, meningioma, pineocytoma, pineoblastoma, and primary brain lymphoma; breast cancer including but not limited to adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, Paget' s disease (including juvenile Paget' s disease) and inflammatory breast cancer; adrenal cancer such as but not limited to pheochromocytom and adrenocortical carcinoma; thyroid cancer such as but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer and anaplastic thyroid cancer; pancreatic cancer such as but not limited to, insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor, and carcinoid or islet cell tumor; pituitary cancers such as but limited to Cushing's disease, prolactin-secreting tumor, acromegaly, and diabetes insipius; eye cancers such as but not limited to ocular melanoma such as iris melanoma, choroidal melanoma, and cilliary body melanoma, and retinoblastoma; vaginal cancers such as squamous cell carcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and Paget' s disease; cervical cancers such as but not limited to, squamous cell carcinoma, and adenocarcinoma; uterine cancers such as but not limited to endometrial carcinoma and uterine sarcoma; ovarian cancers such as but not limited to, ovarian epithelial carcinoma, borderline tumor, germ cell tumor, and stromal tumor; cervical carcinoma; esophageal cancers such as but not limited to, squamous cancer, adenocarcinoma, adenoid cyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; stomach cancers such as but not limited to, adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading, diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; colon cancers; KRAS- mutated colorectal cancer; colon carcinoma; rectal cancers; liver cancers such as but not limited to hepatocellular carcinoma and hepatoblastoma, gallbladder cancers such as adenocarcinoma; cholangiocarcinomas such as but not limited to pappillary, nodular, and diffuse; lung cancers such as KRAS-mutated non-small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large-cell carcinoma and small-cell lung cancer; lung carcinoma; testicular cancers such as but not limited to germinal tumor, seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma, embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sac tumor), prostate cancers such as but not limited to, androgen-independent prostate cancer, androgen-dependent prostate cancer, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; penal cancers; oral cancers such as but not limited to squamous cell carcinoma; basal cancers; salivary gland cancers such as but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; pharynx cancers such as but not limited to squamous cell cancer, and verrucous; skin cancers such as but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, acral lentiginous melanoma; kidney cancers such as but not limited to renal cell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitional cell cancer (renal pelvis and/or uterer); renal carcinoma; Wilms' tumor; bladder cancers such as but not limited to transitional cell carcinoma, squamous cell cancer, adenocarcinoma, carcinosarcoma. In addition, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma and papillary
adeno carcinomas .
[00415] In certain embodiments cancers that can be prevented and/or treated in accordance with the methods provided herein include, the following: pediatric solid tumor, Ewing's sarcoma, Wilms tumor, neuroblastoma, neurofibroma, carcinoma of the epidermis, malignant melanoma, cervical carcinoma, colon carcinoma, lung carcinoma, renal carcinoma, breast carcinoma, breast sarcoma, metastatic breast cancer, HIV-related Kaposi's sarcoma, prostate cancer, androgen-independent prostate cancer, androgen-dependent prostate cancer, neurofibromatosis, lung cancer, non-small cell lung cancer, KRAS-mutated non-small cell lung cancer, malignant melanoma, melanoma, colon cancer, KRAS-mutated colorectal cancer, glioblastoma multiforme, renal cancer, kidney cancer, bladder cancer, ovarian cancer, hepatocellular carcinoma, thyroid carcinoma, rhabdomyosarcoma, acute myeloid leukemia, and multiple myeloma.
[00416] In certain embodiments, cancers and conditions associated therewith that are prevented and/or treated in accordance with the methods provided herein are breast carcinomas, lung carcinomas, gastric carcinomas, esophageal carcinomas, colorectal carcinomas, liver carcinomas, ovarian carcinomas, thecomas, arrhenoblastomas, cervical carcinomas, endometrial carcinoma, endometrial hyperplasia, endometriosis, fibrosarcomas, choriocarcinoma, head and neck cancer, nasopharyngeal carcinoma, laryngeal carcinomas, hepatoblastoma, Kaposi's sarcoma, melanoma, skin carcinomas, hemangioma, cavernous hemangioma, hemangioblastoma, pancreas carcinomas, retinoblastoma, astrocytoma, glioblastoma, Schwannoma,
oligodendroglioma, meduUoblastoma, neuroblastomas, rhabdomyosarcoma, osteogenic sarcoma, leiomyosarcomas, urinary tract carcinomas, thyroid carcinomas, Wilm's tumor, renal cell carcinoma, prostate carcinoma, abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), or Meigs' syndrome. In specific embodiment, the cancer an astrocytoma, an oligodendroglioma, a mixture of oligodendroglioma and an astrocytoma elements, an ependymoma, a meningioma, a pituitary adenoma, a primitive neuroectodermal tumor, a medullblastoma, a primary central nervous system (CNS) lymphoma, or a CNS germ cell tumor. In specific embodiments, the cancer treated in accordance with the methods provided herein is an acoustic neuroma, an anaplastic astrocytoma, a glioblastoma multiforme, or a meningioma. In other specific embodiments, the cancer treated in accordance with the methods provided herein is a brain stem glioma, a craniopharyngioma, an ependyoma, a juvenile pilocytic astrocytoma, a meduUoblastoma, an optic nerve glioma, primitive
neuroectodermal tumor, or a rhabdoid tumor.
[00417] Specific examples of conditions that can be prevented and/or treated in accordance with the methods described herein include cystic fibrosis, muscular dystrophy, polycystic autosomal-dominant kidney disease, cancer-induced cachexia, benign prostatic hyperplasia, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, retinopathies (including diabetic retinopathy and retinopathy of prematurity), retrolental fibroplasia, neovascular glaucoma, age- related macular degeneration, exudative macular degeneration, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca, viral infections, inflammation associated with viral infections, chronic
inflammation, lung inflammation, nephrotic syndrome, preeclampsia, ascites, pericardial effusion (such as that associated with pericarditis), pleural effusion, Sjogren's syndrome, acne rosacea, phylectenulosis, syphilis, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infection, Herpes zoster infections, protozoan infections, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, Paget's disease, scleritis, Stevens-Johnson's disease, pemphigoid, radial keratotomy, Eales' disease, Behcet's disease, sickle cell anemia, pseudoxanthoma elasticum, Stargardt's disease, pars planitis, chronic retinal detachment, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, ocular histoplasmosis, Mycobacteria infections, Lyme's disease, Best's disease, myopia, optic pits, hyperviscosity syndromes, toxoplasmosis, sarcoidosis, trauma, post-laser complications, diseases associated with rubeosis (neovascularization of the iris and of the angle), and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of prolific vitreoretinopathy. Certain examples of non-neoplastic conditions that can be prevented and/or treated in accordance with the methods described herein include viral infections, including but not limited to, those associated with viruses belonging to Flaviviridae, flavivirus, pestivirus, hepacivirus, West Nile virus, hepatitis C virus (HCV) or human papilloma virus (HPV).
[00418] In certain embodiments, a compound of Formula (I) or a form thereof is used in a method described herein to prevent and/or treat a disease identified in Table 2, supra, as associated with a gene(s) in Table 2.
KITS
[00419] In one aspect, provided herein are pharmaceutical or assay kits comprising a compound of Formula (I) or a form thereof, in one or more containers, and instructions for use. In one embodiment, a pharmaceutical or assay kit comprises, in a container, a compound of Formula (I) or a form thereof, or a composition thereof provided herein, a vehicle control or composition of a vehicle control in another container, and instructions for use. In certain embodiments, the compound or the compound and vehicle, in separate containers, are accompanied by a reagent or reagents necessary for carrying out an assay(s) described herein. In a specific embodiment, the pharmaceutical or assay kit comprises, in a container, a compound of Formula (I) or a form thereof, and further comprises, in one or more containers, components for isolating RNA. In another specific embodiment, the pharmaceutical or assay kit comprises, in a container, a compound of Formula (I) or a form thereof, and further comprises, in one or more containers, components for conducting RT-PCR or RT-qPCR. In further embodiments, the compound, in one or more containers, is accompanied by an apparatus or apparati necessary for administering the compound or composition thereof to a subject. In certain embodiments, the compound is chosen from Formula (la) or Formula (lb) or forms thereof. In yet other embodiments, the compound is any compound disclosed herein.
EXAMPLES
[00420] To describe in more detail and assist in understanding the present description, the following non-limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed. These examples illustrate the testing of certain compounds described herein in vitro and/or in vivo and demonstrate the usefulness of the compounds for treating a disease associated with the aberrant amount of RNA transcripts.
[00421] Example 1
[00422] Described below is a method of contacting cells with a compound described herein and determining changes in RNA transcript levels of said cells compared to cells that have not been contacted with the compound.
[00423] Cells from a cell line of interest are cultured in conditions sufficient to yield the number of cells capable of generating enough RNA for subsequent sequencing steps. Cells from the tested cell line are contacted with a compound described herein.
[00424] To culture said cells, they are seeded, at appropriate concentrations in a volume of media in a cell culture container and incubated for 4, 5, 6, 7, 8, 9, 10, or more hours. A concentrated solution of compound in a vehicle (e.g., DMSO) is then added in sufficient volume to result in the intended final concentration of the compound, for example 100 nM, 500 nM, 1 μΜ, 5 μΜ, 10 μΜ, 15 μΜ, 20 μΜ, or more. The cells may also be treated with vehicle alone, as a control. A number of replicates of each concentration or control may be made (e.g., 2 replicates). The cells are then incubated at a constant temperature appropriate for cell culture of the particular cell line (e.g., 37 °C) for 6, 12, 18, 24, 48, or more hours. After incubation, the growth medium is removed and the cells are washed with the appropriate buffer (e.g., PBS). Cells are then removed from adherence to the cell culture container by treatment with a solution containing trypsin, and the trypsin subsequently quenched with the appropriate volume of buffer (e.g., DMEM-FBS). The cells are then pelleted with gentle centrifugation (e.g., < 90 x g centrifugal force) and resuspended in a buffer to lyse the cells for extraction of RNA. The cell lysates may then be frozen (e.g., at -80 °C) or, alternately, may immediately be used in a procedure to purify the RNA (e.g. by use of the RNEASY PLUS® minikit). The RNA from cell lysates is eluted in the appropriate volume of buffer (e.g., RNEASE-FREE H20®). The resulting purified RNA may then be sequenced (e.g., using RNASeq) or analyzed using a human exon array (e.g., by GENECHIP® human exon array) to determine changes in the RNA levels in those cells treated with compound compared to those cells treated only with DMSO. The purified RNA may also be quantified by other methods known in the art.
[00425] Using the RNA data obtained from sequencing, exon array, or other methods, a statistical analysis can reveal changes in the RNA levels of compound-treated compared with control. For example, t-test p-values may be calculated for the data obtained through sequencing and exon array methods in order to compare compound-treated cells to those treated with the DMSO control. RNA sequences whose levels have been determined to have significantly changed may then be mapped onto known genes, using an appropriate database. Analysis of the sequencing and exon array data may then also yield predictions about the cause of the aberrant amount of an RNA transcript in the cells (e.g., perturbation of RNA splicing, RNA transcription, or RNA stability). These predictions may be further confirmed by methods known in the art. For example, RT-PCR and RT-qPCR may be used to confirm the change in amount of RNA transcripts for one or more particular transcripts of interest.
[00426] Example 2
[00427] mRNA RT-QPCR SPLICING ASSAY IN CULTURED CELLS [00428] Described below is a method of contacting cells with varying concentrations of a compound described herein and determining changes in RNA transcript levels of said cells that occur with changes of concentration.
[00429] Cells are plated at a certain density in an appropriate medium in 96-well flat-bottom plates. The plate is immediately swirled to ensure even distribution of the cells to ensure the formation of an even monolayer of cells and incubated for 6 - 24 hrs at 37°C. Cells are then treated with serially diluted test compound (e.g., 3.16-fold dilution factor, 0.5% final
concentration of DMSO), in duplicate, for desired time under appropriate conditions (e.g., 37°C, 5% C02, 100% relative humidity). After supernatant removal, cells are lysed (e.g., in Cells-To- Ct lysis buffer, Life Technologies). The levels of RNA of interest, and a reference RNA (e.g., GAPDH mRNA) are quantified (e.g., by using Taqman-based RT-qPCR) by assays designed to detect each mRNA of interest specifically. The forward and reverse primers are used at the appropriate concentration (e.g., 0.1 - 1 μΜ), as well as the probe (e.g., 0.1 to 0.3 μΜ). GAPDH primers are typically at 0.1 μΜ and the probe at 0.075 μΜ. RT-qPCR is carried out using an appropriate protocol. One example of such a protocol is the following temperatures for indicated time: Step 1 : 48°C (15 min); Step 2: 95°C (10 min); Step 3 : 95°C (15 sec); Step 4: 60°C (1 min); then, repeat Steps 3 and 4 for a total of 40 cycles. Fluorescence is recorded in each cycle at the end of the Step 4 incubation. Each PCR contains one or more primer(s) and probe(s) for the RNA of interest and reference RNA (multiplex design), allowing simultaneous measurement of the levels of two transcripts. The Ct values for each mRNA are converted to mRNA abundance using actual PCR efficiencies, and may be calculated essentially as described in Liu and Saint (Anal Biochem 302:52). RNA of interest abundance is first normalized to the reference RNA to account for well-to-well variability. The reference RNA-normalized abundances of RNA of interest in compound-treated wells are then normalized to a control (e.g., a DMSO control) and plotted as fold change relative to control (e.g., DMSO).
[00430] Example 3
[00431] This example provides methods for identifying compounds within Formula (I) that modulate the splicing of RNA transcripts encoded by certain genes.
[00432] Materials and Methods
[00433] RT-qPCR analysis of SMN2 full length (FL) and Δ7 mRNAs in cultured cells.
GM03813 (Coriell Institute) and PNN 1-46 fibroblasts (Columbia University) derived from SMA Type I patients are plated at 5,000 cells/well in 200 μΐ, Dulbecco's modified Eagle's medium (DMEM) with GlutaMAX and 10% fetal bovine serum (FBS) (Life Technologies, Inc.) in 96-well plates, and incubated for 6 hours in a cell culture incubator (37°C, 5% C02, 100% relative humidity). Cells are then treated with a compound described herein at different concentrations (0.5% DMSO) in duplicate for 24 hours. After supernatant removal, cells are lysed in Cells-To-Ct lysis buffer (Life Technologies, Inc.) according to the manufacturer's recommendations. The mRNA levels of SMN2 FL, SMN2 Δ7 and GAPDH are quantified using Taqman-based RT-qPCR and SMN2-specific primers and probes in Table 4 (purchased from Life Technologies, Inc.). The SMN forward and reverse primers are each used at a final concentration of 0.4 μΜ. The SMN probe is used at a final concentration of 0.15 μΜ. GAPDH primers are used at final concentrations of 0.1 μΜ and the probe at 0.075 μΜ. RT-qPCR is carried out at the following temperatures for indicated times: Step 1 : 48°C (15 min); Step 2: 95°C (10 min); Step 3 : 95°C (15 sec); Step 4: 60°C (1 min); Steps 3 and 4 are repeated for 40 cycles. The Ct values for each mRNA are converted to mRNA abundance using actual PCR efficiencies. SMN2 FL and Δ7 mRNAs are normalized to GAPDH and DMSO controls and plotted as fold change over DMSO.
Table 4
Figure imgf000208_0001
[00434] RNA sequencing data generation. PNN 1-46 cells derived from a Type I SMA patient are treated with a compound described herein at 500 nM for 24 hours. RNA is purified with the RNeasy Mini Kit (Qiagen) for mRNA sequencing on HiSeq 2500 (Illumina Inc., San Diego, CA). The quality of the total RNA is assessed using UV spectrophotometry and agarose gel electrophoresis. Template DNA molecules suitable for cluster generation are prepared from 1 μg of total RNA samples using the TruSeq RNA Sample Preparation Kit v2 (Illumina Inc., San Diego, CA) according to the manufacturer's instructions. The size distribution of the libraries is estimated by electrophoresis on Agilent High Sensitivity Bioanalyzer microfluidic chips. The minimum and average sizes of the amplified libraries are determined to be >200 nucleotides and 300-340 nucleotides, respectively. Libraries are quantified using the KAPA Library
Quantification Kit (KK4824, Kapa Biosystems, Boston, MA). The libraries are pooled at equimolar concentrations and diluted prior to loading onto the flow cell of the HiSeq 2500 (Illumina Inc., San Diego, CA) for both clustering and sequencing. The libraries are extended and bridge-amplified to create single sequence clusters using the TruSeq Rapid PE Cluster Kit - HS (Illumina Inc., San Diego, CA). Amplified clusters in the flow cell are then sequenced with 50-bp paired-end reads using the TruSeq Rapid SBS Kit - HS (Illumina Inc., San Diego, CA) in rapid run mode. Real time image analysis and base calling are performed on the the HiSeq 2500 instrument using the HiSeq Sequencing Control Software (HCS). CASAVA software version 1.8 is used for de-multiplexing and production of FASTQ sequence files.
[00435] RNA sequencing and data analysis. In order to estimate gene expression levels, paired-end RNAseq reads are subsequently mapped to RefSeq human transcripts (release 60) and the human genome (hgl9) by using the short read aligner Bowtie2 (Langmead et al., 2012. Nature methods 9:357). The number of mapped reads for all transcript variants of a gene (counts) are combined into a single value and normalized denoted as rpkms (number of mapped reads per kilobase transcript per million sequenced reads, (Mortazavi et al, 2008. Nature methods 5:621)). The splice-site analysis is performed by mapping the paired-end RNASeq reads to RefSeq human transcripts using the alignment software GSNAP with default parameters and the option 'sam-multiple-primaries' in order to account for reads that are mapped multiple times to different splice variants. The number of reads spanning splice-sites is determined by applying the samtools mpileup software with default parameters for each transcript. Reads having an alignment start or end exactly on the splice-site are excluded from the analysis (Wu et al., 2005, Bioinformatics 21 : 1859; Wu et al., 2010, Bioinformatics 26:873; Li et al., 2009, Bioinformatics 25:2078).
[00436] Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.
[00437] Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims as described herein.

Claims

What is claimed is:
1. A method of modulating the amount of a gene product, comprising administering to a subject a compound of Formula (I):
Figure imgf000211_0001
or a form thereof, wherein:
wi and w2 are C-Ri or C-R2; wherein, one of wi and w2 is C-Ri and the other is C-R2, provided that, when wi is C-Ri, then w2 is C-R2; or, when wi is C-R2, then w2 is
Ri is Ci_8alkyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, Ci_8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl)2-amino, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl,
Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, amino-Ci_8alkyl-amino, (amino-Ci_8alkyl)2-amino, (amino-Ci_8alkyl)(Ci_8alkyl)amino,
Ci_8alkyl-amino-C i.salkyl-amino, (C i_8alkyl-amino-C i_8alkyl)2-amino, (Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino, amino-Ci_8alkoxy, Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkyl)2-amino-Ci_8alkoxy,
Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, amino-C2_8alkenyl,
Ci_8alkyl-amino-C2-8alkenyl, (Ci_8alkyl)2-amino-C2-8alkenyl, amino-C2-8alkynyl, Ci_8alkyl-amino-C2-8alkynyl, (Ci_8alkyl)2-amino-C2-8alkynyl,
halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, (halo-Ci_8alkyl)(Ci_8alkyl)amino, hydroxy-Ci_8alkyl, hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-Ci_8alkyl-amino, (hydroxy-Ci_8alkyl)2-amino, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino, hydroxy-Ci_8alkyl-amino-Ci_8alkyl, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl,
hydroxy-Ci_8alkyl-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkoxy,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy,
hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)2-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino,
(hydroxy-C i_8alkyl)2-amino-C i_8alkyl-amino,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino,
[(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino,
[(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl](Ci_8alkyl)amino, heterocyclyl, heterocyclyl-Ci_salkyl, heterocyclyl-Ci_salkoxy, heterocyclyl-amino,
(heterocyclyl)(Ci_8alkyl)amino, heterocyclyl-amino-Ci_8alkyl,
heterocyclyl-Ci_8alkyl-amino, (heterocyclyl-Ci_8alkyl)2-amino,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino, heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl-oxy,
heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino,
(aryl-C i_8alkyl)2-amino, (aryl-C i_salkyl)(C i_8alkyl)amino,
aryl-Ci_8alkyl-amino-C i_salkyl, (aryl-C i_8alkyl)2-amino-C i_galkyl,
(aryl-C i_galkyl)(C i_8alkyl)amino-C i_8alkyl, heteroaryl, heteroaryl-C i_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino,
(heteroaryl-Ci_8alkyl)2-amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, (heteroaryl-C i_8alkyl)2-amino-Ci_8alkyl or (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl;
wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R3 substituents and one additional, optional R4 substituent; and, wherein, alternatively, each instance of heterocyclyl and heteroaryl is optionally
substituted with one, two, three or four R3 substituents;
R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R6 substituents and one additional, optional R7 substituent; Ra is, in each instance, independently selected from hydrogen, halogen, Ci_galkyl or deuterium;
Rb is hydrogen, halogen, Ci_galkyl, Ci_galkoxy or deuterium;
R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo, Ci.galkyl, halo-Ci_galkyl, Ci_galkyl-carbonyl, Ci_galkoxy, halo-Ci_galkoxy, Ci_galkoxy-Ci_galkyl, Ci_galkoxy-carbonyl, amino, Ci_galkyl-amino,
(Ci_galkyl)2-amino, amino-Ci_galkyl, Ci_galkyl-amino-Ci_galkyl,
(Ci_galkyl)2-amino-Ci_galkyl, amino-Ci_galkyl-amino,
Ci_galkyl-amino-Ci_galkyl-amino, (Ci_galkyl)2-amino-Ci_galkyl-amino,
Ci_galkoxy-Ci_galkyl-amino, Ci_galkyl-carbonyl-amino,
Ci_galkoxy-carbonyl-amino, hydroxy-Ci_galkyl, hydroxy-Ci_galkoxy-Ci_galkyl, hydroxy-Ci_galkyl-amino, (hydroxy-Ci_galkyl)2-amino or
(hydroxy-C i_galkyl)(C i_8alkyl)amino;
R4 is C3_i4cycloalkyl, C3_i4cycloalkyl-Ci_8alkyl, C3_i4cycloalkyl-amino, aryl-Ci_8alkyl, aryl-Ci_8alkoxy-carbonyl, aryl-sulfonyloxy-Ci_8alkyl, heterocyclyl or heterocyclyl-Ci_8alkyl; wherein, each instance of C3_i4cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents; R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro,
Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino, Ci_galkyl-amino,
(Ci_galkyl)2-amino or Ci_galkyl-thio;
Re is, in each instance, independently selected from halogen, hydroxy, cyano, nitro,
Ci.galkyl, C2_galkenyl, halo-Ci_galkyl, hydroxy-C i_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino or Ci_galkyl-thio; and,
R7 is C3_i4cycloalkyl, C3_i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl,
wherein the gene product is encoded by ABll, ACKR3, ADAM9, ALDH4A1, AMT, ANKMY1, ANKRD28, ANKZF1, APAF1, APLP2, ARHGAP8, ARHGAP12, ARHGEFl, ARMCIO, ATP1B3, ATXNIO, B3GNT8, B3GNTL1, BAIAP2, BCAP31, BCL6B, BCLAFl, BPHL, BZW2, C3orfl7, C5orf38, Cl lorf73, CACNAIC, CANDl, CAST, CBFA2T2, CD3EAP, CD46, CECR1, CLK4, CNOT1, COL5A2, COL6A2, CORIN, CPT1B, CPT1C, CREG2, CREM, CRNKL1, CRYZL1, CUL4A, CYP3A5, DIAPH3, DBNDD2, DCAF5, DCAF6, DCST2, DENND5A, DK 3, DLAT, DNAJC17, DNAJC7, DRD4, DTNBP1, DYNLRB2, ECI2, ENTPD6, EPB41, ERBB2IP, ERC2, EYA3, FAM120A, FCGR2A, FEZ1, FLNB, FN1, FOXM1, FOXP1, FOXREDl, GAL3ST2, GAL3ST3, GALC, GGCT, GIGYF2, GJB2, GNPDA1, GPI, GPR88, GPS2, GRB10, GTF2I, HAGHL, HAUS4, HLA-A, HLA-B, HLA-C, HLTF, HMBS, HMGA1, HMHA1, HNRNPD, HNRNPK, HNRNPUL1, HOGA1, HVCN1, IL15RA, INSL6, INTS3, ITSNl, KCNG2, KIAA1462, KRT18, LARP7, LRBA, LRIFl, LYRM2, LZTSl, MAP2K4, MATR3, MBTD1, MCL1, MECR, MGRN1, MICB, MPI, MYOIB, NADK, NAV2, NEURL4, NFATC3, NFATC4, NR3C1, NREP, NUMB, OR1Q1, OR2C1, P2RX5, PALD1, PAPD4, PDDC1, PDXDC2P, PDXDC1, PELI3, PHF16, PHTF2, PICALM, PITPNB, PLEKHH1, PP2D1, PPHLN1, PREPL, PSG8, PSMD1, PUS10, PYCRl, RAB34, RBFOX3, RBM33, RCCl, RGS3, RIFl, RIPK1, RPL3, RPN2, RTKN, RUSC1, SARNP, SC5D, SCRN1, SEC31A, SGMS2, SIRPA, SLC22A1, SLC24A3, SLC25A17, SLC35E2B, SLC37A3, SLC39A13, SLC39A3, SLIT1, SLIT3, SLPI, SMARCA4, SMARCE1, SNX14, SPATS2L, SPI1, SRD5A2, SSFA2, STAT6, STRN3, SV2C, SYTL2, TARS, TBC1D25, TEX21P, TGFA, TMEM150A, TMEM254, TOP3B, TRIM6, TSC22D3, TUSC3, TXLNG, UBE3B, VPS29, WDR5, WRAP53, WWTR1, ZKSCAN8, ZMYND11, ZNF185, ZNF512, ZNF540, ZNF542 or ZNF619.
2. A method of modulating the amount of a gene product, comprising contacting a cell with a compound of Formula (I):
Figure imgf000214_0001
(I)
or a form thereof, wherein:
wi and w2 are C-Ri or C-R2; wherein, one of wi and w2 is C-Ri and the other is C-R2, provided that, when wi is C-Ri, then w2 is C-R2; or, when wi is C-R2, then w2 is _8alkyl, amino, Ci_8alkyl-amino, (Ci_8alkyl)2-amino, Ci_8alkoxy-Ci_8alkyl-amino, (Ci_8alkoxy-Ci_8alkyl)2-amino, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkyl)2-amino-Ci_8alkyl,
Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkyl, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, amino-Ci_8alkyl-amino, (amino-Ci_8alkyl)2-amino, (amino-Ci_8alkyl)(Ci_8alkyl)amino,
Ci_8alkyl-amino-C i.salkyl-amino, (C i.galkyl-amino-C i_8alkyl)2-amino,
(Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino, [(Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino, amino-Ci_8alkoxy,
Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkyl)2-amino-Ci_8alkoxy,
Ci_8alkoxy-Ci_8alkyl-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (Ci_8alkoxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy, amino-C2-8alkenyl,
Ci_8alkyl-amino-C2-8alkenyl, (Ci_8alkyl)2-amino-C2-8alkenyl, amino-C2-8alkynyl, Ci_8alkyl-amino-C2-8alkynyl, (Ci_8alkyl)2-amino-C2_8alkynyl,
halo-Ci_8alkyl-amino, (halo-Ci_8alkyl)2-amino, (halo-Ci_8alkyl)(Ci_8alkyl)amino, hydroxy-C i_salkyl, hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-C i_8alkyl-amino, (hydroxy-C i_8alkyl)2-amino, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino,
hydroxy-Ci_8alkyl-amino-Ci_8alkyl, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl,
hydroxy-Ci_8alkyl-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)2-amino-Ci_8alkoxy, (hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy,
hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)2-amino,
(hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino,
(hydroxy-C i_8alkyl)2-amino-C i_8alkyl-amino,
(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino,
[(hydroxy-Ci_8alkyl)2-amino-Ci_8alkyl](Ci_8alkyl)amino,
[(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl](Ci_8alkyl)amino, heterocyclyl, heterocyclyl-Ci_salkyl, heterocyclyl-C i_salkoxy, heterocyclyl-amino,
(heterocyclyl)(Ci_8alkyl)amino, heterocyclyl-amino-Ci_8alkyl,
heterocyclyl-Ci.salkyl-amino, (heterocyclyl-Ci_8alkyl)2-amino, (heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino, heterocyclyl-Ci_8alkyl-amino-Ci_8alkyl, (heterocyclyl-Ci_8alkyl)2-amino-Ci_8alkyl,
(heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl, heterocyclyl-oxy,
heterocyclyl-carbonyl, heterocyclyl-carbonyl-oxy, aryl-Ci_8alkyl-amino,
(aryl-C i_8alkyl)2-amino, (aryl-C i_salkyl)(C i_8alkyl)amino,
aryl-Ci_8alkyl-amino-C i_salkyl, (aryl-C i_8alkyl)2-amino-C i_8alkyl,
(aryl-C i_8alkyl)(C i_8alkyl)amino-C i_8alkyl, heteroaryl, heteroaryl-C i_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-amino,
(heteroaryl-Ci_8alkyl)2-amino, (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino,
heteroaryl-Ci_8alkyl-amino-Ci_8alkyl, (heteroaryl-C i_8alkyl)2-amino-Ci_8alkyl or (heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl;
wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R3 substituents and one additional, optional R4 substituent; and, wherein, alternatively, each instance of heterocyclyl and heteroaryl is optionally
substituted with one, two, three or four R3 substituents;
R2 is aryl, aryl-amino, aryl-amino-carbonyl, heterocyclyl, heteroaryl or heteroaryl-amino; wherein, each instance of aryl, heterocyclyl and heteroaryl is optionally substituted with one, two or three R6 substituents and one additional, optional R7 substituent;
Ra is, in each instance, independently selected from hydrogen, halogen, Ci_8alkyl or
deuterium;
Rb is hydrogen, halogen, Ci_salkyl, Ci_8alkoxy or deuterium;
R3 is, in each instance, independently selected from cyano, halogen, hydroxy, oxo,
Ci_8alkyl, halo-Ci_8alkyl, Ci_8alkyl-carbonyl, Ci_8alkoxy, halo-Ci_8alkoxy, Ci_8alkoxy-Ci_8alkyl, Ci_8alkoxy-carbonyl, amino, Ci_8alkyl-amino,
(Ci_8alkyl)2-amino, amino-Ci_8alkyl, Ci_8alkyl-amino-Ci_8alkyl,
(Ci_8alkyl)2-amino-Ci_8alkyl, amino-Ci_8alkyl-amino,
Ci_8alkyl-amino-Ci_8alkyl-amino, (Ci_8alkyl)2-amino-Ci_8alkyl-amino,
Ci_8alkoxy-Ci_8alkyl-amino, Ci_8alkyl-carbonyl-amino,
Ci_8alkoxy-carbonyl-amino, hydroxy-Ci_8alkyl, hydroxy-Ci_8alkoxy-Ci_8alkyl, hydroxy-Ci_8alkyl-amino, (hydroxy-Ci_8alkyl)2-amino or
(hydroxy-C i_8alkyl)(C i_8alkyl)amino; P is C3_i4cycloalkyl, C3-i4cycloalkyl-Ci_galkyl, C3-i4cycloalkyl-amino, aryl-Ci_galkyl, aryl-Ci.galkoxy-carbonyl, aryl-sulfonyloxy-Ci_galkyl, heterocyclyl or heterocyclyl-Ci_8alkyl; wherein, each instance of C3_i4Cycloalkyl, aryl and heterocyclyl is optionally substituted with one, two or three R5 substituents;
R5 is, in each instance, independently selected from halogen, hydroxy, cyano, nitro,
Ci_galkyl, halo-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino or Ci_galkyl-thio;
Re is, in each instance, independently selected from halogen, hydroxy, cyano, nitro,
Ci.galkyl, C2-galkenyl, halo-Ci_galkyl, hydroxy-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino, Ci_galkyl-amino, (Ci_galkyl)2-amino or Ci_galkyl-thio; and,
R7 is C3_i4cycloalkyl, C3_i4cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl,
wherein the gene product is encoded by APLP2, ARHGAP8, ARHGAP12, ARMC10, C3orfl7, C5or08, Cl lorf73, CD46, CECR1, CNOT1, DIAPH3, DENND5A, FEZ1, FLNB, FNl, GALC, GPS2, HAUS4, HLTF, HNRNPD, HNRNPULl, IL15RA, MATR3, MPI, NEURL4, NR3C1, PAPD4, PDXDC2P, PDXDC1, PHTF2, PITPNB, PPHLN1, RAB34, RCC1, RGS3, RPL3, RTKN, SLC35E2B, SLC37A3, SPATS2L, STAT6, STRN3, TBC1D25, TEX21P, VPS29, or WRAP53.
3. The method of claim 1 or 2, wherein the compound is selected from Formula (la) or
Formula (lb):
Figure imgf000217_0001
(la), and (ib);
or a form thereof.
4. The method of claim 1 or 2, wherein the form is selected from a free acid, free base, salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
5. The method of claim 4, wherein the salt form is a chloride, hydrobromide, hydrochloride, dihydrochloride, acetate, trifluoroacetate or trifluoroacetic acid salt.
6. The method of claim 1 or 2, wherein the compound is selected from:
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-benzoxazol-2-yl]-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[7-(trifluoromethyl)- 1 ,3-benzoxazol-2-yl]-2H-chromen-2-one
2- oxo-N-phenyl-7-(piperazin- 1 -yl)-2H-chromene-3-carboxamide
3- (l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(7-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-ylmethyl)-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one
7- [(propan-2-ylamino)methyl] -3 - [4-(trifluoromethyl)- 1 ,3 -benzothiazol-2-yl]-2H-chromen-
2- one
3- (4-chloro-l,3-benzothiazol-2-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one 7-(4-methylpiperazin- 1 -yl)-3 - [3 -(trifluoromethyl)phenyl] -2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyridin-3-yl)-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one 3-(l,3-benzothiazol-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(5-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
3-(4-methyl-l,3-benzoxazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-methyl-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2- one
3-(3-fluorophenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyridin-4-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(4-methylpiperazin-l-yl)carbonyl]-2H-chromen-2- one
7-(piperazin-l-yl)-3-(lH-pyrazol-5-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2-oxo-N-phenyl-2H-chromene-3-carboxamide
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(4-methyl-l,3-benzoxazol-2-yl)-2H-chromen-2- one
7-(piperazin- 1 -yl)-3-(pyridin-2-ylamino)-2H-chromen-2-one 7-(piperazin- 1 -yl)-3-(pyrimidin-2-ylamino)-2H-chromen-2-one
3-(imidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[2-(propan-2-ylamino)ethyl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[3-(propan-2-ylamino)propyl]-2H-chromen-2-one
3-(4-methyl-l,3-thiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(1 -methyl- lH-pyrazol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(4-fluoro-l,3-benzoxazol-2-yl)-2H-chromen-2- one
3-(4-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-2-oxo-2H-chromen-7-yl piperazine- 1 -carboxylate
3-(4-chloro-l,3-benzothiazol-2-yl)-2-oxo-2H-chromen-7-yl piperazine- 1 -carboxylate benzyl 4- [3 -( 1 -methyl- 1 H-benzimidazol-2-yl)-2-oxo-2H-chromen-7-yl]piperazine- 1 - carboxylate
3-(8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-(4-phenyl-l,3-thiazol-2-yl)-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
3-(l ,3-benzoxazol-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(l ,3-benzoxazol-2-yl)-7-[3-(dimethylamino)pyrrolidin- 1 -yl]-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-{[2-(dimethylamino)ethyl](methyl)amino}-2H-chromen-2-one
3-(5-phenyl-l,2,4-oxadiazol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(3S)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7- [(3R)-pyrrolidin-3 -yloxy] -2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(2S)-pyrrolidin-2-ylmethoxy]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-[(diethylamino)methyl]-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(diethylamino)methyl]-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7-(piperidin- 1 -ylmethyl)-2H-chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperidin-l-ylmethyl)-2H-chromen-2-one
3-[(3-methylpyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
3-[(4-methylpyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
3-[(5-methylpyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
3-[(6-methylpyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
3-[(5-chloropyridin-2-yl)amino]-7-(piperazin-l-yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyridin-3-ylamino)-2H-chromen-2-one 3-(4-iodo-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzoxazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-chloro-l,3-benzoxazol-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2- one
3-(4-chloro-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-( 1 -methyl- 1 H-pyrazol-3-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-( 1 -phenyl- 1 H-pyrazol-3-yl)-2H-chromen-2-one
3-(phenylamino)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3 -[4-(trifluoromethyl)pyridin-2-yl] -2H-chromen-2-one
3-(3-methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7-[(methylamino)methyl] -2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-{[(2-hydroxyethyl)(methyl)amino]methyl}-2H-chromen-2-one
3-(4-methyl-lH-pyrazol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-chromen-2-one
3-(l,3-benzoxazol-2-yl)-7-(2,5-dimethylpiperazin-l-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(piperazin-l -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin-l-yl)-3-[6-(trifluoromethyl)pyridin-2-yl]-2H-chromen-2-one
3-(l H-indazol-5-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(2R,5S)-2,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2- one
3-(3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 3-(l,3-benzothiazol-2-yl)-7-{[(l,3-dihydroxypropan-2-yl)amino]methyl}-2H-chromen-2- one
7-(4-ethylpiperazin- 1 -yl)-3-(8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
7-[4-(2-hydroxyethyl)piperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(6-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H-chrom
2- one
3- (6-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
tert-butyl {(3S)-l-[3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-2-oxo-2H-chromen-7- yl]pyrrolidin-3-yl} carbamate
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chrom one
7-(4-ethylpiperazin-l-yl)-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-propylpiperazin- 1 -yl)-2H-chromen-2-one
3-([ 1 ,3]oxazolo[4,5-b]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-([l,3]oxazolo[4,5-b]pyridin-2-yl)-2H-chromen-2-one 3-(6-chloroimidazo[l,2-a]pyridin-2-yl)-4-methyl-7-(piperazin-l-yl)-2H-chromen-2-one 3-(5-chloropyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[7-(trifluoromethyl)imidazo[l,2-a]pyridm^ 2H-chromen-2-one
3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H-chromen-
2- one
3- (8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-2H- chromen-2-one
3-(7-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
7-(piperazin- 1 -yl)-3 -[2-(trifluoromethyl)pyridin-3 -yl] -2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3 - [2-(trifluoromethyl)pyridin-3 -yl]-2H-chromen-2-one 3-(3-fluoropyridin-4-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7- {[(3R)- 1 -ethylpyrrolidin-3-yl]oxy} -2H-chromen-2-one
3-(imidazo[l,2-b]pyridazin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(lS,4S)-2,5-diazabicyclo[2.2 ]hept-2-yl]-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H- chromen-2-one
7- { [2-(dimethylamino)ethyl] (methyl)amino } -3 -(imidazo [ 1 ,2-a]pyrimidin-2-yl)-2H- chromen-2-one
3-(7-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(5-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen^
3-(5-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen^
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-fluoroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-o 7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(m^
3-(imidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-2H-chrome one
3-(3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(l ,3-benzothiazol-2-yl)-7-[ 1 -(dimethylamino)ethyl]-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-7-[ 1 -(propan-2-ylamino)ethyl]-2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3 -( 1 ,3 -benzothiazol-2-yl)-7- { [2-(dimethylamino)ethy 1] (methyl)amino } -2H-chromen-2-one
3-(l,3-benzothiazol-2-yl)-4-methyl-7-(piperazin-l-yl)-2H-chromen-2-one
7- { [(2-hydroxy ethyl)(methyl)amino]methyl} -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-(2-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H- chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen- 2-one 7- [3-(dimethylamino)pyrrolidin- 1 -yl]-3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H- chromen-2-one
8- fluoro-7-(piperazin- 1 -yl)-3-(pyridin-2-yl)-2H-chromen-2-one
8-fluoro-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2- 3-(l ,3-benzothiazol-2-yl)-6-fluoro-7-(piperazin- 1 -yl)-2H-chromen-2-one
6- fluoro-3 -(6-methylimidazo [1, 2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 3-(l,3-benzoxazol-2-yl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(l ,3-benzothiazol-2-yl)-5-fluoro-7-(piperazin- 1 -yl)-2H-chromen-2-one
5-fluoro-7-(piperazin- 1 -yl)-3-(pyridin-2-yl)-2H-chromen-2-one
5 -fluoro-3 -(6-methylimidazo [l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one 3-(6-methylpyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7- (4-methylpiperazin-l-yl)-3-(6-methylpyridin-3-yl)-2H-chromen-2-one
3-(2-methoxypyridin-4-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(2R,5S)-2,5-dimethylpiperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[2,l-b][l ,3]thiazol-6-yl)-2H-chromen-
2- one
3- [7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-7-[(3R,5S)-3,4,5-trimethylpiperazin-l- yl]-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7- [( 1 S ,4S)-2,5 -diazabicyclo [2.2.1 ]hept-2-yl]-3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7- { [2-(dimethy lamino)ethyl] (methyl)amino } -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(l,4-diazepan-l-yl)-3 -(6-methylimidazo [l,2-a]pyridin-2-yl)-2H-chromen-2-one tert-butyl {(3S)-l-[3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2-oxo-2H-chromen-7- yl]pyrrolidin-3-yl} carbamate
7-(4-ethylpiperazin- 1 -yl)-3-(3-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(3-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-
2- one
3- (2-chloropyridin-4-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[methyl(l -methylpyrrolidin-3-yl)amino]-2H-chromen- 2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-(3-methylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H- chromen-2-one 3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chrom one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(3-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(pyrazolo[ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -3 -(pyrazolo [ 1 ,5 -a]pyridin-2-yl)-2H-chromen-2-one
7-[4-(2-hydroxyethyl)piperazin-l-yl]-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3 -(pyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3 -(pyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-ethylpiperazin-l-yl)-3-(pyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-propylpiperazin- 1 -yl)-3 -(pyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
7-[4-(propan-2-yl)piperazin- 1 -yl] -3 -(pyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
7-[(dimethylamino)methyl]-3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3-(imidazo[2,l-b][l,3]thiazol-6-yl)-7-[(propan-2-ylamino)methyl]-2H-chromen-2-one
7-[3-(dimethylamino)piperidin-l-yl]-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H-ch^
2- one
7-(4-ethylpiperazin- 1 -yl)-3-(imidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
7- {[2-(dimethylamino)ethyl](methyl)amino} -3-(imidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H- chromen-2-one
3- (imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(4-methyl- 1 ,4-diazepan-l -yl)-2H-chromen-2-one 3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one 3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one 7-(l ,4-diazepan- 1 -yl)-3-(imidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
2- [7-(4-methylpiperazin- 1 -yl)-2-oxo-2H-chromen-3-yl]imidazo[ 1 ,2-a]pyridine-6- carbonitrile
7-(piperazin- 1 -yl)-3-[8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-[8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[^
2H-chromen-2-one
3- (8-chloroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(l ,4-diazepan- 1 -yl)-2H-chromen-2-one 3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S
one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2^ one
7-(3,3-dimethylpiperazin-l-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2
7-(l,4-diazepan-l-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(6-methoxypyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-aminopiperidin-l-yl)-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2^ one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[methyl(pyridin-3-ylmethyl)amino]-2H- chromen-2-one
7-(3,3-dimethylpiperazin-l-yl)-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-2H chromen-2-one
7- { [2-(dimethy lamino)ethyl] (methyl)amino } -3 -(7-methylimidazo [ 1 ,2-a]pyrimidin-2-yl)- 2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3 -(7-methylimidazo [l,2-a]pyrimidin-2-yl)-2H-chromen-2- one
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
3- (7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7-(l,4-diazepan-l-yl)-3 -(7-methylimidazo [l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
3-(2-methylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-
2- one
3- (2-methylimidazo[2,l-b][l,3]thiazol-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
7-(l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3- (4-methoxypyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4-chloropyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one 7-[(3S)-3-methylpiperazin-l-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chrom one
7-[(3R)-3-methylpiperazin-l-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2 one
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-2H chromen-2-one
3-(8-cyclopropylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2- one
3-(8-bromoimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(3,3-dimethylpiperazin-l-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(6-methylimid^
one
7-{[(l-hydroxypropan-2-yl)amino]methyl}-3-(6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7- [(4-hydroxypiperidin- 1 -yl)methyl] -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H-chromen-
2- one
7- [(3 -hydroxypyrrolidin- 1 -yl)methyl] -3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
5-fluoro-7-(piperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one
3 - (6-methylimidazo [l,2-a]pyridin-2 -yl)-7-(octahydro-6H-pyrrolo [3, 4-b]pyridin-6-yl)-2H- chromen-2-one
3-(2-ethoxypyridin-3-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-methoxypyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3 -(1 -methyl- lH-indol-3-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(1 -methyl- lH-indol-3-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
3- (6-chloro-8-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l^ 2H-chromen-2-one
7-[(lS,4S)-2,5-diazabicyclo[2.2 ]hept-2-yl]-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H- chromen-2-one
7-[(3R)-3-methylpiperazin- 1 -yl]-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-[7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]^^ chromen-2-one
7-(3 ,3 -dimethylpiperazin- 1 -yl)-3 - [7-(trifluoromethyl)imidazo [ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-{[(l-hydroxypropan-2-yl)amino]methyl}-2H- chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-{[(2-hydroxyethyl)(methyl)amino]methyl}-2H chromen-2-one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(3-hydroxypyrrolidin-l-yl)methyl]-2H-chromen-2 one
3-(4-chloro-l,3-benzothiazol-2-yl)-7-[(4-hydroxypiperidin-l-yl)methyl]-2H-chromen-2- one
3-(2-methylpyrimidin-4-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-[7-(trifluoromethyl)imidazo[l,2-a]pyridin-2-yl]-2H-chromen-2- one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-[7-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
7-[(2R,5S)-2,5-dimethylpiperazin-l-yl]-3-[7-(M
2H-chromen-2-one
3-(2-cyclopropylpyrimidin-4-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(piperazin-l-yl)-3-[2-(propan-2-yl)pyrimidin-4-yl]-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
3 -(6-methylimidazo [ 1 ,2-a]pyridin-2-yl)-7- [methyl( 1 -methylpiperidin-4-yl)amino]-2H- chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(4-methyl-l,3-thiazol-2-yl)-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(4-methyl-l ,3-thiazol-2-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(4-methyl- 1 ,3-thiazol-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(4-methyl-l,3-thiazol-2-yl)-2H-chromen-2-one 3-(7-ethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(7-ethylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one 7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-ethylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(3,5-difluorophenyl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,5-difluorophenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
5-fluoro-3-(4-fluoro-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-[8-(trifluoromethyl)imidazo[ 1 ,2-a]pyridin-2-yl]-2H- chromen-2-one
3-(6-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one 3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2H-chromen-
2- one
7-(4-methylpiperazin- 1 -yl)-3 -(2-methylpyrimidin-4-yl)-2H-clironien-2-one
3 - (2-cyclopropylpyrimidin-4-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(2S,5R)-2,5-dimethylpiperazin- 1 -yl]-3-(4-methyl- 1 ,3-thiazol-2-yl)-2H-chromen-2-one 7-[(3R)-3-methylpiperazin-l-yl]-3-(4-metliyl-l,3-tliiazol-2-yl)-2H-clironien-2-one 7-(3,3-dimethylpiperazin-l-yl)-3-(4-metliyl-l,3-tliiazol-2-yl)-2H-clironien-2-one
3 -(5 -niethylpyrazolo [ 1 ,5 -a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin-l-yl)-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H- chromen-2-one
7-(3 ,3 -dimethylpiperazin- 1 -yl)-3 -(5 -methylpyrazolo [ 1 ,5 -a]pyridin-2-yl)-2H-chromen-2- one
7- [(3R)-3 -methylpiperazin- 1 -yl]-3 -(5 -methylpyrazolo [ 1 ,5 -a]pyridin-2-yl)-2H-chromen-2- one
7-(4-ethylpiperazin- 1 -yl)-3 -(5 -methylpyrazolo [ 1 ,5-a]pyridin-2-yl)-2H-chromen-2-one
3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(5-methylpyrazolo[l,5-a]pyridin-2-yl)-2H-chromen-2- one
5-fluoro-3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 5-fluoro-3-(imidazo[l,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(9H-purin-8-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methoxypyridin-2-yl)-2H-chromen-2-one 3-(3,4-dimethoxyphenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4-methylthiophen-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one 7-(piperazin- 1 -yl)-3-(thiophen-3-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-(thiophen-3-yl)-2H-chromen-2-one
3-(imidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen^
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3 -(imidazo [2, 1 -b] [ 1 ,3 ]thiazol-6-yl)-7- [(3R)-pyrrolidin-3 -yloxy] -2H-chromen-2-one
3-(2-methylimidazo[2,l-b][l,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2- one
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one 3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen^ 3-(6-fluoro-8-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-fluoro-8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-ch^
2- one
3- (6-fluoro-8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-^
2H-chromen-2-one
3-(8-ethyl-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H- chromen-2-one
3-(7-ethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(8-ethyl-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
5 -fluoro-3 -(imidazo [ 1 ,2-a]pyrimidin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-(l,4-diazepan-l-yl)-5 -fluoro-3 -(imidazo [l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
3-(6-chloroimidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methyl- 1 ,4-diazepan- l-yl)-2H-chromen-2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H-chromen-
2- one
3- (8-ethyl-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-
2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-ethyl-6-methylimidazo[l,2-a]pyridin-2-yl)- 2H-chromen-2-one
3- (8-chloro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]- 2H-chromen-2-one
3-(8-chloro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen- 2-one 3-(8-chloro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan-l -yl)-2H- chromen-2-one
7- {[(2-hydroxyethyl)(methyl)amino]methyl} -3-(imidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-2H- chromen-2-one
7-[(4-hydroxypiperidin- 1 -yl)methyl]-3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H-chromen-2- one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H- chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2 one
5-fluoro-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-5-fluoro-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H- chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chrom
2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)- 2H-chromen-2-one
3- (8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H- chromen-2-one
3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(8-ethylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-methoxypyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin-l-yl)-3-(6-methoxypyridin-2-yl)-2H-chromen-2-one
3 -(6-methoxypyridin-2-yl)-7- [(3R)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3 -(6-methoxypyridin-2-yl)-7- [(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
7-(piperazin- 1 -yl)-3-(thiophen-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(thiophen-2-yl)-2H-chromen-2-one
3-(3,5-difluorophenyl)-5-fluoro-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
5-fluoro-3-(4-fluoro-l,3-benzoxazol-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-5-fluoro-3-(4-fluoro-l,3-benzoxazol-2-yl)-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-5-fluoro-3-(4-fluoro- 1 ,3-benzoxazol-2-yl)-2H-chromen-2-one
5-fluoro-3-(4-fluoro-l ,3-benzoxazol-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
3-(lH-benzimidazol-2-yl)-5-fluoro-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one 3-(lH-benzimidazol-2-yl)-7-[(3R,5S)-3,5-dim
one
5-fluoro-3-(imidazo[2,l-b][l,3]thiazol-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2- one
5-fluoro-3-(imidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-
2- one
3- (lH-benzimidazol-2-yl)-7-(l,4-diazepan-l-yl)-5-fluoro-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6-chloroimidazo[l ,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7- [( 1 -benzylpyrrolidin-3 -yl)(methyl)amino]-3 -(7-methylimidazo [ 1 ,2-a]pyrimidin-2-yl)- 2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one
7- [(3 S)-3,4-dimethylpiperazin-l-yl] -3 -(7-methylimidazo [l,2-a]pyridin-2 -yl)-2H-chromen-
2- one
3- (6-fluoropyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-ethoxypyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
7-(piperazin-l-yl)-3-[6-(propan-2-yloxy)pyridin-2-yl]-2H-chromen-2-one
7-(piperazin- 1 -yl)-3-[6-(pyrrolidin- 1 -yl)pyridin-2-yl]-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(3,5-dimethoxyphenyl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-5-fluoro- 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-
2- one
3- (8-chloroimidazo[l,2-a]pyridin-2-yl)-5-fluoro-7-[(3R)-3-methylpiperazin-l-yl]-2H- chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -5 -fluoro-3 - [7-(trifluoromethyl)imidazo [ 1 ,2- a]pyridin-2-yl]-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-5-fluoro-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3 -(4-methyl- 1 H-benzimidazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(5-fluoro- lH-benzimidazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(lH-benzimidazol-2-yl)-7-[(dimethylamino)methyl]-2H-chromen-2-one
5-fluoro-7-(hydroxymethyl)-3-(imidazo[2,l-b][l,3]thiazol-6-yl)-2H-chromen-2-one 3-[8-(methylsulfanyl)imidazo[ 1 ,2-a]pyrazin-2-yl]-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-[8-(methylsulfanyl)imidazo[ 1 ,2-a]pyrazin-2-yl]-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-[8-(methylsulfanyl)imidazo[l,2-a]pyrazin-2-yl] 2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-[8-(methylsulfanyl)imidazo[l,2-a]pyrazin-2-yl]-2H- chromen-2-one
3-(8-methoxyimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(8-methoxyimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-^
3-(3,4-dimethoxyphenyl)-5-fluoro-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-5-fluoro-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-5-fluoro-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3-(l -benzothiophen-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l-benzothiophen-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(l -benzothiophen-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one
3-(l-benzothiophen-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,5-dimethoxyphenyl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2-one
3-(3,5-dimethoxyphenyl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3 -(3 ,5 -dimethoxyphenyl)-7-[(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-[6-(cyclobutyloxy)pyridin-2-yl]-7-(piperazin-l-yl)-2H-chromen-2-one
3 - [6-(cyclobutyloxy)pyridin-2-yl] -7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(3,4-dimethoxyphenyl)-5-fluoro-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-methoxyimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(8-methoxyimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2- one
3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H- chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
5-fluoro-3-(imidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
5-fluoro-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen^
2- one
5-fluoro-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen- 2-one 7-(3,3-dimethylpiperazin- 1 -yl)-3-(8-fl
chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2-one
3-(2-ethylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-(2-ethylimidazo[2, 1 -b] [1 ,3]thiazol-6-yl)-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(2-ethylimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-2H-chromen-2-one
3-(2-ethylimidazo[2,l-b][l,3]thiazol-6-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin- 1 -yl]-3-[ 1 -(pyridin-2-yl)- lH-imidazol-4-yl]-2H- chromen-2-one
3-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(7-methoxyimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-[(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(imidazo[2,l- b][l,3]thiazol-6-yl)-2H-chromen-2-one
7-( 1 ,4-diazabicyclo [3.2.2]non-4-yl)-3 -(imidazo [2, 1 -b] [ 1 ,3 ]thiazol-6-yl)-2H-chromen-2-one
7-[(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(imidazo[l,2- a]pyrimidin-2-yl)-2H-chromen-2-one
7-(l ,4-diazabicyclo [3.2.2]non-4-yl)-3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-2H-chromen-2-one 3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-
2- one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)- 2H-chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(pyridin-2-yl)-2H-chromen-2-one
3 - [6-(methylsulfany l)pyridin-2-yl] -7-(piperazin- 1 -yl)-2H-chromen-2-one
7-[(lS,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(3,4-dimethoxyphenyl)-5-fluoro-2H- chromen-2-one
3- (4-methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4-methoxyphenyl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b][ 1 ,3,4]thiadiazol-6-yl)-2H-chromen-2-one
7-(4-methyl- 1 ,4-diazepan- 1 -yl)-3-(2-methylimidazo[2, 1 -b] [ 1 ,3 ,4]thiadiazol-6-yl)-2H- chromen-2-one 7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -3 -( 1 -phenyl- 1 H-imidazol-4-yl)-2H-chromen-2-one
7-(4-methyl- 1 ,4-diazepan- 1 -yl)-3 -[2-methyl- 1 -(pyridin-2-yl)- 1 H-imidazol-4-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(imidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrazin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(imidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(imidazo[l,2-c]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(imidazo[l,2-c]pyrimidin-2-yl)-2H-chromen-2- one
3-(imidazo[ 1 ,2-c]pyrimidin-2-yl)-7-(4-methyl-l ,4-diazepan- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(quinoxalin-2-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
3- (3,4-dimethoxyphenyl)-5-fluoro-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one 3-(2,4-dimethoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -(2,4-dimethoxyphenyl)-7- [(3R)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-(2,4-dimethoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
5-fluoro-3-(6-methoxypyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
5-fluoro-3-(6-methoxypyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7- { [2-(dimethylamino)ethyl] amino } -3 -(7-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H-chromen-
2- one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3- (3,4-dimethoxyphenyl)-7-[(2S)-2-methylpiperazin-l-yl]-2H-chromen-2-one
3-(2-chloroimidazo[2,l-b][l,3]thiazol-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(l-methylpiperidin-4-yl)amino]-2H-chromen-2- one
7- { [3 -(dimethylamino)propyl]amino } -3 -(7-methylimidazo [ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(2-chloroimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one 3-(2-chloroimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(4-methyl- 1 ,4-diazepan-l -yl)-2H-chromen-
2- one
3- (6-fluoroimidazo[l,2-a]pyrimidin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-o
3-(6-fluoroimidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(2-methylimidazo[2,l-b][l,3,4]thiadiazol-6-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(3-chloro-4-fluorophenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3-chloro-4-fluorophenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(l ,3-benzodioxol-5-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l,3-benzodioxol-5-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(l,3-benzodioxol-5-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3 -( 1 ,3 -benzodioxol-5 -yl)-7- [(3 S)-3 -methylpiperazin- 1 -yl]-2H-chromen-2-one
7- [(3 S)-3 -methylpiperazin- 1 -yl] -3 - [3 -(trifluoromethyl)phenyl]-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-fluoroimidazo[l,2-a]pyrimidin-2-yl)-2H- chromen-2-one
3-(6-fluoroimidazo[l,2-a]pyrimidin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7-(4-methyl-l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(2-chloroimidazo[2, 1 -b][ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-(piperidin-4-ylamino)-2H-chromen-2-one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H-chromen-2-on^
3-(6-cyclopropyl-8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l- yl]-2H-chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H- chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2- one
7-(l ,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-2H-chromen-2- one
3-(6-fluoroimidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-cyclopropyl-8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H- chromen-2-one 3-(6-cyclopropyl-8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H- chromen-2-one
7-(l,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-
2- one
7-(3,8-diazabicyclo[3.2 ]oct-3-yl)-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
7-(3,3-dimethylpiperazin-l-yl)-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chrome 7-(3,3-dimethylpiperazin-l-yl)-3-(6-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chrom
3 -(3 -chlorophenyl)-7- [(3 S)-3 -methylpiperazin- 1 -yl]-2H-chromen-2-one
3- (2-chloro-4-fluorophenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3-methylphenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3 -(3 -methylphenyl)-7- [(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-(2,3-dihydro-l,4-benzodioxin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(2,3-dihydro-l,4-benzodioxin-6-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-^
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-
2- one
3- (6,8-difluoroimidazo[l ,2-a]pyridin-2-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-(l,4-diazabicyclo[3.2.2]non-4-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-
2- one
3- (6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-on^
3-(6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chrom
2- one
3- (8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2H-chromen-2- one
3-(8-chloroimidazo[l,2-a]pyridin-2-yl)-7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-2H-chromen-2- one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-2H-chromen-2-one 3-(indolizin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-2H-chromen-2-one
3-(6,8-difluoroimidazo[l,2-a]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(7-methylimidazo[l,2-a]pyridin-2- yl)-2H-chromen-2-one
7-[(lR,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl]-3-(7-methylimidazo[l,2-a]pyridin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chrom
2- one
3- (3,5-difluoro-2-methoxyphenyl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(3,5-difluoro-2-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(3,5-difluoro-2-methoxyphenyl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chrom one
3 -(4-methoxy-3 -methylphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -(4-methoxy-3 -methylphenyl)-7-[(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
7- [(3R,5 S)-3 ,5 -dimethylpiperazin- 1 -yl] -3 -(4-methoxy-3 -methylphenyl)-2H-chromen-2-one
3 -(3 -fluoro-4-methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(3-fluoro-4-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3 -(2,3 -difluorophenyl)-7- [(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3-[6-(dimethylamino)pyridin-3-yl]-7-(piperazin-l-yl)-2H-chromen-2-one
3-[6-(dimethylamino)pyridin-3-yl]-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(pyridin-4-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-5-fluoro-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(indolizin-2-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(l -methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(l-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2-one 7-(4-methylpiperazin- 1 -yl)-3-( 1 -methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-(4-methyl-l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2 one
3-(8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
7-(l ,4-diazabicyclo[3.2.2]non-4-yl)-3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-ylamino)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-ylamino]-2H-chromen-2 one
3-(indolizin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H-chromen-2- one
3-(8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3 -(3 -methoxy-4-methylphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3 -(3 -methoxy-4-methylphenyl)-7-[(3 S)-3 -methylpiperazin- 1 -yl] -2H-chromen-2-one
3 -(4-fluoro-3 -methoxyphenyl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4-fluoro-3-methoxyphenyl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(8-fluoroimidazo[ 1 ,2-a]pyridin-2-yl)-7-(octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(piperazin-l-yl)-3-(pyrrolo[l,2-a]pyrimidin-7-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(pyrrolo[l,2-a]pyrimidin-7-yl)-2H-chromen-2- one
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H-chromen-2-on^
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-pyrrolidin-3-ylamino]-2H- chromen-2-one 3-(8-fluoro-6-methylimidazo[l,2-a]pyrid^
chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(8-fluoroimidazo[l,2-a]pyridin-2-yl)-2H-chrom
2- one
7-[(3R)-3-methylpiperazin-l-yl]-3-(l-methylpyrrolo[l ,2-a]pyrazin-7-yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(l -methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3- (3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
7-(4-methyl-l ,4-diazepan- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-(4-methylpiperazin- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
5-fluoro-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
5-fluoro-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
5-fluoro-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
7-(5,8-diazaspiro[3.5]non-8-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2- one
7-(6,9-diazaspiro[4.5]dec-9-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(7-methylimidazo[l,2-a]pyridin-2-yl)-2H-chromen-
2- one
7-(5,8-diazaspiro[3.5]non-8-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(6,9-diazaspiro[4.5]dec-9-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
7-(2,5-diazabicyclo[2.2.2]oct-2-yl)-3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-2H- chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2- one
3-(l -benzofuran-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l-benzofuran-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(l-benzofuran-2-yl)-7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R,5S)-3,4,5-trimethylpiperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2H- chromen-2-one 7-(l ,4-diazepan- 1 -yl)-3-[6-methyl-8-(trifluoromethyl)imidazo[ 1 ,2-a]pyrazin-2-yl]-2H- chromen-2-one
7-(l ,4-diazepan- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-5-fluoro-2H-chromen-2- one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(8aR)-hexahydropyrrolo[l,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(8-fluoro-6-methylimidazo[l,2-a]pyridin-2-yl)-7-(octahydro-2H-pyrido[l,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(8-fluoro-6-methylimidazo[ 1 ,2-a]pyridin-2-yl)-7-(8-methyl-3,8-diazabicyclo[3.2.1 ]oct-3- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-5-fluoro-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H- chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-[methyl( 1 -methylpyrrolidin-3 -yl)amino] - 2H-chromen-2-one
7- [( 1 -benzylpyrrolidin-3 -yl)(methyl)amino] -3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-b]pyridazin-2-yl)-2H- chromen-2-one
7-(4-ethyl-l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-(azetidin-3-ylamino)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{methyl[(3S)-pyrrolidin-3-yl]amino}-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
7- [( 1 S ,4S)-2,5 -diazabicyclo [2.2.1 ]hept-2-yl] -3 -(6-methylimidazo [ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
3 -(6-methylimidazo [l,2-b]pyridazin-2-yl)-7- [(3 S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-2H- chromen-2-one
7- [(3 S)-4-ethyl-3-methylpiperazin-l-yl] -3 -(6-methylimidazo [l,2-a]pyrazin-2 -yl)-2H- chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen- 2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(thieno[3,2-c]pyridin-2-yl)-2H-chromen-2-one 7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(thieno[3,2-c]pyridin-2-yl)-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(6-methylimidazo[l,2-b]pyridazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7- yl)-2H-chromen-2-one
7-[(3R)-3-methylpiperazin-l-yl]-3-(3-methylpyrrolo[l ,2-a]pyrazin-7-yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(2-methylpyrrolo[l,2-b]pyridazin-6-yl)-2H- chromen-2-one
7-(4-ethylpiperazin- 1 -yl)-3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3-(2-methylpyrrolo[l,2-b]pyridazin-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(l-methylpyrrolo[l,2-a]pyrazin-7- yl)-2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7- yl)-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(3-methylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(octahydro-2H-pyrido[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(3S)-3-methylpiperazin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2- one
7-[(lS,4S)-2,5-diazabicyclo[2.2 ]hept-2-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(2-methylimidazo[l,2-a]pyrimidin-
6- yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chrom
2- one
7- [(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(2-methylimidazo[l,2-a]pyridin-6- yl)-2H-chromen-2-one
3- (2-methylimidazo[l,2-a]pyridin-6-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one 7-(4-methyl-l,4-diazepan-l-yl)-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chrom one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{methyl[(3S)-l-methylpyrrolidin-3- yl] amino } -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3S)- 1 -methylpyrro lidin-3-yl] amino } -2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-methyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-5-fluoro-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-2H- chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-
2- one
7-(4-methyl-l,4-diazepan-l-yl)-3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-2H-chromen-2- one
7-(l,4-diazepan-l-yl)-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-2-one
3- (2-methylimidazo[l,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(3-ethylpiperazin-l-yl)-2H-chromen-2-one
7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-(4-ethyl- 1 ,4-diazepan-l -yl)-3 -(3 -methylpyrro lo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-
2- one
3- (l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(8aR)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(4-ethyl-l ,4-diazepan- 1 -yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(8aS)-hexahydropyrrolo[ 1 ,2-a]pyrazin- 2(1 H)-yl] -2H-chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2-one 7-[(3S)-3,4-dimethylpiperazin-l-yl]-3^
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(3-ethyl-4-methylpiperazin- 1 -yl)-2H- chromen-2-one
3-(2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2^
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-4-ethyl-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3S)-3-methylpiperazin- 1 -yl]-2H-chromen-
2- one
3- (l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-(4-methyl- 1 ,4-diazepan- 1 -yl)-2H-chromen-2- one
7-(l ,4-diazepan- 1 -yl)-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H-chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-(octahydro-2H-pyrido[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7- [4-(2-hydroxyethyl)piperazin- 1 -yl] -3 -(3 -methylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-2H-chromen-
2- one
3- (l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[4-(2-hydroxyethyl)piperazin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol- 1 (2H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-5-methylhexahydropyrrolo[3,4- b]pyrrol- 1 (2H)-yl]-2H-chromen-2-one
7-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl]-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
3 -(3 -methylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin- 1 -yl]-2H-chromen-2- one
7-[(3R)-3-(dimethylamino)pyrrolidin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-2H- chromen-2-one
3-(2-methyl-l,3-benzoxazol-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-methyl-2,5- diazabicyclo[2.2.1]hept-2-yl]-2H-chromen-2-one 7- [(3 S)-3 -(dimethylamino)pyrrolidin- 1 -yl] -3 -( 1 ,3 -dimethylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(5-methylmro[3,2-b]pyridin-2-yl)-7-(4-m
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3R)-3-methylpiperazin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {methyl[(3R)-pyrrolidin-3-yl]amino} -2H- chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(6-methyl-8-nitroimidazo[l,2-a]pyridm^ 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3-exo)-9-methyl-9-azabicyclo[3.3.1 ]non- 3-yl]amino} -2H-chromen-2-one
3-(6-methyl-8-nitroimidazo[l,2-a]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H^ chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aR)-l-methylhexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl]-2H-chromen-2-one
3-(2,4-dimethylthieno[2,3-d]pyrimidin-6-yl)-7-(piperazin-l-yl)-2H-chromen-2
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aS,6aS)-l-methylhexahydropyrrolo[3,4^ b]pyrrol-5(lH)-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- (methyl[(3R)- 1 -methylpyrrolidin-3- yl] amino } -2H-chromen-2-one
7-[(3R)-3-(dimethylamino)pyrrolidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-
2- one
3- (6-chloro-8-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(8aR)-hexahydropyrrolo[ 1 ,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H- chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H- chromen-2-one
7-(4-aminopiperidin-l-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2-one
7-[4-(dimethylamino)piperidin-l-yl]-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-[4-(dimethylamino)piperidin-l-yl]-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chrom 2-one
7-[(3S)-3-(dimethylamino)pyrrolidin-l-yl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H chromen-2-one 7-[(3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl]-3-(6-methylimidazo[l ,2-a]pyrazin-
2- yl)-2H-chromen-2-one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-2H-chromen-2-one
7-[(3R,5S)-3,5-dimethylpiperazin-l-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)-2H-chrom
2- one
7-[(8aR)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)- 2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(5-methylfuro[3,2-b]pyridin-2-yl)- 2H-chromen-2-one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
tert-butyl {(3S)- 1 -[3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2-oxo-2H-chromen-7- yl]pyrrolidin-3-yl} carbamate
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3S)-3-(propan-2-ylamino)pyrrolidin-l-yl]- 2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2^ chromen-2-one
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyraz
chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-{[(lR,5S)-9-methyl-9-azabicyclo[3.3.1]non- 3-yl]amino} -2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3aS,6aS)- 1 -methylhexahydropyrrolo[3,4- b]pyrrol-5(lH)-yl]-2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7- { [(3 R)- 1 -methy lpyrrolidin-3 -yljamino } -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -ethylpyrrolidin-3-yl]amino} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(2-hydroxyethyl)pyrrolidin-3- yl] amino } -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(propan-2-yl)pyrrolidin-3- yl] amino } -2H-chromen-2-one
7-[(3R,4R)-3-(dimethylamino)-4-hydroxypyrrolidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2- a]pyrazin-7-yl)-2H-chromen-2-one
7-[3-(diethylamino)pyrrolidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(3,3-dimethylpiperazin-l-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(3,3,4-trimethylpiperazin-l-yl)-2H- chromen-2-one 7- [(3 S ,4S)-3 -(dimethylamino)-4-hydroxypyrrolidin- 1 -yl] -3 -(6,8-dimethylimidazo [ 1 ,2- a] pyrazin-2-yl)-2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-[(3 ' S ,4 ' S)-4 ' -hydroxy- 1,3' -bipyrrolidin- 1 ' - yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l,2,3,6-tetrahydropyridin-4-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-(2- hydroxyethyl)hexahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-(propan-2- yl)hexahydropyrrolo[3,4-c]pyrrol-2(lH)-yl]-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(3-methylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-
2- one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)- yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin- 1 -yl)-5-fluoro-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3aR,6aS)-5-ethylhexahydropyrrolo[3,4- c]pyrrol-2(lH)-yl]-2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazm^^
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-ethylpiperidin-4-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(2-hydroxyethyl)piperidin-4-yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[l ,2-a]pyrazin-7-yl)-7-[(3 'R,4'R)-4'-hydroxy-l ,3 ' -bipyrrolidin- 1 '- yl]-2H-chromen-2-one
7-(4-cyclopropylpiperazin-l-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-
2- one
3 - (3 -methylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)- 1 ,4-diazepan- 1 -yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[4-(propan-2-yl)- 1 ,4-diazepan- 1 -yl]-2H- chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3aR,6aR)- 1 -methylhexahydropyrrolo[3,4- b] pyrrol-5(lH)-yl]-2H-chromen-2-one
3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-7-[(3aR,6aS)-5-methylhexahydropyrrolo[3,4- c] pyrrol-2(lH)-yl]-2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[3-(morpholin-4-yl)pyrrolidin- 1 -yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(7R,8aS)-7-hydroxyhexahydropyrrolo[ 1 ,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one 7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-m
2H-chromen-2-one
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-hydroxy-6-methylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-[(lR,5S,6s)-6-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-3-(6,8- dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-(4-cyclopropylpiperazin- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-on^
3-(6-chloro-8-methylimidazo[ 1 ,2-a]pyra
2- one
3- (6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-(dimethylamino)pyrroli yl]-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-(4-ethylpiperazin-l-yl)-2H-chrom one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(7R,8aS)-7-hydroxyhexahydropyrrolo[ 1 ,2- a]pyrazin-2( 1 H)-yl] -2H-chromen-2-one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7-[(3S)-3-methyl-4-(propan-2-yl)piperazin- 1 - yl]-2H-chromen-2-one
3-(2-methyl-l,3-benzothiazol-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(2-methyl-l,3-benzothiazol-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
7-(l,4-diazepan-l-yl)-3-(2-methyl-l,3-benzothiazol-6-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3S)-3-ethylpiperazin- 1 -yl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(propan-2-yl)piperidin-4-yl]-2H- chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-hydroxyethyl)piperazin-l-yl]-2H- chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-methyl-l,4-diazepan-l-yl)-2H-chromen-2- one
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(2 -methyl- l,3-benzothiazol-6-yl)-2H-chromen-2- one
7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-3-(2-methyl-l,3-benzothiazol-6-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-ethyl-4-methylpiperazin-l-yl]-2H- chromen-2-one
7-[(3S)-3,4-diethylpiperazin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-2,5-diazabicyclo[2.2.1]hept- 2-yl]-2H-chromen-2-one 3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-methyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H- chromen-2-one
7-[4-(aminomethyl)piperidin- 1 -yl]-3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-(2-hydroxyethyl)octahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aR,7aR)-l-ethyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-methyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl]-2H-chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-ethylpiperazin-l-yl)-2H-chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2- one
3-(l ,3-dimethylpyrrolo[ 1 ,2-a]pyrazin-7-yl)-7- {4-[(propan-2-ylamino)methyl]piperidin- 1 - yl} -2H-chromen-2-one
3-(6-chloro-8-methylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-ethyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(lS,4S)-5-ethyl-2,5- diazabicyclo[2.2.1 ]hept-2-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4- b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-l-methyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(4aS,7aS)- 1 -(2-hydroxyethyl)octahydro- 6H-pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
7-[(3R,5S)-4-ethyl-3,5-dimethylpiperazin-l-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7-(4-cyclopropylpiperazin-l-yl)-3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[4-(2-methoxyethyl)piperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-methyl-l,2,3,6-tetrahydropyridin-4-yl) 2H-chromen-2-one 3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(2-hydroxyethyl)-l, 2,3,6- tetrahydropyridin-4-yl]-2H-chromen-2-one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(propan-2-yl)-l,2,3,6-tetrahydropyridin-
4- yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(4aS,7aS)-l-ethyloctahydro-6H- pyrrolo[3,4-b]pyridin-6-yl]-2H-chromen-2-one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2 one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3S)-3,4-dimethylpiperazin-l-yl]-2H-chromen^
2- one
3- (5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R)-3-methylpiperazin-l-yl]-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-[(3R)-3,4-dimethylpiperazin-l-yl]-2H-chromen^
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-(propan-2-yl)piperazin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-methyl-3-(propan-2-yl)piperazin-l- yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-ethyl-3-(propan-2-yl)piperazin-l- yl]-2H-chromen-2-one
7-(4-cyclopropylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2- one
7-(4-tert-butylpiperazin-l-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3 -( 1 ,3 -dimethylpyrrolo [ 1 ,2-a]pyrazin-7-yl)-7- [(3R)-3 -methyl-4-(propan-2-yl)piperazin- 1 - yl]-2H-chromen-2-one
7-(4-cyclobutylpiperazin-l-yl)-3-(l,3-dimethylpyrrolo[l,2-a]pyrazin-7-yl)-2H-chromen-2- one
3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-7-(4-propylpiperazin-l-yl)-2H-chromen-2-one
7-[4-(cyclopropylmethyl)piperazin-l-yl]-3-(5,7-dimethylfuro[2,3-c]pyridin-2-yl)-2H- chromen-2-one
3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
7-(2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-3-(piperazin- 1 -yl)-2H-chromen-2-one
3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(4,6-dimethylthieno[3,2-c]pyridin-2-yl)-7-[4-(2-methoxyethyl)piperazin-l-yl]-2H- chromen-2-one
7-(l-cyclobutylpiperidin-4-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
7-(4-cyclobutylpiperazin- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2- one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin- 1 -yl]-2H- chromen-2-one
3-(8-ethyl-6-methylimidazo[l,2-a]pyrazin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-(l-methylpiperidin-4-yl)-2H-chromen-
7-(l-ethylpiperidin-4-yl)-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyridin-6-yl)-7-[l-(oxetan-3-yl)piperidin-4-yl]-2H-chrome one
7-[l-(2-hydroxyethyl)piperidin-4-yl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chrome
2- one
3- (8-ethyl-6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-methylpiperazin- 1 -yl)-2H-chromen-
2- one
3- (4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one
3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2- one
3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-7-(l-methylpiperidin-4-yl)-2H-chromen-2-one
7-(l-ethylpiperidin-4-yl)-3-(2-methylimidazo[l,2-a]pyrimidin-6-yl)-2H-chromen-2-^
7-[4-(2-hydroxyethyl)piperazin- 1 -yl]-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(4-cyclobutylpiperazin- 1 -yl)-3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(oxetan-3-yl)piperazin-l-yl]-2H-chromen-2- one
3-(4,6-dimethylfuro[3,2-c]pyridin-2-yl)-7-[4-(propan-2-yl)piperazin-l-yl]-2H-chromen-2- one
3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-(l-methylpiperidin-4-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-propylpiperidin-4-yl)-2H-chromen-2-one
7-[l-(2-hydroxyethyl)piperidin-4-yl]-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(l-ethylpiperidin-4-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-[2-methyl-3-(l,2,3,6-tetrahydropyridin-4-yl)imidazo[l,2-b]pyridazin-6-yl]-7-(l,2,3,6- tetrahydropyridin-4-yl)-2H-chromen-2-one
7-[(dimethylamino)methyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-l-ylmethyl)-2H-chromen-2-on^
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperazin-l-ylmethyl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(4-methylpiperazin- 1 -yl)methyl]-2H- chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazm^
one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(lH-imidazol-l-ylmethyl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(4-ethyl-3-methylpiperazin- 1 -yl)-2H- chromen-2-one
3-(4,6-dimethylpyrazolo[l,5-a]pyrazin-2-yl)-7-(l-ethylpiperidin-4-yl)-2H-chromen-2-one
7-(l-cyclopropylpiperidin-4-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(oxetan-3-yl)piperidin-4-yl]-2H- chromen-2-one
3-(2-methyl-2H-indazol-5-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
7-[3-(dimethylamino)propyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(propan-2-ylamino)propyl]-2H-chromen-
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[3-(piperazin- 1 -yl)propyl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[3-(4-methylpiperazin- 1 -yl)propyl]-2H- chromen-2-one
7-[l-(2-hydroxyethyl)piperidin-4-yl]-3-(2-methyl-2H-indazol-5-yl)-2H-chromen-2-one
3-(2-methyl-2H-indazol-5-yl)-7-(l-methylpiperidin-4-yl)-2H-chromen-2-one
7-(l-ethylpiperidin-4-yl)-3-(2-methyl-2H-indazol-5-yl)-2H-chromen-2-one
7-[2-(dimethylamino)ethyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(propan-2-ylamino)ethyl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[2-(piperazin- 1 -yl)ethyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(l -methylpiperidin-4-yl)oxy]-2H-chromen-
2- one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one
7-(l-cyclobutylpiperidin-4-yl)-3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxyethyl)amino]ethyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxyethyl)(methyl)amino]ethyl} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(l -hydroxypropan-2-yl)amino]ethyl} - 2H-chromen-2-one
7- {2-[(l ,3-dihydroxypropan-2-yl)amino]ethyl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2- yl)-2H-chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2R)-2-(hydroxymethyl)pyrrolidin- 1 - yl]ethyl} -2H-chromen-2-one
7- {2-[bis(2-hydroxyethyl)amino]ethyl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[2-(dimethylamino)ethoxy]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(propan-2-ylamino)ethoxy]-2H-chromen-
2- one
3- (6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(oxetan-3-yl)piperidin-4-yl]-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2-hydroxyethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2- hydroxyethyl)(methyl)amino]propyl}-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(l -hydroxypropan-2-yl)amino]propyl} - 2H-chromen-2-one
7- {3-[(l ,3-dihydroxypropan-2-yl)amino]propyl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2- yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2R)-2-(hydroxymethyl)pyrrolidin- 1 - yl]propyl} -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(morpholin-4-yl)propyl]-2H-chromen-2 one
7-{3-[bis(2-hydroxyethyl)amino]propyl}-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(morpholin-4-yl)ethyl]-2H-chromen-2- one
3-(6-methylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(l -propylpiperidin-4-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[(3 S)-4-(2-hydroxyethyl)-3- methylpiperazin- 1 -yl] -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -methylpyrrolidin-3-yl]oxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -ethylpyrrolidin-3-yl]oxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(propan-2-yl)pyrrolidin-3-yl]oxy} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(2-hydroxyethyl)pyrrolidin-3- yl]oxy } -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {[(3R)- 1 -(1 -hydroxypropan-2-yl)pyrrolidin- 3-yl]oxy} -2H-chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyra
yl]-2H-chromen-2-one
7-[2-(diethylamino)ethoxy]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chrom one
7- {2-[bis(2-hydroxyethyl)amino]ethoxy} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(l-ethylpiperidin-4-yl)oxy]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{[l-(2-hydroxyethyl)piperidin-4-yl]oxy}- 2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-(3-fluoropropyl)-3-methylpiperazin- 1 -yl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{[l-(propan-2-yl)piperidin-4-yl]oxy}-2H- chromen-2-one
7-[4-(dimethylamino)butyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {4-[(2-hydroxyethyl)(methyl)amino]butyl} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {4-[(2R)-2-(hydroxymethyl)pyrrolidin- 1 - yl]butyl} -2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(piperazin- 1 -yl)butyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(3-fluoropropyl)piperidin-4-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-4-(3-hydroxypropyl)-3- methylpiperazin- 1 -yl] -2H-chromen-2-one
7-[3-(dimethylamino)propyl]-3-(2-methylimidazo[l,2-a]pyridin-6-yl)-2H-chromen-2-one
7-[3-(dimethylamino)propyl]-3-(8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one
7-[3-(dimethylamino)propyl]-3-(8-ethyl-2-methylimidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(methylamino)ethyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(methylamino)propyl]-2H-chromen-2- one
3 -(8-fluoro-2-methylimidazo [ 1 ,2-a]pyridin-6-yl)-7- [3 -(methylamino)propyl] -2H-chromen-
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[ 1 -(2-methylpropyl)piperidin-4-yl]-2H- chromen-2-one
7-{[l-(l,3-dihydroxypropan-2-yl)piperidin-4-yl]oxy}-3-(6,8-dimethylimidazo[l,2- a]pyrazin-2-yl)-2H-chromen-2-one 3-(6-methylimidazo[l,2-a]pyrazin-2-yl)-7-[l-(2-methylpropyl)piperidin-4-yl]-2H- chromen-2-one
7- [ 1 -(3 -fluoropropyl)piperidin-4-yl] -3 -(6-me
2- one
3- (6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[2-(pyrrolidin- 1 -yl)ethoxy]-2H-chromen-2- one
7-(4-aminopiperidin-l-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2
7-(4-amino-4-methylpiperidin- 1 -yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[4-(dimethylamino)piperidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl^ chromen-2-one
7-[4-(diethylamino)piperidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[4-(propan-2-ylamino)piperidin- 1 -yl]-2H- chromen-2-one
7-[4-(cyclobutylamino)piperidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{4-[(l-hydroxypropan-2-yl)amino]piperidin- 1 -yl} -2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(ethylamino)propyl]-2H-chromen-2-one
7-(3-aminopropyl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7- {4-[bis(2-hydroxyethyl)amino]piperidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2- yl)-2H-chromen-2-one
7- {4-[(l ,3-dihydroxypropan-2-yl)amino]piperidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(ethylamino)ethoxy]-2H-chromen-2-o^
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(2-methoxyethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(tetrahydrofuran-2- ylmethyl)amino]propyl}-2H-chromen-2-one
7-[3-(benzylamino)propyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(thiophen-3-ylmethyl)amino]propyl} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(pyridin-2-ylmethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {3-[(pyridin-4-ylmethyl)amino]propyl} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[ethyl(methyl)amino]ethoxy} -2H- chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[ethyl(2-hydroxyethyl)amino]ethoxy } - 2H-chromen-2-one
3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-7-[3 -(tetrahydrofuran-3 -ylamino)propyl] -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(3R)-3-hydroxypyrrolidin- 1 -yljethoxy} - 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-[3-(2-methylpiperidin- 1 -yl)azetidin- 1 -yl]- 2H-chromen-2-one
7-[3-(dimethylamino)azetidin- 1 -yl]-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-[3-(diethylamino)azetidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7-(2,7-diazaspiro[4^]non-2-yl)-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(2-{[(2R)-l-hydroxypropan-2- yl] amino } ethoxy)-2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7-(2- {[(2S)- 1 -hydroxypropan-2- yl] amino } ethoxy)-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(2R)-pyrrolidin-2-ylmethoxy]-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(2,2,6,6-tetramethyl-l, 2,3,6- tetrahydropyridin-4-yl)-2H-chromen-2-one
7-[(3R)-3-(aminomethyl)pyrrolidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[3-(piperidin-l-yl)azetidin-l-yl]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(methylamino)butyl]-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(piperidin-l-yl)ethoxy]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-{2-[(3S)-3-hydroxypyrrolidin-l-yl]ethoxy}- 2H-chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(l -hydroxy-2-methylpropan-2- yl)amino]ethoxy}-2H-chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(morpholin-4-yl)ethoxy]-2H-chromen-2- one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[2-(4-hydroxypiperidin-l-yl)ethoxy]-2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(l-ethyl-4-fluoropiperidin-4-yl)-2H- chromen-2-one 3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxyethyl)amino]ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-methoxyethyl)amino]ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-7- {2-[(2-hydroxypropyl)amino]ethoxy} -2H- chromen-2-one
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[4-(2-hydroxy-2-methylpropyl)piperazin-l- yl]-2H-chromen-2-one
7-[3-(aminomethyl)azetidin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one
7- [(3 S)-3 -(aminomethyl)pyrrolidin- 1 -yl] -3 -(6, 8-dimethylimidazo [ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
7- {(3R)-3-[(dimethylamino)methyl]pyrrolidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
7- {3-[(dimethylamino)methyl]azetidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)- 2H-chromen-2-one
7- {(3S)-3-[(dimethylamino)methyl]pyrrolidin- 1 -yl} -3-(6,8-dimethylimidazo[ 1 ,2- a]pyrazin-2-yl)-2H-chromen-2-one
7-[2-(diethylamino)ethyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-^
7-[3-(diethylamino)propyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2 one
7-[4-(diethylamino)butyl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2-one
7-(2,6-diazaspiro[3.3]hept-2-yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-
2- one
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(6-methyl-2,6-diazaspiro[3.3]hept-2-yl)-2H- chromen-2-one
2- [3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7- yl]hexahydropyrrolo[l,2-a]pyrazin-6(2H)-one
1- [3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2-oxo-2H-chromen-7-yl]piperidine-4- carbonitrile
3- (6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-(4-hydroxypiperidin-l-yl)-2H-chromen-2- one
7-(2,7-diazaspiro[3.5]non-7-yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H-chromen-
2- one
7-(6-amino-2-azaspiro[3.3]hept-2-yl)-3-(6,8-dimethylimidazo[ 1 ,2-a]pyrazin-2-yl)-2H- chromen-2-one
3- (imidazo[l,2-a]pyridin-6-yl)-7-(4-methylpiperazin-l-yl)-2H-chromen-2-one
7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl]-3-(imidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one
3-(imidazo[l,2-a]pyridin-6-yl)-7-(piperazin-l-yl)-2H-chromen-2-one 3-(imidazo[l,2-a]pyridin-6-yl)-7-[(3S)-3-methylpiperazin-l-yl]-2H-chromen-2-one
3-(8-fluoro-2-methylimidazo[l,2-a]pyridm^
2- one
3- (8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-7-[(8aS)-hexahydropyrrolo[l,2-a]pyrazin^ 2(1 H)-yl] -2H-chromen-2-one
3-(8-fluoro-2-methylimidazo[ 1 ,2-a]pyri
chromen-2-one
7-(2,6-diazaspiro[33]hept-2-yl)-3-(8-fluoro-2-methylimidazo[l,2-a]pyridin-6-yl)-2H- chromen-2-one, and
3-(8-fluoro-2-methylimidazo[ 1 ,2-a]pyridin-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one;
or a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
7. The method of claim 6, wherein the compound is selected from:
7-(piperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one
trifluoroacetate
7-(piperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one hydrochloride
7-(piperazin-l-yl)-3-[7-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one
trifluoroacetate
7-(piperazin-l-yl)-3-[7-(trifluoromethyl)-l,3-benzoxazol-2-yl]-2H-chromen-2-one hydrochloride
2- oxo-N-phenyl-7-(piperazin- 1 -yl)-2H-chromene-3-carboxamide trifluoroacetate
3- (l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(4-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(7-chloro-l,3-benzothiazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(4-chloro- 1 ,3-benzothiazol-2-yl)-7-(piperidin-4-yl)-2H-chromen-2-one hydrochloride
3-(5-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
3-(4-methyl- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
3-(4-fluoro- 1 ,3-benzoxazol-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one trifluoroacetate
7-(piperazin- 1 -yl)-3-[4-(trifluoromethyl)- 1 ,3-thiazol-2-yl]-2H-chromen-2-one hydrochloride
7-(4-methylpiperazin-l-yl)-3-[4-(trifluoromethyl)-l,3-thiazol-2-yl]-2H-chromen-2-one trifluoroacetate
3-(4-iodo-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(4-chloro-l,3-benzoxazol-2-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-([ 1 ,3]oxazolo[4,5-b]pyridin-2-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one hydrochloride
7-[(lS,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2- one hydrochloride (1 :3) 3-(3-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-(piperazin- 1 -yl)-2H-chromen-2-one
hydrochloride (1 :3)
7-(l,4-diazepan-l-yl)-3-(imidazo[l,2-a]pyrimidin-2-yl)-2H-chromen-2-one hydrochloride
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-(piperidin-4-yloxy)-2H-chromen-2-one hydrochloride
3-(2-methylpyrimidin-4-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
3-(2-cyclopropylpyrimidin-4-yl)-7-(piperazin-l-yl)-2H-chromen-2-one hydrochloride
7-(piperazin- 1 -yl)-3-[2-(propan-2-yl)pyrimidin-4-yl]-2H-chromen-2-one hydrochloride
3-(imidazo[ 1 ,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(7-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(7-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3 -(imidazo [2, 1 -b] [ 1 ,3 ]thiazol-6-yl)-7- [(3R)-pyrrolidin-3 -yloxy] -2H-chromen-2-one
hydrochloride (1 :2)
3-(2-methylimidazo[2, 1 -b] [ 1 ,3]thiazol-6-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(6-methylimidazo[l,2-a]pyridin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
3-(6-methylimidazo[l,2-a]pyrimidin-2-yl)-7-[(3R)-pyrrolidin-3-yloxy]-2H-chromen-2-one hydrochloride (1 :2)
7-[(l-benzylpyrrolidin-3-yl)(methyl)am
chromen-2-one acetate
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-methoxy-6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one acetate (1 :2)
7-[(3R)-3,4-dimethylpiperazin-l-yl]-3-(8-hydroxy-6-methylimidazo[l,2-a]pyrazin-2-yl)-2H- chromen-2-one acetate
7-[(3S)-3,4-dimethylpiperazin-l-yl]-3-(2 -methyl- l,3-benzothiazol-6-yl)-2H-chromen-2-one acetate (2: 1)
7-[(3S)-4-ethyl-3-methylpiperazin-l-yl]-3-(2 -methyl- l,3-benzothiazol-6-yl)-2H-chromen-2-one acetate
3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-7-[(3S)-3-ethyl-4-methylpiperazin-l-yl]-2H- chromen-2-one acetate, and
7-[(3S)-3,4-diethylpiperazin-l-yl]-3-(6,8-dimethylimidazo[l,2-a]pyrazin-2-yl)-2H-chromen-2- one acetate (1 :2);
or a free base, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or
tautomer thereof.
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9499521B2 (en) 2014-12-11 2016-11-22 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
US10195202B2 (en) 2013-12-19 2019-02-05 Ptc Therapeutics, Inc. Methods for modulating the amount of RNA transcripts
US10668171B2 (en) 2015-05-30 2020-06-02 Ptc Therapeutics, Inc. Methods for modulating RNA splicing
CN111254200A (en) * 2020-03-28 2020-06-09 中国医学科学院北京协和医院 New application of Gal3st3 gene
US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
US10874672B2 (en) 2015-12-10 2020-12-29 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
WO2021169762A1 (en) * 2020-02-25 2021-09-02 苏州大学 Neutral mitochondrial fluorescence marker based on nitrogen-containing heterocycle, and preparation method therefor and application thereof
US11370803B2 (en) 2019-09-18 2022-06-28 Takeda Pharmaceutical Company Limited Heteroaryl plasma kallikrein inhibitors
US11382918B2 (en) 2017-06-28 2022-07-12 Ptc Therapeutics, Inc. Methods for treating Huntington's Disease
US11395822B2 (en) 2017-06-28 2022-07-26 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11407753B2 (en) 2017-06-05 2022-08-09 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11608501B2 (en) 2017-06-14 2023-03-21 Ptc Therapeutics, Inc. Methods for modifying RNA splicing
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease
US11702646B2 (en) 2016-11-28 2023-07-18 Ptc Therapeutics, Inc. Methods for modulating RNA splicing
US11780839B2 (en) 2018-03-27 2023-10-10 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11787796B2 (en) 2019-09-18 2023-10-17 Takeda Pharmaceutical Company Limited Plasma Kallikrein inhibitors and uses thereof
US11858941B2 (en) 2018-06-27 2024-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating Huntington's disease
WO2024006287A3 (en) * 2022-06-27 2024-02-15 University Of Kansas Antiviral compounds useful against sars-cov-2

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170546A1 (en) * 2011-06-06 2012-12-13 University Of Iowa Research Foundation Methods of inhibiting muscle atrophy
WO2013059606A1 (en) * 2011-10-21 2013-04-25 Tufts Medical Center, Inc. Compounds and methods for the treatment of muscular disease, and related screening methods
WO2013101974A1 (en) * 2011-12-30 2013-07-04 Ptc Therapeutics, Inc. Compounds for treating spinal muscular atrophy

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170546A1 (en) * 2011-06-06 2012-12-13 University Of Iowa Research Foundation Methods of inhibiting muscle atrophy
WO2013059606A1 (en) * 2011-10-21 2013-04-25 Tufts Medical Center, Inc. Compounds and methods for the treatment of muscular disease, and related screening methods
WO2013101974A1 (en) * 2011-12-30 2013-07-04 Ptc Therapeutics, Inc. Compounds for treating spinal muscular atrophy

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SEO ET AL.: "Spinal muscular atrophy: An update on therapeutic progress", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1832, 27 August 2013 (2013-08-27), pages 2180 - 2190, XP028768883, DOI: doi:10.1016/j.bbadis.2013.08.005 *
TSAI, L.: "Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets", NEURAL PLASTICITY, vol. 2012, 2012, pages 1 - 13 *

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US10195202B2 (en) 2013-12-19 2019-02-05 Ptc Therapeutics, Inc. Methods for modulating the amount of RNA transcripts
US10688099B2 (en) 2013-12-19 2020-06-23 Ptc Therapeutics, Inc. Methods for modulating the amount of RNA transcripts
US9944628B2 (en) 2014-12-11 2018-04-17 President And Fellows Of Harvard College Inhibitors of cellular necrosis and related methods
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US10730874B2 (en) 2018-03-13 2020-08-04 Shire Human Genetic Therapies, Inc. Inhibitors of plasma kallikrein and uses thereof
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