WO2015095446A1 - Procédés pour la modulation de la quantité de produits de la transcription d'arn - Google Patents

Procédés pour la modulation de la quantité de produits de la transcription d'arn Download PDF

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Publication number
WO2015095446A1
WO2015095446A1 PCT/US2014/071029 US2014071029W WO2015095446A1 WO 2015095446 A1 WO2015095446 A1 WO 2015095446A1 US 2014071029 W US2014071029 W US 2014071029W WO 2015095446 A1 WO2015095446 A1 WO 2015095446A1
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Prior art keywords
amino
alkyl
isochromen
pyrazin
formula
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PCT/US2014/071029
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English (en)
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Nikolai Naryshkin
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Ptc Therapeutics, Inc.
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Publication of WO2015095446A1 publication Critical patent/WO2015095446A1/fr

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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
    • A61K31/495—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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems

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.
  • 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.
  • RNA transcripts or associated proteins Often, 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)
  • 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.
  • 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.
  • methods for modulating one, two, three or more R A 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.
  • 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 (II), Formula (III), Formula (IV) or Formula (V) 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 (II), Formula (III), Formula (IV) or Formula (V) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA transcripts ⁇ e.g., pre-mRNA or mRNA transcripts or isoforms thereof
  • methods for modulating the amount of one, two, three or more RNA transcripts ⁇ e.g., pre-mRNA or mRNA transcripts or isoforms thereof) of a gene 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 e.g., pre-mRNA or mRNA transcripts or isoforms thereof
  • methods for modulating the amount of one, two, three or more RNA transcripts 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 (II), Formula (III), Formula (IV) or Formula (V) 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 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.
  • a disease associated with aberrant expression of a gene product e.g., an 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 (II), Formula (III), Formula (IV) or Formula (V) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • RNA isoforms encoded by 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 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.
  • 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 (II), Formula (III), Formula (IV) or Formula (V) 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 (II), Formula (III), Formula (IV) or Formula (V) 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 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 (II), Formula (III), Formula (IV) or Formula (V) 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 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 (II), Formula (III), Formula (IV) or Formula (V) described infra.
  • a compound of Formula (I) is a compound selected from a compound described herein.
  • Figure 1 shows changes in RNA abundance as a result of treatment with Compound 65 (also referred infra in Example 3 as Table 3).
  • 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
  • RNA isoforms of one, two, three or more genes are 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 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 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 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 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 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 is C-Rb Or N
  • w 2 and w 6 are C-Ri or C-R 2 ;
  • w 3 , W4 and w 5 are C-R a or N;
  • one of w 2 and w 6 is C-Ri and the other is C-R 2 , provided that, when w 2 is C-Ri, then w 6 is C-R 2 ; or, when w 2 is C-R 2 , then w 6 is C-Ri; and,
  • any one, two or three of the remaining w ls w 3 , w 4 and w 5 may simultaneously be N;
  • Ri is Ci_galkyl, amino, Ci.galkyl-amino, (Ci_8alkyl) 2 -amino,
  • 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,
  • heterocyclyl (Ci_ 8 alkyl)amino
  • heterocyclyl-amino-Ci.salkyl heterocyclyl-Ci_ 8 alkyl-amino
  • heterocyclyl-Ci_8alkyl 2 -amino
  • 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_ 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_8alkyl, heteroaryl-Ci_8alkoxy, heteroaryl-amino, heteroaryl-Ci_8alkyl-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
  • each instance of heterocyclyl and heteroaryl is optionally substituted with one, two or three R 3 substituents and one additional, optional R 4 substituent; and, [0028] wherein, alternatively, 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 Re 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_ 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,
  • 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, aryl-sulfonyloxy-Ci_ 8 alkyl, 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, C 2 _ 8 alkenyl, halo-Ci_ 8 alkyl, hydroxy-Ci_ 8 alkyl, Ci_ 8 alkoxy, halo-Ci_ 8 alkoxy,
  • R 7 is C 3 _i 4 cycloalkyl, C 3 _i 4 cycloalkyl-oxy, aryl, heterocyclyl or heteroaryl.
  • wi is C-Rt,; w 3 is C-R a ; w 4 is C-R a ; w 5 is C-R a ; and, one of w 2 and w 6 is C-Ri and the other is C-R 2 , provided that, when w 2 is C-Ri, then w 6 is C-R 2 ; or, when w 2 is C-R 2 , then w 6 is C-Ri.
  • wi is C-Rt,; w 3 is C-R a ; w 4 is N; W5 is C-R ⁇ ; and, one of w 2 and w 6 is C-Ri and the other is C-R 2 , provided that, when w 2 is C-Ri, then w 6 is C-R 2 ; or, when w 2 is C-R 2 , then w 6 is C-Ri.
  • wi is C-Rt,; w 3 is N; w 4 is C-Ra; W5 is C-R ⁇ ; and, one of w 2 and w 6 is C-Ri and the other is C-R 2 , provided that, when w 2 is C-Ri, then w 6 is C-R 2 ; or, when w 2 is C-R 2 , then w 6 is C-Ri.
  • wi is N; w 3 is C-R a ; w 4 is C-Ra; W5 is C-R ⁇ ; and, one of w 2 and w 6 is C-Ri and the other is C-R 2 , provided that, when w 2 is C-Ri, then w 6 is C-R 2 ; or, when w 2 is C-R 2 , then w 6 is C-Ri.
  • wi is C-Rt,; w 3 is C-R a ; w 4 is C-R a ; w 5 is N; and, one of w 2 and w 6 is C-Ri and the other is C-R 2 , provided that, when w 2 is C-Ri, then w 6 is C-R 2 ; or, when w 2 is C-R 2 , then w 6 is C-Ri.
  • wi is C-Rt,; w 2 is C-Ri; w 3 is C-R a ; w 4 is C-R ⁇ ; w 5 is C-R ⁇ ; and, w 6 is C-R 2 .
  • wi is C-R t ,; w 2 is C-R 2 ; w 3 is C-R a ; w 4 is C-R a ; w 5 is C-R a ; and, w 6 is C-Ri.
  • wi is C-Rt,; w 2 is C-Ri; w 3 is C-R a ; w 4 is N; w 5 is C-R ⁇ ; and, w 6 is C-R 2 .
  • wi is C-Rt,; w 2 is C-R 2 ; w 3 is C-R a ; w 4 is N; w 5 is C-R a ; and, w 6 is C-Ri.
  • wi is C-Rt,; w 2 is C-Ri; w 3 is N; w 4 is C-R ⁇ ; w 5 is C-R a ; and, w 6 is C-R 2 .
  • wi is C-Rt,; w 2 is C-R 2 ; w 3 is N; w 4 is C-R a ; w 5 is C-R a ; and, w 6 is C-Ri.
  • wi is N; w 2 is C-Ri; w 3 is C-Ra; w 4 is C-R ⁇ ; w 5 is C-R ⁇ ; and, w 6 is C-R 2 .
  • wi is N; w 2 is C-R 2 ; w 3 is C-R a ; w 4 is C-R a ; w 5 is C-R a ; and, w 6 is C-Ri.
  • wi is C-Rb; w 2 is C-Ri; w 3 is C-R a ; w 4 is C-R a ; w 5 is N; and, w 6 is C-R 2 .
  • wi is C-Rb.
  • wi is N.
  • w 2 is C-Ri, provided that W6 is C-R 2 .
  • w 2 is C-R 2 , provided
  • w 6 is C-Ri, provided that w 2 is C-R 2 .
  • w 6 is C-R 2 , provided
  • w 3 is C-Ra.
  • w 3 is N.
  • w 4 is C-Ra.
  • w 4 is N.
  • w 5 is C-R a .
  • w 5 is N.
  • Ri is Ci_galkyl, amino, Ci.galkyl-amino, (Ci_8alkyl) 2 -amino,
  • Ci_8alkyl-amino-C i.salkyl-amino (C i.galkyl-amino-C i_8alkyl) 2 -amino,
  • heterocyclyl-Ci_salkyl heterocyclyl-Ci_salkoxy, heterocyclyl-amino
  • heterocyclyl (Ci_ 8 alkyl)amino
  • heterocyclyl-amino-Ci_ 8 alkyl 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
  • heteroaryl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl; wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with R 3 and R4 substituents.
  • Ri is amino, (Ci_ 8 alkyl) 2 -amino, Ci_ 8 alkoxy-Ci_ 8 alkyl-amino,
  • Ci_ 8 alkoxy-Ci_ 8 alkyl 2 -amino, amino-Ci.salkyl, Ci_ 8 alkyl-amino-Ci_ 8 alkyl, (Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl, Ci_ 8 alkoxy-Ci_ 8 alkyl-amino-Ci_ 8 alkyl,
  • heterocyclyl (Ci_ 8 alkyl)amino
  • heterocyclyl-amino-Ci_ 8 alkyl 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_salkyl, heteroaryl-Ci_galkoxy, heteroaryl-Ci_galkyl-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
  • heteroaryl-Ci_ 8 alkyl (Ci_ 8 alkyl)amino-Ci_ 8 alkyl; wherein, each instance of heterocyclyl and heteroaryl is optionally substituted with R 3 and R4 substituents.
  • 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-5-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,
  • heterocyclyl is optionally substituted with R 3 and R 4 substituents.
  • Ri is substituted heterocyclyl selected from 4-methyl-l,4-diazepan-l-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 with R 3 and R4 substituents.
  • 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 with R 3 and R4 substituents.
  • 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 with R 3 and R4 substituents.
  • 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 alkoxy 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 with R 3 and R4 substituents.
  • 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 with R 3 and R 4 substituents.
  • 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 selected from azetidin-3-yl-amino, pyrrolidin-3-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 with R 3 and R 4 substituents.
  • 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.galkyl wherein heterocyclyl is selected from tetrahydrofuranyl; and, wherein, each instance of heterocyclyl is optionally substituted with R 3 and R 4 substituents.
  • 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_8alkyl selected from 3-(tetrahydrofuran-3-yl-amino)propyl; wherein, each instance of heterocyclyl is optionally substituted with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • Ri is heterocyclyl-oxy, wherein heterocyclyl is selected from pyrrolidinyl or piperidinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R 3 and R 4 substituents.
  • 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-oxy selected from pyrrolidin-3-yl-oxy or piperidin-4-yl-oxy; wherein, each instance of heterocyclyl is optionally substituted with R 3 and R 4 substituents.
  • 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 wherein heterocyclyl is selected from piperazinyl; and, wherein, each instance of heterocyclyl is optionally substituted with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • 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; and, wherein, each instance of aryl is optionally substituted with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • Ri is heteroaryl, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R 3 and R 4 substituents.
  • Ri is heteroaryl selected from pyridin-4-yl; wherein, each instance of heteroaryl is optionally substituted with R 3 and R 4 substituents. [0094] In one embodiment of the use of a compound of Formula (I), Ri is
  • heteroaryl-Ci_galkyl wherein heteroaryl is selected from lH-imidazolyl; and, wherein, each instance of heteroaryl is optionally substituted with R 3 and R 4 substituents.
  • 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 selected from IH-imidazol-l-yl-methyl; wherein, each instance of heteroaryl is optionally substituted with R 3 and R 4 substituents.
  • 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 (Ci_ 8 alkyl)amino, wherein heteroaryl is selected from pyridinyl; and, wherein, each instance of heteroaryl is optionally substituted with R 3 and R 4 substituents.
  • 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
  • each instance of heteroaryl is optionally substituted with R 3 and R 4 substituents.
  • 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 with R 3 and R 4 substituents.
  • R 3 is selected from cyano, halogen, hydroxy, oxo, Ci_salkyl, halo-Ci_salkyl, Ci_ 8 alkyl-carbonyl, Ci_ 8 alkoxy, halo-Ci_galkoxy, Ci_ 8 alkoxy-Ci_ 8 alkyl, Ci_ 8 alkoxy-carbonyl, amino, Ci_galkyl-amino,
  • R 3 is selected from cyano, halogen, hydroxy, oxo, Ci_ 8 alkyl, halo-Ci_ 8 alkyl, Ci_ 8 alkoxy, Ci_ 8 alkoxy-Ci_ 8 alkyl,
  • Ci_ 8 alkoxy-carbonyl amino, Ci_ 8 alkyl-amino, (Ci_ 8 alkyl) 2 -amino, amino-Ci_ 8 alkyl, Ci_ 8 alkyl-amino-Ci_ 8 alkyl, (Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl, Ci_ 8 alkyl-amino-Ci_ 8 alkyl-amino,
  • Ci_ 8 alkoxy-Ci_ 8 alkyl-amino Ci_galkoxy-carbonyl-amino, hydroxy-C i_galkyl,
  • R 3 is Ci_galkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.
  • 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_galkyl 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-C i_galkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • R 3 is
  • hydroxy-C i_galkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • R 3 is Ci_galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
  • R 3 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 3 is
  • Ci_galkoxy-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_ 8 alkyl.
  • R a is, in each instance, optionally and independently deuterium.
  • R b is hydrogen, halogen, Ci_galkyl, Ci_ 8 alkoxy.
  • R b is deuterium
  • R 4 is C 3 _i 4 cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C 3 _i 4 cycloalkyl is optionally substituted with R 5 substituents.
  • R 4 is C 3 _ 8 Cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; wherein, each instance of C 3 _ 8 cycloalkyl is optionally substituted with R 5 substituents.
  • R 4 is
  • C 3 _i 4 cycloalkyl-Ci_galkyl 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 with R 5 substituents.
  • R 4 is
  • C 3 _gcycloalkyl-Ci_ 8 alkyl wherein C 3 _ 8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C 3 _ 8 cycloalkyl is optionally substituted with R 5 substituents.
  • R 4 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 with R 5 substituents.
  • R 4 is
  • C 3 _ 8 cycloalkyl-amino wherein C 3 _ 8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; and, wherein, each instance of C 3 _ 8 cycloalkyl is optionally substituted with R 5 substituents.
  • R 4 is aryl-Ci_galkyl, aryl-Ci_galkoxy-carbonyl or aryl-sulfonyloxy-Ci_galkyl, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R 5 substituents.
  • R 4 is aryl-Ci_ 8 alkyl or aryl-Ci_ 8 alkoxy-carbonyl, wherein each instance of aryl is optionally substituted with R5 substituents.
  • R 4 is heterocyclyl selected from oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,3-dioxanyl or morpholinyl, wherein each instance of heterocyclyl is optionally substituted with R 5 substituents.
  • 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 with R5 substituents.
  • 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 with R 5 substituents.
  • R 4 is
  • heterocyclyl-Ci_ 8 alkyl selected from pyrrolidin-l-yl-Ci_ 8 alkyl or piperidin-l-yl-Ci_ 8 alkyl, wherein each instance of heterocyclyl is optionally substituted with R 5 substituents.
  • R 5 is selected from halogen, hydroxy, cyano, nitro, halo-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, amino,
  • R5 is hydroxy
  • R 5 is Ci_galkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
  • R5 is Ci_galkyl selected from ethyl, propyl, isopropyl or tert-butyl.
  • R5 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 fiuoro, chloro, bromo or iodo.
  • R 5 is Ci.galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
  • R5 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 2 is aryl selected from phenyl optionally substituted with and R 7 substituents.
  • R 2 is aryl-amino, wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R 6 and R 7 substituents.
  • R 2 is aryl-amino selected from phenyl-amino; wherein, each instance of aryl is optionally substituted with R ⁇ and R 7 substituents.
  • R 2 is
  • aryl-amino-carbonyl wherein aryl is selected from phenyl; and, wherein, each instance of aryl is optionally substituted with R ⁇ 5 and R 7 substituents.
  • R 2 is
  • aryl-amino-carbonyl selected from phenyl-amino-carbonyl; wherein, each instance of aryl is optionally substituted with 5 and R 7 substituents.
  • R 2 is heterocyclyl selected from 1,2,3,6-tetrahydropyridinyl, 1,3-benzodioxolyl or 2,3-dihydro-l,4-benzodioxinyl; wherein, each instance of heterocyclyl is optionally substituted with 5 and R 7 substituents.
  • 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, lH-indolyl, 2H-indolyl, lH-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, lH-benzimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl,
  • R 2 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, lH-indol-5-yl, lH-indol-6-yl, lH-indazol-5-yl, 2H-inda
  • each instance of heteroaryl is optionally substituted with R 6 and R 7 substituents.
  • R 2 is substituted heteroaryl selected from 4-methylthien-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
  • R 2 is heteroaryl-amino, wherein heteroaryl is selected from pyridinyl or pyrimidinyl; and, wherein, each instance of heteroaryl is optionally substituted with 5 and R 7 substituents.
  • 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 with R 6 and R 7 substituents.
  • a compound of Formula (I) 5 is selected from halogen, hydroxy, cyano, nitro, Ci_galkyl, halo-Ci_galkyl, hydroxy-Ci_galkyl, Ci_galkoxy, halo-Ci_galkoxy, Ci_galkoxy-Ci_galkyl, (Ci_galkyl) 2 -amino or Ci_galkyl-thio; wherein, halogen and halo is selected from fluoro, chloro, bromo or iodo.
  • Ci_galkyl selected from methyl, ethyl, propyl, isopropyl or tert-butyl.
  • Ci_ 8 alkyl selected from ethyl, propyl, isopropyl or tert-butyl.
  • Re is C 2 _galkenyl selected from ethenyl, allyl or buta-l,3-dienyl.
  • a compound of Formula (I) is C 2 _ 8 alkenyl selected from ethenyl or allyl.
  • Re 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.
  • 3 ⁇ 4 is hydroxy-Ci_salkyl selected from hydroxy-methyl, hydroxy-ethyl, hydroxy-propyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • hydroxy-Ci-galkyl selected from hydroxy-methyl, dihydroxy-propyl, hydroxy-butyl or dihydroxy-butyl.
  • Ci_galkoxy selected from methoxy, ethoxy, propoxy or isopropoxy.
  • 3 ⁇ 4 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 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 oxetanyl, 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 C3_ 8 Cycloalkyl or C 3 _ 8 cycloalkyl-oxy, wherein each instance of C 3 _ 8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • R 7 is aryl selected from phenyl.
  • R 7 is heterocyclyl selected from oxetanyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridinyl.
  • R 7 is heterocyclyl selected from oxetan-3-yl, 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 of Formula (I), used in a method disclosed herein is a compound selected from Formula
  • the compound of Formula (I), used in a method disclosed herein is a compound selected from Formula (Ial) or Formula (Ia2):
  • the compound of Formula (I), used in a method disclosed herein is a compound selected from Formula (II), Formula (III), Formula (IV) or Formula (V):
  • the compound of Formula (I), used in a method disclosed herein is a compound selected from Formula (Ila), Formula (Ilia), Formula (IV a) and Formula (Va), respectively:
  • the compound of Formula (I), used in a method disclosed herein is a compound selected from Formula (Hal) or Formula (IIa2):
  • the compound of Formula (I), used in a method disclosed herein is a compound s
  • the compound of Formula (I), used in a method disclosed herein is a compound selected from Formula (IVal) or Formula (IVa2):
  • the compound of Formula (I), used in a method disclosed herein is a compound selected from Formula (Val) or Formula (Va2):
  • the compound of Formula (I) used in a method disclosed herein is a compound selected 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:
  • Compounds of Formula (I) can be prepared using reagents and methods known in the art, including the methods provided in International Application No. PCT/US2013/023067, filed on January 25, 2013, and published as International Publication No. WO 2013/112788 on August 1, 2013, the entire contents which are incorporated herein by reference (see in particular, General Synthetic Methods, Schemes A-D, at paragraphs [00579] to [00591]; and Specific Synthetic Examples, at paragraphs [00592] to [00673] and Table 1).
  • Ci_ 8 alkyl 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.
  • Ci_ 8 alkyl includes, but is not limited to, Ci_ 6 alkyl, Ci_ 4 alkyl and the like.
  • a Ci_ 8 alkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
  • C 2 - 8 alkenyl 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.
  • ethenyl also referred to as vinyl
  • allyl allyl
  • propenyl and the like.
  • C 2 - 8 alkenyl includes, but is not limited to, C 2 - 6 alkenyl, C 2 _ 4 alkenyl and the like.
  • a C 2 -salkenyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
  • C 2 - 8 alkynyl 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.
  • C 2 -salkynyl includes, but is not limited to, C 2 - 6 alkynyl, C 2 _ 4 alkynyl and the like.
  • a C 2 -salkynyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
  • Ci.galkoxy generally refers to saturated hydrocarbon radicals having from one to eight carbon atoms in a straight or branched chain configuration of the formula: -0-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.
  • Ci_galkoxy includes, but is not limited to, Ci_ 6 alkoxy, Ci_ 4 alkoxy and the like.
  • a Ci_ 8 alkoxy radical is optionally substituted with substituent species as described herein where allowed by available valences.
  • C 3 _i 4 Cycloalkyl 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.
  • cyclopropyl cyclobutyl
  • cyclopentyl cyclohexyl
  • cyclohexenyl cycloheptyl
  • cyclooctyl lH-indanyl
  • indenyl tetrahydro-naphthalenyl and the like.
  • C 3 _i 4 cycloalkyl includes, but is not limited to, C 3 -scycloalkyl, Cs-scycloalkyl, C 3 _iocycloalkyl and the like.
  • a C 3 _i 4 cycloalkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.
  • 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.
  • 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), pyr
  • 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.
  • 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, triazolidin
  • 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.
  • Ci_ 8 alkoxy-Ci_ 8 alkyl refers to a radical of the
  • Ci_ 8 alkoxy-Ci_ 8 alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-0-Ci_ 8 alkyl.
  • (Ci_ 8 alkoxy-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N(Ci_ 8 alkyl-0-Ci_ 8 alkyl) 2 .
  • Ci_ 8 alkoxy-Ci_ 8 alkyl-amino-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-NH-Ci_ 8 alkyl-0-Ci_ 8 alkyl.
  • (Ci_ 8 alkoxy-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-N(Ci_ 8 alkyl-0-Ci_ 8 alkyl) 2 .
  • (Ci_ 8 alkoxy-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-N(Ci_ 8 alkyl)(Ci_ 8 alkyl-0-Ci_ 8 alkyl).
  • Ci_ 8 alkoxy-Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-Ci_ 8 alkyl-0-Ci_ 8 alkyl.
  • (Ci_ 8 alkoxy-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl-0-Ci_ 8 alkyl) 2 .
  • (Ci_ 8 alkoxy-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl)(Ci_ 8 alkyl-0-Ci_ 8 alkyl).
  • Ci_ 8 alkoxy-carbonyl refers to a radical of the
  • Ci_ 8 alkoxy-carbonyl-C 2 - 8 alkenyl refers to a radical of the formula: -C 2 _ 8 alkenyl-C(0)-0-Ci_ 8 alkyl.
  • Ci_ 8 alkoxy-carbonyl-amino refers to a radical of the formula: -NH-C(0)-0-Ci_ 8 alkyl.
  • Ci_ 8 alkyl-amino refers to a radical of the
  • (Ci_ 8 alkyl) 2 -amino refers to a radical of the
  • Ci_ 8 alkyl-amino-C 2 - 8 alkenyl refers to a radical of the formula: -C 2 _ 8 alkenyl-NH-Ci_ 8 alkyl.
  • (Ci_ 8 alkyl) 2 -amino-C 2 - 8 alkenyl refers to a radical of the formula: -C2-8alkenyl-N(Ci_8alkyl) 2 .
  • Ci_ 8 alkyl-amino-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-NH-Ci_ 8 alkyl.
  • (Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-N(Ci_ 8 alkyl) 2 .
  • Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-Ci_ 8 alkyl.
  • (Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl) 2 .
  • Ci_ 8 alkyl-amino-Ci_ 8 alkyl-amino refers to a radical of the formula: -NH-C i_ 8 alkyl-NH-C i_ 8 alkyl.
  • (Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-N(Ci_ 8 alkyl) 2 .
  • (Ci_ 8 alkyl-amino-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N(Ci_ 8 alkyl-NH-Ci_ 8 alkyl) 2 .
  • the term "[(Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl] 2 -amino” refers to a radical of the formula: -N[Ci_8alkyl-N(Ci_ 8 alkyl) 2 ]2.
  • (Ci_ 8 alkyl-amino-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-NH-Ci_ 8 alkyl).
  • Ci_ 8 alkyl-amino-C 2 - 8 alkynyl refers to a radical of the formula: -C 2 - 8 alkynyl-NH-Ci_ 8 alkyl.
  • (Ci_ 8 alkyl) 2 -amino-C 2 - 8 alkynyl refers to a radical of the formula: -C 2 _ 8 alkynyl-N(Ci_ 8 alkyl) 2 .
  • Ci_ 8 alkyl-carbonyl refers to a radical of the
  • Ci_ 8 alkyl-carbonyl-amino refers to a radical of the formula: -NH-C(0)-Ci_ 8 alkyl.
  • Ci_ 8 alkyl-thio refers to a radical of the
  • amino-C 2 - 8 alkenyl refers to a radical of the
  • amino-Ci_ 8 alkoxy refers to a radical of the
  • amino-Ci_ 8 alkyl refers to a radical of the
  • amino-Ci_ 8 alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-NH 2 .
  • (amino-Ci_ 8 alkyl) 2 -amino) refers to a radical of the formula: -N(Ci_ 8 alkyl-NH 2 )2.
  • (amino-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-NH 2 ).
  • amino-C 2 - 8 alkynyl refers to a radical of the
  • aryl-Ci_ 8 alkoxy-carbonyl refers to a radical of the formula: -C(0)-0-Ci_ 8 alkyl-aryl.
  • aryl-Ci_ 8 alkyl refers to a radical of the
  • aryl-Ci_ 8 alkyl-amino refers to a radical of the
  • (aryl-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N(Ci_ 8 alkyl-aryl) 2 .
  • (aryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-aryl).
  • aryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-Ci_ 8 alkyl-aryl.
  • (aryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl-aryl) 2 .
  • (aryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl)(Ci_ 8 alkyl-aryl).
  • aryl-amino refers to a radical of the formula: -NH-aryl.
  • aryl-amino-carbonyl refers to a radical of the
  • aryl-sulfonyloxy-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-0-S0 2 -aryl.
  • benzoxy-carbonyl refers to a radical of the
  • C 3 _i 4 Cycloalkyl-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-C 3 _i 4 Cycloalkyl.
  • C 3 _i 4 Cycloalkyl-amino refers to a radical of the formula: -NH-C 3 _i 4 cycloalkyl.
  • C 3 _i 4 Cycloalkyl-oxy refers to a radical of the
  • halo or halogen generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.
  • halo-Ci_8alkoxy refers to a radical of the
  • Ci_galkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.
  • halo-Ci_ 8 alkyl refers to a radical of the
  • Ci_8alkyl-halo wherein Ci_8alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.
  • halo-Ci_8alkyl-amino refers to a radical of the
  • halo-Ci_8alkyl)(Ci_8alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-halo).
  • halo-Ci_8alkyl) 2 -amino refers to a radical of the formula: -N(Ci_8alkyl-halo)2.
  • heteroaryl-C i_8alkoxy refers to a radical of the
  • heteroaryl-C i_ 8 alkyl refers to a radical of the
  • heteroaryl-C i.salkyl-amino refers to a radical of the formula: -NH-Ci.galkyl-heteroaryl.
  • heteroaryl-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N(Ci_8alkyl-heteroaryl) 2 .
  • heteroaryl-Ci_8alkyl)(Ci_8alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-heteroaryl).
  • heteroaryl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-Ci_ 8 alkyl-heteroaryl.
  • heteroaryl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-heteroaryl) 2 .
  • heteroaryl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl)(Ci_ 8 alkyl-heteroaryl).
  • heteroaryl-amino refers to a radical of the
  • heterocyclyl-Ci_8alkoxy refers to a radical of the formula: -O-Ci.galkyl-heterocyclyl.
  • heterocyclyl-Ci_ 8 alkyl refers to a radical of the
  • heterocyclyl-Ci_8alkyl-amino refers to a radical of the formula: -NH-C i.galkyl-heterocyclyl.
  • heterocyclyl-Ci_8alkyl 2 -amino refers to a radical of the formula: -N(Ci_8alkyl-heterocyclyl)2.
  • heterocyclyl-Ci_8alkyl)(Ci_8alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-heterocyclyl).
  • heterocyclyl-Ci_ 8 alkyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-NH-Ci_8alkyl-heterocyclyl.
  • heterocyclyl-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl-heterocyclyl) 2 .
  • heterocyclyl-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-N(Ci_8alkyl)(Ci_8alkyl-heterocyclyl).
  • heterocyclyl-amino refers to a radical of the
  • (heterocyclyl)(Ci_ 8 alkyl)amino refers to a radical of the formula: -N(Ci_8alkyl)(heterocyclyl).
  • heterocyclyl-amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_8alkyl-NH-heterocyclyl.
  • heterocyclyl-carbonyl refers to a radical of the
  • heterocyclyl-carbonyl-oxy refers to a radical of the formula: -0-C(0)-heterocyclyl.
  • heterocyclyl-oxy refers to a radical of the
  • hydroxy refers to a radical of the formula: -OH.
  • hydroxy-Ci.galkoxy-Ci.galkyl refers to a radical of the formula: -Ci_ 8 alkyl-0-Ci_ 8 alkyl-OH.
  • hydroxy-Ci_ 8 alkyl refers to a radical of the
  • hydroxy-Ci_8alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-OH.
  • (hydroxy-Ci_ 8 alkyl) 2 -amino refers to a radical of the formula: -N(Ci_ 8 alkyl-OH) 2 .
  • hydroxy-Ci_8alkyl)(Ci_8alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-OH).
  • hydroxy-Ci.galkyl-amino-Ci.galkyl refers to a radical of the formula: -Ci_ 8 alkyl-NH-Ci_ 8 alkyl-OH.
  • (hydroxy-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl-OH) 2 .
  • hydroxy-Ci_ 8 alkyl)(Ci_ 8 alkyl)amino-Ci_ 8 alkyl refers to a radical of the formula: -Ci_ 8 alkyl-N(Ci_ 8 alkyl)(Ci_ 8 alkyl-OH).
  • hydroxy-Ci_8alkyl-amino-Ci_8alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-NH-Ci_ 8 alkyl-OH.
  • (hydroxy-Ci_ 8 alkyl) 2 -amino-Ci_ 8 alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-N(Ci_ 8 alkyl-OH) 2 .
  • hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkoxy refers to a radical of the formula: -0-Ci_ 8 alkyl-N(Ci_ 8 alkyl)(Ci_ 8 alkyl-OH).
  • hydroxy-Ci_8alkyl-amino-Ci_8alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-NH-Ci_ 8 alkyl-OH.
  • hydroxy-Ci_8alkyl-amino-Ci_8alkyl) 2 -amino refers to a radical of the formula: -N(Ci_ 8 alkyl-NH-Ci_ 8 alkyl-OH) 2 .
  • (hydroxy-Ci_8alkyl) 2 -amino-Ci_8alkyl-amino refers to a radical of the formula: -NH-Ci_ 8 alkyl-N(Ci_ 8 alkyl-OH) 2 .
  • hydroxy-Ci_8alkyl-amino-Ci_8alkyl)(Ci_8alkyl)amino refers to a radical of the formula: -N(Ci_ 8 alkyl)(Ci_ 8 alkyl-NH-Ci_ 8 alkyl-OH).
  • the term "[(hydroxy-Ci_8alkyl) 2 -amino-Ci_8alkyl](Ci_8alkyl)amino” refers to a radical of the formula: -N(Ci_ 8 alkyl)[Ci_ 8 alkyl-N(Ci_ 8 alkyl-OH) 2 ].
  • the term "(hydroxy-Ci_8alkyl)(Ci_8alkyl)amino-Ci_8alkyl-amino” refers to a radical of the formula: -NH-Ci_ 8 alkyl-N(Ci_ 8 alkyl,Ci_ 8 alkyl-OH).
  • substituted 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.
  • each selected refers 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.
  • 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.
  • each instance of when used in a phrase such as "...aryl, aryl-Ci_ 8 alkyl, heterocyclyl and heterocyclyl-Ci_ 8 alkyl, 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-Ci_galkyl and heterocyclyl-Ci.galkyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • aberrant amount 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.
  • 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.
  • the term "substantial change" in the context of the amount of one or more R A transcripts e.g., rR A, tR A, 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.
  • 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.
  • the subject is a mammal or a warm-blooded vertebrate animal.
  • the subject is a non-human animal.
  • the subject is a human.
  • a compound of Formula (I) or a form thereof is used to inclusively refer to a compound of Formula (la) or a form thereof, a compound of Formula (lal) or a form thereof, a compound of Formula (Ia2) or a form thereof, a compound of Formula (II) or a form thereof, a compound of Formula (Ila) or a form thereof, a compound of Formula (Hal) or a form thereof, a compound of Formula (IIa2) or a form thereof, a compound of Formula (III) or a form thereof, a compound of Formula (Ilia) or a form thereof, a compound of Formula (Illal) or a form thereof, a compound of Formula (IIIa2) or a form thereof, a compound of Formula (IV) or a form thereof, a compound of Formula (IVa form thereof, a compound of Formula (IVa form thereof, a compound of Formula (IVa form thereof, a compound of Formula (IVa form thereof, a compound of Formula (IVa form
  • a compound of Formula (I) is intended to be inclusive of compounds of Formula (la), Formula (Ial), Formula (Ia2), Formula (II), Formula (Ila), Formula (Hal), Formula (IIa2), Formula (III), Formula (Ilia), Formula (Illal), Formula (IIIa2), Formula (IV), Formula (IVa), Formula (IVal), Formula (IV a2), Formula (V), Formula (Va), Formula (Val) and Formula (Va2).
  • 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.
  • the form of the compound of Formula (I) is a selected from a salt, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
  • the form of the compound of Formula (I) is a selected from a free acid, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
  • the form of the compound of Formula (I) is a selected from a free base, isotopologue, stereoisomer, racemate, enantiomer, diastereomer or tautomer thereof.
  • the form of the compound of Formula (I) is a free acid, free base or salt thereof.
  • the form of the compound of Formula (I) is an isotopologue thereof.
  • the form of the compound of Formula (I) is a stereoisomer, racemate, enantiomer or diastereomer thereof.
  • the form of the compound of Formula (I) is a tautomer thereof.
  • the form of the compound of Formula (I) is a pharmaceutically acceptable form.
  • the compound of Formula (I) or a form thereof is isolated for use.
  • 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.
  • 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.
  • Prodrugs of a compound of Formula (I) or a form thereof are also contemplated herein.
  • 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 Principles and Springer Press, 2007.
  • a prodrug 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.
  • a prodrug 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.
  • a prodrug 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • the compounds of Formula (I) described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer.
  • the compounds of Formula (I) described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer.
  • 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.
  • 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.
  • 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%.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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 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 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 optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher'
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered part of this description.
  • salts salts, prodrugs and transformed prodrugs of all contemplated isotopologues, stereoisomers, racemates or tautomers of the instant compounds.
  • 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.
  • isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as H 2 , H 3 , C 13 , C 14 , N 15 , O 18 , O 17 , P 31 , P 32 , S 35 , F 18 , CI 35 and CI 36 , respectively, each of which is also within the scope of this description.
  • isotopically-enriched compounds described herein are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., H 3 ) and carbon-14 (i.e., C 14 ) 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.
  • the deuterium-to-hydrogen ratio on the deuterated atoms of the molecule substantially exceeds the naturally occurring deuterium- to-hydrogen ratio.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • hydrate means a solvate wherein the solvent molecule is water.
  • RNA transcripts e.g., pre-mRNA or mRNA transcripts or isoforms thereof
  • the gene is not the SMN2 gene.
  • RNA transcripts e.g., pre-mRNA or mRNA transcripts or isoforms thereof
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • RNA transcript e.g., an mRNA transcript
  • 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 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.
  • a negative control e.g., a vehicle
  • 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.
  • 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.
  • 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.
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA 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.
  • a negative control e.g
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA 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
  • the RNA transcript is an RNA transcript encoded by a gene in Table 1 , Table 2, or Table 4 infra.
  • 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.
  • the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
  • RNA transcript e.g., an mRNA transcript
  • 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-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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • RNA transcript e.g., an mRNA transcript
  • 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 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.
  • a negative control e.g.,
  • the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors.
  • the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors.
  • the cell-free system comprises purely synthetic RNA and nuclear extract.
  • the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract.
  • the cell-free system comprises purely synthetic RNA and whole cell extract.
  • the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract.
  • the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs).
  • the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra.
  • 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.
  • 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 regulatory RNAs (e.g., microRNAs).
  • the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra.
  • 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.
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the splicing of an RNA 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
  • the cell-free system comprises purely synthetic RNA, synthetic or recombinant (purified) enzymes, and protein factors.
  • the cell-free system comprises RNA transcribed from a synthetic DNA template, synthetic or recombinant (purified) enzymes, and protein factors.
  • the cell-free system comprises purely synthetic RNA and nuclear extract.
  • the cell-free system comprises RNA transcribed from a synthetic DNA template and nuclear extract.
  • the cell-free system comprises purely synthetic RNA and whole cell extract.
  • the cell-free system comprises RNA transcribed from a synthetic DNA template and whole cell extract.
  • the cell-free system additionally comprises regulatory RNAs (e.g., microRNAs).
  • the RNA transcript is an RNA transcript encoded by a gene Table 1, Table 2, or Table 4, infra.
  • 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.
  • the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
  • RNA transcript ⁇ e.g., an mRNA transcript
  • 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA 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
  • the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra.
  • 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.
  • 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
  • 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.
  • RNA transcript e.g., an mRNA transcript
  • the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a primary cell(s) from a subject.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell.
  • the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is from a cell line.
  • 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.
  • 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.
  • 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.
  • the cell(s) contacted or cultured with a compound of Formula (I) or a form thereof is a cancer cell line.
  • 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, Ku
  • RNA transcript ⁇ e.g., an mRNA transcript
  • 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • RNA transcript e.g., an mRNA transcript
  • 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 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.
  • a negative control e.g., a vehicle control, such as PBS or DMSO
  • tissue sample containing cells may be used in the accordance with these methods.
  • 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.
  • the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra.
  • 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.
  • 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.
  • 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.
  • the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
  • a dose-response assay is performed.
  • 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • 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.
  • a negative control e.g., a vehicle control such as PBS or DMSO
  • 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.
  • 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).
  • a negative control e.g. , a vehicle control such as PBS or DMSO
  • 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.
  • 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 R A 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.
  • 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.
  • a dose-response assay is performed as described in Example 2, infra.
  • 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.
  • 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.
  • 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 ⁇ , 0.05 ⁇ , 1 ⁇ , 2 ⁇ , 5 ⁇ , 10 ⁇ , 15 ⁇ , 20 ⁇ , 25 ⁇ , 50 ⁇ , 75 ⁇ , 100 ⁇ , or 150 ⁇ .
  • 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 ⁇ , 200 ⁇ , 250 ⁇ , 275 ⁇ , 300 ⁇ , 350 ⁇ , 400 ⁇ , 450 ⁇ , 500 ⁇ , 550 ⁇ 600 ⁇ , 650 ⁇ , 700 ⁇ , 750 ⁇ , 800 ⁇ , 850 ⁇ , 900 ⁇ , 950 ⁇ or 1 mM.
  • 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.
  • 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 ⁇ to 0.1 ⁇ , 0.1 ⁇ to 1 ⁇ , 1 ⁇ to 50 ⁇ , 50 ⁇ to 100 ⁇ , 100 ⁇ to 500 ⁇ , 500 ⁇ 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.
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA 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.
  • an RNA transcript e.g., an mRNA transcript
  • RNA transcript e.g., an mRNA transcript
  • a method for determining whether a compound of Formula (I) or a form thereof modulates the amount of an RNA 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 modul
  • 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.
  • 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.
  • 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.
  • the RNA transcript is an RNA transcript encoded by a gene in Table 1 or Table 2, infra.
  • 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.
  • 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.
  • 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.
  • the amount of the RNA transcript(s) or splice variant(s) encoded by the SMN2 gene are not measured.
  • the compound of Formula (I) or a form thereof is administered in a subject in a pharmaceutically acceptable carrier, excipient or diluent.
  • 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 (II), Formula (III), Formula (IV) or Formula (V).
  • 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.
  • RNA transcript(s) may be determined using techniques known to one skilled in the art.
  • 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).
  • 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).
  • the amount of multiple RNA transcripts is measured using an exon array, such as the
  • 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. [00373] In some embodiments, a statistical analysis or other analysis is performed on data from the assay utilized to measure an R A 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.
  • the student t-test value of those RNA transcripts with the alternation is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%.
  • p value of those RNA transcripts with the alternation is 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%.
  • 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.
  • 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 RNA transcript(s).
  • 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
  • SAGE serial analysis of gene expression
  • DD differential display analysis
  • RAP RNA arbitrarily primer
  • READS restriction endonuclease-lytic analysis of differentially expressed sequences
  • AFP amplified restriction fragment-length polymorphism
  • TOGA total gene expression analysis
  • RT-PCR RT-qPCR
  • RNA transcripts are determined by Northern blots, RNase protection, or slot blots.
  • 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.
  • an inhibitor of transcription such as a-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D.
  • 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.
  • an inhibitor of transcription such as a-amanitin, DRB, flavopiridol, triptolide, or actinomycin-D
  • 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.
  • the amount of alternatively spliced forms of the RNA transcripts of a particular gene 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.
  • 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).
  • the levels of spliced forms of RNA are quantified by RT-PCR, RT-qPCR, or northern blotting.
  • sequence-specific techniques may be used to detect the levels of an individual spliceoform.
  • splicing is measured in vitro using nuclear extracts.
  • 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 RNA transcript of a gene and alterations in the amount of an isoform encoded by a gene.
  • a compound of Formula (I) or a form thereof is preferably administered as a component of a composition that optionally comprises a
  • compositions 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.
  • Methods of administration include, but are not limited to, parenteral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracoluar, intratumoral, 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.
  • 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.
  • 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.
  • 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 (xi) reduces or amelior
  • 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.
  • 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.
  • 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.
  • a gene e.g., a gene in Table 1 or Table 2, infra
  • 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).
  • 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.
  • 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.
  • 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 RNA 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.
  • 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.
  • an isoform of gene e.g. , a gene in Table 1 or Table 2, infra
  • Non-limiting examples of effective amounts of a compound of Formula (I) or a form thereof are described herein.
  • 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.
  • a disease associated with the aberrant amount of an mRNA transcript of gene e.g., a gene in Table 1 or Table 2, infra
  • 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.
  • 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.
  • 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.
  • Embodiments described herein include the use of a compound of Formula (I) or a form thereof in a pharmaceutical composition.
  • 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.
  • the human subject is a patient with a disease associated with the aberrant amount of an mRNA transcript(s).
  • 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.
  • 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.
  • 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.
  • carrier refers to a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle with which a therapeutic agent is administered.
  • 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.
  • 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.
  • 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.
  • 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.
  • dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art.
  • excipients that can be used in oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants.
  • RNA transcripts e.g. , pre-mRNA or mRNA transcripts or isoforms thereof
  • a method for modulating the amount of one or more RNA transcripts comprising contacting a compound of Formula (I) or a form thereof with a cell(s).
  • the RNA transcript(s) is not encoded by the SMN2 gene.
  • RNA transcripts e.g. , pre -mRNA or mRNA transcripts or isoforms thereof
  • a method for modulating the amount of one, two or more RNA transcripts comprising contacting a compound of Formula (I) or a form thereof with a cell(s).
  • 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).
  • the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture.
  • 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.
  • RNA isoforms encoded by one or more genes, comprising contacting a compound of Formula (I) or a form thereof with a cell(s).
  • the RNA isoform(s) is not encoded by the SMN2 gene.
  • 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).
  • the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture.
  • 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.
  • 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).
  • the protein isoform(s) is not encoded by the SMN2 gene.
  • 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).
  • the cell(s) is contacted with a compound of Formula (I) or a form thereof in cell culture.
  • 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.
  • RNA transcripts e.g., pre-mRNA or mRNA transcripts or iso forms thereof
  • a method for modulating the amount of one or more RNA transcripts comprising culturing a cell(s) in the presence of a compound of Formula (I) or a form thereof.
  • the RNA transcript(s) is not encoded by the SMN2 gene.
  • 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.
  • 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.
  • 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.
  • the RNA isoform(s) is not encoded by the SMN2 gene.
  • a methods 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.
  • 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.
  • 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.
  • the protein isoform(s) is not encoded by the SMN2 gene.
  • 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.
  • 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. [00401] 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).
  • 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.
  • 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, Ku81
  • 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.
  • 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.
  • 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 ⁇ , 0.05 ⁇ , 1 ⁇ , 2 ⁇ , 5 ⁇ , 10 ⁇ , 15 ⁇ , 20 ⁇ , 25 ⁇ , 50 ⁇ , 75 ⁇ , 100 ⁇ , or 150 ⁇ .
  • 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 ⁇ , 200 ⁇ , 250 ⁇ , 275 ⁇ , 300 ⁇ , 350 ⁇ , 400 ⁇ , 450 ⁇ , 500 ⁇ , 550 ⁇ 600 ⁇ , 650 ⁇ , 700 ⁇ , 750 ⁇ , 800 ⁇ , 850 ⁇ , 900 ⁇ , 950 ⁇ or 1 mM.
  • 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.
  • 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,
  • 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 ⁇ to 0.1 ⁇ , 0.1 ⁇ to 1 ⁇ , 1 ⁇ to 50 ⁇ , 50 ⁇ to 100 ⁇ , 100 ⁇ to 500 ⁇ , 500 ⁇ 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.
  • 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 R A transcript (e.g., an mR A transcript), an alternatively spliced variant, or an isoform of a gene in Table 1 or Table 2, infra.
  • a compound of Formula (I) e.g., an mR A transcript
  • an alternatively spliced variant e.g., an isoform of a gene in Table 1 or Table 2, infra.
  • RNA transcripts e.g. , pre-mRNA or mRNA transcripts or isoforms thereof
  • a method for modulating the amount of one or more RNA transcripts 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.
  • 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.
  • the RNA transcript(s) is not encoded by the SMN2 gene.
  • RNA transcripts e.g. , pre -mRNA or mRNA transcripts or isoforms thereof
  • 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.
  • 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.
  • a subject e.g., a non-human animal or a human
  • 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.
  • 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
  • RNA isoform(s) is not encoded by the SMN2 gene.
  • a methods 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.
  • 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.
  • a subject e.g., a non-human animal or a human
  • a pharmaceutical composition comprising a compound of Formula (I) or a form thereof and a pharmaceutically acceptable carrier, excipient, or diluent.
  • the protein isoform(s) is not encoded by the SMN2 gene.
  • 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.
  • a subject e.g., a non-human animal or a human
  • 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.
  • 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 (II), Formula (III), Formula (IV) or Formula (V).
  • 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.
  • 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.
  • a compound of Formula (I) or a form thereof modulates the stability of an RNA transcript (e.g., mRNA transcript) of one, two, three or more genes in Table 1 or Table 2, infra.
  • 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.
  • 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.
  • 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.
  • 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.
  • a compound of Formula (I) or a form thereof may perturb a component of the pre-mRNA splicing process.
  • 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).
  • B3GNTL1 146712 transferase activity, transferring glycosyl groups
  • CN0T1 23019 poly(A)-specific ribonuclease activity
  • DRD4 1815 dopamine neurotransmitter receptor activity
  • DTNBP1 84062 positive regulation of neurotransmitter secretion
  • ENTPD6 955 guanosine-5'-triphosphate,3 '-diphosphate diphosphatase activity
  • EPB41 2035 structural constituent of cytoskeleton
  • GNPDA1 10007 glucosamine-6-phosphate deaminase activity
  • GPR88 54112 G-protein coupled receptor activity Gene GenelD Example of Associated Function

Abstract

La présente invention concerne des procédés permettant de moduler la quantité d'un produit génétique et des composés destinés à être utilisés dans de tels procédés. Plus particulièrement, l'invention concerne des procédés permettant de moduler la quantité d'un produit de la transcription d'ARN ou d'un produit protéinique résultats de l'expression génétique et des composés destinés à être utilisés dans de tels procédés.
PCT/US2014/071029 2013-12-19 2014-12-18 Procédés pour la modulation de la quantité de produits de la transcription d'arn WO2015095446A1 (fr)

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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
US10668171B2 (en) 2015-05-30 2020-06-02 Ptc Therapeutics, Inc. Methods for modulating RNA splicing
US11602567B2 (en) 2015-05-30 2023-03-14 Ptc Therapeutics, Inc. Methods for modulating RNA splicing
US10874672B2 (en) 2015-12-10 2020-12-29 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US10881658B2 (en) 2015-12-10 2021-01-05 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11638706B2 (en) 2015-12-10 2023-05-02 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11702646B2 (en) 2016-11-28 2023-07-18 Ptc Therapeutics, Inc. Methods for modulating RNA splicing
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
US11395822B2 (en) 2017-06-28 2022-07-26 Ptc Therapeutics, Inc. Methods for treating Huntington's disease
US11382918B2 (en) 2017-06-28 2022-07-12 Ptc Therapeutics, Inc. Methods for treating Huntington's Disease
US11780839B2 (en) 2018-03-27 2023-10-10 Ptc Therapeutics, Inc. Compounds for treating Huntington's disease
US11685746B2 (en) 2018-06-27 2023-06-27 Ptc Therapeutics, Inc. Heteroaryl compounds for treating Huntington's disease
US11858941B2 (en) 2018-06-27 2024-01-02 Ptc Therapeutics, Inc. Heterocyclic and heteroaryl compounds for treating Huntington's disease

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