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WO2025099307A1 - Compounds and pharmaceutical compositions thereof for the treatment of diseases - Google Patents

Compounds and pharmaceutical compositions thereof for the treatment of diseases Download PDF

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Publication number
WO2025099307A1
WO2025099307A1 PCT/EP2024/081787 EP2024081787W WO2025099307A1 WO 2025099307 A1 WO2025099307 A1 WO 2025099307A1 EP 2024081787 W EP2024081787 W EP 2024081787W WO 2025099307 A1 WO2025099307 A1 WO 2025099307A1
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WIPO (PCT)
Prior art keywords
alkyl
cancer
independently selected
alkoxy
optionally substituted
Prior art date
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Pending
Application number
PCT/EP2024/081787
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French (fr)
Inventor
Jacques Huck
Sandrine Marie Helene Vendeville
Kenneth GOOSSENS
Pierre Jean-Marie Bernard Raboisson
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Galapagos NV
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Galapagos NV
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Publication of WO2025099307A1 publication Critical patent/WO2025099307A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D411/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and/or treatment of proliferative diseases by administering the compounds of the invention.
  • the compounds of the invention may inhibit SMARCA2 and/or SMARCA4.
  • l ldependent chromatin remodelers with vital roles in various cellular processes, including transcription, DNA repair, and replication, achieved by regulating DNA accessibility.
  • SWI/SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A member 2 (SMARCA2, Brahma, or BRM) and SWI/SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A, member 4 (SMARCA4 or BRG1)
  • SMARCA2 Stimulon-associated, Actin-dependent Regulator of Chromatin, subfamily A member 2
  • SMARCA4 or BRG1 stand out as subunits that contain catalytic ATPase domains, essential for the SWI/SNF complex function. They perturb histone-DNA contacts, thereby providing access points for transcription factors and DNA elements that regulate gene activation and repression.
  • SMARCA2 and SMARCA4 share a high degree of similarity, up to 75%, and both contain a DNA- stimulated, conserved ATPase domain driving chromatin-remodeling activity.
  • SMARCA4 is frequently mutated, particularly in lung, melanoma, liver, and pancreatic cancers.
  • SMARCA4-deleted cancer cells SMARCA2's ATPase activity becomes critical for chromatin remodeling, which is essential for functions like cell proliferation, survival, and growth. Consequently, targeting SMARCA2 may hold promise as a therapeutic approach for SMARCA4-deleted or deficient cancers, e.g.
  • SMARCA4 represents a therapeutic strategy for the treatment of SMARCA2-deficient cancers (Ehrenhbfer-Wblfer et al. 2019).
  • the present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of proliferative diseases.
  • the compounds of the invention may be ATPase inhibitors, and more particularly SMARCA2 and/or SMARCA4 inhibitors.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of proliferative diseases by administering the compounds of the invention.
  • A is phenyl or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;
  • X is N or CH
  • R 3 is H or C1-6 alkyl; each R 4a and R 4b is independently H or C1-6 alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy;
  • R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R 7 ;
  • R 6 is H, halo, or C1-6 alkyl; each R 7 is independently selected from oxo,
  • Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO 2 R 9a or Ci -4 alkoxy,
  • Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci- 4 alkoxy,
  • C3-6 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,
  • each R 8a is independently H or C1-4 alkyl
  • each R 8b is independently H, C1-4 alkyl or -C(O)Ci. 2 alkyl
  • each R 9a is independently selected from hydrogen and C1-4 alkyl
  • R 9b is hydrogen, C1-4 alkyl or C1-4 alkoxy, or R 9a and R 9b together with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compounds of the invention are provided for use in the prophylaxis and/or treatment of proliferative diseases.
  • Certain compounds according to the invention may also exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and/or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drugdrug interaction (DDI) or CYP -interaction characteristics, etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.
  • improved safety characteristics e.g. relating to hERG inhibition, drugdrug interaction (DDI) or CYP -interaction characteristics, etc
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • the further therapeutically active ingredient is an agent for the treatment of proliferative diseases.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly proliferative diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine.
  • the pharmaceutical composition is for use in the prophylaxis and/or treatment of proliferative diseases.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • -CONH2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group.
  • a squiggly line on a chemical group as shown, for example ⁇ / ⁇ '''' ⁇ indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.
  • C u -v indicates that the following group has from u to v carbon atoms.
  • C1-8 alkyl indicates that the alkyl group has from 1 to 8 carbon atoms.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the singular forms "a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • Alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), w-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), w-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-C(CH 3 ) 3 ), sec-butyl (-CH(CH3)-CH 2 CH 3 ), isobutyl (-CH 2 -CH(CH 3 )2), w-pcntyl (-CH2-CH2-CH2-CH3), w-hcx l (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CH(CH3)-CH(CH3)-CH2-CH3).
  • Particular alkyl groups have between 1 and 4 carbon atoms.
  • Alkylene refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.
  • Alkoxy refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified.
  • the term refers to the group -O-Ci e alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, w-propoxy. isopropoxy, w-butoxy. /c/7-butoxy. scc-butoxy. w-pcntoxy. w-hcxoxy. and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Amino refers to the radical -NH2.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • Cycloalkyl refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified.
  • a cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Cyano refers to the radical -CN.
  • Halo or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • polycyclic refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described previously such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • Heteroaryl means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the aromatic ring structure may have from 5 to 9 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • Heterocycloalkyl means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1 -tetrahydrofuranyl, 2-tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1 -tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g.
  • fused bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
  • bridged bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N or CH.
  • each Y is selected from -CH2-, -NH-, -O- and -S-.
  • Haldroxyl refers to the radical -OH.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • substituted with one or more refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic acid addition salts and base addition salts.
  • salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011).
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, and such as, e.g., sodium hydroxide for forming basic salts.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, EtOH, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. 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.
  • Solvate’ encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans.
  • the terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
  • Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylaxis is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treating” or “treatment” relates to slowing the progression of the disease.
  • the term ‘proliferative disease(s)’ refers to diseases associated with excessive proliferation of cells and turnover of cellular matrix.
  • the term refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis.
  • cancer e.g. uterine leiomyosarcoma or prostate cancer
  • myeloproliferative disorders e.g. polycythemia vera, essential thrombocytosis and myelofibrosis
  • leukemia e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia
  • multiple myeloma
  • Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof selectively target SMARCA2.
  • certain compounds of formula (I), or a pharmaceutically acceptable salt thereof selectively target SMARCA2 over SMARCA4.
  • certain compounds of formula (I), or a pharmaceutically acceptable salt thereof are at least about 3 fold (e.g. at least about 4-, 5- , 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-fold, or more) more selective for SMARCA2 than for SMARCA4.
  • the term "selectivity" of a compound refers to the compound having more potent activity at the first target than the second target.
  • a fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value of a compound for the second target (e.g., SMARCA4) by the IC50 value of the same compound for the first target (e.g., SMARCA2).
  • An IC50 value can be determined by any method known in the art. For example, an IC50 value can be determined as described in the assays below.
  • cancer refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel.
  • a cancer tends to infiltrate into adjacent tissue and spread (metastasize) to distant organs, for example to bone, liver, lung or the brain.
  • cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer,
  • cancer refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, reti
  • leukemia refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
  • leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), chlorine-37 ( 37 C1), fluorine-18 ( 18 F) iodine-123 ( 123 I), iodine-125 ( 125 I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • an artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e 2 H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as n C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Tomography
  • stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • An optical isomer with unknown absolute configuration may be depicted with an asterix (*) at the .
  • stereocenters with unknown absolute configuration may be depicted with an asterix (*), e.g. R* and/or S*.
  • the present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of proliferative diseases.
  • the compounds of the invention may be SMARCA2 and/or SMARCA4 inhibitors, and more particularly SMARCA2 inhibitors.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of proliferative diseases by administering the compounds of the invention.
  • A is phenyl or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;
  • X is N or CH
  • R 3 is H or C1-6 alkyl; each R 4a and R 4b is independently H or C1-6 alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy;
  • R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R 7 ;
  • R 6 is H, halo, or Ci-6 alkyl; each R 7 is independently selected from oxo,
  • Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO 2 R 9a or Ci -4 alkoxy,
  • Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci- 4 alkoxy,
  • C3-6 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,
  • each R 8a is independently H or C1-4 alkyl
  • each R 8b is independently H, C1-4 alkyl or -C(O)Ci. 2 alkyl
  • each R 9a is independently selected from hydrogen and C1-4 alkyl
  • R 9b is hydrogen, C1-4 alkyl or C1-4 alkoxy, or R 9a and R 9b together with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
  • Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and/or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP-interaction characteristics, etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.
  • improved safety characteristics e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP-interaction characteristics, etc
  • the compound of the invention is according to Formula I, wherein R 3 is H.
  • the compound of the invention is according to Formula I, wherein R 3 is Ci-6 alkyl.
  • R 3 is -CH3, -CH2CH3, -CH(CH3)2, -C(CHs)3, -CH2CH2CH3, -CH 2 CH(CH 3 )2, -CH(CH 3 )CH 2 CH3, -CH 2 C(CH 3 )3, -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 )2CH 2 CH3,
  • R 3 is -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -CH2CH2CH3, -CH 2 CH(CH 3 )2, or -CH(CH 3 )CH 2 CH3. In a most particular embodiment, R 3 is -CH3.
  • the compound of the invention is according to Formula I, wherein R 4a is H.
  • the compound of the invention is according to Formula I, wherein R 4a is C1-6 alkyl.
  • R 4a is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH 2 CH(CH 3 )2, -CH(CH 3 )CH 2 CH3, -CH 2 C(CH 3 )3, -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 )2CH 2 CH3,
  • R 4a is -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -CH2CH2CH3, -CH 2 CH(CH 3 )2, or -CH(CH 3 )CH 2 CH3. In a most particular embodiment, R 4a is -CH3.
  • the compound of the invention is according to Formula II: wherein A, X, Li, R 1 , R 2 , R 5 , R 6 , and the subscript n are as previously described.
  • the compound of the invention is according to Formula I or II, wherein X is N.
  • the compound of the invention is according to Formula I or II, wherein X is CH.
  • the compound of the invention is according to Formula I or II, wherein R 6 is H.
  • the compound of the invention is according to Formula I or II, wherein R 6 is halo.
  • R 6 is F, Cl, or Br.
  • R 6 is F or Cl.
  • the compound of the invention is according to Formula I or II, wherein R 6 is C1-6 alkyl.
  • R 6 is -CH3, -CH2CH3, -CH(CH3)2, -C(CHs)3, -CH2CH2CH3, -CH 2 CH(CH 3 )2, -CH(CH 3 )CH 2 CH3, -CH 2 C(CH 3 )3, -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 )2CH 2 CH3,
  • R 6 is -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 )CH 2 CH 3 . In a most particular embodiment, R 6 is -CH 3 .
  • the compound of the invention is according to Formula III:
  • the compound of the invention is according to any one of Formulae I-III, wherein A is phenyl.
  • the compound of the invention is according to any one of Formulae I-III, wherein A is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • A is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl.
  • A is pyrrolyl, pyrazolyl, imidazolyl, 1,2, 3 -triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl.
  • R 1 is pyrrolyl.
  • the compound of the invention is according to Formula IVa or IVb:
  • the compound of the invention is according to any one of Formulae I-IVb, wherein n is 0.
  • the compound of the invention is according to any one of Formulae I-IVb, wherein n is i.
  • the compound of the invention is according to any one of Formulae I-IVb, wherein n is 2.
  • the compound of the invention is according to Formula Va or Vb:
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R 1 is Ci-6 alkyl.
  • R 1 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)s, -CH2CH2CH3, -CH 2 CH(CH 3 )2, -CH(CH 3 )CH 2 CH3, -CH 2 C(CH 3 )3, -CH(CH 3 )CH(CH 3 )2, -C(CH 3 )2CH 2 CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2.
  • R 1 is -CH3, -CH2CH3, -CH(CH 3 ) 2 , -CH2CH2CH3, -CH 2 CH(CH 3 )2, or -CH(CH3)CH2CH3. In a most particular embodiment, R 1 is -CH 3 .
  • each R 2 is independently selected C1-6 alkyl.
  • each R 2 is independently -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH2CH2CH3, -CH 2 CH(CH 3 )2, -CH(CH 3 )CH 2 CH3, -CH 2 C(CH 3 )3, -CH(CH 3 )CH(CH 3 )2, -C(CH 3 )2CH 2 CH3, -CH(CH 3 )C(CH 3 )3, or -C(CH3)2C(CH 3 ) 2 .
  • each R 2 is independently -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH 2 CH(CH 3 )2, or -CH(CH3)CH2CH3. In a most particular embodiment, each R 2 is -CH3.
  • R 1 and one R 2 together with the atoms onto which they are attached form a 1,1-dioxidotetrahydrothiophenyl, l .
  • the compound of the invention is according to Formula Va, wherein R 1 and one R 2 together with the atoms onto which they are attached form
  • the compound of the invention is according to Formula Via, VIb, or Vic:
  • the compound of the invention is according to any one of Formulae I-VIc, wherein Li is a bond.
  • the compound of the invention is according to any one of Formulae I-VIc, wherein Li is Ce-io aryl.
  • Li is phenyl or naphthyl.
  • Li is phenyl.
  • Li is a most particular embodiment, Li is
  • the compound of the invention is according to any one of Formulae I-VIc, wherein Li is Ce-io aryl substituted with one or more independently selected halo, C1.4 alkyl, or C1-4 alkoxy.
  • Li is phenyl or naphthyl, each of which is substituted with one or more independently selected halo, C1-4 alkyl, or C1-4 alkoxy.
  • Li is Ce-io aryl substituted with one, two, or three independently selected halo, C1.4 alkyl, or C1.4 alkoxy.
  • Li is Ce-io aryl substituted with one or more independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH 3 ) 2 , -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • Li is phenyl or naphthyl, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH 3 ) 2 , -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • Li is phenyl substituted with one, two, or three independently selected F, Cl, -CH3, or-O-CH ,.
  • Li is , each of which is substituted with one, two, or three independently selected F, Cl, -CH3, or -O-CH3.
  • the compound of the invention is according to any one of Formulae I-VIc, wherein Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • Li is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl.
  • Li is pyrazolyl or pyridinyl.
  • Li is pyrazolyl or pyridinyl.
  • Li is pyrazolyl or pyridinyl.
  • Li is pyrazolyl or pyridinyl.
  • the compound of the invention is according to any one of Formulae I-VIc, wherein Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected halo, C1-4 alkyl, or C1-4 alkoxy.
  • Li is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl, each of which is substituted with one or more independently selected halo, C1-4 alkyl, or C1-4 alkoxy.
  • Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected halo, C1-4 alkyl, or C1-4 alkoxy.
  • Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • Li is phenyl or naphthyl, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • Li is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl, each of which is substituted with one, two, or three independently selected F, Cl, -CH3, or -O-CH3. In a most particular embodiment, , each of which is substituted with one, two, or three independently selected F, Cl, -CH3, or -O-CH3.
  • the compound of the invention is according to any one of Formulae I-VIc,
  • R 5 is as previously described.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl.
  • R 5 is phenyl or naphthyl.
  • R 5 is phenyl.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl substituted with one or more independently selected R 7 .
  • R 5 is phenyl or naphthyl, each of which is substituted with one or more independently selected R 7 .
  • R 5 is Ce-io aryl substituted with one, two, or three independently selected R 7 .
  • R 5 is phenyl or naphthyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 5 is phenyl substituted with one, two, or three independently selected R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R 5 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridin
  • R 5 is pyridinyl, pyrazolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2, 3, 4- tetrahydroisoquinolinyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinyl.
  • R 5 is pyridinyl, pyrazolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2, 3, 4- tetrahydroisoquinolinyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinyl.
  • R 5 is pyridinyl, pyrazolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2, 3, 4- tetrahydroisoquinolinyl, 3,4-dihydro-2H-pyrido[3,2-b][
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected R 7 .
  • R 5 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridin
  • R 5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected R 7 .
  • R 5 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl
  • R 5 is pyrazolyl or indolyl, each of which is substituted with one, two, or three independently selected R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R 5 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
  • R 5 is piperidinyl or morpholinyl.
  • R 5 is .
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 5 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R 7 .
  • R 5 is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R 7 .
  • R 5 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 5 is piperidinyl, piperazinyl, or morpholinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 5 is piperidinyl, piperazinyl, or morpholinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , R 7 is -NR 8a R 8b , and R 8a and R 8b are independently H or Ci-4 alkyl. In a particular embodiment, R 8a and R 8b are both H.
  • R 8a and R 8b are H, and the other is C1-4 alkyl. In yet another particular embodiment, R 8a and R 8b are both independently C1-4 alkyl. In a more particular embodiment, one of R 8a and R 8b is H, and the other is -CH3, -CH2CH3, or -CH( CHV. In another more particular embodiment, R 8a and R 8b are both independently -CH3, -CH2CH3, or -CH( 013)2. In a most particular embodiment, R 8a and R 8b are both -CH3.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , and R 7 is C1-4 alkyl.
  • R 7 is -CH3, -CH2CH3, -CH( 013)2.
  • R 7 is -CH3.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , and R 7 is C1-4 alkyl substituted with one or more independently selected halo, -CN, or C1.4 alkoxy.
  • R 7 is -CH3, -CH2CH3, -CHfCHV. each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy.
  • R 7 is C1-4 alkyl substituted with one, two, or three independently selected halo, -CN, or C1.4 alkoxy.
  • R 7 is C1.4 alkyl substituted with one or more independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • R 7 is -CH3, -CH2CH3, -CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • R 7 is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected F, -CN, or -O-CH3.
  • R 7 is -CHF2, -CF3, -CH2CN, or -CH2CH2CN.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , and R 7 is C1.4 alkoxy.
  • R 7 is -O-CH3, -O-CH2CH3, -O-CH(CH3)2.
  • R 7 is -O-CH3.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , and R 7 is C1-4 alkoxy substituted with one or more independently selected halo, -CN, or C1-4 alkoxy.
  • R 7 is -O-CH3, -O-CH2CH3, -O-CH(CH3)2, each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy.
  • R 7 is C1.4 alkoxy substituted with one, two, or three independently selected halo, -CN, or C1.4 alkoxy.
  • R 7 is C1.4 alkoxy substituted with one or more independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • R 7 is -O-CH3, -O-CH2CH3, -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • R 7 is -O-CH3 or -O-CH2CH3, each of which is substituted with one, two, or three independently selected F, -CN, or -O-CH3.
  • R 7 is -O-CHF2, -O-CFs. or -O-CH2CH2-O-CH3.
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , and R 7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S.
  • R 7 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5- thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 1- azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4-azaspiro[2.4]heptanyl,
  • R 7 is azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, or 2- oxaspiro [3.3 ]heptanyl .
  • the compound of the invention is according to any one of Formulae I-VIIr, wherein R 5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R 7 , and R 7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy.
  • R 7 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4- azaspiro[2.3]hexanyl, 5-thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4- oxaspiro[2.3]hexanyl, l-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4- azaspiro[2.4]heptanyl, 4-
  • R 7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1-4 alkoxy.
  • R 7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2.
  • R 7 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5- thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 1- azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4-azaspiro[2.4]heptanyl, 4-azaspiro
  • R 7 is azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, or 2- oxaspiro[3.3]heptanyl, each of which is substituted with one, two, or three independently selected oxo, F, Cl, Br, -OH, -CN, -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -O-CH3, -O-CH2CH3, or -O-CH(CH 3 ) 2 .
  • oxo F, Cl, Br, -OH, -CN, -CH 3 , -CH2CH3, -CH(CH 3 ) 2 , -O-CH3, -O-CH2CH3, or -O-CH(CH 3 ) 2 .
  • the compound of the invention is selected from:
  • N-([3,4'-bipyridin]-2'-ylmethyl)-4-methyl-3-(methylsulfonyl)benzamide N-((4-phenylpyridin-2-yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide, 4-methyl-N-((4-(l-methyl-lH-indol-3-yl)pyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((4-phenylpyridin-2-yl)methyl)benzamide,
  • the compound of the invention is N-((4-([l,l'-biphenyl]-3-yl)pyridin-2- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. [0131] In one embodiment, the compound of the invention is not N-((4-([l,l'-biphenyl]-3-yl)pyridin-2- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.
  • the compound of the invention is N-((4-([l,T-biphenyl]-3-yl)pyridin-2- yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide.
  • the compound of the invention is not N-((4-([l,T-biphenyl]-3-yl)pyridin-2- yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide.
  • a compound of the invention is provided in a natural isotopic form.
  • a compound of the invention is provided in an unnatural variant isotopic form.
  • the unnatural variant isotopic form is a form in which deuterium (i.e. 2 H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention.
  • the atoms of the compounds of the invention are in an isotopic form which is not radioactive.
  • one or more atoms of the compounds of the invention are in an isotopic form which is radioactive.
  • radioactive isotopes are stable isotopes.
  • the unnatural variant isotopic form is a pharmaceutically acceptable form.
  • a compound of the invention whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms.
  • unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of the compound.
  • a preferred group of compounds according to the invention are those of formula 1-1
  • R 1 is C1-4 alkyl, C1-3 alkoxy(Ci-3)alkyl, or hydroxy(Ci-3)alkyl;
  • R 2b is hydrogen, fluoro, chloro, methyl or ethyl (preferably hydrogen);
  • R 3 is hydrogen or C1-2 alkyl (preferably hydrogen); each of R 4a andR 4b is independently hydrogen, methyl or ethyl;
  • R 5 is phenyl, pyridyl, pyrimidinyl, pyrrolyl, each of which is optionally substituted with one, two or three independently selected R 7 ; or L1-R 5 together is an indole or benzofuran group, each of which is optionally substituted with one, two or three independently selected R 7 ;
  • R 6 is hydrogen, fluoro or methyl (preferably hydrogen); each R 7 is independently selected from
  • C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -CO2R 9a or Ci -4 alkoxy, Ci-4 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci -4 alkoxy,
  • C3-6 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, morpholino (preferably 1 -morpholino), oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl and
  • each R 8a is independently hydrogen or C1-4 alkyl
  • each R 8b is independently hydrogen, C1-4 alkyl or -C(O)Ci-2 alkyl
  • each R 9a is independently selected from hydrogen and C1-4 alkyl
  • R 9b is hydrogen, C1-4 alkyl or C1-4 alkoxy; or R 9a and R 9b together with the atoms onto which they are attached form a 5-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, Ci -4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
  • Another preferred group of compounds according to the invention are those of formula 1-2
  • R 1 is C1-2 alkyl (preferably methyl), C1-2 alkoxy (Ci-2)alkyl (preferably methoxymethyl), or hydroxy (C 1 _3)alkyl ;
  • R 2a is hydrogen, fluoro, chloro or C1-2 alkyl (preferably chloro or methyl); or R 1 and R 2a together with the atoms onto which they are attached form , which is optionally substituted with one or more independently selected halogens (preferably fluoro);
  • R 2b is hydrogen, fluoro, or methyl(preferably hydrogen);
  • R 3 is hydrogen or methyl (preferably hydrogen); each of R 4a and R 4b is independently hydrogen, or methyl;
  • R 5 is phenyl or pyridyl, each of which is optionally substituted with one or two independently selected R 7 ; each R 7 is independently selected from
  • Ci- 2 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -CO 2 R 9a or Ci- 2 alkoxy,
  • Ci- 2 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci- 2 alkoxy,
  • C3-6 cycloalkyl which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-2 alkyl, or C1-2 alkoxy, morpholino (preferably 1 -morpholino), oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl, and
  • each R 8a is independently hydrogen or C1-2 alkyl
  • each R 8b is independently hydrogen, C1-2 alkyl or -C(O)Ci. 2 alkyl
  • each R 9a is independently selected from hydrogen and C1-2 alkyl
  • R 9b is hydrogen, C1-2 alkyl or C1-2 alkoxy, or R 9a and R 9b together with the atoms onto which they are attached form a 5-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, Ci- 2 alkyl; and
  • Another preferred group of compounds according to the invention are those of formula 1-3 wherein,
  • R 1 is Cn 2 alkyl (preferably methyl), Ci- 2 alkoxy (Ci. 2 )alkyl (preferably methoxymethyl), or hydroxy (C i _3)alkyl ;
  • R 2 is hydrogen, fluoro, chloro or Ci- 2 alkyl (preferably chloro or methyl); substituted with one or more independently selected halogens (preferably fluoro);
  • R 3 is hydrogen or methyl (preferably hydrogen); each of R 4a andR 4b is independently hydrogen, or methyl (preferably both are hydrogen);
  • R 5 is phenyl or pyridyl, each of which is optionally substituted with one or two independently selected R 7 ; each R 7 is independently selected from
  • Cn 2 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -CO 2 R 9a or Ci- 2 alkoxy, Ci-2 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci -2 alkoxy, morpholino (preferably 1 -morpholino), and oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl; each R 8a is independently hydrogen or C1-2 alkyl; each R 8b is independently hydrogen, C1-2 alkyl or -C(O)Ci-2 alkyl; each R 9a is independently selected from hydrogen and C1-2 alkyl;
  • R 9b is hydrogen, or C1-2 alkyl
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, A-alkylmorpholinc esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
  • a compound of the invention When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a proliferative diseases treatment agent.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a cancer treatment agent.
  • the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-
  • the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblasto
  • the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a leukemia treatment agent.
  • a leukemia treatment agent refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphoblastic leukemia
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention according to Lormula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • a compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • a compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences (Remington & Gennaro 1985).
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • a compound ofthe invention according to Formula I may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
  • a compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75 °C and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of cancer.
  • the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • types of tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer
  • the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblasto
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cancer.
  • the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • types of tissue carcinoma such as but not limited to, color
  • the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblasto
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with cancer, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • types of tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma,
  • the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblasto
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of leukemia.
  • the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphoblastic leukemia
  • the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of leukemia.
  • the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphoblastic leukemia
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with leukemia, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • Injection dose levels range from about 0. 1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders
  • therapeutic agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.
  • the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
  • the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.
  • any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.
  • the compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer.
  • Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBridge BEH C18 OBD 30 mm ID x 100/150 mm L columns and ACN/water gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in water, or 10 mM NH4HCO3 in water (adjusted to pH 10 with ammonia), or on a Buchi® Pure C-850 Flash with UV and ESDL detection using Buchi® C18 AQ 100 A 250 x 20 mm column and using ACN/water gradients with either 0.1% formic acid in both mobile phases or 0.05% NH4OH in both mobile phases.
  • Step i To a solution of carboxylic acid (1 eq.) in DCM are added oxalyl chloride (2 eq.) and then a few drops of DMF (cat.). The reaction is stirred at RT for 30 min to 4 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to give the desired acyl chloride.
  • Step ii To a solution of acyl chloride (1.2 eq.) and amine (1 eq.) in DCM is added TEA (3 eq.). The reaction is stirred at RT for 30 min to 24 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to give the desired amide.
  • Pd(dppf)C12 (7.5 mg, 0.010 mmol, 0.1 eq.) was added to an N2-purged mixture of Int 50 (50 mg, 0.10 mmol, 1.0 eq.), 2-bromo-4-iodopyridine (CAS# 100523-96-4; 31 mg, 0.10 mmol, 1.0 eq.) and K2CO3 (20 mg, 0.21 mmol, 2.00 eq.) in 1,4-dioxane (2.0 mL) and H2O (0.6 mL). The reaction mixture was stirred at 60 °C for 1 h.
  • Pd(dppf)C12 (11 mg, 0.015 mmol, 0.1 eq.) was added to an nitrogen purged mixture of 2-bromo-4- iodopyridine (45 mg, 0.15 mmol, 1.0 eq.) 4 , 4-methyl-3-methylsulfonyl-N-[[4-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)-2-pyridyl]methyl]benzamide 3 (0.1 g, 0.15 mmol, 1.0 eq.) and K2CO3 (31 mg, 0.31 mmol, 2.0 eq.) in 1,4-dioxane (2.0 mL) containing H2O (0.6 mL) and the reaction mixture was heated at 60 °C for 4 h.
  • reaction mixture was filtered over a pad of celite® and then the filtrate was evaporated to dryness.
  • Int 37 is synthetized from Int 36 and 1,2,3,4-tetrahydroquinoline (CAS# 635-46-1) following general method C.
  • Int 38 is synthetized from Int 37 following general method E2.
  • the reaction mixture was cooled down to RT and diluted with water (10 mL) and DCM (30 mL) and the layers were separated. The aqueous one was extracted with DCM (2 x 20 mL) and the combined organic extracts were washed with water, brine, dried over MgSCL, fdtered and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 60/40) to give Int 60.
  • the sealed bomb was filled with CO (5 bars). The mixture was heated at 120 °C for 18 h. The mixture was cooled to RT, then water was added, and the aqueous layer was washed with EtOAc (2 x) then the aqueous layer was acidified with HC1 (3 N) aqueous solution and the mixture evaporated to dryness to afford Int
  • NBS (CAS# 128-08-5; 716 mg, 4.02 mmol, 1.0 eq.) and benzoyl peroxide (CAS# 94-36-0; 201 mg, 0.80 mmol, 0.2 eq.) were added to a stirred solution of methyl 4-methyl-3-methylsulfonyl-benzoate (CAS# 906816-32-8; 918 mg, 4.02 mmol, 1.0 eq.) in CCU (13.0 mL) and the reaction mixture was heated at 75 °C for 16 h. The mixture was cooled to RT, washed with water and brine, dried with Na2SC>4, and the filtrate was evaporated to dryness to Int 91.
  • TEA 152 pL, 1.09 mmol, 1.5 eq.
  • hydroxylamine hydrochloride 36 pL, 0.87 mmol, 1.2 eq.
  • Int 110 220 mg, 0.73 mmol, 1.0 eq.
  • EtOH 7.3 mL
  • the reaction mixture was stirred at 50 °C for 4 h.
  • the mixture was concentrated and dissolved into water/EtOAc.
  • the layers were separated, the aqueous layer was extracted with EtOAc, the combined organic layers dried over Na2SO4 and evaporated to dryness to afford Int 111.
  • Ttrimethylsilylacetylene (CAS# 1066-54-2; 42.76 mg, 0.062 mL, 0.44 mmol, 2.0 eq.) was added and the reaction mixture was stirred at 90 °C for 1 h. The solvent was evaporated to dryness. The crude was purified on a 10g Sfar HC column (Biotage®), eluting with DCM/MeOH from 100/0 to 97/3) to afford Int 123.
  • the reaction mixture was degassed with nitrogen (3 x) then was stirred at 25 °C for 5 minutes.
  • Bromocyclobutane (CAS# 4399-47-7; 19.28 g, 142.78 mmol, 13.44 mL, 2.5 eq.) was added dropwise at RT then the reaction mixture was stirred at 63 °C for 16 hrs.
  • the mixture was cooled to RT and NiCh glyme (CAS# 29046-78-4; 1.25 g, 5.71 mmol, 0.1 eq.), tBuPyBCam (CAS# 003061-14-8; 1.25 g, 5.71 mmol, 0.1 eq.) and Zn (CAS# 7440-66-6; 9.39 g, 143.60 mmol, 2.51 eq.) were added.
  • the reaction mixture was degassed with nitrogen (3 x) then was stirred at RT for 5 minutes.
  • the aqueous phase was extracted with DCM (2 x) and the combined organic extracts were washed with water, brine, dried over Na2SC>4, fdtered and evaporated to dryness.
  • the crude was purified by preparative HPLC, then by column chromatography on silica gel (eluting with DCM/acetone from 100/0 to 80/20) to afford 232.
  • 1,4-dioxane (2.5 mb) was added to the mixture and the reaction mixture was heated and stirred at 90 °C for 18 h.
  • the reaction mixture was cooled down to RT then 4-(2-bromopyridin-4-yl)morpholine (CAS# 1049023-41-7 ; 56.1 mg, 0.23 mmol, 1.1 eq.), Cs2CO3 (205 mg, 0.63 mmol, 3.0 eq.), Xphos Pd G3 (17.7 mg, 0.021 mmol, 0.1 eq.) and water (0.2 mL) were added, the mixture was degassed with nitrogen (3 x) then stirred and heated at 100 °C for 18 h.
  • reaction mixture was stirred at RT 18 h.
  • the reaction mixture was quenched with NH4CI saturated aqueous solution and extracted twice with EtOAc.
  • the combined organic layers were combined and dried over Na2SC>4, fdtered and evaporated to dryness.
  • the residue was purified by column chromatography on silica gel on a 100g Star HC column Biotage® (eluting with DCM/MeOH from 100/0 to 97/3) to afford Int 27.
  • Step 4 Cpd 106 according to method B 1
  • Step 1 Int 74
  • 1,4-dioxane (12.0 mL) was added to the vial through the septum.
  • the reaction mixture was degassed by bubbling nitrogen for 5 min then was stirred at 80 °C for 60 h.
  • the reaction mixture was cooled down to RT, diluted with water and EtOAc and the layers were separated.
  • the aqueous layer was extracted with EtOAc (2 x) and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated to dryness.
  • the residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/0 to 75/25 then DCM/DCM:MeOH (80:20 with 0.1% Et 3 N) 85/15) to afford Int 65.
  • Step 3 Cpd 236 according to method Bl pW
  • the ADP-GloTM assay is a luminescent technology assay which measures the ADP formed from a helicase reaction.
  • the helicase reactions consisted of the metabolism of ATP to ADP using pCMV-dR8.91 plasmid as a substrate by SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2 (635-1331, N-ter FLAG, Active Motif, Cat# 81439) or SMARCA4 (658-1328, N-ter FLAG, Active Motif, Cat# 81440).
  • SMARCA2 (635-1331, N-ter FLAG, Active Motif, Cat# 81439
  • SMARCA4 658-1328, N-ter FLAG, Active Motif, Cat# 81440.
  • the ADP is converted into ATP and this newly synthesized ATP is measured by using a luciferase/luciferin reaction.
  • the generated light is measured using an EnVision plate reader, wherein the luminescent signal obtained positively correlates with the helicase activity.
  • test compounds were prepared as a 10-point dilution series with 1/5 dilution steps in 100% DMSO starting from 2 mM highest concentration, diluted 1/20 in water and 1 pL was transferred to the assay plates (Revvity Inc., Cat# 6007290).
  • the enzyme-substrate mixture was prepared by adding the enzyme and the substrate to the assay buffer (final concentration 25 mM Hepes pH7.5, 0.25 mM EGTA, 5% glycerol, 0.005% Tween 20, 5 mM MgCl 2 and 1 mM DTT).
  • the reaction was started by adding 2 pL of ATP (diluted in the assay buffer, (final concentration 10 pM)) on the assay plates. Plates were centrifuged for a few seconds at 300 xg, followed by an incubation at RT for 120 min.
  • ADP was converted to ATP and luciferase and luciferin was introduced to detect ATP by adding 10 pL Kinase Detection Reagent (Promega, Cat# V913B + V914B) to the reaction. The plates were centrifuged for a few seconds at 300xg and incubated at RT for 30 min (ADP detection).
  • Luminescence was measured on an EnVision plate reader (Revvity Inc.). 2.1.1.3. Assay variant with high ATP concentration
  • Keratin, type II cytoskeletal 80 is a gene that is transcriptionally regulated downstream of SMARCA2 and is known to be a biomarker for SMARCA2 inhibition in SMARCA4 deficient cells, such as A549.
  • the KRT80 mRNA transcription assay aims at measuring the reduction of KRT80 gene expression levels in A549 cells upon treatment with possible SMARCA2 inhibitors using quantitative Polymerase Chain Reaction (qPCR) as a readout.
  • qPCR Quantifying Polymerase Chain Reaction
  • B2M glucuronidase beta
  • test compounds were prepared as a 10-point 1/5 dilution series in 100% DMSO starting from 10 mM.
  • A549 cells (ATCC, Cat# CCL-185) were seeded (7000 cells in 45 pL per well) in DMEM assay medium supplemented with 2% heat-inactivated fetal bovine serum (FBS) and 1% Penicillin-Streptomycin (P/S) in 384-well cell plates. The plates were briefly centrifuged at 300xg and stored at RT for 15-30 min to allow cells to distribute evenly in the wells.
  • FBS heat-inactivated fetal bovine serum
  • P/S Penicillin-Streptomycin
  • the cells were lysed by adding 25 pL of Cells-to-Ct lysis buffer (Thermo Fisher Scientific Inc., Cat# 4391851C). The plates were incubated on an orbital shaker for 5 min. 2.5 pL of Cells-to-Ct STOP solution was added on top of the lysis buffer and the plates were incubated 2 min on the orbital shaker.
  • Cells-to-Ct lysis buffer Thermo Fisher Scientific Inc., Cat# 4391851C.
  • a PCR plate was filled with 20 pL of reverse transcription mix containing 50% Fast Advanced reverse transcription buffer, 5% Fast Advanced reverse transcription enzyme mix (Thermo Fisher Scientific Inc., Cat# A39110), and 20% nuclease-free water (Qiagen GmbH, Cat# 129117).
  • RT-PCR was performed in a thermal cycler to generate cDNA: samples were incubated for 30 min at 37 °C, 5 min at 95 °C followed by cooling to 4 °C. Sample plates were then kept on ice or frozen at -20 °C for later use.
  • a PCR plate was filled with 6 pL of a mix (60% of the total reaction volume) containing 50% of TaqMAN Fast Universal PCR Master Mix (Thermo Fisher Scientific Inc., Cat# 4444557), 1.7% of TaqMAN KRT80 gene expression assay (Thermo Fisher Scientific Inc., Cat# 4351368) (250 nM final), 1.7% of TaqMAN B2M expression assay (Thermo Fisher Scientific Inc., Cat# 4448491) (250 nM final) and 6.6% of nuclease-free water (Qiagen GmbH, Cat# 129117).
  • Raw data were generated by the ViiA7 Real-Time PCR System and the cycle threshold (Ct) calculations were done by the ViiATM 7 software (Thermo Fisher Scientific Inc.) for both genes, KRT80 and B2M. These data were imported into the Phaedra software (Open Analytics NV) for automated calculation of Delta Ct (DCt) and Normalized Relative Quantities (NRQ). Based on the control wells, data were converted to percentage of inhibition (PIN) and concentration-response curves were generated. From those curves, IC50 values were determined, all using Phaedra.
  • Ct cycle threshold
  • SK-MEL-5 (ATCC, Cat# HTB-70) is a SMARCA4 mutant melanoma cell line which is highly dependent on SMARCA2 to grow.
  • the SK-MEL-5 proliferation assay aims at measuring the effect of possible SMARCA2 inhibitors on the proliferation of the SK-MEL-5 cells by using an ATPliteTM readout (Revvity, Inc.). ATP is a marker for cell viability because it is present in all metabolically active cells. SMARCA2 inhibitors are able to decrease SK-MEL-5 cell proliferation and thus the amount of ATP, which results in a decrease in ATPliteTM luminescent signal.
  • test compounds were prepared as 8-point serial dilutions with 1/4 dilution steps in 100% DMSO starting from 10 mM highest concentration (final highest concentration 30 pM) in 384 well plates.
  • SK-MEL-5 cells were thawed and seeded in T175 flasks, 2.0* 10 6 cells per flask, in 25 mL culture medium (EMEM containing 10% heat inactivated Fetal Bovine Serum (FBS) and 1% Penicillin - Streptomycin (P/S)). After 24 h incubation at 37 °C, 5% CO2, the medium was refreshed, and the cells were further incubated in an incubator at 37 °C and 5% CO2 for 72 h
  • SK-MEL-5 cells were harvested using 0.25% Trypsin-EDTA and counted. 2000 cells were seeded in only the inner wells of a 384 well cell plate, in 70 pL assay medium (EMEM containing 2% heat inactivated FBS and 1% P/S) per well. The outer wells were filled with 70 pL of phosphate-buffered saline. The plates were briefly centrifuged at 300xg and stored at RT for 15-30 min to allow cells to distribute evenly in the wells.
  • EMEM containing 2% heat inactivated FBS and 1% P/S 70 pL assay medium
  • thermodynamic solubility is determined in Fasted State Simulated Gastric Fluid (FaSSGF, pH 1.6), Fed State Simulated Intestine Fluid (FeSSIF v2, pH 5.8), Fasted State Simulated Intestine Fluid (FaSSIF v2, pH 6.5) and phosphate buffer (pH7.4).
  • test compound stock solution is prepared at a concentration of 1 mg/mL in DMSO and diluted to cover the calibration range from 0.0001 - 0.1 mg/mL.
  • Peak areas are analysed and are plotted against the standard curve to obtain the solubility of the compound.
  • Turbidimetric solubility allows rapid determination of solubility using small amounts of compound. Briefly, compound’s DMSO solutions (prepared at specific concentrations) are spiked into aqueous buffer and turbidity is measured using VIS spectrophotometry at 620 nm. Sulfaphenazole and a- naphtoflavone are used as assay controls.
  • the plate absorbance at 620 nm is read on a Microplate reader (Tecan, Infinite F500 or Spark).
  • the absorbance is proportionally increased with concentration of insoluble particles.
  • Compound/control samples are compared to a solvent control in aqueous buffer (DMSO 1% final concentration), where significant increase of sample absorbance is considered when its absorbance is 3- fold standard deviation of average DMSO absorbance.
  • Results are accepted depending on solubility values obtained for assay controls: a-naphtoflavone: ⁇ 10 pM sulfaphenazole: >10 pM
  • Results are expressed as an average of three replicas ( ⁇ 10 pM or >10 pM) for one concentration set-up.
  • test compound The binding of the test compound to plasma proteins is tested by equilibrium dialysis using a Teflon unit from HTDialysis, performed on a Freedom EVO liquid handling unit.
  • dialysis membranes (Dialysis membranes MW cut-off 12- 14kDa - HTDialysis - Cat# 1101) are soaked in deionised water for 60 min, transferred and left overnight in 20% ethanol. On the day of experiment, compound and control stock solutions are diluted, spiked into plasma in order to achieve a final concentration of 5 pM (0.5% DMSO).
  • Matrix matched samples are further mixed with six volumes of STOP solution (acetonitrile: methanol, 2: 1 v/v with an internal standard (IS)). After brief mixing and centrifugation (at 4500 rpm for 30 min, at +4°C), the supernatant is transferred into new plates and analysed and quantified by LC-MS/MS.
  • STOP solution acetonitrile: methanol, 2: 1 v/v with an internal standard (IS)
  • Cplasma Peak area of the compound in the plasma / Peak area of the IS in the plasma
  • Cbuffer Peak area of the compound in the buffer / Peak area of the IS in the buffer
  • the recovery is a control, it allows to be sure that the compound has not a non-specific binding to the plates or it is not stable in the plasma in these conditions.
  • Buffer (ratio of the peak area of the compound/peak area of IS) in Buffer compartment after 4 h
  • Plasma (ratio of the peak area of the compound/peak area of IS) in Plasma compartment after 4 h
  • Recovery ratio at TO of the peak area of the compound in the well recovery / peak area of the IS in the well recovery
  • Hydralazine (Sigma, Cat# H1753) (selective inhibitor of aldehyde oxidase; final concentration of 100 pM) or miliQ water are added for incubations with and without addition of selective inhibitor, respectively. After pre-warming for 5 min at 37 °C, the reaction is initiated by addition of test compound to the incubation mixture (final concentration in the incubation mixture of 1 pM, 0.4%DMSO). After 0, 3, 6, 12, 18 and 30 min of incubation, the reaction (aliquot of 100 pL) is terminated with 300 pL of acetonitrile methanol (2: 1) mixture with 1% acetic acid and the analytical internal standard. Samples are mixed, centrifuged and the supernatant analysed by LC-MS/MS (Table 2 and Table 3). Phthalazine (Aldrich, Cat# P38706) is included as a positive control.
  • test compound is diluted from DMSO stock solution to obtain a final concentration of 1 pM in the final incubation mix (final DMSO 0.03%).
  • ANADPH generating system (Cofactor solution) is prepared by adding to a 50 mM PBS pH 7.4 buffer, NADP (Sigma, N0505), G6P (Sigma, G6526), MgCLxOILO (Sigma, M2670) and G6P DH (Sigma, G637) to obtain in the final incubation mix NADP at 0.5 mM , G6P at 5 mM , MgC12.6H2O at 0.5 mM and G6P DH at 1.5 U/mL.
  • Liver microsomes (Coming; Discovery Life Sciences) solution is prepared from 20 mg/mL stock concentration to obtain a final concentration in the incubation mix of 0.5 mg/mL.
  • Test compounds are incubated at 37 °C with and without cofactors and reaction is started by adding cofactors or buffer (for negative control) to incubation mix. Time points are taken at 0, 10, 25 and 40 min. At the desired incubation time point, a STOP solution (acetonitrile: methanol, 2: 1 v/v) is added at a ratio 3: 1 to the incubation mix. Samples are then centrifuged (at 4500 rpm, at 4 °C, for 30 min). The supernatant is then analyzed using a LC-MS/MS method.
  • cofactors or buffer for negative control
  • % remaining (peak area ratios of test compound vs IS at appointed time)/(peak area ratios of test compound vs IS at 0 min) x 100
  • test compound is diluted from DMSO stock solution to obtain a final concentration of 1 pM in the final incubation mix.
  • the test compound is incubated in dog, monkey, human, mouse and rat hepatocytes (BioIVT, mouse Cat. No. M005052, rat Cat. No. M00005, dog, Cat. No. M00205, monkey Cat. No. M00305, human Cat. No. X008001) (final concentration: 0.5x106 cells/mL), resuspended in Krebs-Henseleit modified buffer for 3 h (except in human - 90 min) at 37 °C.
  • Bi-directional Caco-2 assays are performed as described below. Cells are seeded at 1 x 105 cells/cm2 in 96-well HTS Transwell plates (Coming). Permeability assays are performed with the cells at days 21-25 post-seeding.
  • This assay is performed in both the apical (A) to basolateral (B) A-B or B-A direction.
  • Compounds and the references are prepared at 10 pM in HBSS-MES (pH 6.5) or HBSS-HEPES (pH 7.4) with a final DMSO concentration of 1 % (v/v).
  • the working solution is then centrifuged and the supernatant is added to the donor side.
  • the assay plate is incubated at 37 °C for 60 min or 40 min for the A-B or B-A assay, respectively. Samples are aliquoted from the donor side at time zero and the end point, and from the receiver side at the end point.
  • Lucifer yellow (LY), a membrane integrity marker, is co-incubated with the test compound at the start of the experiment to assess integrity of the cell layers.
  • LY a membrane integrity marker
  • TEER Transepithelial electrical resistance
  • Reference compounds namely, Propranolol (highly permeable), Labetalol (moderately permeable), Ranitidine (poorly permeable), and Colchicine (P-glycoprotein substrate) are included in this assay. Samples are analysed by LC/MS-MS.
  • V chamber volume
  • Tine incubation time.
  • Efflux ratios as an indication of active efflux from the apical cell surface, are calculated using the ratio of Papp B>A/ Papp A>B.
  • the following assay acceptance criteria are used: If at least 3 out of 4 control molecules are in these ranges determined by the historical data, the assay is validated.
  • MDCKII-MDR1 cells are Madin-Darby canine kidney epithelial cells, over-expressing human multi-drug resistance (MDR1) gene, coding for P-glycoprotein (P-gp). Cells are obtained from Netherlands Cancer Institute and used after a 3-4 day cell culture in 24-well Millicell cell culture insert plates (Millipore, PSRP010R5). Bi-directional MDCKII-MDR1 permeability assay is performed as described below.
  • 3x105 cells/mL (1.2x105 cells/well) are seeded in plating medium consisting of DMEM + 1% Glutamax-100 + 1% Antibiotic/Antimycotic + 10% FBS (Biowest, S1810). Cells are left in CO2 incubator for 3-4 days. The medium is changed 24 h after seeding and on the day of experiment.
  • Test and reference compounds are prepared in Dulbecco’s phosphate buffer saline (D-PBS, pH7.4) and added to either the apical (400 pL) or basolateral (800 pL) chambers of the Millicell cell culture insert plates assembly at a final concentration of 10 pM (0.5 pM in case of amprenavir) with a final DMSO concentration of 1%
  • Lucifer Yellow 100 pM Lucifer Yellow (Sigma) is added to the all-donor buffer solutions, in order to assess integrity of the cell monolayers by monitoring Lucifer Yellow permeation. Lucifer yellow is a fluorescent marker for the parace llular pathway, and it is used as an internal control in every monolayer to verify tight junction integrity during the assay.
  • Lucifer yellow is measured with a Fluoroscan Ascent FL Thermo Scientific (Ex 485 nm and Em 530 nm) in a 96 well plate containing 150 pL of liquid from all receiver wells (basolateral or apical side).
  • A surface area of the cell monolayer (0.11 cm2)
  • Conscentration is the ratio between compound and internal standard peak areas.
  • the Papp value has a dimension of a rate (xlO-6 cm/sec).
  • Permeability values are classified as follows: low permeability: ⁇ 2x l0 -6 cm/sec, moderate permeability: 2-10x 10' 6 cm/sec, high permeability: >10* 10' 6 cm/sec.
  • Efflux ratio Papp (B2A)/Papp (A2B).
  • a compound is considered to be a possible P-gp substrate when the efflux ratio is > 2.
  • Mass balance results should be evaluated as follows: Mass balance between 80-120%: acceptable, Mass balance between 50-80% and 120-135% should be interpreted with caution, Mass balance ⁇ 50% and >135% should be discarded.
  • Wistar-Han rats male, 200-225g are obtained from Janvier (France).
  • CD-I Mice male, 25 -30g are obtained from Janvier (France).
  • Animals are acclimatized for at least 7 days before treatment and are kept on a 12 h light/dark cycle (0700 - 1900). Temperature is maintained at approximately 22 °C, and food and water are provided ad libitum.
  • Test compounds are formulated in DMSO/10% hydroxylpropyl-P-cyclodextrine (5/95) for the intravenous route and in a suitable solution for the oral route.
  • Test compounds are orally dosed as a single oesophageal gavage at 5 mg/kg under a dosing volume of 10 mL/kg (group of 3 animals) and intravenously dosed as a bolus via the caudal vein at 0.5 mg/kg under a dosing volume of 5 mL/kg. (groups of 2 animals).
  • Blood samples are collected at the retro-orbital sinus with EDTA as anti-coagulant at the following time points: 0.05, 1, 3, 6 and 24 h (intravenous route), and 0.25, 1, 3, 6, and 24 h (oral route).
  • Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20 °C pending analysis. 3.9.3. Quantification of compound levels in plasma
  • Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode.
  • Pharmacokinetic parameters are calculated for each individual animal and for each analyte by noncompartmental analysis.
  • Single CHO cells are used for recording hERG currents at near physiological temperature (34- 35 °C) using the whole-cell patch-clamp technique with an Axopatch 700A amplifier/pClamp software (Molecular Devices, Sunnyvale CA).
  • Electrodes (5-7 MQ resistance) are prepared from GC 150-10 glass capillary tubes (Harvard Apparatus, Cambridge, UK) and filled with intracellular solution (in mM: KC1 120; Na2ATP 4; HEPES 10; EGTA 10; MgCl 2 1.75; CaCl 2 5.374, pH 7.2 adjusted with KOH).
  • the patch-clamp recording chamber is perfused with control extracellular solution (in mM: NaCl 145; KC1 4; MgC12 1; HEPES, 10; glucose 10; CaCl 2 2 at pH 7.4 adjusted with NaOH).
  • control extracellular solution in mM: NaCl 145; KC1 4; MgC12 1; HEPES, 10; glucose 10; CaCl 2 2 at pH 7.4 adjusted with NaOH).
  • the cell membrane is then voltage-clamped at a holding potential of -80 mV and depolarised to +20 mV for 2 sec followed by a negative pulse at -40 mV for 1.6 sec, before returning to -80 mV at a frequency of 0.1 Hz.
  • Electrophysiological recordings are made from a Chinese Hamster Ovary cell line stably expressing the full-length ion channel. Single cell ionic currents are measured in whole-cell configuration at RT (21- 23 °C) using a QPatch II (Sophion Bioscience).
  • the internal solution for hERG contains (mM): 120 KC1, 20 KF, 10EGTA, 10 HEPES and is buffered to pH 7.3.
  • the external solution contains (mM): 138 NaCl, 4.5 KC1, 1.8 CaCl 2 , 1.0 MgCl 2 , 10 HEPES, 10 glucose, buffered to pH 7.4.
  • Cells are clamped at a holding potential of -80 mV before a step to +20 mV for 500 ms, and then - 40 mV for 500 ms. The test pulse is applied every 10 seconds. Currents are measured from the -40 mV step and referenced to the holding current.

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Abstract

The present invention discloses compounds according to Formula (I) wherein A, X, L1, R1, R2, R3, R4a, R4b, R5, R6, and the subscript n are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of proliferative diseases by administering a compound of the invention.

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF DISEASES
FIELD OF THE INVENTION
[0001] The present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and/or treatment of proliferative diseases by administering the compounds of the invention. In particular, the compounds of the invention may inhibit SMARCA2 and/or SMARCA4.
BACKGROUND OF THE INVENTION
[0002] l ldependent chromatin remodelers with vital roles in various cellular processes, including transcription, DNA repair, and replication, achieved by regulating DNA accessibility.
[0003] Approximately 20% of all human cancers exhibit mutations in the genes encoding the nearly 20 canonical SWI/SNF subunits (Kadoch et al. 2013). These mutations are most frequently found in rhabdoid tumors, female-specific cancers (such as ovarian, uterine, cervical, and endometrial cancers), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal cancer, and renal clear cell carcinoma.
[0004] Within these SWI/SNF complexes, SWI/SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A member 2 (SMARCA2, Brahma, or BRM) and SWI/SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A, member 4 (SMARCA4 or BRG1) stand out as subunits that contain catalytic ATPase domains, essential for the SWI/SNF complex function. They perturb histone-DNA contacts, thereby providing access points for transcription factors and DNA elements that regulate gene activation and repression.
[0005] SMARCA2 and SMARCA4 share a high degree of similarity, up to 75%, and both contain a DNA- stimulated, conserved ATPase domain driving chromatin-remodeling activity. In primary tumors, SMARCA4 is frequently mutated, particularly in lung, melanoma, liver, and pancreatic cancers. In SMARCA4-deleted cancer cells, SMARCA2's ATPase activity becomes critical for chromatin remodeling, which is essential for functions like cell proliferation, survival, and growth. Consequently, targeting SMARCA2 may hold promise as a therapeutic approach for SMARCA4-deleted or deficient cancers, e.g. non-small cell lung carcinoma, Burkitt lymphoma, childhood medulloblastoma, pancreatic adenocarcinoma, ovarian clear cell carcinoma, and melanoma (Wilson et al. 2014). Conversely, inhibition of SMARCA4 represents a therapeutic strategy for the treatment of SMARCA2-deficient cancers (Ehrenhbfer-Wblfer et al. 2019).
[0006] Hence, there is a need for therapeutic compounds that can inhibit SMARCA2 and/or SMARCA4 for the prophylaxis and/or treatment of the above mentioned diseases.
SUMMARY OF THE INVENTION
[0007] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of proliferative diseases. In particular, the compounds of the invention may be ATPase inhibitors, and more particularly SMARCA2 and/or SMARCA4 inhibitors. The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of proliferative diseases by administering the compounds of the invention.
[0008] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:
Figure imgf000003_0001
I wherein,
A is phenyl or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;
X is N or CH;
Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, Ci-4 alkyl, C1.4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl):, morpholino, -CH=CHCC>2R9a , C1-4 alkoxy, C1-4 haloalkoxy or oxetane; n is 0, 1, or 2;
R1 is C1-6 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(CI-3 alkyl )2 or hydroxy(Ci-3)alkyl; each R2 is independently selected from halogen and C1-6 alkyl, which alkyl is optionally substituted with C1.4 alkoxy; or R1 and one R2 together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the -S(=O)2- of formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro);
R3 is H or C1-6 alkyl; each R4a and R4b is independently H or C1-6 alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy;
R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;
R6 is H, halo, or C1-6 alkyl; each R7 is independently selected from oxo,
- -OH, - -CN,
- -P(O)(Ci.4alkyl)2, halo,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a or Ci -4 alkoxy,
Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci- 4 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; and each R8a is independently H or C1-4 alkyl; each R8b is independently H, C1-4 alkyl or -C(O)Ci.2 alkyl; each R9a is independently selected from hydrogen and C1-4 alkyl; and
R9b is hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9a and R9b together with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
[0009] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and/or treatment of proliferative diseases.
[0010] Certain compounds according to the invention may also exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and/or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drugdrug interaction (DDI) or CYP -interaction characteristics, etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.
[0011] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of proliferative diseases.
[0012] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
[0013] In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly proliferative diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
[0014] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and/or treatment of proliferative diseases.
[0015] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
[0016] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
[0017] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0018] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0019] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. [0020] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.
[0021] A dash
Figure imgf000006_0001
that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
[0022] A wavy line drawn through a line in a structure indicates a point of attachment of a group. Similarly, a squiggly line on a chemical group as shown, for example \/^''''^ indicates a point of attachment, i.e., it shows the broken bond by which the group is connected to another described group.
[0023] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-8 alkyl” indicates that the alkyl group has from 1 to 8 carbon atoms.
[0024] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.
[0025] Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
[0026] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), w-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), w-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-C(CH3)3), sec-butyl (-CH(CH3)-CH2CH3), isobutyl (-CH2-CH(CH3)2), w-pcntyl (-CH2-CH2-CH2-CH2-CH3), w-hcx l (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CH(CH3)-CH(CH3)-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.
[0027] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.
[0028] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci e alkyl. Particular alkoxy groups are methoxy, ethoxy, w-propoxy. isopropoxy, w-butoxy. /c/7-butoxy. scc-butoxy. w-pcntoxy. w-hcxoxy. and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[0029] ‘ Amino’ refers to the radical -NH2.
[0030] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.
[0031] ‘Cycloalkyl’refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[0032] ‘Cyano’ refers to the radical -CN.
[0033] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0034] As used herein, term ‘polycyclic’ refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.
[0035] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described previously such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom. [0036] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. [0037] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
[0038] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0039] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
[0040] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
[0041] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
[0042] Examples of representative heteroaryls include the following:
Figure imgf000008_0001
wherein each Y is selected from >C=O, NH, O and S.
[0043] ‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1 -tetrahydrofuranyl, 2-tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1 -tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4- tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. [0044] Particular examples of monocyclic rings are shown in the following illustrative examples:
Figure imgf000009_0001
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
[0045] Particular examples of fused bicyclic rings are shown in the following illustrative examples:
Figure imgf000009_0002
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
[0046] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:
Figure imgf000009_0003
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N or CH.
[0047] Particular examples of spirocyclic rings are shown in the following illustrative examples:
Figure imgf000009_0004
wherein each Y is selected from -CH2-, -NH-, -O- and -S-.
[0048] ‘Hydroxyl’ refers to the radical -OH.
[0049] ‘ Oxo’ refers to the radical =0.
[0050] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
[0051] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.
[0052] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[0053] ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [0054] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic acid addition salts and base addition salts. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011). The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, and such as, e.g., sodium hydroxide for forming basic salts. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
[0055] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
[0056] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
[0057] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. 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. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[0058] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
[0059] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. [0060] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[0061] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[0062] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.
[0063] As used herein the term ‘proliferative disease(s)’ refers to diseases associated with excessive proliferation of cells and turnover of cellular matrix. In particular, the term refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to cancer, leukemia, and multiple myeloma.
[0064] Certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target SMARCA2. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, selectively target SMARCA2 over SMARCA4. For example, certain compounds of formula (I), or a pharmaceutically acceptable salt thereof, are at least about 3 fold (e.g. at least about 4-, 5- , 6-, 7-, 8-, 9-, 10-, 15-, 20-, 30-, 40-, 50-fold, or more) more selective for SMARCA2 than for SMARCA4.
[0065] As used herein, the term "selectivity" of a compound refers to the compound having more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value of a compound for the second target (e.g., SMARCA4) by the IC50 value of the same compound for the first target (e.g., SMARCA2). An IC50 value can be determined by any method known in the art. For example, an IC50 value can be determined as described in the assays below.
[0066] As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasize) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term ‘cancer’ refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.
[0067] As used herein the term ‘leukemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
[0068] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Eormula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits. [0069] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.
[0070] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.
[0071] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
[0072] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulfur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
[0073] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as nC, 18F, 15O and 13N, and would be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.
[0074] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.
[0075] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
[0076] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.
[0077] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
[0078] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
[0079] An optical isomer with unknown absolute configuration may be depicted with an asterix (*) at the
Figure imgf000014_0001
. Likewise, when a chemical structure possessing one or more asymmetric centers is described using its chemical name, stereocenters with unknown absolute configuration may be depicted with an asterix (*), e.g. R* and/or S*.
[0080] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
[0081] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. THE INVENTION
[0082] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and/or treatment of proliferative diseases. In particular, the compounds of the invention may be SMARCA2 and/or SMARCA4 inhibitors, and more particularly SMARCA2 inhibitors.
[0083] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and/or treatment of proliferative diseases by administering the compounds of the invention.
[0084] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:
Figure imgf000015_0001
I wherein,
A is phenyl or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;
X is N or CH;
Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, Ci-4 alkyl, C1.4 haloalkyl, -NH2, -NH(CI-4 alkyl), or -N(CI-4 alkyl):, morpholino, -CH=CHCC>2R9a , C1-4 alkoxy, C1-4 haloalkoxy or oxetane; n is 0, 1, or 2;
R1 is C1-6 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(CI-3 alkyl )2 or hydroxy(Ci-3)alkyl; each R2 is independently selected from halogen and C1-6 alkyl, which alkyl is optionally substituted with C1.4 alkoxy; or R1 and one R2 together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the -S(=O)2- of formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro);
R3 is H or C1-6 alkyl; each R4a and R4b is independently H or C1-6 alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy;
R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7; R6 is H, halo, or Ci-6 alkyl; each R7 is independently selected from oxo,
- -OH,
- -CN,
- -P(O)(Ci.4alkyl)2, halo,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, -CO2R9a or Ci -4 alkoxy,
Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci- 4 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy,
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; and each R8a is independently H or C1-4 alkyl; each R8b is independently H, C1-4 alkyl or -C(O)Ci.2 alkyl; each R9a is independently selected from hydrogen and C1-4 alkyl; and
R9b is hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9a and R9b together with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
[0085] Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and/or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP-interaction characteristics, etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.
[0086] In one embodiment, the compound of the invention is according to Formula I, wherein R3 is H.
[0087] In one embodiment, the compound of the invention is according to Formula I, wherein R3 is Ci-6 alkyl. In a particular embodiment, R3 is -CH3, -CH2CH3, -CH(CH3)2, -C(CHs)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3,
-CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2. In a more particular embodiment, R3 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R3 is -CH3.
[0088] In one embodiment, the compound of the invention is according to Formula I, wherein R4a is H.
[0089] In one embodiment, the compound of the invention is according to Formula I, wherein R4a is C1-6 alkyl. In a particular embodiment, R4a is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3,
-CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2. In a more particular embodiment, R4a is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R4a is -CH3.
[0090] In one embodiment, the compound of the invention is according to Formula II:
Figure imgf000017_0001
wherein A, X, Li, R1, R2, R5, R6, and the subscript n are as previously described.
[0091] In one embodiment, the compound of the invention is according to Formula I or II, wherein X is N.
[0092] In one embodiment, the compound of the invention is according to Formula I or II, wherein X is CH.
[0093] In one embodiment, the compound of the invention is according to Formula I or II, wherein R6 is H.
[0094] In one embodiment, the compound of the invention is according to Formula I or II, wherein R6 is halo. In a particular embodiment, R6 is F, Cl, or Br. In a more particular embodiment, R6 is F or Cl.
[0095] In one embodiment, the compound of the invention is according to Formula I or II, wherein R6 is C1-6 alkyl. In a particular embodiment, R6 is -CH3, -CH2CH3, -CH(CH3)2, -C(CHs)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3,
-CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2. In a more particular embodiment, R6 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R6 is -CH3.
[0096] In one embodiment, the compound of the invention is according to Formula III:
Figure imgf000018_0001
III wherein A, Li, R1, R2, R5, and the subscript n are as previously described.
[0097] In one embodiment, the compound of the invention is according to any one of Formulae I-III, wherein A is phenyl.
[0098] In one embodiment, the compound of the invention is according to any one of Formulae I-III, wherein A is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S. In a particular embodiment, A is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl. In a more particular embodiment, A is pyrrolyl, pyrazolyl, imidazolyl, 1,2, 3 -triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl. In a most particular embodiment, R1 is pyrrolyl.
[0099] In one embodiment, the compound of the invention is according to Formula IVa or IVb:
Figure imgf000018_0002
IVa IVb wherein Li, R1, R2, R5, and the subscript n are as previously described.
[0100] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein n is 0.
[0101] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein n is i.
[0102] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein n is 2.
[0103] In one embodiment, the compound of the invention is according to Formula Va or Vb:
Figure imgf000019_0001
Va Vb wherein Li, R1, R2, and R5 are as previously described.
[0104] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R1 is Ci-6 alkyl. In a particular embodiment, R1 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)s, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2. In a more particular embodiment, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R1 is -CH3.
[0105] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein each R2 is independently selected C1-6 alkyl. In a particular embodiment, each R2 is independently -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2. In a more particular embodiment, each R2 is independently -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, each R2 is -CH3.
[0106] In one embodiment, the compound of the invention is according to any one of Formulae I-Va, wherein R1 and one R2 together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising -S(=O)2- and zero, one, or two additional heteroatoms independently selected from N, O, and S. In a particular embodiment, R1 and one R2 together with the atoms onto which they are attached form a 1,1-dioxidotetrahydrothiophenyl, l . l -dioxidotctrahydro-2//- thiopyranyl, 1,1-dioxidothiomorpholinyl, 4,4-dioxido-l,4-oxathianyl, l,l-dioxido-l,4-dithianyl, 1,1- dioxidothiepanyl, 4,4-dioxido-l,4-oxathiepanyl, l,l-dioxido-l,4-thiazepanyl, or l,l-dioxido-l,4- dithiepanyl. In a more particular embodiment, the compound of the invention is according to Formula Va, wherein R1 and one R2 together with the atoms onto which they are attached form
Figure imgf000019_0002
Figure imgf000019_0003
[0107] In one embodiment, the compound of the invention is according to Formula Via, VIb, or Vic:
Figure imgf000020_0001
Via VIb Vic wherein Li and R5 are as previously described.
[0108] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, wherein Li is a bond.
[0109] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, wherein Li is Ce-io aryl. In a particular embodiment, Li is phenyl or naphthyl. In a more particular embodiment, Li is phenyl. In a most particular embodiment, Li is
Figure imgf000020_0002
[0110] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, wherein Li is Ce-io aryl substituted with one or more independently selected halo, C1.4 alkyl, or C1-4 alkoxy. In a particular embodiment, Li is phenyl or naphthyl, each of which is substituted with one or more independently selected halo, C1-4 alkyl, or C1-4 alkoxy. In another particular embodiment, Li is Ce-io aryl substituted with one, two, or three independently selected halo, C1.4 alkyl, or C1.4 alkoxy. In yet another particular embodiment, Li is Ce-io aryl substituted with one or more independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, Li is phenyl or naphthyl, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, Li is phenyl substituted with one, two, or three independently selected F, Cl, -CH3, or-O-CH ,.
In a most particular embodiment, Li is
Figure imgf000020_0003
, each of which is substituted with one, two, or three independently selected F, Cl, -CH3, or -O-CH3.
[OlH] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, wherein Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S. In a particular embodiment, Li is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl. In a more particular embodiment, Li is pyrazolyl or pyridinyl. In a further more particular embodiment, Li is pyrazolyl or pyridinyl. In a most particular embodiment, Li is
Figure imgf000020_0004
, ,
[0112] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, wherein Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected halo, C1-4 alkyl, or C1-4 alkoxy. In a particular embodiment, Li is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl, each of which is substituted with one or more independently selected halo, C1-4 alkyl, or C1-4 alkoxy. In another particular embodiment, Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected halo, C1-4 alkyl, or C1-4 alkoxy. In yet another particular embodiment, Li is 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, Li is phenyl or naphthyl, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, Li is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, or triazinyl, each of which is substituted with one, two, or three independently selected F, Cl, -CH3, or -O-CH3. In a most particular embodiment,
Figure imgf000021_0001
, each of which is substituted with one, two, or three independently selected F, Cl, -CH3, or -O-CH3.
[0113] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc,
Figure imgf000021_0002
Figure imgf000022_0001
wherein R5 is as previously described.
[0115] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl. In a particular embodiment, R5 is phenyl or naphthyl. In a more particular embodiment, R5 is phenyl.
[0116] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl substituted with one or more independently selected R7. In a particular embodiment, R5 is phenyl or naphthyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R5 is Ce-io aryl substituted with one, two, or three independently selected R7. In a more particular embodiment, R5 is phenyl or naphthyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R5 is phenyl substituted with one, two, or three independently selected R7.
[0117] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R5 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridinyl, 3 ,4-dihydro-2H- 1 ,4-benzoxazinyl, 2,3 -dihydro- IH-pyrido [2,3 -b] [ 1 ,4]oxazinyl, 2,3 - dihydro- IH-pyrido [3 ,4-b] [ 1 ,4]oxazinyl, 3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]oxazinyl, 3 ,4-dihydro-2H- pyrido[4,3-b][l,4]oxazinyl, 1,2,3,4-tetrahydroisoquinolinyl, l,2,3,4-tetrahydro-l,5-naphthyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, l,2,3,4-tetrahydro-l,7-naphthyridinyl, l,2,3,4-tetrahydro-l,8- naphthyridinyl, l,2,3,4-tetrahydro-2,6-naphthyridinyl, l,2,3,4-tetrahydro-2,7-naphthyridinyl, 5, 6,7,8- tetrahydro-l,6-naphthyridinyl, 5,6,7,8-tetrahydro-l,7-naphthyridinyl, or 1,2,3,4-tetrahydroquinolinyl. In a more particular embodiment, R5 is pyridinyl, pyrazolyl, indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2, 3, 4- tetrahydroisoquinolinyl, 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazinyl. In a most particular embodiment, R5
Figure imgf000023_0001
[0118] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one or more independently selected R7. In a particular embodiment, R5 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridinyl, 3,4-dihydro-2H-
1.4-benzoxazinyl, 2,3 -dihydro- IH-pyrido [2,3 -b] [ 1 ,4]oxazinyl, 2,3 -dihydro- IH-pyrido [3,4- b] [ 1 ,4]oxazinyl, 3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]oxazinyl, 3 ,4-dihydro-2H-pyrido [4,3 -b] [ 1 ,4]oxazinyl,
1.2.3.4-tetrahydroisoquinolinyl, 1 ,2,3 ,4-tetrahydro- 1 ,5 -naphthyridinyl, 1 ,2,3 ,4-tetrahydro- 1,6- naphthyridinyl, 1 ,2,3 ,4-tetrahydro- 1 ,7-naphthyridinyl, 1 ,2,3 ,4-tetrahydro- 1 , 8-naphthyridinyl, 1 ,2,3 ,4- tetrahydro-2,6-naphthyridinyl, l,2,3,4-tetrahydro-2,7-naphthyridinyl, 5,6,7,8-tetrahydro-l,6- naphthyridinyl, 5,6,7,8-tetrahydro-l,7-naphthyridinyl, or 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is substituted with one, two, or three independently selected R7. In a more particular embodiment, R5 is pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, imidazothiazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl, indazolyl, pyrazolopyridinyl, 3,4-dihydro-2H-
1.4-benzoxazinyl, 2,3 -dihydro- IH-pyrido [2,3 -b] [ 1 ,4]oxazinyl, 2,3 -dihydro- IH-pyrido [3,4- b] [ 1 ,4]oxazinyl, 3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]oxazinyl, 3 ,4-dihydro-2H-pyrido [4,3 -b] [ 1 ,4]oxazinyl,
1.2.3.4-tetrahydroisoquinolinyl, 1 ,2,3 ,4-tetrahydro- 1 ,5 -naphthyridinyl, 1 ,2,3 ,4-tetrahydro- 1,6- naphthyridinyl, 1 ,2,3 ,4-tetrahydro- 1 ,7-naphthyridinyl, 1 ,2,3 ,4-tetrahydro- 1 , 8-naphthyridinyl, 1 ,2,3 ,4- tetrahydro-2,6-naphthyridinyl, l,2,3,4-tetrahydro-2,7-naphthyridinyl, 5,6,7,8-tetrahydro-l,6- naphthyridinyl, 5,6,7,8-tetrahydro-l,7-naphthyridinyl, or 1,2,3,4-tetrahydroquinolinyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R5 is pyrazolyl or indolyl, each of which is substituted with one, two, or three independently selected R7. In a most particular embodiment,
Figure imgf000023_0002
[0119] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R5 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R5 is piperidinyl or morpholinyl. In a most particular embodiment, R5 is
Figure imgf000024_0001
.
[0120] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected R7. In a particular embodiment, R5 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R5 is 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected R7. In a more particular embodiment, R5 is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R5 is piperidinyl, piperazinyl, or morpholinyl, each of which is substituted with one, two, or three independently selected R7. In a most particular embodiment,
Figure imgf000024_0002
[0121] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is oxo, -OH, -CN, halo, or -S(=O)2-Ci-4 alkyl. In a particular embodiment, R7 is oxo, -OH, -CN, F, Cl, Br, -S(=O)2-CH3, -S(=O)2-CH2CH3, or -S(=O)2-CH(CH3)2. In a more particular embodiment, R7 is oxo, -OH, -CN, F, Cl, Br, or -S(=O)2-CH3.
[0122] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, R7 is -NR8aR8b, and R8aand R8b are independently H or Ci-4 alkyl. In a particular embodiment, R8a and R8b are both H. In another particular embodiment, one of R8a and R8b is H, and the other is C1-4 alkyl. In yet another particular embodiment, R8a and R8b are both independently C1-4 alkyl. In a more particular embodiment, one of R8a and R8b is H, and the other is -CH3, -CH2CH3, or -CH( CHV. In another more particular embodiment, R8a and R8b are both independently -CH3, -CH2CH3, or -CH( 013)2. In a most particular embodiment, R8a and R8b are both -CH3.
[0123] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is C1-4 alkyl. In a particular embodiment, R7 is -CH3, -CH2CH3, -CH( 013)2. In a more particular embodiment, R7 is -CH3.
[0124] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is C1-4 alkyl substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In a particular embodiment, R7 is -CH3, -CH2CH3, -CHfCHV. each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another particular embodiment, R7 is C1-4 alkyl substituted with one, two, or three independently selected halo, -CN, or C1.4 alkoxy. In yet another particular embodiment, R7 is C1.4 alkyl substituted with one or more independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R7 is -CH3, -CH2CH3, -CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, R7 is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected F, -CN, or -O-CH3. In yet a further more particular embodiment, R7 is -CHF2, -CF3, -CH2CN, or -CH2CH2CN.
[0125] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is C1.4 alkoxy. In a particular embodiment, R7 is -O-CH3, -O-CH2CH3, -O-CH(CH3)2. In a more particular embodiment, R7 is -O-CH3.
[0126] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is C1-4 alkoxy substituted with one or more independently selected halo, -CN, or C1-4 alkoxy. In a particular embodiment, R7 is -O-CH3, -O-CH2CH3, -O-CH(CH3)2, each of which is substituted with one or more independently selected halo, -CN, or C1.4 alkoxy. In another particular embodiment, R7 is C1.4 alkoxy substituted with one, two, or three independently selected halo, -CN, or C1.4 alkoxy. In yet another particular embodiment, R7 is C1.4 alkoxy substituted with one or more independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R7 is -O-CH3, -O-CH2CH3, -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, Br, -CN, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, R7 is -O-CH3 or -O-CH2CH3, each of which is substituted with one, two, or three independently selected F, -CN, or -O-CH3. In most particular embodiment, R7 is -O-CHF2, -O-CFs. or -O-CH2CH2-O-CH3.
[0127] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S. In a particular embodiment, R7 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5- thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 1- azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4-azaspiro[2.4]heptanyl, 1- thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 5-thiaspiro[2.4]heptanyl, 4-thiaspiro[2.4]heptanyl, 1- oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 5 -oxaspiro [2.4]heptanyl, or 4-oxaspiro[2.4]heptanyl. In a more particular embodiment, R7 is azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, or 2- oxaspiro [3.3 ]heptanyl .
[0128] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIr, wherein R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl, heteroaryl, or heterocycloalkyl is substituted with one or more independently selected R7, and R7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy. In a particular embodiment, R7 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4- azaspiro[2.3]hexanyl, 5-thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4- oxaspiro[2.3]hexanyl, l-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4- azaspiro[2.4]heptanyl, l-thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 5-thiaspiro[2.4]heptanyl, 4- thiaspiro[2.4]heptanyl, l-oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 5 -oxaspiro [2.4]heptanyl, or 4- oxaspiro[2.4]heptanyl, each of which is substituted with one or more independently selected oxo, halo, -OH, -CN, Ci-4 alkyl, or Ci-4 alkoxy. In another particular embodiment, R7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one, two, or three independently selected oxo, halo, -OH, -CN, C1.4 alkyl, or C1-4 alkoxy. In yet another particular embodiment, R7 is 4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is substituted with one or more independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R7 is azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxanyl, piperazinyl, 5-azaspiro[2.3]hexanyl, 4-azaspiro[2.3]hexanyl, 5- thiaspiro[2.3]hexanyl, 4-thiaspiro[2.3]hexanyl, 5-oxaspiro[2.3]hexanyl, 4-oxaspiro[2.3]hexanyl, 1- azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl, 4-azaspiro[2.4]heptanyl, 1- thiaspiro[3.3]heptanyl, 2-thiaspiro[3.3]heptanyl, 5-thiaspiro[2.4]heptanyl, 4-thiaspiro[2.4]heptanyl, 1- oxaspiro[3.3]heptanyl, 2-oxaspiro[3.3]heptanyl, 5-oxaspiro[2.4]heptanyl, or 4-oxaspiro[2.4]heptanyl, each of which is substituted with one, two, or three independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, R7 is azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, or 2- oxaspiro[3.3]heptanyl, each of which is substituted with one, two, or three independently selected oxo, F, Cl, Br, -OH, -CN, -CH3, -CH2CH3, -CH(CH3)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a most particular
Figure imgf000027_0001
[0129] In one embodiment, the compound of the invention is selected from:
N-((4-(3,4-dihydroquinolin-l(2H)-yl)pyridin-2-yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8- carboxamide 1,1 -dioxide,
N-((4-(3,4-dihydroisoquinolin-2(lH)-yl)pyridin-2-yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-
8-carboxamide 1,1 -dioxide,
N-((4-(4-(2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl)phenyl)pyridin-2-yl)methyl-2,3-dihydro-5H- benzo[e] [ 1 ,4]oxathiepine-8-carboxamide 1 , 1 -dioxide,
N-((4-(4-(2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl)phenyl)pyridin-2-yl)methyl)-4-methyl-3-
(methylsulfonyl)benzamide,
N-((4-(3-(2,3-dihydro-4H-pyrido[3,2-b][l,4]oxazin-4-yl)phenyl)pyridin-2-yl)methyl)-2,3-dihydro-5H- benzo[e] [ 1 ,4]oxathiepine-8-carboxamide 1 , 1 -dioxide,
N-((4-([l,r-biphenyl]-4-yl)pyridin-2-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((4-([l,r-biphenyl]-4-yl)pyridin-2-yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8- carboxamide 1,1 -dioxide,
N-([4,4'-bipyridin]-2-ylmethyl)-4-methyl-3-(methylsulfonyl)benzamide,
N-([3,4'-bipyridin]-2'-ylmethyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((4-phenylpyridin-2-yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide, 4-methyl-N-((4-(l-methyl-lH-indol-3-yl)pyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((4-phenylpyridin-2-yl)methyl)benzamide,
N-((4-([ 1 , 1 '-biphenyl]-4-yl)pyridin-2-yl)methyl)- 1 -(methylsulfonyl)- lH-pyrrole-3-carboxamide, N-((4-([l,r-biphenyl]-3-yl)pyridin-2-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((4-([l,l'-biphenyl]-4-yl)pyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((4-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, N-([2,4'-bipyridin]-2'-ylmethyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((5-phenylpyridazin-3-yl)methyl)benzamide, 4-methyl-N-((5-methyl-4-phenylpyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, 4-methyl-N-((4-( 1 -( 1 -methylpiperidin-4-yl)- lH-pyrazol-4-yl)pyridin-2-yl)methyl)-3- (methylsulfonyl)benzamide,
4-methyl-3-(methylsulfonyl)-N-((4-(l-(piperidin-4-yl)-lH-pyrazol-4-yl)pyridin-2-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((4-(l-phenyl-lH-pyrazol-4-yl)pyridin-2-yl)methyl)benzamide, 4-methyl-N-((4-(3-(4-methylpiperazin-l-yl)phenyl)pyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, N-((6-((2S,6R)-2,6-dimethylmorpholino)-[2,4'-bipyridin]-2'-yl)methyl)-4-methyl-3- (methylsulfonyl)benzamide,
4-methyl-3-(methylsulfonyl)-N-((6-morpholino-[2,4'-bipyridin]-2'-yl)methyl)benzamide, N-((4-([l,l'-biphenyl]-3-yl)pyridin-2-yl)methyl)-3-(methylsulfonyl)benzamide, N-((4-([l,l'-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8- carboxamide 1,1-dioxide, 4-methyl-3-(methylsulfonyl)-N-((5-phenyl-[2,4'-bipyridin]-2'-yl)methyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((4-(3-morpholinophenyl)pyridin-2-yl)methyl)benzamide, N-((4-(3-methoxyphenyl)pyridin-2-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((4-(3-(pyridin-3-yl)phenyl)pyridin-2-yl)methyl)benzamide,
N-((4-(3'-(dimcthylamino)-| 1. 1 '-biphenyl |-3-yl)pyridin-2-yl)mcthyl)-4-mcthyl-3- (methylsulfonyl)benzamide,
N-((4-(4'-cyano- [ 1 , 1 '-biphenyl] -3 -yl)pyridin-2-yl)methyl)-4-methyl-3 -(methylsulfonyl)benzamide, 4-methyl-3-(methylsulfonyl)-N-((4-(3-(pyridin-2-yl)phenyl)pyridin-2-yl)methyl)benzamide, N-((4-(3-bromophenyl)pyridin-2-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, N-((4-(4-methoxyphenyl)pyridin-2-yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide, and 4-methyl-3-(methylsulfonyl)-N-((4-(3-(pyridin-4-yl)phenyl)pyridin-2-yl)methyl)benzamide.
[0130] In one embodiment, the compound of the invention is N-((4-([l,l'-biphenyl]-3-yl)pyridin-2- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide. [0131] In one embodiment, the compound of the invention is not N-((4-([l,l'-biphenyl]-3-yl)pyridin-2- yl)methyl)-4-methyl-3-(methylsulfonyl)benzamide.
[0132] In one embodiment, the compound of the invention is N-((4-([l,T-biphenyl]-3-yl)pyridin-2- yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide.
[0133] In one embodiment, the compound of the invention is not N-((4-([l,T-biphenyl]-3-yl)pyridin-2- yl)methyl)-2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxamide 1,1-dioxide.
[0134] In one embodiment, a compound of the invention is provided in a natural isotopic form.
[0135] In one embodiment, a compound of the invention is provided in an unnatural variant isotopic form.
In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably, the unnatural variant isotopic form is a pharmaceutically acceptable form.
[0136] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
[0137] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.
[0138] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.
[0139] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt of the compound. [0140] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
[0141] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of the compound.
[0142] A preferred group of compounds according to the invention are those of formula 1-1
Figure imgf000029_0001
1-1 wherein, Li is phenyl, or pyridyl, which phenyl or pyridyl is optionally substituted with one or more independently selected halogen, C1-3 alkyl, -CH=CHCC>2R9a , morpholino, C1-3 alkoxy, C1-3 haloalkoxy or oxetane;
R1 is C1-4 alkyl, C1-3 alkoxy(Ci-3)alkyl, or hydroxy(Ci-3)alkyl;
R2a is hydrogen, fluoro, chloro or C1-3 alkyl (preferably chloro or methyl); or R1 and R2a together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the -S(=O)2- of formula 1-1 and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro); or R1 and R2a together with the atoms onto which they are attached form
Figure imgf000030_0001
, which is optionally substituted with one or more independently selected halogens (preferably fluoro);
R2b is hydrogen, fluoro, chloro, methyl or ethyl (preferably hydrogen);
R3 is hydrogen or C1-2 alkyl (preferably hydrogen); each of R4a andR4b is independently hydrogen, methyl or ethyl;
R5 is phenyl, pyridyl, pyrimidinyl, pyrrolyl, each of which is optionally substituted with one, two or three independently selected R7; or L1-R5 together is an indole or benzofuran group, each of which is optionally substituted with one, two or three independently selected R7;
R6 is hydrogen, fluoro or methyl (preferably hydrogen); each R7 is independently selected from
- -OH,
- -P(O)(Ci.4alkyl)2, halogen,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -NHC(O)CI-2 alkyl,
- -N(CI-2 alkyl)C(O)Ci-2 alkyl,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -CO2R9a or Ci -4 alkoxy, Ci-4 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci -4 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, morpholino (preferably 1 -morpholino), oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl and
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; each R8a is independently hydrogen or C1-4 alkyl; each R8b is independently hydrogen, C1-4 alkyl or -C(O)Ci-2 alkyl; each R9a is independently selected from hydrogen and C1-4 alkyl; and
R9b is hydrogen, C1-4 alkyl or C1-4 alkoxy; or R9a and R9b together with the atoms onto which they are attached form a 5-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, Ci -4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
[0143] Another preferred group of compounds according to the invention are those of formula 1-2
Figure imgf000031_0001
1-2 wherein,
R1 is C1-2 alkyl (preferably methyl), C1-2 alkoxy (Ci-2)alkyl (preferably methoxymethyl), or hydroxy (C 1 _3)alkyl ;
R2a is hydrogen, fluoro, chloro or C1-2 alkyl (preferably chloro or methyl); or R1 and R2a together with the atoms onto which they are attached form
Figure imgf000031_0002
, which is optionally substituted with one or more independently selected halogens (preferably fluoro);
R2b is hydrogen, fluoro, or methyl(preferably hydrogen);
R3 is hydrogen or methyl (preferably hydrogen); each of R4a and R4b is independently hydrogen, or methyl;
R5 is phenyl or pyridyl, each of which is optionally substituted with one or two independently selected R7; each R7 is independently selected from
- -OH,
- -CN,
- -P(O)(Ci.2 alkyl)2, halogen,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -NHC(O)CI-2 alkyl,
- -N(CI.2 alkyl)C(O)Ci.2 alkyl,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Ci-2 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -CO2R9a or Ci-2 alkoxy,
Ci-2 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci-2 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-2 alkyl, or C1-2 alkoxy, morpholino (preferably 1 -morpholino), oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl, and
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; each R8a is independently hydrogen or C1-2 alkyl; each R8b is independently hydrogen, C1-2 alkyl or -C(O)Ci.2 alkyl; each R9a is independently selected from hydrogen and C1-2 alkyl;
R9b is hydrogen, C1-2 alkyl or C1-2 alkoxy, or R9a and R9b together with the atoms onto which they are attached form a 5-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, Ci-2 alkyl; and
R10 is hydrogen, halogen, C1-3 alkyl, -CH=CHCO2R9a , morpholino, C1-3 alkoxy, C1-3 haloalkoxy or oxetane; or a pharmaceutically acceptable salt and/or solvate thereof. [0144] Another preferred group of compounds according to the invention are those of formula 1-3
Figure imgf000033_0001
wherein,
R1 is Cn2 alkyl (preferably methyl), Ci-2 alkoxy (Ci.2)alkyl (preferably methoxymethyl), or hydroxy (C i _3)alkyl ;
R2 is hydrogen, fluoro, chloro or Ci-2 alkyl (preferably chloro or methyl);
Figure imgf000033_0002
substituted with one or more independently selected halogens (preferably fluoro);
R3 is hydrogen or methyl (preferably hydrogen); each of R4a andR4b is independently hydrogen, or methyl (preferably both are hydrogen);
R5 is phenyl or pyridyl, each of which is optionally substituted with one or two independently selected R7; each R7 is independently selected from
- -OH,
- -CN,
- -P(O)(Ci.2 alkyl)2, fluoro, chloro,
- alkyl,
Figure imgf000033_0003
- -NHC(O)CI.2 alkyl,
- -N(CI.2 alkyl)C(O)Ci.2 alkyl,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Cn2 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, -CO2R9a or Ci-2 alkoxy, Ci-2 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci -2 alkoxy, morpholino (preferably 1 -morpholino), and oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl; each R8a is independently hydrogen or C1-2 alkyl; each R8b is independently hydrogen, C1-2 alkyl or -C(O)Ci-2 alkyl; each R9a is independently selected from hydrogen and C1-2 alkyl;
R9b is hydrogen, or C1-2 alkyl; and
R10 is hydrogen, fluoro, chloro, C1-2 alkyl, -CH=CHCO2R9a , , C1-3 alkoxy, C1-3 haloalkoxy or oxetane; or a pharmaceutically acceptable salt and/or solvate thereof.
[0145] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.
[0146] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
[0147] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.
[0148] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, A-alkylmorpholinc esters and the like.
[0149] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention. PHARMACEUTICAL COMPOSITIONS
[0150] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
[0151] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.
[0152] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a proliferative diseases treatment agent. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
[0153] In a particular embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a cancer treatment agent. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma
[0154] In a further particular embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a leukemia treatment agent. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
[0155] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
[0156] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Lormula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
[0157] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring. [0158] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
[0159] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
[0160] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[0161] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
[0162] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences (Remington & Gennaro 1985).
[0163] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets
[0164] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
Formulation 2 - Capsules
[0165] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule). Formulation 3 - Liquid
[0166] A compound ofthe invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[0167] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
Formulation 5 - Injection
[0168] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
Formulation 6 - Topical
[0169] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75 °C and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
METHODS OF TREATMENT
[0170] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
[0171] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
[0172] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma. [0173] In additional methods of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, and multiple myeloma.
[0174] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of cancer. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma.
[0175] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of cancer. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma.
[0176] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with cancer, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term refers to both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). More particularly, the term refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. Most particularly, the term refers to non-small cell lung cancer, Burkitt lymphoma, medulloblastoma, pancreatic cancer, ovarian cancer, and melanoma.
[0177] In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of leukemia. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). [0178] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and/or treatment of leukemia. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
[0179] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with leukemia, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term refers to neoplastic diseases of the blood and blood forming organs. More particularly, the term refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
[0180] Injection dose levels range from about 0. 1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
[0181] For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
[0182] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
[0183] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[0184] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[0185] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen. [0186] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.
[0187] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin®), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva®, Erbitux®), VEGF inhibitors (e.g. Avastin®), proteasome inhibitors (e.g. Velcade®), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.
[0188] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.
CHEMICAL SYNTHETIC PROCEDURES
General
[0189] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0190] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2006).
[0191] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
[0192] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Biotage® Sfar KP -Amino D, Biotage® Star HC D, or Interchim® PuriFlash® Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g. , Cat# 120-1907-E) are used for aqueous phase separation. ’H NMR spectra are recorded on a Bruker Avance NEO 400 NMR spectrometer (400 MHz), a Bruker Avance 400 NMR spectrometer (400 MHz), a Bruker Avance III HD NMR spectrometer (400 MHz), or a Bruker Avance DRX 500 spectrometer (500 MHz). Chemical shifts (5) for ’H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (5 0.00) or the appropriate residual solvent peak, e.g. CHCI3 (5 7.26), MeOH (5 3.31), or DMSO (5 2.50 ppm), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30/50 mm L; Waters Acquity UPLC CSH C18 1.7 pm, 2.1 mm ID x 50/100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 pm, 2.1 mm ID x 100 mm L; Waters Acquity UPLC HSS PFP 1.8 pm, 2.1 mm ID x 100 mm L. The methods are using ACN/water or MeOH/water gradients with either 0.1% formic acid in both mobile phases, 0.05% NFLOH in both mobile phases, or 10 mM NH4HCO3 in water (adjusted to pH 10 with ammonia). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBridge BEH C18 OBD 30 mm ID x 100/150 mm L columns and ACN/water gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in water, or 10 mM NH4HCO3 in water (adjusted to pH 10 with ammonia), or on a Buchi® Pure C-850 Flash with UV and ESDL detection using Buchi® C18 AQ 100 A 250 x 20 mm column and using ACN/water gradients with either 0.1% formic acid in both mobile phases or 0.05% NH4OH in both mobile phases.
Table I. List of abbreviations used in the experimental section:
Figure imgf000044_0001
Figure imgf000044_0002
Figure imgf000045_0002
Figure imgf000045_0001
Figure imgf000046_0002
Figure imgf000046_0001
Figure imgf000047_0001
SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION
Example 1. General synthetic methods
1.1. Synthetic methods overview
General method Al: amide coupling with HATU
General method A2: amide coupling with acyl chloride
General method Bl: Suzuki coupling
General method B2: Suzuki coupling
General method C: Buchwald coupling
General method DI: nitrile reduction with Raney/Ni
General method D2: nitrile reduction with Pd/C
General method D3: nitrile reduction with Pd/C and B0C2O
General method D4: nitrile reduction with Raney/Ni and B0C2O
General method El: Boc removal with HC1
General method E2: Boc removal with TFA
General method Fl: Miyaura borylation
General method F2: Miyaura borylation
General method Gl: Saponification with NaOH
General method G2: Saponification with LiOH
General method Hl: Nucleophilic substitution from amine
General method H2: Nucleophilic substitution from thiol
General method J: Stille coupling
General method K: Oxydation by m-CPBA
General method L: Acetylation
1.2. General methods
1.2.1. General method Al: amide coupling with HATU
Figure imgf000048_0001
[0193] To a solution of carboxylic acid (0.87 to 1.0 eq) and amine (1 to 1.2 eq.) in DMF or DCM is added HATU (1.2 to 1.5 eq.). The reaction mixture is stirred at RT for 10 min and DIPEA (2 to 10 eq.) is then added. The reaction is stirred at RT for 5 min to 24 h. The crude is directly evaporated to dryness or poured out into water, extracted with DCM, the organic layers are combined, washed with water and brine, dried over Na2SC>4, and evaporated to dryness. The residue is purified either by column chromatography on silica gel or by preparative HPLC to give the desired amide. 1.2.1.1. Illustrative synthesis of Int 27
Figure imgf000049_0001
[0194] To a solution of 3 -methanesulfonyl -4-methylbenzoic acid (CAS# 51522-22-6; 1.0 g, 4.67 mmol, 1 eq.) and l-(4-bromopyridin-2-yl)methanamine (CAS# 865156-50-9; 0.96 g, 5.13 mmol, 1.1 eq.) in DMF (10 mL) were added HATU (2.31 g, 6.07 mmol, 1.3 eq.) and DIPEA (2.4 m , 11.67 mmol, 2.5 eq.). The reaction was stirred at RT for 18 h. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography on silica gel (eluting with DCM to DCM/MeOH 99/1) to afford Int 27.
1.2.1.2. Illustrative synthesis of Cpd 28
Figure imgf000049_0002
[0195] To a solution of 2,3-dihydro-5H-benzo[e][l,4]oxathiepine-8-carboxylic acid 1,1-dioxide (CAS# 2771132-16-0, synthesis ref.: WO2022/103899A1 page 177; 25 mg, 0.11 mmol, 1 eq.) and Int 20 (35 mg, 0.11 mmol, 1 eq.) in DMF (3 mL) were added HATU (52 mg, 0.14 mmol, 1.3 eq.) and DIPEA (0.1 mL, 0.55 mmol, 5 eq.). The reaction was stirred at RT for 2 h. The reaction mixture was quenched with few drops of water and then filtered through a 0.45 pm PTFE membrane. The resulting solution was purified by preparative HPLC to afford Cpd 28.
1.2.1.3. Illustrative synthesis of Cpd 13
Figure imgf000049_0003
[0196] To a solution of l-(methylsulfonyl)pyrrole-3 -carboxylic acid (CAS# 1521806-48-3; 28 mg, 0.15 mmol, 1 eq.) and Int 18 (50 mg, 0.15 mmol, 1 eq.) in DMF (3 mL) were added HATU (74 mg, 0.20 mmol, 1.3 eq.) and DIPEA (0.14 mL, 0.82 mmol, 5 eq.). The reaction was stirred at RT until completion. The reaction mixture was quenched with a few drops of water and then filtered through a 0.45 pm PTFE membrane. The resulting solution was purified by preparative HPLC to afford Cpd 13.
1.2.2. General method A2: amide coupling with acyl chloride
Figure imgf000049_0004
[0197] Step i: To a solution of carboxylic acid (1 eq.) in DCM are added oxalyl chloride (2 eq.) and then a few drops of DMF (cat.). The reaction is stirred at RT for 30 min to 4 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to give the desired acyl chloride.
[0198] Step ii: To a solution of acyl chloride (1.2 eq.) and amine (1 eq.) in DCM is added TEA (3 eq.). The reaction is stirred at RT for 30 min to 24 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to give the desired amide.
1.2.2.1. Step i: Illustrative synthesis of 4-methyl-3-(methylsulfonyl)benzoyl chloride
Figure imgf000050_0001
[0199] DMF (2 drops, cat.) was added to a stirred solution of 3 -methylsulfonyl benzoic acid (CAS# 51522- 22-6; 95 mg, 0.47 mmol, 1 eq.) and oxalyl chloride (78 pL, 0.90 mmol, 1.9 eq.) in DCM (4.7 m ). The mixture was stirred at RT for 30 min. The reaction mixture was evaporated to dryness to afford 4-methyl- 3 -(methylsulfonyl)benzoyl chloride .
1.2.2.2. Step ii: Illustrative synthesis of Cpd 14
Figure imgf000050_0002
[0200] To a solution of 4-methyl-3-(methylsulfonyl)benzoyl chloride (25 mg, 0.11 mmol, 1.2 eq.) and Int 20 (30 mg, 0.09 mmol, 1 eq.) in DCM (1 mb) was added TEA (38 pL, 0.27 mmol, 3 eq.). The reaction was stirred at RT for 16 h. The reaction mixture was evaporated to dryness and purified by preparative HPLC to give Cpd 14.
1.2.3. General method Bl: Suzuki coupling
Figure imgf000050_0003
[0201] To a stirred solution of the iodo, bromo, or chloro derivative (1.0 to 1.3 eq.) and the boronic acid or ester derivative (1.0 to 3.3 eq.) in 1,4-dioxane is added either CS2CO3 or K2CO3 (2.0 to 6 eq.) previously diluted in water. The mixture is degassed either with argon or nitrogen for 5 min. Pd(dppf)C12'DCM (0.05 eq. or 0.15 eq.) or Pd(dppf)C12 (0.1 eq.) or XPhos Pd G3 (0.05 eq) or Pd(Cy)3 Pd G4 (0.10 eq.) is then added and the reaction is stirred at 50 °C, 80 °C, 90 °C, 100 °C or 120 °C (conventional or microwave heating) for 30 min to 6 days. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to give the desired compound.
1.2.3.1. Illustrative synthesis of Cpd 17
Figure imgf000050_0004
[0202] To a stirred solution of Int 27 (50 mg, 0.13 mmol, 1.0 eq.) and (1 -methyl- lH-pyrazol-4-yl)boronic acid (CAS# 847818-55-7; 16 mg, 0.13 mmol, 1 eq.) in 1,4-dioxane (2 mL) was added CS2CO3 (85 mg, 0.26 mmol, 2 eq.) previously diluted in water (0.25 mL). The mixture was degassed with argon for 5 min. Pd(dppf)C12-DCM (5 mg, 0.006 mmol, 0.05 eq.) was then added and the reaction was stirred at 100 °C for 2 h. The crude was evaporated to dryness and the residue was purified by column chromatography on a Biotage® Star KP -Amino D chromatography cartridge (eluting with DCM to DCM/MeOH 99/1) to afford Cpd 17.
1.2.3.2. Illustrative synthesis of Int 3
Figure imgf000051_0001
[0203] To a stirred solution of 5-bromo-3-chloropyridazine (CAS# 1196155-33-5; 317 mg, 1.64 mmol, 1 eq.) and phenylboronic acid (CAS# 98-80-6; 200 mg, 1.64 mmol, 1 eq.) in 1,4-dioxane (4 mL) was added CS2CO3 (1.068 g, 3.28 mmol, 2 eq.) previously diluted in water (0.8 mL). The mixture was degassed with argon for 5 min. Pd(dppf)C12'DCM (676 mg, 0.082 mmol, 0.05 eq.) was then added and the reaction was stirred at 100 °C for 1 h. The crude was evaporated to dryness and the residue was purified by column chromatography on silica gel (eluting with DCM) to afford Int 3.
1.2.3.3. Illustrative synthesis of Int 9
Figure imgf000051_0002
[0204] To a stirred solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (CAS# 741709-62-6; 200 mg, 0.87 mmol, 1 eq.) and l-bromo-4-iodobenzene (CAS# 589-87-7; 295 mg, 1.04 mmol, 1.2 eq.) in 1,4-dioxane (5 mL) was added K2CO3 (240 mg, 1.74 mmol, 2 eq.) previously diluted in water (1 mL). The mixture was degassed with nitrogen for 5 min and then Pd(dppf)CL (64 mg, 0.082 mmol, 0.1 eq.) was added and the reaction was stirred at 75 °C for 2 h. The crude was evaporated to dryness and the residue was purified by preparative HPLC to afford Int 9.
1.2.4. General method B2: Suzuki coupling
[0205] To a stirred solution of the dihalogenoaryl (iodo, bromo derivative) (1 eq.) and the boronic ester derivative (1.0 eq.) in 1,4-dioxane is added K2CO3 (2.0 eq.) previously diluted in water. The mixture is degassed either with argon or nitrogen for 5 min. Pd(dppf)C12 (0.10 eq.) is then added, and the reaction is stirred at 60 °C or 80 °C for 2 h to 4 h. Then boronic acid or ester derivative (1.2 to 1.3 eq.) and Pd(dppf)CL (0.10 eq.). The reaction is purged under nitrogen or argon flux and is stirred at 100 °C for 1 h to 16 h. NaHC’Cf saturated aqueous solution is added, and the mixture is extracted with EtOAc. The organic layer is dried, and the solvent is evaporated to dryness and purified either by column chromatography on silica gel and/or by preparative HPLC to give the desired compound 1.2.4.1. Illustrative synthesis of Cpd 134
Figure imgf000052_0001
[0206] Pd(dppf)C12 (7.5 mg, 0.010 mmol, 0.1 eq.) was added to an N2-purged mixture of Int 50 (50 mg, 0.10 mmol, 1.0 eq.), 2-bromo-4-iodopyridine (CAS# 100523-96-4; 31 mg, 0.10 mmol, 1.0 eq.) and K2CO3 (20 mg, 0.21 mmol, 2.00 eq.) in 1,4-dioxane (2.0 mL) and H2O (0.6 mL). The reaction mixture was stirred at 60 °C for 1 h. Then, 4-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]morpholine (CAS# 852227-95-3; 36 mg, 0.12mmol, 1.2 eq.) and Pd(dppf)C12 (7.5 mg, 0.010 mmol, 0.1 eq.) were added to nitrogen purged mixture and the resulting mixture was stirred at 100 °C for 1 h. Then NaHCOs saturated aqueous solution and EtOAc were added to the reaction mixture. The organic layers were washed with saturated NaHCOs, aqueous solution, brine, dried with Na2SC>4 and fdtered. The solvent was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 0/100 then with DCM/MeOH from 100/0 to 90/10), then by preparative HPLC to afford Cpd 134.
1.2.4.2. Illustrative synthesis of cpd 152
Figure imgf000052_0002
Pd(dppf)C12 (11 mg, 0.015 mmol, 0.1 eq.) was added to an nitrogen purged mixture of 2-bromo-4- iodopyridine (45 mg, 0.15 mmol, 1.0 eq.) 4 , 4-methyl-3-methylsulfonyl-N-[[4-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)-2-pyridyl]methyl]benzamide 3 (0.1 g, 0.15 mmol, 1.0 eq.) and K2CO3 (31 mg, 0.31 mmol, 2.0 eq.) in 1,4-dioxane (2.0 mL) containing H2O (0.6 mL) and the reaction mixture was heated at 60 °C for 4 h. Then, Pd(dppf)C12 (0.011 g, 0.015 mmol, 0.1 eq.) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)benzoic acid 5 (51 mg, 0.20 mmol, 1.3 eq.) were added to the N2-purged mixture and the resulting mixture was stirred at 100 °C for 16 h. After NaHCCf saturated aqueous solution and EtOAc were added to the reaction mixture. The organic layers were washed with NaHCO; saturated aqueous solution, brine, dried with Na2SO4, filtered, and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Heptane/EtOAc 100/0 to 0/100 then with DCM/MeOH 100/0 to 90/10) then purified by preparative HPLC using basic gradient to afford cpd 152. 1.2.5. General method C: Buchwald coupling
Figure imgf000053_0001
[0207] To a stirred solution of the iodo, bromo, or chloro derivative (1 eq.) and the amine (1 to 4 eq.) in 1,4-dioxane or THF or Toluene is added CS2CO3 (2 to 3 eq.) or NaO/Bu (2 M) in THF. The mixture is degassed with nitrogen for 5 min. XantPhos Pd G3 (0.1 eq. to 0.2 eq.) is then added, and the reaction is stirred at 70 to 110 °C for 1 to 92 h. Filtration on celite®. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to afford the desired product.
1.2.5.1. Illustrative synthesis oflnt 10
Figure imgf000053_0002
[0208] To a solution of lnt 9 (80 mg, 0.31 mmol, 1 eq.) and 3,4-dihydro-2H-pyrido[3,2-b][l,4]oxazine (CAS# 20348-23-6; 42 mg, 0.31 mmol, 1 eq.) in 1,4-dioxane (5 m ) was added CS2CO3 (201 mg; 0.62 mmol, 2 eq.) The mixture was degassed with nitrogen for 5 min. XantPhos Pd G3 (59 mg, 0.062 mmol, 0.1 eq.) was then added, and the reaction was stirred at 70 °C for 4 h. The reaction medium was evaporated to dryness and the residue was purified by preparative HPLC to afford Int 10.
1.2.5.2. Illustrative synthesis oflnt 85
Figure imgf000053_0003
[0209] Under inert atmosphere, Int 86 (25 mg, 0.093 mmol, 1 eq.) and morpholine (CAS# 110-91-8; 8.19 pL, 0.093 mmol, 1 eq.) and NaO/Bu (2 M) in THF (69.8 pL, 0.14 mmol, 1.5 eq.) in toluene (0.396 m ) were degassed under nitrogen atmosphere. XantPhos Pd G3 (17.66 mg, 0.019 mmol, 0.2 eq.) was added and the mixture was degassed again with nitrogen atmosphere and was stirred at 90 °C for 18 h. Water and DCM were added. The layers were separated. The aqueous layer was extracted once with DCM. The combined organic layers were washed 3 times with brine, dried over MgSCL, concentrated under vacuum then purified by column chromatography on silica gel (eluting from Heptane/EtOAc 95/5 to 50/50). The fractions containing product were combined and evaporated to dryness to afford Int 85.
1.2.6. General method DI: nitrile reduction with Raney nickel
Figure imgf000053_0004
[0210] To a solution of the nitrile derivative (1 eq.) in a mixture of ammonia 2 N in EtOH and DCM is added Raney nickel (0.5 to 3 eq.) and the suspension is stirred at RT under hydrogen atmosphere (1 atm) for 1 to 16 h. The reaction mixture is fdtered through either a 0.45 pm PTFE membrane or Celite®. The fdtrate is evaporated to dryness to afford the crude expected product.
1.2.6.1. Illustrative synthesis of Int 24
Figure imgf000054_0001
[0211] To a solution of Int 23 (83 mg, 0.43 mmol, 1 eq.) in ammonia 2N in EtOH (5 mL) and DCM (5 mL) was added Raney nickel (75 mg, 1.28 mmol, 3 eq.) under nitrogen atmosphere. The suspension was degassed under vacuum and purged three times with hydrogen. The mixture was stirred at RT overnight under hydrogen atmosphere (1 atm) for 18 h. The reaction was fdtered through Celite® and the cake was washed with methanol. The fdtrate was evaporated to dryness to afford Int 24.
1.2.7. General method D2: nitrile reduction with Pd/C
Figure imgf000054_0002
[0212] To a solution of the nitrile derivative (1 eq.) in EtOH is added either 5 wt.% loading Pd/C or 10 wt.% loading Pd/C (0.02 to 0.5 eq.) and the suspension is stirred at RT under hydrogen atmosphere (1 atm) for 1 to 16 h. The reaction mixture is fdtered through a 0.45 pm PTFE membrane. The fdtrate is evaporated to dryness to afford the crude desired compound.
1.2. 7.1. Illustrative synthesis of Int 5
Figure imgf000054_0003
[0213] To a solution of Int 4 (36 mg, 0.20 mmol, 1 eq.) in EtOH (2 mL) was added 5 wt.% loading Pd/C (36 mg, 0.017 mmol, 0.085 eq.). The mixture was stirred at RT under hydrogen atmosphere (1 atm) for 16 h. The reaction mixture was fdtered through a 0.45 pm PTFE membrane. The fdtrate was evaporated to dryness to afford the crude Int 5.
1.2.8. General method D3: nitrile reduction with Pd/C and BOC2O
Figure imgf000054_0004
[0214] To a solution of the nitrile derivative (1 eq.) and BOC2O (5 eq.) in EtOH and DCM is added either 5 wt.% loading Pd/C or 10 wt.% loading Pd/C (0.02 to 0.5 eq.) and the suspension is stirred at RT under hydrogen atmosphere (1 atm) for 1 to 16 h. The reaction mixture is fdtered through a 0.45 pm PTFE membrane. The fdtrate is evaporated to dryness to afford the crude desired compound. 1.2.8.1. Illustrative synthesis oflnt 33
Figure imgf000055_0001
[0215] To a solution of lnt 32 (116 mg, 0.45 mmol, 1 eq.) in a mixture of EtOH (17.0 mL) and DCM (5.0 mL) were added 10 wt.% Pd/C (40 mg, 0.038 mmol, 0.09 eq.) and BOC2O (491 mg, 2.25 mmol, 5 eq.). The suspension was stirred at RT under hydrogen atmosphere (1 atm) for 16 h. The reaction mixture was filtered through a 0.45 pm PTFE membrane and the filtrate was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with heptane/EtOAc 100/0 to 0/100) to afford Int 33.
Figure imgf000055_0002
[0216] To a solution of the nitrile derivative (1.0 eq.) and BOC2O (3.0 to 5.0 eq.) and EtsN (3.0 to 5.6 eq.) in THF or trifluoroethanol under nitrogen is added Raney Ni (0.3 to 0.9 eq.). The suspension is stirred at RT under hydrogen atmosphere (1 atm) for 3 to 22 h. The reaction mixture is fdtered over celite®. The fdtrate is evaporated to dryness and purified by column chromatography on silica gel to afford the desired product.
1.2.9.1. Illustrative synthesis oflnt 52
Figure imgf000055_0003
A stirred solution of Int 51 (130 mg, 0.45 mmol, 1 eq.), Boc2O (493.74 mg, 0.48 mL, 2.26 mmol, 5 eq.) and TEA (254.41 mg, 0.35 mL, 2.51 mmol, 5.6 eq.) in trifluoroethanol (6.0 mL) was purged with vacuo/nitrogen. Raney nickel (25 mg, 0.0028 mL, 0.43 mmol, 0.94 eq.) was added. The reaction mixture was purged with H2 (3 x), then stirred under H2 atmosphere (latm) at RT.
The reaction mixture was filtered over a pad of celite® and then the filtrate was evaporated to dryness.
The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to afford Int 52.
1.2.10. General method El: Boc removal with HCl
R2
R 'H
Figure imgf000055_0004
[0217] To a solution of the Boc-protected amine (1 eq.) in DCM is added a HCl (4 M) solution in 1,4- dioxane (5 to 40 eq.) for 30 min to 18 h. The reaction mixture is evaporated to dryness to afford the crude desired compound as HCl salt. 1.2.10.1. Illustrative synthesis oflnt !8
Figure imgf000056_0001
[0218] To a solution of Int 17 (105 mg, 0.28 mmol, 1 eq.) in DCM (3 mb) was added a HC1 4M solution in 1,4-dioxane (1 mb, 4 mmol, 30 eq.). The reaction mixture was stirred at RT for 1 h. The solvents were evaporated to dryness to give Int 18.
1.2.11. General method E2: Boc removal with TFA
Figure imgf000056_0002
[0219] To a solution of the Boc-protected amine (1 eq.) in DCM is added TFA (10.0 to 20.0 eq.) for 1 to 16 h. DCM is added to the reaction mixture and the pH is adjusted to 9 by addition of a saturated NaHCOs aqueous solution. The mixture is fdtered over an hydrophobic frit and the organic layer is evaporated to dryness. The residue is purified by column chromatography on silica gel to afford the desired product.
1.2.11.1. Illustrative synthesis of Cpd 22
Figure imgf000056_0003
[0220] To a stirred solution of Int 35 (80 mg, 0.14 mmol, 1 eq.) in DCM (3 mb) was added TFA (210 pL, 2.89 mmol, 20 eq.). The reaction mixture was stirred at RT for 16 h. The crude was evaporated to dryness. DCM was added to the reaction mixture and the pH was adjusted to 9 by addition of a saturated NaHCOs aqueous solution. The mixture was filtered over a phase separator and the organic layer was evaporated to dryness. The residue was purified by column chromatography on a Biotage® Star KP-Amino D chromatography cartridge (eluting with DCM to DCM/MeOH 97/3) to afford Cpd 22.
1.2.12. General method Fl: Miyaura borylation
Figure imgf000056_0004
[0221] To a stirred solution of the iodo or bromo substrate (1 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 1.5 eq.) in 1,4-dioxane is added AcOK (2.0 eq.). The mixture is degassed with argon for 5 min. Pd(dppf)C12-DCM or CatacXium A Pd G3 (0.05 eq to 0.1 eq.) is then added and the reaction is stirred and heated at 80 °C to 150 °C (conventional or microwave heating) for 1 to 16 h. The crude is evaporated to dryness and purified either by column chromatography on silica gel or by preparative HPLC to afford the desired compound or trituration of the crude with heptane/E^O. 1.2.12.1. Illustrative synthesis of Int 29
Figure imgf000057_0001
[0222] To a stirred solution of Int 27 (330 mg, 0.86 mmol, 1.0 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 328 mg, 1.29 mmol, 1.5 eq.) in 1,4-dioxane (10.0 mb) was added AcOK (169 mg, 1.72 mmol, 2.0 eq.). The mixture was degassed with argon for 5 min. Pd(dppf)C12'DCM (35 mg, 0.043 mmol, 0.05 eq.) was then added and the reaction was stirred at 80 °C for 2 h. The crude was evaporated to dryness and the residue was purified by preparative HPLC to afford Int 29.
1.2.12.2. Illustrative synthesis of Int 69
Figure imgf000057_0002
[0223] To a stirred solution of Int 68 (392 mg, 0.51 mmol, 1 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 258 mg, 1.01 mmol, 2 eq.) in 1,4-dioxane (4.0 mb) was added AcOK (149 mg, 1.52 mmol, 3 eq.). The mixture was degassed with nitrogen for 5 min. CatacXium A Pd G3 (37 mg, 0.051 mmol, 0. 1 eq.) was then added and the reaction mixture was stirred at 150 °C using a single mode microwave with a power output ranging from 0 to 850 W for 30 min. The crude was fdtered over celite®, and the fdtrate was evaporated to dryness. The residue was triturated with heptane/Et2O to afford Int 69.
1.2.13. General method F2: Miyaura borylation
R,'X
Figure imgf000057_0003
[0224] To a stirred solution of the bromo substrate (1 eq.) and 4,4,4',4',5,5,5',5'-Octaethyl-2,2'-bi(l,3,2- dioxaborolane) (CAS# 2247367-07-1; 1.1 to 1.5 eq.) in 1,4-dioxane is added AcOK (3 eq.). The mixture is degassed with argon for 5 min. Pd(dppf)C12 (0. 1 eq) is then added, and the reaction is stirred at 100 °C for 20 h. Water and EtOAc are added to the reaction mixture. The layers are separated, and the aqueous layer is extracted with EtOAc (3x). Combined organic layers are washed with brine, dried over Na2SO4. The solids are removed by filtration and the filtrate is evaporated to dryness. The crude is purified either by column chromatography on silica gel or by preparative HPLC to afford the desired compound.
1.2.13.1. Illustrative synthesis of Int 50
Figure imgf000057_0004
[0225] To a stirred solution of the Int 27 (7.21 g, 11.3 mmol, 1.0 eq.) and 4,4,4',4',5,5,5',5'-Octaethyl-2,2'- bi(l,3,2-dioxaborolane) (CAS# 2247367-07-1; 4.69 g, 12.4 mmol, 1.1 eq.) in 1,4-dioxane (100 mL) was added AcOK (3.36 g, 33.9 mmol, 3.0 eq.). The mixture is degassed with argon for 5 min. Pd(dppf)C12 (0.83 g, 1.13 mmol, 0. 1 eq) was then added and the reaction is stirred at 100 °C for 20 h. Water and EtOAc were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). Combined organic layers were washed with brine, dried over Na2SO4. The solids were removed by fdtration and the fdtrate was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with heptane/EtOAc 100/0 to 0/100) to afford Int 50.
1.2.14. General method Gl: Saponification with NaOH
.COOR .COOH
Ri Ri
[0226] To a stirred solution of ester (1 eq.) in MeOH or EtOH or in EtOH/THF or THF is added NaOH (1 or 2 M) aqueous solution (1.2 to 2.0 eq.). The reaction mixture is stirred at RT or 65 °C or 80 °C for 16 to 72 h, then the reaction mixture is evaporated to dryness. The residue is diluted with water and HC1 (2 M) aqueous solution (2 eq.). The crude is evaporated to dryness and purified by preparative HPLC to afford the desired compound.
1.2.14.1. Illustrative synthesis of Int 93
Figure imgf000058_0001
[0227] NaOH (1 M) aqueous solution (2.06 mL, 2.06 mmol, 1.5 eq.) was added to a stirred solution of Int 92 (354 mg, 1.37 mmol, 1.0 eq.) in MeOH (1.0 mL) and THF (3.0 mL) and the reaction mixture was stirred at RT for 2 h. The mixture was quenched with HC1 (2 N) aqueous solution to reach pH 3. The reaction mixture was concentrated to keep 2.0 mL. The solids were filtered off and dried under vacuum. The powder was dissolved in THF and concentrated to dryness to Int 93.
1.2.14.2. Illustrative synthesis of Cpd 79
Figure imgf000058_0002
[0228] To a stirred solution of cpd 74 (37 mg, 0.072 mmol, 1.0 eq.) in MeOH (2 mL) was added NaOH (2 M) aqueous solution (72 pL, 0.14 mmol, 2.0 eq.). The reaction mixture was stirred at 65 °C for 72 h, then the reaction mixture was evaporated to dryness. The residue was diluted with water and HC1 (2 M) aqueous solution (72 pL. 0.14 mmol, 2.0 eq.). The crude was evaporated to dryness. The residue was purified by column chromatography on a Biotage® Star 12 g C18 chromatography cartridge eluting with gradient 0- 100% ((ACN/0. 1% formic acid) / water/0.1% formic acid) to afford Cpd 79. 1.2.14.3. Illustrative synthesis of Cpd 113
Figure imgf000059_0001
[0229] To a stirred solution of cpd 105 (26 mg, 0.048 mmol, 1.0 eq.) in EtOH (1 mL) and THF (1.0 mL) was added NaOH (2 M) aqueous solution (0.048 mL, 0.096 mmol, 2.0 eq.) at RT. The reaction mixture was stirred at 80 °C for 16 h. HC1 (2 M) aqueous solution (0.048 mL, 0.096 mmol, 2.0 eq.) was added and the reaction mixture was evaporated to dryness. The residue was purified column chromatography on a Biotage 12 g C18 chromatography cartridge eluting with gradient 0-100% (ACN/0.1% formic acid) / water/0.1% formic acid) to afford Cpd 113.
1.2.15. General method G2: Saponification with LiOH
.COOR .COOH
Ri Ri
[0230] To a stirred solution of ester (1.0 eq.) in a solution of MeOH or THF/ MeOH is added LiOH (2.0 to 3.0 eq.) in water. This reaction is stirred at RT for 2 h to 18 h. The reaction mixture is evaporated to dryness or HC1 (3 M) aqueous solution is added and the precipitate is fdtered, washed with water then is dried to afford the desired compound.
1.2.15.1. Illustrative synthesis of Cpd 228
Figure imgf000059_0002
[0231] To a stirred solution of 227 (89.0 mg, 0.15 mmol, 1.0 eq.) in THF (1.25 mL) and MeOH (0.31 mL) was added LiOH (12.8 mg, 0.31 mmol, 2.0 eq.) in water (0.27 mL). The reaction mixture was stirred at RT for 18 h. HC1 (3 N) aqueous solution (3.0 mL) was added to the reaction mixture until pH = 3. The solid formed was fdtered, washed with water (5.0 mL) and dried under high vacuum at 50 °C for 4 h to afford compound 228.
1.2.15.2. Illustrative synthesis Cpd 177
Figure imgf000059_0003
[0232] To a stirred solution of Int 94 (80 mg, 0.15 mmol, 1.0 eq.) in MeOH (1.5 mL) and water (0.5 mL) was added LiOH (10.8 mg, 0.45 mmol, 3.0 eq.). The reaction mixture was stirred at RT for 1 h then LiOH (10.8 mg, 0.45 mmol, 3.0 eq.) was added and the reaction mixture was stirred at RT for 18 h more. This crude was fdtered and dissolved in DMSO and was purified by preparative HPLC to afford 177.
1.2.16. General method Hl: Substitution nucleophile with amine
Figure imgf000060_0001
[0233] To a stirred solution of bromopyridine (1.0 eq.) in DMF or DMSO is added K2CO3 (3.0 eq.) or CS2CO3 (1.0 eq.). This reaction mixture is stirred at RT for 5 minutes then amine (1.0 to 1.5 eq.) is added and the reaction mixture is stirred at 100 °C or 120 °C for 1 to 18 h. The reaction mixture is directly evaporated to dryness or extracted with H2O and EtOAc then the organic layer was separated, washed with brine, dried with MgSO4 and the solvent is evaporated to dryness. The residue is purified either by column chromatography on silica gel or by preparative HPLC to afford the desired compound.
1.2.16.1. Illustrative synthesis of Int 83
Figure imgf000060_0002
To a solution of a mixture of 2-bromo-4-fluoropyridine (CAS# 357927-50-5; 100 mg, 0.57 mmol, 1.0 eq.) in DMSO (0.3 mL) was added cis-2,6-dimethylmorpholine (CAS# 6485-55-8; 98.17 mg, 0.106 mL, 0.85 mmol, 1.5 eq.) and K2CO3 (235.59 mg, 1.705 mmol, 3.0 eq.). The mixture was purged with nitrogen and then stirred at 100 °C for 18 h. H2O was added and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was evaporated to dryness to afford Int 83.
1.2.16.2. Illustrative synthesis of Int 30
Figure imgf000060_0003
[0234] To a stirred solution of 2,6-dibromopyridine (CAS# 626-05-1; 100 mg, 0.42 mmol, 1.0 eq.) in DMF (0.5 mL) were added CS2CO3 (137 mg, 0.42 mmol, 1.0 eq.) and cA-2,6-dimethylmorpholine (CAS# 6485- 55-8; 52 pL, 0.42 mmol, 1.0 eq.). The reaction mixture was stirred at 120 °C for 1 h. The crude was evaporated to dryness and the residue was purified by column chromatography on silica gel (eluting with DCM) to afford Int 30. 1.2.1. General method H2: Substitution nucleophile with thiol
Figure imgf000061_0001
[0235] To a solution of thiol (1.0 eq.) and DIPEA (1.6 eq.) in DCM dry cooled at 0 °C is added dropwise alkyl halide (1.2 to 1.82 eq.) The reaction mixture is stirred at RT for 18 h. The mixture is quenched with water and extracted with DCM. The organic layer is dried, fdtrated and the solvent is evaporated to dryness. The crude is purified by column chromatography on silica gel to afford the desired compound.
1.2.1.1. Illustrative synthesis oflnt 61
Figure imgf000061_0002
[0236] A solution of 5-bromo-2-methylbenzene-l-thiol (CAS# 69321-55-7; 150 mg, 0. 1 m , 0.702 mmol, 1.0 eq.) and DIPEA (0.2 mb, 1.12 mmol, 1.6 eq.) in dry DCM (5.0 mL) was cooled at 0 °C, then bromo(methoxy)methane (CAS# 13057-17-5; 105.21 mg, 0.069 mL, 0.84 mmol, 1.2 eq.) was added dropwise, then the mixture was left to warmed up at RT for 18 h. Water was added, the organic layer was decanted and dried with a chromabond® PTS and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc 100/0 to 80/20) to give Int 61.
1.2.1.2. Illustrative synthesis oflnt 80
Figure imgf000061_0003
[0237] To a solution of 5-bromo-2-methylbenzene-l-thiol (CAS# 69321-55-7; 300 mg, 1.403 mmol, 1.0 eq.) and DIPEA (290.19 mg, 0.39 mL, 2.25 mmol, 1.6 eq.) in DCM dry (10 mL) cooled at 0 °C was added dropwise 2-bromoethanol (CAS# 540-51-2; 320 mg, 0.18 mL, 2.56 mmol, 1.82 eq.) The reaction mixture was warmed up at RT for 18 h. The mixture was quenched with water and extracted with DCM (3 x). The combined organic layers were dried under Na2SC>4, filtrated and the solvent was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 70/30) to afford Int 80.
1.2.2. General method J: Stille Coupling
Figure imgf000061_0004
[0238] Under argon atmosphere, to a stirred solution of aryl iodide (1.0 eq.) in toluene or trifluorotoluene is added aryl stannane (1.0 to 2. 1 eq.) then Pd(PPhs)4 (0.08 eq. to 0.2 eq.). This reaction mixture is degassed with nitrogen flux and is stirred at 100 °C or 120 °C or 150 °C for 2 h to 4 days. This reaction mixture is evaporated to dryness. The residue is purified either by column chromatography on silica gel or by preparative HPLC to afford a desired compound.
1.2.2.1. Illustrative synthesis oflnt 58
Figure imgf000062_0001
[0239] To a stirred solution of 4-bromo-l -ethoxy-2 -iodobenzene (CAS# 855836-00-9; 195 mg, 0.6 mmol, 1 eq.) in toluene was added 2- (tributylstannyl)pyridine (CAS# 17997-47-6; 219.57 mg, 0.19 mL, 0.6 mmol, 1 eq.) at RT. The reaction mixture was degassed with argon for 5 minutes. Pd(PPhs)4 (55.13 mg, 0.048 mmol, 0.08 eq.) was added and the reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was evaporated to dryness. The crude was purified by column chromatography on a Biotage® Star HC 25 g chromatography cartridge (eluting with heptane/EtOAc from 100/0 to 50/50) to afford Int 58.
1.2.2.2. Illustrative synthesis oflnt 74
Figure imgf000062_0002
[0240] To a stirred solution of 4-bromo-2-iodo-l -methoxybenzene (CAS# 98273-59-7; 100 mg, 0.32 mmol, 1 eq.) in toluene (2.00 mb) was added (tributylstannyl)pyridine (CAS# 17997-47-6; 117.7 mg, 0.102 mb, 0.32 mmol, 1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 minutes. Pd(PPhs)4 (29.5 mg, 0.026 mmol, 0.08 eq.) was added and the reaction mixture was stirred at 100 °C for 23 h. The reaction mixture was evaporated to dryness. The crude was purified on Biotage® Star HC chromatography cartridge on silica deposit (eluting with heptane/EtOAc from 100/0 to 0/100). The product fraction was evaporated to dryness to afford Int 74.
1.2.2.3. Illustrative synthesis oflnt 86
Figure imgf000062_0003
[0241] To a stirred solution of l-bromo-4-chloro-2 -iodobenzene (CAS# 148836-41-3; 250 mg, 0.79 mmol, 1.0 eq.) in trifluorotoluene (0.970 mL) was added 2-(tributylstannyl)pyridine (CAS# 17997-47-6; 319.0 mg, 0.277 mL, 0.87 mmol, 1.1 eq.) at RT. The reaction mixture was degassed with nitrogen for 5 minutes. Pd(PPhs)4 (91.0 mg, 0.079 mmol, 0.1 eq.) was added and the resulting mixture was heated at 150 °C using one single mode microwave with a power output ranging from 0 to 850 W for 1 h. 2- (tributylstannyl)pyridine (CAS# 17997-47-6; 290.0 mg, 252 pL, 0.79 mmol, 1.0 eq.) and Pd(PPh,)4 (91.0 mg, 0.079 mmol, 0.1 eq.) were added to the reaction mixture and degassed with nitrogen for 5 minutes. The resulting mixture was heated at 150 °C using one single mode microwave with a power output ranging from 0 to 850 W for 1 hour. The reaction mixture was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 70/30) then, by preparative HPLC to afford Int 86.
1.2.3. General method K: Oxidation by m-CPBA
Figure imgf000063_0001
[0242] At 0 °C, to a solution of thioalkyl compound (1.0 eq.) in DCM is added m-CPBA (2.1 eq.). The reaction mixture is warmed to RT and is stirred for 18 h. The reaction mixture is quenched with NaOH (3 N) aqueous solution and extracted then dried with Na2SC>4 and the solvent is evaporated to dryness to afford the desired compound.
1.2.3.1. Illustrative synthesis of Int 62
Figure imgf000063_0002
[0243] To a solution of Int 61 (183 mg, 0.66 mmol, 1.0 eq.) in DCM (5.0 mL) cooled at 0 °C was added m-CPBA (341.15 mg, 0.609 mL, 1.38 mmol, 2.1 eq.), then, the mixture was left to warm up at RT for 18 h. The reaction was quenched with NaOH (3 N) aqueous solution and extracted with DCM, the organic layer was washed with water dried over Na2SO4 and evaporated to dryness to afford Int 62.
1.2.3.2. Illustrative synthesis of Int 81
Figure imgf000063_0003
To a solution of Int 80 (260 mg, 1.052 mmol, 1.0 eq.) in DCM (5.45 mL) cooled at 0 °C was added m- CPBA (CAS# 937-14-4; 544.6 mg, 2.209 mmol, 2.1 eq.) then, the mixture was stirred at RT for 18 h. The reaction was quenched with NaOH (3 N) aqueous solution and extracted with DCM, the organic layer was washed with water, dried over Na2SO4 and the solvent was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 50/50) to afford Int 81. 1.2.4. General method L: Acetylation
Figure imgf000064_0001
[0244] To a solution of Amino (1 eq), DIPEA or TEA (2.2 to 5.0 eq.) in THF or DCM anhydrous is added dropwise acetyl chloride (1.1 to 1.5 eq.). The reaction mixture is stirred at RT for 16 to 18 h. The reaction is quenched with HC1 ( 1 M or 3 M) aqueous solution and is extracted then washed with brine or NaHCOs aqueous solution and is dried then evaporated to afford the desired compound.
1.2.4.1. Illustrative synthesis oflnt 95
Figure imgf000064_0002
[0245] A mixture of 3-(methylsulfamoyl)benzoic acid (CAS# 35623-11-1; 300 mg, 1.39 mmol, 1.0 eq.), acetyl chloride (149 pL, 2.09 mmol, 1.5 eq.) and TEA (426 pL. 3.07 mmol, 2.2 eq.) in THF anhydrous (6.85 mL) was stirred at RT for 16 h. The reaction mixture was quenched with HC1 (I M) aqueous solution and extracted twice with EtOAc. The combined organic layers were washed with brine (3x), dried over MgSCE, fdtered and was evaporated to dryness to afford Int 95.
1.2.4.2. Illustrative synthesis oflnt 125
Figure imgf000064_0003
[0246] To a stirred solution of -bromo-2-methoxy-N-methylaniline (CAS# 76328-91-1; 80.0 mg, 0.37 mmol, 1.0 eq.) and DIPEA (0.32 mL, 1.85 mmol, 5.0 eq.) in DCM anhydrous (2.0 mL) at RT under nitrogen flux was added dropwise acetyl chloride (CAS# 75-36-5; 31.97 mg, 0.029 mL, 0.407 mmol, 1.1 eq.) and the solution was allowed to stir at RT for 18 h. The solution was diluted in DCM, washed twice with HC1 (3 M) aqueous solution, twice with NaHCOs saturated aqueous solution. The organic layer was dried over MgSO4, filtered and evaporated to dryness to afford Int 125. Example 2. Preparation of the compounds of the invention
1.3. Int 4
Figure imgf000065_0001
[0247] To a stirred solution of Int 3 (70 mg, 0.37 mmol, 1.0 eq.) in DMA (1 mL) was added Zn(CN)2 (25 mg, 0.22 mmol, 0.6 eq.). The reaction mixture was degassed with argon for 5 min. Zn (1 mg, 0.015 mmol, 0.04 eq.) and Pd(dppf)C12'DCM (12 mg, 0.015 mmol, 0.04 eq.) were then added. The reaction mixture was stirred at 120 °C for 16 h. The crude was evaporated to dryness and the residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/0 to 99/1) to afford Int 4.
1.4. Int 38
Figure imgf000065_0002
1.4.1. Step i: Int 36
[0248] To a stirred solution of (4-chloro-2-pyridyl)methanamine (CAS# 180748-30-5; 0.161 mL, 1.39 mmol, 1.0 eq.) in dry DCM (3 mL) were added BOC2O (364 mg, 1.67 mmol, 1.2 eq.) and TEA (0.387 mL, 2.78 mmol, 2.0 eq.). The reaction mixture was stirred at RT for 2 h. The crude was evaporated to dryness and the residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 20/1) to afford Int 36.
1.4.2. Step ii: Int 37
[0249] Int 37 is synthetized from Int 36 and 1,2,3,4-tetrahydroquinoline (CAS# 635-46-1) following general method C.
1.4.3. Step Hi: Int 38
[0250] Int 38 is synthetized from Int 37 following general method E2.
1.5. Int 59
Figure imgf000065_0003
[0251] Under N2, to a stirred solution of triethyl phosphonoacetate (CAS# 867-13-0; 2.16 g, 1.91 mL, 9.65 mmol, 1.5 eq.) in THF (20 mL) at 0 °C, NaH (60%) in oil (0.51 g, 12.87 mmol, 2.0 eq.) was added portion wise and the reaction mixture was stirred at 0 °C for 30 min. 4-bromo-2 -iodobenzaldehyde (CAS# 1261470- 87-4; 2 g, 6.43 mmol, 1.0 eq.) in THF (5.0 mL) was added slowly and the reaction mixture was stirred at 0 °C for 2 h. Water was added, the reaction mixture was extracted twice with EtOAc, the organic layers were combined, washed with brine, dried over MgSCL and evaporated to dryness. The residue was suspended in heptane, the suspension was stirred at RT for 1 h, the solid was fdtered off, washed with heptane and dried (50 °C, vacuum) to afford Int 59.
1.6. Int 60
Figure imgf000066_0001
[0252] In microwave vial, Int 59 (150 mg, 0.39 mmol, 1.0 eq.), phenylboronic acid (CAS# 98-80-6; 52.8 mg, 0.43 mmol, 1.1 eq.), aqueous solution of K2CO3 2 M (590 pL, 1.18 mmol, 3.0 eq.) and Pd(PPhs)4 (45.49 mg, 0.039 mmol, 0.1 eq.). The mixture is degassed with nitrogen for 5 min. Toluene (4.2 mL) and ethanol (1.1 mL) were added. The reaction mixture was degassed with nitrogen for 5 min then heated to 90 °C for 3 h. The reaction mixture was cooled down to RT and diluted with water (10 mL) and DCM (30 mL) and the layers were separated. The aqueous one was extracted with DCM (2 x 20 mL) and the combined organic extracts were washed with water, brine, dried over MgSCL, fdtered and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 60/40) to give Int 60.
1. 7. Int 63
Figure imgf000066_0002
[0253] In a sealed bomb were added Int 62 (185 mg, 0.59 mmol, 1.0 eq.) and TEA (0.5 mL, 3.54 mmol,
6.0 eq.) in H2O (2.0 mL) and DMF (13.0 mL) then Pd(dppf)C12'DCM (48.17 mg, 0.059 mmol, 0.1 eq.).
The sealed bomb was filled with CO (5 bars). The mixture was heated at 120 °C for 18 h. The mixture was cooled to RT, then water was added, and the aqueous layer was washed with EtOAc (2 x) then the aqueous layer was acidified with HC1 (3 N) aqueous solution and the mixture evaporated to dryness to afford Int
63.
1.8. Int 78
Figure imgf000066_0003
[0254] To a solution of 4-carboxylphenylboronic acid pinacol ester (CAS# 180516-87-4; 100 mg, 0.403 mmol, 1.0 eq.) and methane sulfonamide (CAS# 3144-09-0; 38.3 mg, 0.403 mmol, 1.0 eq.) in DCM (3.00 mL) were added EDCI (CAS# 1892-57-5; 92.7 mg, 0.48 mmol, 1.2 eq.), DMAP (CAS# 1122-58-3; 9.85 mg, 0.0806 mmol, 0.2 eq.) and then DIPEA (62.5 mg, 0.084 mL, 0.48 mmol, 1.2 eq.). The reaction mixture was stirred at RT for 16 h. The reaction was poured into HC1 (I N) aqueous solution and extracted with DCM (3 x). The combined organic layers were dried and concentrated under reduced pressure. The crude was dissolved in DMSO and was purified by preparative HPLC to afford Int 78.
1.9. Int 82
Figure imgf000067_0001
[0255] In a sealed bomb were added Int 81 (120 mg, 0.43 mmol, 1.0 eq.) and TEA (0.36 m , 2.58 mmol, 6.0 eq.) in H2O (0.71 m ) and Dioxane (4.44 mb) then Pd(dppf)C12'DCM (35.1 mg, 0.043 mmol, 0.1 eq.). The sealed bomb was filled with CO (5 bar). The mixture was heated at 120 °C for 18 h. HC1 (1 M) aqueous solution was added, and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to afford Int 82.
1.10. Int 88
Figure imgf000067_0002
[0256] At room temperature in a round bottom flask was introduced Int 87 (4.35 g, 9.94 mmol, 1.0 eq.) in AcOH (60.0 mb). Zn (CAS# 7440-66-6; 0.33 g, 4.97 mmol, 0.5 eq.) was added to the solution. The reaction mixture was stirred at 70 °C for 1 h 30 then at 90 °C for 2 h 30 then performed for 3 days more. The solvent was evaporated. The crude was purified by column chromatography on silica gel (eluting with DCM/MeOH (+1% TEA) from 100/0 to 90/10) to afford Int 88.
1.11. Int 89
Figure imgf000067_0003
[0257] In a round bottom flask was introduced Int 88 (2.7 g, 8.43 mmol, 1.0 eq.), N-phenyl- bis(trifhroromethanesulfonimide) (CAS# 37595-74-7; 3.91 g, 10.96 mmol, 1.3 eq.), TEA (7.03 mb, 50.57 mmol, 6.0 eq.) in DCM (41.2 mb) at RT for 16 h. The solvent was evaporated to dryness and the crude was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/0 to 96/4) to give afford Int 89. 1.12. Int 91
Figure imgf000068_0001
[0258] NBS (CAS# 128-08-5; 716 mg, 4.02 mmol, 1.0 eq.) and benzoyl peroxide (CAS# 94-36-0; 201 mg, 0.80 mmol, 0.2 eq.) were added to a stirred solution of methyl 4-methyl-3-methylsulfonyl-benzoate (CAS# 906816-32-8; 918 mg, 4.02 mmol, 1.0 eq.) in CCU (13.0 mL) and the reaction mixture was heated at 75 °C for 16 h. The mixture was cooled to RT, washed with water and brine, dried with Na2SC>4, and the filtrate was evaporated to dryness to Int 91.
1.13. Int 92
Figure imgf000068_0002
[0259] /BuOK (1 mol/L) in THF (3.47 mL, 3.47 mmol, 2.0 eq.) was added to a stirred solution of Int 91 (0.53 g, 1.74 mmol, 1.0 eq.) in MeOH (30.0 mL) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated, and the residue was dissolved in EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried with Na2SC>4, fdtered, and evaporated to dryness to afford Int 92.
1.14. Int 101
Figure imgf000068_0003
[0260] A solution of ethyl 2-(2-bromo-4-chloro-phenyl)acetate (CAS# 52864-55-8; 10.7 g, 38.6 mmol, 1.0 eq.) in anhydrous Toluene (50.0 mL) was added dropwise to a stirred solution of diethyl carbonate (CAS# 105-58-8; 18.7 mL, 154 mmol, 4.0 eq.) and NaH (60%) in oil (3.08 g, 77.1 mmol, 2.0 eq.) in anhydrous Toluene (50.0 mL) and the mixture was heated to 80 °C for 16 h then was cooled to RT. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and the solvent was evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 70/30) to afford Int 101. 1.15. Int 110
Figure imgf000069_0001
[0261] At -78 °C, under nitrogen atmosphere, w-BuLi (1.6 M) in hexane (2.2 mL, 3.48 mmol, 1.5 eq.) was added to a vigorously stirred solution of Int 109 (720 mg, 2.32 mmol, 1.0 eq.) in anhydrous THF (23.0 mL). After 15 min, A.3-dimcthoxy-A-mcthylpropanamidc (CAS# 132289-57-7; 651 mg, 4.64 mmol, 2.0 eq.) was added in one portion, the mixture stirred at -78 °C for 30 min and then was slowly warmed to RT. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layers were washed with brine, dried over Na2SC>4 and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 70/30) to afford Int 110.
1.16. Int 111
Figure imgf000069_0002
[0262] TEA (152 pL, 1.09 mmol, 1.5 eq.) was added to a stirred solution of hydroxylamine hydrochloride (36 pL, 0.87 mmol, 1.2 eq.) and Int 110 (220 mg, 0.73 mmol, 1.0 eq.) in EtOH (7.3 mL). The reaction mixture was stirred at 50 °C for 4 h. The mixture was concentrated and dissolved into water/EtOAc. The layers were separated, the aqueous layer was extracted with EtOAc, the combined organic layers dried over Na2SO4 and evaporated to dryness to afford Int 111.
1.17. Int 112
Figure imgf000069_0003
[0263] Under nitrogen atmosphere, Pd/C 10% (80 mg) was added to Int 111 (156 mg, 0.49 mmol, 1.0 eq.) in MeOH (9.0 mL). The atmosphere was replaced with hydrogen bubbling through the vigorously stirred solution at 35 °C for 16 h. The reaction mixture was cooled to RT, diluted with MeOH and filtered through a plug of celite®. The filtrate was evaporated to dryness to afford Int 112.
1.18. Int 114
Figure imgf000070_0001
[0264] To a solution of 6-morpholino-[l,T-biphenyl]-3-amine (CAS# 1187929-69-6; 30 mg, 0.12 mmol, 1.0 eq.) and APTS (60.94 mg, 0.35 mmol, 3.0 eq.,) in acetonitrile (2.0 mL) at 0°C was added dropwise a solution of sodium nitrite (16.28 mg, 0.24 mmol, 2.0 eq.) and KI (48.95 mg, 0.29 mmol, 2.5 eq.) in water (0.5 mL). The mixture was stirred at 0 °C for 10 min then allowed to warm to 20 °C for 4 h. The reaction mixture was taken up in ethyl acetate and NaHCOs saturated aqueous solution. The combined organic layers were dried over MgSCL and concentrated to dryness. The residue was purified by column chromatography on a Biotage® Sfar HC 5 g chromatography cartridge (eluting with Heptane to Heptane/EtOAc 70/30) to afford Int 114.
1.19. Int 121
Figure imgf000070_0002
[0265] At 0 °C, MeMgBr (3.4 M) in Et2O (1.7 mL, 5.85 mmol, 3.0 eq.) was added to a stirred solution of Int 120 (500 mg, 1.95 mmol, 1.0 eq.) in THF dry (21.7 mL). The reaction mixture was then warmed to RT and stirred for 15 min. The reaction mixture was diluted with MeOH (21.7 mL), BOC2O (852 mg, 3.90 mmol, 2.0 eq.), DIPEA (1.02 mL, 5.85 mmol, 3.0 eq.) and NaBH4 (148 mg, 3.90 mmol, 2.0 eq.) were added and the mixture stirred at RT for 2 h. Water was added and the aqueous layer was extracted with DCM and EtOAc. The combined organic layers were washed brine, dried over Na2SO4 and evaporated to dryness. The crude was purified by column chromatography on silica gel (eluting with Heptane/EtOAc from 100/0 to 50/50) to afford Int 121.
1.20. Int 123
Figure imgf000070_0003
[0266] Under nitrogen, to a stirred solution of Int 36 (100 mg, 0.22 mmol, 1.0 eq.) in THF (3.0 mL) were added TEA (90.8 pL, 0.65 mmol, 3.0 eq.), Pd(dppf)C12 • DCM (17.78 mg, 0.022 mmol, 0.1 eq.) and Cui (4.15 mg, 0.022 mmol, 0.1 eq.) at RT. The reaction mixture was degassed with argon for 5 minutes. Ttrimethylsilylacetylene (CAS# 1066-54-2; 42.76 mg, 0.062 mL, 0.44 mmol, 2.0 eq.) was added and the reaction mixture was stirred at 90 °C for 1 h. The solvent was evaporated to dryness. The crude was purified on a 10g Sfar HC column (Biotage®), eluting with DCM/MeOH from 100/0 to 97/3) to afford Int 123.
1.21. Int 124
Figure imgf000071_0001
[0267] To a stirred solution of Int 123 (94 mg, 0.2 mmol, 1.0 eq.) in THF (2.0 mL) was added dropwise TBAF (CAS# 429-41-4; 0.3 mL, 0.3 mmol, 1.5 eq.). The reaction mixture was stirred at 0 °C for 30 minutes. Water was added and the reaction mixture was extracted with twice EtOAc. The combined organic layer was dried on Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on a Biotage® Sfar 10 g HC chromatography cartridge (eluting with DCM/MeOH from 100/0 to 97/3) to afford Int 124.
1.22. Int 126
Figure imgf000071_0002
[0268] To a solution of tert-Butyl 6-bromo-2H-pyrido[3,2-b][l,4]oxazine-4(3H)-carboxylate (CAS# 959992-64-4; 18 g, 57.11 mmol, 1.0 eq.) in DMA (180 mL) was added Zn (CAS# 7440-66-6; 9.58 g, 146.51 mmol, 2.57 eq.), tBuPyBCam (CAS# 3003061-14-8; 1.25 g, 5.71 mmol, 0.1 eq.) and NiCh glyme (CAS# 29046-78-4; 1.25 g, 5.71 mmol, 0.1 eq.). The reaction mixture was degassed with nitrogen (3 x) then was stirred at 25 °C for 5 minutes. Bromocyclobutane (CAS# 4399-47-7; 19.28 g, 142.78 mmol, 13.44 mL, 2.5 eq.) was added dropwise at RT then the reaction mixture was stirred at 63 °C for 16 hrs. The mixture was cooled to RT and NiCh glyme (CAS# 29046-78-4; 1.25 g, 5.71 mmol, 0.1 eq.), tBuPyBCam (CAS# 003061-14-8; 1.25 g, 5.71 mmol, 0.1 eq.) and Zn (CAS# 7440-66-6; 9.39 g, 143.60 mmol, 2.51 eq.) were added. The reaction mixture was degassed with nitrogen (3 x) then was stirred at RT for 5 minutes. Bromocyclobutane (CAS# 4399-47-7; 19.28 g, 142.78 mmol, 13.44 mL, 2.5 eq.) was added dropwise then the reaction mixture was stirred at 63 °C for 16 hrs. After cooling, the mixture was diluted with EtOAc and filtered through the celite®. H2O was added to the filtrate and this mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with Petroleum ether/THF from 100/0 to 87/13) to afford Int
126.
1.23. Cpd 21
Figure imgf000072_0001
[0269] To a stirred solution of Cpd 22 (54 mg, 0.12 mmol, 1.0 eq.) and formaldehyde 37 wt.% in H2O (36 pL, 0.48 mmol, 4.0 eq.) in DCE (2 mL) and MeOH (0.5 mL) was added AcOH (7 pL, 0.12 mmol, 1.0 eq.). The reaction mixture was stirred at RT for 10 min and then NaBH(OAc)3 (25 mg, 0. 12 mmol, 1.0 eq.) was added. The reaction mixture was stirred at RT for 30 min. The crude was evaporated to dryness and the residue was purified by column chromatography on a Biotage® Sfar KP-Amino D chromatography cartridge (eluting with DCM to DCM/MeOH 99/1) to afford Cpd 21.
Figure imgf000072_0002
[0270] In a vial was introduced 112 (50.0 mg, 0. 12 mmol, 1.0 eq.) in DMF (2.0 mL). Then was added at room temperature NaNs (10.0 mg, 0.15 mmol, 1.25 eq.), proline (4.26 mg, 0.0032 mL, 0.037 mmol, 0.3 eq.) The reaction mixture was heated to 110 °C for 18 h. NaNs (10.0 mg, 0.15 mmol, 1.25 eq.) was added and the reaction mixture was stirred at 100 °C for 2 h more. NaNs QO.O mg, 0.15 mmol, 1.25 eq.) was added and the mixture was heated at 110 °C for 16 h. NaNs (10.0 mg, 0.15 mmol, 1.25 eq.) was added and this reaction was stirred at 110 °C for 16 h. NaNs (10.0 mg, 0.15 mmol, 1.25 eq.) was added and the reaction mixture was stirred at 110 °C for 16 h. The crude was fdtered and purified by preparative HPLC to afford Cpd 125.
1.25. Cpd 128
Figure imgf000072_0003
[0271] To a mixture of Int 124 (50.0 mg, 0.12 mmol, 1.0 eq.) in DMSO (1.00 mL) in a vial was added NaNs (8.84 mg, 0.14 mmol, 1.1 eq.), CuSCL (0.99 mg, 0.0062 mmol, 0.05 eq.), sodium ascorbate (4.9 mg, 0.025 mmol, 0.2 eq.). The reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was filtered, and the crude was purified by column chromatography on silica gel to afford Cpd 128. 1.26. Cpd 232
Figure imgf000073_0001
[0272] To a solution of Int 68 (186.8 mg, 0.25 mmol, 1.0 eq.) in 1,4-dioxane (2.0 mL) was added bis(pinacolato)diboron (CAS# 73183-34-3; 125.2 mg, 0.49 mmol, 2.0 eq.) and KOAc (72.6 mg, 0.74 mmol, 3.0 eq.). The resulting mixture was degassed with nitrogen and catacxium A Pd G3 (17.96 mg, 0.025 mmol, 0.1 eq.) was added. The resulting mixture was heated at 150 °C using a single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 30 min. The reaction mixture was cooled down to rt then 3-bromo-JV, /V-dimethylaniline (CAS# 16518-62-0; 59.2 mg, 0.3 mmol, 1.2 eq.), CS2CO3 (241 mg, 0.74 mmol, 3.0 eq.), Pd(dppf)C12'DCM (20.14 mg, 0.025 mmol, 0.1 eq.) and water (0.3 mL) were added. The resulting mixture was degassed with nitrogen then heated at 120 °C for 0.5 h. The reaction mixture was cooled down to RT and diluted with NH4CI (10 %) aqueous solution and DCM and the layers were separated. The aqueous phase was extracted with DCM (2 x) and the combined organic extracts were washed with water, brine, dried over Na2SC>4, fdtered and evaporated to dryness. The crude was purified by preparative HPLC, then by column chromatography on silica gel (eluting with DCM/acetone from 100/0 to 80/20) to afford 232.
1.27. Cpd 249
Figure imgf000073_0002
[0273] A mixture of Int 119 (108 mg, 0.21 mmol, 1.0 eq.), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (CAS# 2247367-07-1; 130 mg, 0.36 mmol, 1.7 eq.), KOAc (61.7 mg, 0.63 mmol, 3 eq.) and Pd(dppf)C12 • DCM (17.1 mg, 0.021 mmol, 0.1 eq.) was degassed with nitrogen (3 x). 1,4-dioxane (2.5 mb) was added to the mixture and the reaction mixture was heated and stirred at 90 °C for 18 h. The reaction mixture was cooled down to RT then 4-(2-bromopyridin-4-yl)morpholine (CAS# 1049023-41-7 ; 56.1 mg, 0.23 mmol, 1.1 eq.), Cs2CO3 (205 mg, 0.63 mmol, 3.0 eq.), Xphos Pd G3 (17.7 mg, 0.021 mmol, 0.1 eq.) and water (0.2 mL) were added, the mixture was degassed with nitrogen (3 x) then stirred and heated at 100 °C for 18 h. An additional amount of Xphos Pd G3 (88.7 mg, 0.105 mmol, 0.5 eq.) and 4-(2-bromopyridin-4-yl)morpholine (CAS# 1049023-41-7 ; 50.9 mg, 0.21 mmol, 1 eq.) were added, the vial was degassed with nitrogen (3 x) and stirred and heated at 120 °C using a single mode microwave (Anton Paar) with a power output ranging from 0 to 850 W for 2 h. The reaction mixture was cooled down to RT, fdtered over celite® and then evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/00 to 80/20) then by preparative HPLC to afford Cpd 249.
1.28. Cpd 74
1.28.1.
Figure imgf000074_0001
Figure imgf000074_0002
[0274] The reaction was performed in a round bottom flask. At 0 °C, to a stirred solution of 3- methanesulfonyl-4-methylbenzoic acid (CAS# 51522-22-6; 2.74 g, 12.8 mmol, 1.0 eq.) and l-(4- bromopyridin-2-yl)methanamine (CAS# 865156-50-9; 2.63 g, 14.077 mmol, 1.1 eq.) in DMF anhydrous (25.0 mb) were added HATU (4.87 g, 12.8 mmol, 1.0 eq.) and DIPEA (4.46 m , 25.59 mmol, 2.0 eq.). The reaction mixture was stirred at RT 18 h. The reaction mixture was quenched with NH4CI saturated aqueous solution and extracted twice with EtOAc. The combined organic layers were combined and dried over Na2SC>4, fdtered and evaporated to dryness. The residue was purified by column chromatography on silica gel on a 100g Star HC column Biotage® (eluting with DCM/MeOH from 100/0 to 97/3) to afford Int 27.
Figure imgf000074_0003
[0275] In a sealed vial under argon atmosphere, to a stirred solution of Int 27 (822 mg, 2.14 mmol, 1.0 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 816.96 mg, 3.22 mmol, 1.5 eq.) in dioxane anhydrous (10.0 mb) was added AcOK (420.98 mg, 4.29 mmol, 2 eq.) at RT. The reaction mixture was degassed with argon for 5 min. Pd(dppf)C12 • DCM (87.57 mg, 0.107 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was evaporated to dryness. The residue was purified by preparative HPLC on a 30g C18 column (Biotage), eluted with gradient 0-100% [ACN/1% NH4OH] in [H2O/1% NH4OH]. to afford Int 29.
Figure imgf000074_0004
Int 29 Cpd 36 [0276] In a sealed vial under argon atmosphere, to a stirred solution of 3 -bromoiodobenzene (CAS# 591- 18-4; 658.8 mg, 0.3 mb, 2.33 mmol, 1.1 eq.) and Int 29 (911 mg, 2.12 mmol, 1.0 eq.) in dioxane (15.0 mb) was added CS2CO3 (1.38 g, 4.23 mmol, 2.0 eq.) in water (1.5 mb) at RT. The reaction mixture was degassed with argon for 5 minutes. Pd(dppf)C12 • DCM (86.44 mg, 0.106 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel on a 28g Sfar Amino column Biotage® (eluting with DCM/MeOH from 100/0 to 99/1) then purified by column chromatography on silica gel on a 25g Star HC column Biotage® (eluting with DCM/MeOH from 100/0 to 97/3) to afford Cpd 36.
Figure imgf000075_0001
[0277] In a sealed vial under argon atmosphere, to a stirred solution of Cpd 36 (40.0 mg, 0.087 mmol, 1.0 eq.) and 3-methoxycarbonylphenylboronic acid (CAS# 99769-19-4; 18.806 mg, 0.104 mmol, 1.2 eq.) in dioxane (2.0 mb) was added CS2CO3 (56.74 mg, 0.17 mmol, 2 0 eq.) in water (0.2 mb) at RT. The reaction mixture was degassed with argon for 5 min. Pd(dppf)C12 • DCM (3.56 mg, 0.0044 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel on a 10g Sfar HC column Biotage® (eluting with DCM/MeOH from 100/0 to 97/3) to afford Cpd 74.
1.29. Cpd 106
1.29.1. Step 1: Int 31
Figure imgf000075_0002
Int 31
[0278] In a round bottom flask and at 0 °C, to a stirred solution of l,l-dioxo-3,5-dihydro-2H-4, IX6- benzoxathiepine-8-carboxylic acid (CAS# 2771132-16-0; 500 mg, 2.064 mmol, 1.0 eq.) and l-(4- bromopyridin-2-yl)methanamine (CAS# 865156-50-9; 424.65 mg, 2.27 mmol, 1.1 eq.) in DMF (5.0 mb) were added HATU (784.8 mg, 2.064 mmol, 1.0 eq.) and DIPEA (0.72 mb, 4.13 mmol, 2.0 eq.) . The reaction mixture was stirred at RT for 30 min. NH4CI saturated aqueous solution was added. The reaction mixture was extracted twice with EtOAc. The combined organic layer was dried overNa2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel on Sfar Amino column Biotage® (eluting with DCM/MeOH from 100/0 to 99/1) to afford Int 31. 1.29.2. Step 2: Int 55
Figure imgf000076_0001
[0279] In a sealed vial under argon atmosphere, to a stirred solution of Int 31 (848 mg, 2.062 mmol, 1 eq.) and bis(pinacolato)diboron (CAS# 73183-34-3; 785.40 mg, 3.093 mmol, 1.5 eq.) in dioxane anhydrous (10.0 mb) was added AcOK (404.72 mg, 4. 12 mmol, 2 eq.) at RT. The reaction mixture was degassed with argon for 5 minutes. Pd(dppf)C12 • DCM (84.19 mg, 0.103 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was evaporated to dryness. The residue was purified on preparative HPLC a 30g C18 column Biotage® (eluting with gradient 0-100% [ACN/1% NH4OH] in [H2O/1% NH4OH]) to afford Int 55.
Figure imgf000076_0002
[0280] In a sealed vial under argon atmosphere, to a stirred solution of 3 -bromoiodobenzene (CAS# 591- 18-4; 433.92 mg, 0.2 mb, 1.53 mmol, 1.0 eq.) and Int 55 (703 mg, 1.53 mmol, 1.0 eq.) in dioxane (10.0 mb) was added CS2CO3 (999.48 mg, 3.068 mmol, 2.0 eq.) in water (1.0 mb) at RT. The reaction mixture was degassed with argon for 5 min. Pd(dppf)C12 • DCM (62.6 mg, 0.077 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was evaporated to dryness. The residue was purified on column chromatography on silica gel on Sfar HC column Biotage® (eluting with DCM/MeOH from 100/0 to 97/3) then purified by preparative HPLC on a 30g C18 column Biotage®, eluting with gradient 0-100% [ACN/1% Formic acid] in [H2O/l%Formic acid) to afford Cpd 80.
1.29.4. Step 4: Cpd 106 according to method B 1
Figure imgf000076_0003
Cpd 80 Cpd 106
[0281] In a sealed vial under argon atmosphere, to a stirred solution of 80 (40.0 mg, 0.082 mmol, 1.0 eq.) and 3-methoxycarbonylphenylboronic acid (CAS# 99769-19-4; 19.202 mg, 0.107 mmol, 1.3 eq.) in dioxane (2.0 mb) was added CS2CO3 (53.48 mg, 0.16 mmol, 2.0 eq.) in water (0.25 mb) at RT. The reaction mixture was degassed with argon for 5 min. Pd(dppf)C12 • DCM (3.35 mg, 0.0041 mmol, 0.05 eq.) was added and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was evaporated to dryness. The residue was purified by column chromatography on silica gel Biotage® Star Amino (eluting with DCM/MeOH from 100/0 to 97/3) to afford cpd 106.
1.30. Cpd 236
1.30.1. Step 1: Int 74
Figure imgf000077_0001
[0282] To a stirred solution of 4-bromo-2-iodo-l -methoxybenzene (CAS# 98273-59-7; 100 mg, 0.32 mmol, 1.0 eq.) in toluene (2.0 mL) was added (tributylstannyl)pyridine (CAS# 17997-47-6; 117.7 mg, 0.102 mL, 0.32 mmol, 1.0 eq.) atRT. The reaction mixture was degassed with nitrogen for 5 min. Pd(PPhs)4 (29.5 mg, 0.026 mmol, 0.08 eq.) was added and the reaction mixture was stirred at 100 °C for 23 h. The reaction mixture was evaporated to dryness. The crude was purified by column chromatography on silica gel on Biotage® Star HC (eluting with Heptane/EtOAc from 100/0 to 0/100) to afford Int 74.
1.30.2. Step 2: Int 65
Figure imgf000077_0002
n
[0283] In a microwave vial, Int 64 (878.5 mg, 1.28 mmol, 1.0 eq.), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (793.89 mg, 2.17 mmol, 1.7 eq.), KOAc (375.504 mg, 3.83 mmol, 3.0 eq.) and Pd(dppf)C12 • DCM (104.15 mg, 0.13 mmol, 0.1 eq.). The vial was capped then set under inert atmosphere via 3 iterations of a cycle vacuum / nitrogen. 1,4-dioxane (12.0 mL) was added to the vial through the septum. The reaction mixture was degassed by bubbling nitrogen for 5 min then was stirred at 80 °C for 60 h. The reaction mixture was cooled down to RT, diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2 x) and the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH from 100/0 to 75/25 then DCM/DCM:MeOH (80:20 with 0.1% Et3N) 85/15) to afford Int 65.
1.30.3. Step 3: Cpd 236 according to method Bl pW
Figure imgf000078_0001
[0284] In a sealed vial under nitrogen and at RT, to a stirred solution of Int 74 (27.0 mg, 0.102 mmol, 1.1 eq.) and Int 65 (48.0 mg, 0.093 mmol, 1.0 eq.) in dioxane (0.76 mL) and water (0.076 mL) was added CS2CO3 (60.56 mg, 0.19 mmol, 2.0 eq.). Pd(dppf)C12 • DCM (3.79 mg, 0.0046 mmol, 0.05 eq.). The reaction mixture was stirred at 120 °C using one single mode microwave (Biotage®) with a power output ranging from 0 to 400 W for 1 h. The mixture was cooled to RT, diluted with DCM and filtrated over a pad of celite®. The solvent was evaporated to dryness. The residue was purified by preparative HPLC (Column YMC - Actus Triart Prep C18-S 150*30mm 5pm Flow rate 50ml/min-Focused gradient ACN/aq.NH4HCO3 0.2% pH=7.9 Focused gradient from 35/65 to 75/25) Pure fractions were combined and the solvent was evaporated. The residue was freeze-dried into a mixture of ACN/H2O (3/10) to afford Cpd 236.
Table II. Intermediates used towards the compounds of the invention.
SM = Starting Material, Mtd = Method, MS Mes’d = Measured mass, NA = not measured
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Table III. llustrative compounds of the invention.
SM = Starting Material, Mtd = Method, MS Mes’d = Measured mass
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Ill
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Table IV. NMR data of illustrative compounds of the invention.
Figure imgf000128_0002
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
BIOLOGICAL EXAMPLES
Example 2. In vitro assays
2.1. Biochemical assays
2.1.1. ADP-Glo™ SMARCA2/4 Assays
2.1.1.1. Overview
[0285] The ADP-Glo™ assay is a luminescent technology assay which measures the ADP formed from a helicase reaction. In this specific study, the helicase reactions consisted of the metabolism of ATP to ADP using pCMV-dR8.91 plasmid as a substrate by SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 (SMARCA2 (635-1331, N-ter FLAG, Active Motif, Cat# 81439) or SMARCA4 (658-1328, N-ter FLAG, Active Motif, Cat# 81440). In a second step the ATPase reactions are terminated, and all the remaining ATP is depleted. In a final step the ADP is converted into ATP and this newly synthesized ATP is measured by using a luciferase/luciferin reaction. The generated light is measured using an EnVision plate reader, wherein the luminescent signal obtained positively correlates with the helicase activity.
2.1.1.2. Protocol with compound pre-incubation
[0286] The test compounds were prepared as a 10-point dilution series with 1/5 dilution steps in 100% DMSO starting from 2 mM highest concentration, diluted 1/20 in water and 1 pL was transferred to the assay plates (Revvity Inc., Cat# 6007290).
[0287] The enzyme-substrate mixture was prepared by adding the enzyme and the substrate to the assay buffer (final concentration 25 mM Hepes pH7.5, 0.25 mM EGTA, 5% glycerol, 0.005% Tween 20, 5 mM MgCl2 and 1 mM DTT).
[0288] 2 pL enzyme-substrate mixture was added to the assay plates, resulting in a final enzyme concentration of 0.625 nM (SMARCA2) and 1.25 nM (SMARCA4) and a final substrate concentration of 2 nM (SMARCA2 assay) and 1 nM (SMARCA4 assay).
[0289] The reaction was started by adding 2 pL of ATP (diluted in the assay buffer, (final concentration 10 pM)) on the assay plates. Plates were centrifuged for a few seconds at 300 xg, followed by an incubation at RT for 120 min.
[0290] The reactions were stopped, and the unconsumed ATP was depleted by adding 5 pL ADP-Glo Reagent (Promega, Cat# V912B) to the reaction. The plates were centrifuged for a few seconds at 300xg and incubated at RT for 40 min (ATP depletion).
[0291] The ADP was converted to ATP and luciferase and luciferin was introduced to detect ATP by adding 10 pL Kinase Detection Reagent (Promega, Cat# V913B + V914B) to the reaction. The plates were centrifuged for a few seconds at 300xg and incubated at RT for 30 min (ADP detection).
[0292] Luminescence was measured on an EnVision plate reader (Revvity Inc.). 2.1.1.3. Assay variant with high ATP concentration
[0293] Besides the standard ADP-Glo™ assay, an assay variant with high ATP concentration was developed, this to mimic the ATP concentration in the intra-cellular environment. In this high ATP variant, an ATP concentration of 1 mM and an enzyme concentration of 7.5 nM was used. The incubation time with luciferin and luciferase (ADP detection step) was increased to 60 min.
Table V. Conditions for human SMARCA helicase ADP-Glo™ assays
Figure imgf000144_0001
2.1.1.4. Data analysis and Results
[0294] Raw data were generated following the read-out performed on the EnVision plate reader, plotted to generate concentration response curves to calculate percentage inhibition (PIN) and IC50 for each SMARCA homologue.
Table VI. SMARCA2 & SMARCA4 ADP-Glo™ assay IC50 of illustrative compounds of the invention.
* > 1000 nM
** > 100 - 1000 nM
*** > 10 - 100 nM
**** 0.01 - lO nM
NA not measured
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
1.1. Cellular assays
2.1.2. KRT80-Based Target Engagement Assay
2.1.2.1. Overview
[0295] Keratin, type II cytoskeletal 80 (KRT80) is a gene that is transcriptionally regulated downstream of SMARCA2 and is known to be a biomarker for SMARCA2 inhibition in SMARCA4 deficient cells, such as A549. The KRT80 mRNA transcription assay aims at measuring the reduction of KRT80 gene expression levels in A549 cells upon treatment with possible SMARCA2 inhibitors using quantitative Polymerase Chain Reaction (qPCR) as a readout. For normalization purposes, glucuronidase beta (B2M) mRNA levels are measured within the same cDNA sample.
2.1.2.2. Protocols
[0296] The test compounds were prepared as a 10-point 1/5 dilution series in 100% DMSO starting from 10 mM.
[0297] A549 cells (ATCC, Cat# CCL-185) were seeded (7000 cells in 45 pL per well) in DMEM assay medium supplemented with 2% heat-inactivated fetal bovine serum (FBS) and 1% Penicillin-Streptomycin (P/S) in 384-well cell plates. The plates were briefly centrifuged at 300xg and stored at RT for 15-30 min to allow cells to distribute evenly in the wells.
[0298] Compounds and controls were diluted 1/10 in assay medium and 5 pL was transferred to the cell plates. The plates containing cells and compounds were briefly centrifuged at 300xg and incubated at 37 °C, 5% CO2 for 15-18 h.
[0299] The supernatant was then removed, and the cells were washed once with cold PBS (4 °C) using a Blue®Washer device (BlueCatBio GmbH).
[0300] Then the cells were lysed by adding 25 pL of Cells-to-Ct lysis buffer (Thermo Fisher Scientific Inc., Cat# 4391851C). The plates were incubated on an orbital shaker for 5 min. 2.5 pL of Cells-to-Ct STOP solution was added on top of the lysis buffer and the plates were incubated 2 min on the orbital shaker.
[0301] Plates were put on ice if the RT-PCR was performed the same day. If the RT-PCR was performed later, plates were sealed with an aluminum seal and kept at -80 °C and later thawed on an orbital shaker (30 min at 500 rpm) and put on ice until the RT-PCR.
[0302] A PCR plate was filled with 20 pL of reverse transcription mix containing 50% Fast Advanced reverse transcription buffer, 5% Fast Advanced reverse transcription enzyme mix (Thermo Fisher Scientific Inc., Cat# A39110), and 20% nuclease-free water (Qiagen GmbH, Cat# 129117).
[0303] 5 pL of the cell lysate was added on top of the reverse transcription mix in the PCR plate and the plate was sealed.
[0304] RT-PCR was performed in a thermal cycler to generate cDNA: samples were incubated for 30 min at 37 °C, 5 min at 95 °C followed by cooling to 4 °C. Sample plates were then kept on ice or frozen at -20 °C for later use. [0305] A PCR plate was filled with 6 pL of a mix (60% of the total reaction volume) containing 50% of TaqMAN Fast Universal PCR Master Mix (Thermo Fisher Scientific Inc., Cat# 4444557), 1.7% of TaqMAN KRT80 gene expression assay (Thermo Fisher Scientific Inc., Cat# 4351368) (250 nM final), 1.7% of TaqMAN B2M expression assay (Thermo Fisher Scientific Inc., Cat# 4448491) (250 nM final) and 6.6% of nuclease-free water (Qiagen GmbH, Cat# 129117).
[0306] With a liquid handler, 4 pL of the cDNA (40% of the total reaction volume) was added on top of the qPCR mix. The PCR plate was sealed, briefly centrifuged, and the qPCR was performed using the following program: 20 s at 95 °C, 40 cycles of 1 s at 95 °C and 20 s at 60 °C.
[0307] Raw data were generated by the ViiA7 Real-Time PCR System and the cycle threshold (Ct) calculations were done by the ViiA™ 7 software (Thermo Fisher Scientific Inc.) for both genes, KRT80 and B2M. These data were imported into the Phaedra software (Open Analytics NV) for automated calculation of Delta Ct (DCt) and Normalized Relative Quantities (NRQ). Based on the control wells, data were converted to percentage of inhibition (PIN) and concentration-response curves were generated. From those curves, IC50 values were determined, all using Phaedra.
2.1.2.3. Results & Outcome
[0308] The data obtained when subjecting illustrative compounds of the invention are described in the table below.
Table VII. KRT80-based target engagement assay results of illustrative compounds of the invention.
* > 10 pM
“ > 5 - 10 pM
*** > 1 pM - 5 pM
**** < 1 pM
Figure imgf000153_0001
Figure imgf000153_0002
Figure imgf000154_0002
Figure imgf000154_0001
2.1.3. Cell Death Based Phenotypic Assay
2.1.3.1. Overview
[0309] SK-MEL-5 (ATCC, Cat# HTB-70) is a SMARCA4 mutant melanoma cell line which is highly dependent on SMARCA2 to grow. The SK-MEL-5 proliferation assay aims at measuring the effect of possible SMARCA2 inhibitors on the proliferation of the SK-MEL-5 cells by using an ATPlite™ readout (Revvity, Inc.). ATP is a marker for cell viability because it is present in all metabolically active cells. SMARCA2 inhibitors are able to decrease SK-MEL-5 cell proliferation and thus the amount of ATP, which results in a decrease in ATPlite™ luminescent signal.
2.1.3.2. Protocols
[0310] The test compounds were prepared as 8-point serial dilutions with 1/4 dilution steps in 100% DMSO starting from 10 mM highest concentration (final highest concentration 30 pM) in 384 well plates. [0311] Four days prior to the start of the assay, SK-MEL-5 cells were thawed and seeded in T175 flasks, 2.0* 106 cells per flask, in 25 mL culture medium (EMEM containing 10% heat inactivated Fetal Bovine Serum (FBS) and 1% Penicillin - Streptomycin (P/S)). After 24 h incubation at 37 °C, 5% CO2, the medium was refreshed, and the cells were further incubated in an incubator at 37 °C and 5% CO2 for 72 h
[0312] SK-MEL-5 cells were harvested using 0.25% Trypsin-EDTA and counted. 2000 cells were seeded in only the inner wells of a 384 well cell plate, in 70 pL assay medium (EMEM containing 2% heat inactivated FBS and 1% P/S) per well. The outer wells were filled with 70 pL of phosphate-buffered saline. The plates were briefly centrifuged at 300xg and stored at RT for 15-30 min to allow cells to distribute evenly in the wells.
[0313] Compounds and controls were diluted 1/22 in assay medium and 5 pL was transferred to the cell plates. The plates with cells and compound were briefly centrifuged at 300xg and incubated at 37 °C, 5% CO2 for 96 h.
[0314] After 96 h incubation, the plates were centrifuged for 1 min at 300xg and 50 pL supernatant was removed from the wells. 25 pL ATPlite™ reagent (Revvity, Cat# 6016739) was added to the wells containing cells and compounds. The plates were briefly centrifuged at 300xg and were incubated at RT for 10 min. [0315] Readout of the luminescent signal was performed on a plate reader, e.g., EnVision (Revvity, Inc.). [0316] Raw data were generated by the plate reader (e.g., EnVision). These raw data were imported into the Phaedra software (Open Analytics NV) for automated calculation of results based on the control wells and the creation of the concentration response curves from which IC50 values were derived.
2.1.3.3. Results & Outcome
[0317] The data obtained when subjecting illustrative compounds of the invention are described in the table below.
Table VIII. SK-MEL-5 cell death assay results of illustrative compounds of the invention.
* > 10 pM
** > 5 - 10 pM
* * * > 1 pM - 5 pM
* * * * < | ,M
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Example 3. Pharmacokinetic, ADME and Toxicity Assays
3.1. Thermodynamic solubility
[0318] The thermodynamic solubility is determined in Fasted State Simulated Gastric Fluid (FaSSGF, pH 1.6), Fed State Simulated Intestine Fluid (FeSSIF v2, pH 5.8), Fasted State Simulated Intestine Fluid (FaSSIF v2, pH 6.5) and phosphate buffer (pH7.4).
[0319] Approximately 1 mg of each compound is weighed into a 12 m clear glass screw cap vial and 1 m of medium is added (final concentration about 1 mg/mL). The sample is placed in a thermodynamic water bath at 37 °C and 120 rpm of orbital shaking for 24 h.
[0320] For HPLC/DAD analysis the sample is filtered through a 0.2 pm PTFE filter mounted onto syringe and then analysed neat and accurately diluted 10 and 100 times.
[0321] The same batch of test compound is used as a standard, assigning the purity of 100%, in order to prepare the calibration curve. Test compound stock solution is prepared at a concentration of 1 mg/mL in DMSO and diluted to cover the calibration range from 0.0001 - 0.1 mg/mL.
[0322] The samples are analysed on HPLC system with a flow rate of 0.5 mL/min. Solvent A is 10 mM ammonium carbonate at pH 10 and solvent B is acetonitrile. The sample is going through a XBridge Cl 8 2.7 pM (2.1 x 50 mm) column, from Waters. The solvent gradient has a total run time of 12 min and ranges from 10% B to 90% B.
[0323] Peak areas are analysed and are plotted against the standard curve to obtain the solubility of the compound.
[0324] Solubility values are reported in pM or pg/mL. 3.2. Aqueous Solubility
[0325] This protocol describes determination of kinetic solubility by turbidimetry.
[0326] Turbidimetric solubility allows rapid determination of solubility using small amounts of compound. Briefly, compound’s DMSO solutions (prepared at specific concentrations) are spiked into aqueous buffer and turbidity is measured using VIS spectrophotometry at 620 nm. Sulfaphenazole and a- naphtoflavone are used as assay controls.
[0327] 10 mM DMSO stock solution is diluted in DMSO (in 96-well V-bottom polypropylene microplates) to a concentration of 1 mM.
[0328] 3 pL of compound ’s/control’s dilution in DMSO in triplicates are added to appropriate wells containing 297 pL of 100 mM PBS solution to the final concentration of 10 pM (1% DMSO; Table 3.; done in 96-well flat bottom microplates)
[0329] The plate is incubated by gently shaking (200-300 rpm) for 45 min at 37 °C and left at RT (without shaking) for 15 min (total incubation time = 1 h).
[0330] The plate absorbance at 620 nm is read on a Microplate reader (Tecan, Infinite F500 or Spark).
[0331] Calculation of solubility range data and resulting curves is made by Excel tools software.
[0332] The absorbance is proportionally increased with concentration of insoluble particles. Compound/control samples are compared to a solvent control in aqueous buffer (DMSO 1% final concentration), where significant increase of sample absorbance is considered when its absorbance is 3- fold standard deviation of average DMSO absorbance.
[0333] Results are accepted depending on solubility values obtained for assay controls: a-naphtoflavone: <10 pM sulfaphenazole: >10 pM
[0334] Results are expressed as an average of three replicas (<10 pM or >10 pM) for one concentration set-up.
3.3. Plasma Protein Binding (Equilibrium Dialysis)
[0335] The binding of the test compound to plasma proteins is tested by equilibrium dialysis using a Teflon unit from HTDialysis, performed on a Freedom EVO liquid handling unit.
[0336] Prior to the start of the experiment, dialysis membranes (Dialysis membranes MW cut-off 12- 14kDa - HTDialysis - Cat# 1101) are soaked in deionised water for 60 min, transferred and left overnight in 20% ethanol. On the day of experiment, compound and control stock solutions are diluted, spiked into plasma in order to achieve a final concentration of 5 pM (0.5% DMSO).
[0337] Immediately after assembly of the Teflon unit, a volume of 100 pL of plasma (spiked with compound/control) is placed on one side of the well and 100 pL of blank PPB buffer (60 mM Na2HPO4, 14 mM KH2PO4, 70 mM NaCl) is added to the other side, respectively, with each compound assayed in duplicate. The test compound is incubated for 4 h at 37 °C with gentle shaking. Thereafter, an aliquot is taken from each side of the well and matrix matched (mix of equal volumes of spiked plasma with blank PPB buffer and samples from buffer compartment with blank plasma). In order to estimate the recovery an aliquot is also taken at t=0 min from spiked plasma solutions and matrix matched as described above.
[0338] Matrix matched samples are further mixed with six volumes of STOP solution (acetonitrile: methanol, 2: 1 v/v with an internal standard (IS)). After brief mixing and centrifugation (at 4500 rpm for 30 min, at +4°C), the supernatant is transferred into new plates and analysed and quantified by LC-MS/MS.
[0339] The percentage bound (PPB) is determined using the following equation:
[0340] PPB = [(Cplasma-Cbuffer)/Cplasma]* 100
[0341] Cplasma = Peak area of the compound in the plasma / Peak area of the IS in the plasma [0342] Cbuffer = Peak area of the compound in the buffer / Peak area of the IS in the buffer
[0343] The recovery is a control, it allows to be sure that the compound has not a non-specific binding to the plates or it is not stable in the plasma in these conditions.
[0344] % recovery = [(Buffer+Plasma)/Recovery]* 100
[0345] Buffer = (ratio of the peak area of the compound/peak area of IS) in Buffer compartment after 4 h [0346] Plasma = (ratio of the peak area of the compound/peak area of IS) in Plasma compartment after 4 h [0347] Recovery = ratio at TO of the peak area of the compound in the well recovery / peak area of the IS in the well recovery
3.4. Aldehyde oxidase stability
[0348] An in vitro metabolic stability in human and rat liver S9 (human: 20-donor pool, mixed gender (Coming, Cat# 452961) and rat: pooled, male Sprague-Dawley (Coming, Cat# 452591)) is done in order to investigate the test compound as substrate of aldehyde oxidase. A 10 mM DMSO stock solution of the test compound is first diluted in DMSO (40 fold) to obtain a 250 pM working solution. Incubation mixtures are prepared by adding liver S9 suspension (final protein concentration of 2 mg/mL) to 50 mM potassium phosphate buffer, pH 7.4. Hydralazine (Sigma, Cat# H1753) (selective inhibitor of aldehyde oxidase; final concentration of 100 pM) or miliQ water are added for incubations with and without addition of selective inhibitor, respectively. After pre-warming for 5 min at 37 °C, the reaction is initiated by addition of test compound to the incubation mixture (final concentration in the incubation mixture of 1 pM, 0.4%DMSO). After 0, 3, 6, 12, 18 and 30 min of incubation, the reaction (aliquot of 100 pL) is terminated with 300 pL of acetonitrile methanol (2: 1) mixture with 1% acetic acid and the analytical internal standard. Samples are mixed, centrifuged and the supernatant analysed by LC-MS/MS (Table 2 and Table 3). Phthalazine (Aldrich, Cat# P38706) is included as a positive control.
[0349] S9 stability, expressed as the percentage of remaining parent compound, is calculated from the peak area ratio of compound and internal standard following different incubation times compared to the same ratio at the t=0 min (100%). The half-life (t 1/2) is calculated in GraphPadPrism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay) with following constrain parameters: Span=100, Plateau=0, K=no constraint). [0350] In vitro intrinsic clearance (CLint) is calculated from the half-life value using following equation: CLint[pL/min/mg] = (ln2/tl/2)*(mL per incubation/mg S9 protein)
3.5. Liver microsomal stability
[0351] The test compound is diluted from DMSO stock solution to obtain a final concentration of 1 pM in the final incubation mix (final DMSO 0.03%). ANADPH generating system (Cofactor solution) is prepared by adding to a 50 mM PBS pH 7.4 buffer, NADP (Sigma, N0505), G6P (Sigma, G6526), MgCLxOILO (Sigma, M2670) and G6P DH (Sigma, G637) to obtain in the final incubation mix NADP at 0.5 mM , G6P at 5 mM , MgC12.6H2O at 0.5 mM and G6P DH at 1.5 U/mL. Liver microsomes (Coming; Discovery Life Sciences) solution is prepared from 20 mg/mL stock concentration to obtain a final concentration in the incubation mix of 0.5 mg/mL.
[0352] Test compounds are incubated at 37 °C with and without cofactors and reaction is started by adding cofactors or buffer (for negative control) to incubation mix. Time points are taken at 0, 10, 25 and 40 min. At the desired incubation time point, a STOP solution (acetonitrile: methanol, 2: 1 v/v) is added at a ratio 3: 1 to the incubation mix. Samples are then centrifuged (at 4500 rpm, at 4 °C, for 30 min). The supernatant is then analyzed using a LC-MS/MS method.
[0353] Metabolic stability, expressed as the percentage of remaining parent compound, is calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after different time of incubation compared to the same ratio at the t=0 min (100%):
[0354] % remaining = (peak area ratios of test compound vs IS at appointed time)/(peak area ratios of test compound vs IS at 0 min) x 100
[0355] The half-life (ti/2) is calculated in GraphPad Prism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay with following constrain parameters: Span=100, Plateau=0, K=no constraint).
[0356] In vitro intrinsic clearance (CLmt) is calculated from half-life using following equation: [0357] CLmt = [pL/min/mg] = 0.693/ti/2 /min x (mL of incubation/mg protein) x 1000
3.6. Hepatocyte stability
[0358] The test compound is diluted from DMSO stock solution to obtain a final concentration of 1 pM in the final incubation mix. The test compound is incubated in dog, monkey, human, mouse and rat hepatocytes (BioIVT, mouse Cat. No. M005052, rat Cat. No. M00005, dog, Cat. No. M00205, monkey Cat. No. M00305, human Cat. No. X008001) (final concentration: 0.5x106 cells/mL), resuspended in Krebs-Henseleit modified buffer for 3 h (except in human - 90 min) at 37 °C. Aliquots are taken at different time points and the reaction is terminated by addition of 3 volumes of STOP solution (acetonitrile methanol = 2: 1 with an internal standard). Aliquots were then centrifuged (at 4500 rpm, at 4 °C, for 30 min). The supernatant is then analysed using a LC-MS/MS method. [0359] Metabolic stability, expressed as the percentage of remaining parent compound, is calculated from the ratio of peak area of the remaining compound and peak area of the internal standard after different time of incubation compared to the same ratio at the t=0 min (100%).
[0360] The half-life (tl/2) is calculated in GraphPadPrism software from % remaining vs. time regression using non-linear regression fit (one phase exponential decay) with following constrain parameters: Span=100, Plateau=0, K=no constraint)
[0361] In vitro intrinsic clearance (CLint) is calculated from half-life using the following equation:
[0362] CLint[pL/min/106cells] = (ln2/tl/2)*(mL per incubation/#cells per incubation)
3. 7. Caco2 Permeability
[0363] Bi-directional Caco-2 assays are performed as described below. Cells are seeded at 1 x 105 cells/cm2 in 96-well HTS Transwell plates (Coming). Permeability assays are performed with the cells at days 21-25 post-seeding.
[0364] This assay is performed in both the apical (A) to basolateral (B) A-B or B-A direction. Compounds and the references (propranolol, labetalol, ranitidine, colchicine) are prepared at 10 pM in HBSS-MES (pH 6.5) or HBSS-HEPES (pH 7.4) with a final DMSO concentration of 1 % (v/v). The working solution is then centrifuged and the supernatant is added to the donor side.
[0365] The assay plate is incubated at 37 °C for 60 min or 40 min for the A-B or B-A assay, respectively. Samples are aliquoted from the donor side at time zero and the end point, and from the receiver side at the end point.
[0366] In addition, Lucifer yellow (LY), a membrane integrity marker, is co-incubated with the test compound at the start of the experiment to assess integrity of the cell layers. As LY cannot freely permeate lipophilic barriers, a high Papp of the Lucifer yellow (measured by fluorescence) indicates poor formation of the cell monolayer.
[0367] Moreover, the Transepithelial electrical resistance (TEER) of each Multiscreen™ well is also evaluated prior to the initiation of the assay so as to evaluate monolayer integrity.
[0368] Reference compounds namely, Propranolol (highly permeable), Labetalol (moderately permeable), Ranitidine (poorly permeable), and Colchicine (P-glycoprotein substrate) are included in this assay. Samples are analysed by LC/MS-MS.
[0369] Apparent permeability (Papp) values are calculated from the relationship:
[0370] Papp = [compound] acceptor final ' Vacceptor / ([COmpOUnd] donor initial ' Vdonor) / Tine ' Vdonor / Surface area ' 60 ' IO-6 cm/s
[0371] V = chamber volume
[0372] Tine = incubation time.
[0373] Surface area = 0.33cm2
[0374] The Efflux ratios, as an indication of active efflux from the apical cell surface, are calculated using the ratio of Papp B>A/ Papp A>B. [0375] The following assay acceptance criteria are used: If at least 3 out of 4 control molecules are in these ranges determined by the historical data, the assay is validated.
[0376] Lucifer yellow permeability: <0.5 10-6 cm/s
[0377] Colchicine: Papp (A>B) value < 1 (xlO-6 cm/s) with Efflux ratio >4
[0378] Labetalol: Papp (A>B) value < 6 (xlO-6 cm/s)
[0379] Propranolol: Papp (A>B) value < 25 (xlO-6 cm/s)
[0380] Ranitidine: Papp (A>B) value < 2 (xlO-6 cm/s)
3.8. MDCKII-MDR1 Permeability
[0381] MDCKII-MDR1 cells are Madin-Darby canine kidney epithelial cells, over-expressing human multi-drug resistance (MDR1) gene, coding for P-glycoprotein (P-gp). Cells are obtained from Netherlands Cancer Institute and used after a 3-4 day cell culture in 24-well Millicell cell culture insert plates (Millipore, PSRP010R5). Bi-directional MDCKII-MDR1 permeability assay is performed as described below.
[0382] 3x105 cells/mL (1.2x105 cells/well) are seeded in plating medium consisting of DMEM + 1% Glutamax-100 + 1% Antibiotic/Antimycotic + 10% FBS (Biowest, S1810). Cells are left in CO2 incubator for 3-4 days. The medium is changed 24 h after seeding and on the day of experiment.
[0383] Test and reference compounds (amprenavir and propranolol) are prepared in Dulbecco’s phosphate buffer saline (D-PBS, pH7.4) and added to either the apical (400 pL) or basolateral (800 pL) chambers of the Millicell cell culture insert plates assembly at a final concentration of 10 pM (0.5 pM in case of amprenavir) with a final DMSO concentration of 1%
[0384] 100 pM Lucifer Yellow (Sigma) is added to the all-donor buffer solutions, in order to assess integrity of the cell monolayers by monitoring Lucifer Yellow permeation. Lucifer yellow is a fluorescent marker for the parace llular pathway, and it is used as an internal control in every monolayer to verify tight junction integrity during the assay.
[0385] After a 1 h incubation at 37 °C while shaking at an orbital shaker at 150 rpm, 75 pL aliquots are taken from both apical (A) and basal (B) chambers and added to 225 pL acetonitrile: water solution (2: 1) containing analytical internal standard (10 ng/mL warfarin) in a 96 well plate. Aliquoting is also performed at the beginning of the experiment from donor solutions to obtain initial (Co) concentration.
[0386] Concentration of compound in the samples is measured by high performance liquid- chromatography/mass spectroscopy (LC-MS/MS).
[0387] Lucifer yellow is measured with a Fluoroscan Ascent FL Thermo Scientific (Ex 485 nm and Em 530 nm) in a 96 well plate containing 150 pL of liquid from all receiver wells (basolateral or apical side).
[0388] The apparent permeability coefficient (Papp) is calculated according to the following equation:
Papp = (dQ/dT)*(l/C0)*(l/A)
[0389] where dQ/dT = permeability rate
[0390] CO = initial concentration in donor compartment
[0391] A = surface area of the cell monolayer (0.11 cm2) [0392] ‘ ‘Concentration” is the ratio between compound and internal standard peak areas.
[0393] The Papp value has a dimension of a rate (xlO-6 cm/sec).
[0394] Permeability values are classified as follows: low permeability: <2x l0-6 cm/sec, moderate permeability: 2-10x 10'6 cm/sec, high permeability: >10* 10'6 cm/sec.
[0395] The Efflux ratio, as an indication of active efflux from the apical cell surface, is calculated using following equation: Efflux ratio = Papp (B2A)/Papp (A2B).
[0396] A compound is considered to be a possible P-gp substrate when the efflux ratio is > 2.
[0397] Mass balance (MB) is calculated from equation: MB = (Md+Mr)/Mo, where Md = mass of drug in donor compartment at time 60 min, Mr = mass of drug in receiver compartment at time 60 min, Mo = mass of drug in donor compartment at time 0 min, Mass of drug = Analyte/IS ratio * volume of compartment (75 pL or 250 pL).
[0398] Mass balance results should be evaluated as follows: Mass balance between 80-120%: acceptable, Mass balance between 50-80% and 120-135% should be interpreted with caution, Mass balance <50% and >135% should be discarded.
[0399] Results are accepted based on obtained data: Lucifer yellow: all Papp values should be <3x10-6 cm/sec, Amprenavir: low permeability (PappA2B <2x10-6 cm/sec), efflux ratio >2, Diclofenac: high permeability (PappA2B >10x10-6 cm/sec), efflux ratio <2
3.9. Pharmacokinetic study in rodents
3.9.1. Animals
[0400] Wistar-Han rats (male, 200-225g) are obtained from Janvier (France).
[0401] CD-I Mice (male, 25 -30g) are obtained from Janvier (France).
[0402] Animals are acclimatized for at least 7 days before treatment and are kept on a 12 h light/dark cycle (0700 - 1900). Temperature is maintained at approximately 22 °C, and food and water are provided ad libitum.
3.9.2. Pharmacokinetic study
[0403] Compounds are formulated in DMSO/10% hydroxylpropyl-P-cyclodextrine (5/95) for the intravenous route and in a suitable solution for the oral route. Test compounds are orally dosed as a single oesophageal gavage at 5 mg/kg under a dosing volume of 10 mL/kg (group of 3 animals) and intravenously dosed as a bolus via the caudal vein at 0.5 mg/kg under a dosing volume of 5 mL/kg. (groups of 2 animals). Blood samples are collected at the retro-orbital sinus with EDTA as anti-coagulant at the following time points: 0.05, 1, 3, 6 and 24 h (intravenous route), and 0.25, 1, 3, 6, and 24 h (oral route). Whole blood samples are centrifuged at 5000 rpm for 10 min and the resulting plasma samples are stored at -20 °C pending analysis. 3.9.3. Quantification of compound levels in plasma
[0404] Plasma concentrations of each test compound are determined by an LC-MS/MS method in which the mass spectrometer is operated in positive or negative electrospray mode.
3.9.4. Determination of pharmacokinetic parameters
[0405] Pharmacokinetic parameters are calculated for each individual animal and for each analyte by noncompartmental analysis.
3.10. Liability for QT prolongation
[0406] Potential for QT prolongation is assessed in the hERG manual patch clamp assay.
3.10.1. Manual patch clamp assay
[0407] Single CHO cells are used for recording hERG currents at near physiological temperature (34- 35 °C) using the whole-cell patch-clamp technique with an Axopatch 700A amplifier/pClamp software (Molecular Devices, Sunnyvale CA).
[0408] Electrodes (5-7 MQ resistance) are prepared from GC 150-10 glass capillary tubes (Harvard Apparatus, Cambridge, UK) and filled with intracellular solution (in mM: KC1 120; Na2ATP 4; HEPES 10; EGTA 10; MgCl2 1.75; CaCl2 5.374, pH 7.2 adjusted with KOH).
[0409] The patch-clamp recording chamber is perfused with control extracellular solution (in mM: NaCl 145; KC1 4; MgC12 1; HEPES, 10; glucose 10; CaCl2 2 at pH 7.4 adjusted with NaOH).
[0410] With the formation of a gigaohm seal, the cell membrane is ruptured to establish the whole-cell configuration. The minimum acceptable seal resistance is 1 gigaohm, and access resistance no greater than 20pF.
[0411] The cell membrane is then voltage-clamped at a holding potential of -80 mV and depolarised to +20 mV for 2 sec followed by a negative pulse at -40 mV for 1.6 sec, before returning to -80 mV at a frequency of 0.1 Hz.
[0412] Once the hERG current is stable, the perfusion is switched to extracellular solution containing test compounds starting from the lowest concentration. Each concentration on the 4pt concentration-response curve is tested for 4 min to achieve steady state.
3.10.2. Automated patch clamp
[0413] Electrophysiological recordings are made from a Chinese Hamster Ovary cell line stably expressing the full-length ion channel. Single cell ionic currents are measured in whole-cell configuration at RT (21- 23 °C) using a QPatch II (Sophion Bioscience).
[0414] The internal solution for hERG contains (mM): 120 KC1, 20 KF, 10EGTA, 10 HEPES and is buffered to pH 7.3.
[0415] The external solution (HEPES-buffered saline, HBPS) contains (mM): 138 NaCl, 4.5 KC1, 1.8 CaCl2, 1.0 MgCl2, 10 HEPES, 10 glucose, buffered to pH 7.4. [0416] Cells are clamped at a holding potential of -80 mV before a step to +20 mV for 500 ms, and then - 40 mV for 500 ms. The test pulse is applied every 10 seconds. Currents are measured from the -40 mV step and referenced to the holding current.
[0417] Compounds are incubated for 120 seconds to allow stabilization of the parameters. Concentrationresponse curves are generated by cumulative addition of compound with concentrations low to high.
FINAL REMARKS
[0418] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.
[0419] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth.
[0420] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.
[0421] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by OpenEye Scientific Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.
REFERENCES
Bundgaard H. 1985. Design of prodrugs, Elsevier.
Clark K et al. 2012. Phosphorylation of CRTC3 by the salt-inducible kinases controls the interconversion of classically activated and regulatory macrophages. Proc. Natl. Acad. Sci. U. S. A. 109, 16986— 16991.
Ehrenhbfer-Wblfer K et al. 2019. SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines. Sci. Rep. 9, 11661.
Kadoch C et al. 2013. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592-601.
Ozanne J, Prescott AR, Clark K. 2015. The clinically approved drugs dasatinib and bosutinib induce antiinflammatory macrophages by inhibiting the salt-inducible kinases. Biochem. J. 465, 271-279. Remington JP, Gennaro AR. 1985. Remington ’s Pharmaceutical Sciences, Mack.
Stahl PH, Wermuth CG. 2011. Pharmaceutical Salts: Properties, Selection, and Use, 2nd Revised Edition Wiley,
S ndberg TB et al. 2014. Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells. Proc. Natl. Acad. Sci. U. S. A. Ill, 12468-12473.
Wilson BG et al. 2014. Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation. Mol. Cell. Biol. 34, 1136-1144.
Wuts PGM, Greene TW. 2006. Greene ’s Protective Groups in Organic Synthesis, 4th Edition \ Wiley.

Claims

1. A compound according to Formula I:
Figure imgf000172_0001
wherein,
A is phenyl or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;
X is N or CH;
Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, Ci-4 alkyl, Ci-4 haloalkyl, -NH2, -NH(CI-4 alkyl), or - N(CI-4 alkyl)2, morpholine, -CH=CHCC>2R9a , C1-4 alkoxy, C1-4 haloalkoxy or oxetane; n is 0, 1, or 2;
R1 is C1-6 alkyl, C1-3 alkoxy(Ci-3)alkyl, -N(CI-3 alkyl)2 or hydroxy(Ci-3)alkyl; each R2 is independently selected from halogen and Ci-e alkyl, which alkyl is optionally substituted with Ci -4 alkoxy; or R1 and one R2 together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the -S(=O)2- of formula I and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro);
R3 is H or C1-6 alkyl; each R4a andR4b is independently H or Ci-e alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy;
R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two, three or four heteroatoms independently selected from N, O, and S, or a 5-10 membered monocyclic or bicyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;
R6 is H, halo, or C1-6 alkyl; each R7 is independently selected from oxo,
- -OH,
- -CN,
- -P(O)(Ci.4alkyl)2, halo,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Ci-4 alkyl optionally substituted with one or more independently selected halo, -OH, -CN, - CO2R9a or Ci-4 alkoxy,
Ci-4 alkoxy optionally substituted with one or more independently selected halo, -OH, -CN, or Ci -4 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, and
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; each R8a is independently H or C1-4 alkyl; each R8b is independently H, C1-4 alkyl or -C(O)Ci.2 alkyl; each R9a is independently selected from hydrogen and C1-4 alkyl; and
R9b is hydrogen, C1-4 alkyl or C1-4 alkoxy, or R9a and R9b together with the atoms onto which they are attached form a 4-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
2. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 wherein A is phenyl or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S;
X is N or CH;
Li is a bond, Ce-io aryl, or 5-6 membered monocyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which aryl or heteroaryl is optionally substituted with one or more independently selected halo, C1.4 alkyl, or C1-4 alkoxy; n is 0, 1, or 2;
R1 is C1-6 alkyl, C1-3 alkoxy(Ci-3)alkyl or hydroxy(Ci-3)alkyl; each R2 is independently selected Ci-e alkyl; or R1 and one R2 together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising -S(=O)2- and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro);
R3 is H or Ci-6 alkyl; each R4a andR4b is independently H or Ci-e alkyl optionally substituted with one or more independently selected halo or C1-4 alkoxy;
R5 is Ce-io aryl, 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, or 5-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more independently selected R7;
R6 is H, halo, or C1-6 alkyl; each R7 is independently selected from oxo,
- -OH,
- -CN,
- -P(O)(Ci.4alkyl)2, halo,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
C1-4 alkyl optionally substituted with one or more independently selected halo, -CN, or C1-4 alkoxy,
C1-4 alkoxy optionally substituted with one or more independently selected halo, -CN, or C1-4 alkoxy, and
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; and each R8a and R8b is independently H or C1-4 alkyl.
3. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or claim 2, wherein R4a is H and R4b is C1-6 alkyl optionally substituted with one or more independently selected halo or C1.4 alkoxy.
4. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1, 2 or 3, wherein R3 is H.
5. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or 2, wherein the compound is according to Formula II:
Figure imgf000175_0001
6. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-5, wherein X is N.
7. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-6, wherein R6 is H.
8. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or 2, wherein the compound is according to Formula IVa or IVb:
Figure imgf000175_0002
9. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-8, wherein Li is a bond, phenyl, pyrazolyl or pyridinyl.
10. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or 2, wherein the compound is according to Formula Vila, Vllb, Vile, Vlld, Vile, Vllf, Vllg, Vllh, Vlli,
Vllj, Vllk, or VIII:
Figure imgf000175_0003
Vila Vllb Vile
Figure imgf000176_0001
11. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or 2, wherein the compound is according to Formula Vlld, Vile, Vllf, Vllg, Vllh, or Vlli:
Figure imgf000176_0002
12. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-11, wherein R5 is phenyl optionally substituted with one or more independently selected R7, and each R7 is independently halo, -CN, -NR8aR8b, Ci-4 alkyl, or Ci-4 alkoxy.
13. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to claim 1 or 2, wherein the compound is according to Formula Vila, Vllb, or Vile:
Figure imgf000176_0003
Vila Vllb Vile.
14. The compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-13, wherein R5 is 5-10 membered monocyclic or bicyclic heteroaryl comprising one, two or three heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R7, and each R7 is independently halo, -CN, C1-4 alkyl, or Ci- 4 alkoxy .
15. A compound according to formula 1-1
Figure imgf000177_0001
wherein,
Li is phenyl, or pyridyl, which phenyl or pyridyl is optionally substituted with one or more independently selected halogen, C1-3 alkyl, -CH=CHCC>2R9a , morpholino, C1-3 alkoxy, C1-3 haloalkoxy or oxetane;
R1 is C1-4 alkyl, C1-3 alkoxy(Ci-3)alkyl, or hydroxy(Ci-3)alkyl;
R2a is hydrogen, fluoro, chloro or C1-3 alkyl (preferably chloro or methyl); or R1 and R2a together with the atoms onto which they are attached form a fused 5-8 membered monocyclic heterocycloalkyl comprising the -S(=O)2- of formula 1-1 and zero, one, or two additional heteroatoms independently selected from N, O, and S, wherein the heterocycloalkyl is optionally substituted with one or more independently selected halogens (preferably fluoro); or R and R a together with the atoms onto which they are attached form
Figure imgf000177_0002
, which is optionally substituted with one or more independently selected halogens (preferably fluoro);
R2b is hydrogen, fluoro, chloro, methyl or ethyl (preferably hydrogen);
R3 is hydrogen or C1-2 alkyl (preferably hydrogen); each of R4a and R4b is independently hydrogen, methyl or ethyl;
R5 is phenyl, pyridyl, pyrimidinyl, pyrrolyl, each of which is optionally substituted with one, two or three independently selected R7; or L1-R5 together is an indole or benzofuran group, each of which is optionally substituted with one, two or three independently selected R7;
R6 is hydrogen, fluoro or methyl (preferably hydrogen); each R7 is independently selected from
- -OH,
- -CN, - -P(O)(Ci.4alkyl)2, halogen,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -NHC(0)CI-2 alkyl,
- -N(CI.2 alkyl)C(O)Ci-2 alkyl,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Ci-4 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, - CO2R9a or Ci-4 alkoxy,
Ci-4 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci -4 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy, morpholino (preferably 1 -morpholino), oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl and
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; each R8a is independently hydrogen or C1-4 alkyl; each R8b is independently hydrogen, C1-4 alkyl or -C(O)Ci-2 alkyl; each R9a is independently selected from hydrogen and C1-4 alkyl; and
R9b is hydrogen, C1-4 alkyl or C1-4 alkoxy; or R9a and R9b together with the atoms onto which they are attached form a 5-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl; or a pharmaceutically acceptable salt and/or solvate thereof.
16. A compound according to formula 1-2
Figure imgf000179_0001
1-2 wherein,
R1 is Ci-2 alkyl (preferably methyl), C1-2 alkoxy (Ci.2)alkyl (preferably methoxymethyl), or hydroxy (C 1 _3)alkyl ;
R2a is hydrogen, fluoro, chloro or C1-2 alkyl (preferably chloro or methyl); or R1 and R2a together with the atoms onto which they are attached form
Figure imgf000179_0002
, which is optionally substituted with one or more independently selected halogens (preferably fluoro);
R2b is hydrogen, fluoro, or methyl(preferably hydrogen);
R3 is hydrogen or methyl (preferably hydrogen); each of R4a and R4b is independently hydrogen, or methyl;
R5 is phenyl or pyridyl, each of which is optionally substituted with one or two independently selected R7; each R7 is independently selected from
- -OH,
- -CN,
- -P(O)(Ci.2 alkyl)2, halogen,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -NHC(0)CI-2 alkyl,
- -N(CI.2 alkyl)C(O)Ci.2 alkyl,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a, Ci-2 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, - CO2R9a or Ci-2 alkoxy,
Ci-2 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or Ci -2 alkoxy,
C3-6 cycloalkyl, which cycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-2 alkyl, or C1-2 alkoxy, morpholino (preferably 1 -morpholino), oxetane, which oxetane is optionally substituted with a hydroxy or C1-2 alkyl, and
4-8 membered monocyclic or spirocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-4 alkyl, or C1-4 alkoxy; each R8a is independently hydrogen or C1-2 alkyl; each R8b is independently hydrogen, C1-2 alkyl or -C(O)Ci-2 alkyl; each R9a is independently selected from hydrogen and C1-2 alkyl;
R9b is hydrogen, C1-2 alkyl or C1-2 alkoxy, or R9a and R9b together with the atoms onto which they are attached form a 5-7 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N, O, and S, which heterocycloalkyl is optionally substituted with one or more independently selected oxo, halo, -OH, -CN, C1-2 alkyl; and
R10 is hydrogen, halogen, C1-3 alkyl, -CH=CHCO2R9a , morpholino, C1-3 alkoxy, C1-3 haloalkoxy or oxetane; or a pharmaceutically acceptable salt and/or solvate thereof; or a compound according to Formula 1-3
Figure imgf000180_0001
wherein,
R1 is C1-2 alkyl (preferably methyl), C1-2 alkoxy (Ci.2)alkyl (preferably methoxymethyl), or hydroxy (C 1 _3)alkyl ;
R2 is hydrogen, fluoro, chloro or C1-2 alkyl (preferably chloro or methyl);
Figure imgf000181_0001
optionally substituted with one or more independently selected halogens (preferably fluoro);
R3 is hydrogen or methyl (preferably hydrogen); each of R4a andR4b is independently hydrogen, or methyl (preferably both are hydrogen);
R5 is phenyl or pyridyl, each of which is optionally substituted with one or two independently selected R7; each R7 is independently selected from
- -OH,
- -CN,
- -P(O)(Ci.2 alkyl)2, fluoro, chloro,
- -S(=O)2-Ci.4 alkyl,
- -NR8aR8b,
- -NHC(O)CI-2 alkyl,
- -N(CI.2 alkyl)C(O)Ci.2 alkyl,
- -CH=CHCO2R9a,
- -S(=O)2NHC(O)CI.2 alkyl,
- -S(=O)2NH2,
- -C(O)NHS(=O)2CI.2 alkyl,
- -CONR9aR9b,
- -CO2R9a,
Ci-2 alkyl optionally substituted with one or more independently selected halo, -CN, -OH, - CO2R9a or Ci-2 alkoxy,
Ci-2 alkoxy optionally substituted with one or more independently selected halogen, -OH, -CN, or C1-2 alkoxy, morpholino (preferably 1 -morpholino), and oxetane, which oxetane is optionally substituted with a hydroxy or Ci-2 alkyl; each R8a is independently hydrogen or Ci-2 alkyl; each R8b is independently hydrogen, Ci-2 alkyl or -C(O)Ci.2 alkyl; each R9a is independently selected from hydrogen and Ci-2 alkyl;
R9b is hydrogen, or Ci-2 alkyl; and
R10 is hydrogen, fluoro, chloro, Ci-2 alkyl, -CH=CHCO2R9a , , C1-3 alkoxy, C1-3 haloalkoxy or oxetane; or a pharmaceutically acceptable salt and/or solvate thereof.
17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-16.
18. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-16, or a pharmaceutical composition according to claim 17 for use in medicine.
19. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-16, or a pharmaceutical composition according to claim 17 for use in the prophylaxis and/or treatment of proliferative diseases.
20. A compound, or a pharmaceutically acceptable salt and/or solvate thereof, according to any one of claims 1-16, or a pharmaceutical composition according to claim 17, for use in the prophylaxis and/or treatment of a disease, disorder or condition that is selected from metastatic tumours (such as but not limited to, melanoma, lymphoma, leukaemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and uterine leiomyosarcoma), acute lymphoblastic leukemia, acute myeloidleukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T -Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, asopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sezary syndrome, skin cancer, small cell Lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, T -cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, Wilms tumor, a neoplastic disease of the blood and blood forming organs, including but not limited to: acute myeloid leukaemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukaemia (CLL), breast cancer (e.g. invasive ductal cancer, invasive lobular cancer), lung cancer (e.g. non-small-cell lung cancer, lung adenocarcinoma, squamous cell lung cancer and small-cell lung cancer), urothelial cancer, bladder cancer (e.g. urothelial bladder cancer, nonmuscle invasive bladder cancer, muscle invasive bladder cancer), upper tract cancer (e.g. urothelial upper tract cancer), urethral cancer, gastric cancer, pancreatic cancer, prostate cancer, colorectal cancer, multiple myeloma, liver cancer, melanoma (e.g. cutaneous melanoma), head and neck cancer (e.g. oral cancer), thyroid cancer, renal cancer (e.g. renal pelvis cancer), glioblastoma, endometrial cancer, cervical cancer, ovarian cancer, and testicular cancer
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