WO2018151678A1 - Composés destinés au traitement du cancer et épigénétique - Google Patents

Composés destinés au traitement du cancer et épigénétique Download PDF

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WO2018151678A1
WO2018151678A1 PCT/SG2018/050071 SG2018050071W WO2018151678A1 WO 2018151678 A1 WO2018151678 A1 WO 2018151678A1 SG 2018050071 W SG2018050071 W SG 2018050071W WO 2018151678 A1 WO2018151678 A1 WO 2018151678A1
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optionally substituted
alkyl
group
heteroaryl
cycloalkenyl
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PCT/SG2018/050071
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English (en)
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Si SI LIEW
Klement Jihao FOO
Chuhui Huang
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Agency For Science, Technology And Research
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D401/12—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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention generally relates to heterocyclic derivatives, methods for their preparation, pharmaceutical compositions containing these compounds and uses of these compounds in the treatment of disorders/conditions/diseases involving, relating to or associated with enzymes having methyltransferase activities.
  • Protein lysine methyltransferases are enzymes that carry out the methylation of lysine residues on target proteins. These enzymes are involved in the methylation of histone substrates where they act as an important regulator of chromatin architecture. This reversible post-translational modification changes the stability and enzymatic activity of the target protein.
  • SMYD3 is a SET and MYND domain containing lysine methyltransferase involved in diverse biological functions, such as: regulation of cell signaling pathways and gene transcription. SMYD3 catalyzes the methylation of histone tails at histone-3-lysine-4 (H3K4) and histone-4-lysine-5 (H4K5), leading to the altered expression of genes.
  • H3K4 histone-3-lysine-4
  • H4K5 histone-4-lysine-5
  • SMYD3 also methylates non-histone substrates like the cytoplasmic protein substrate, MAP3K2.
  • MAP3K2 the cytoplasmic protein substrate
  • SMYD3 expression in mice is required for chemically induced liver and colon cancer formation.
  • the nuclear role of SMYD3 using chromatin immunoprecipitation (ChIP) data indicates that SMYD3 is bound to regulatory regions of MYC, CTNNB 1, JAK1, and JAK2 in chemically induced liver tumors. Thus, suggesting a role in activating JAK-STAT3 signaling pathway.
  • SMYD3 also promotes the epithelial-to-mesenchymal transition and loss of contact inhibition between hepatocytes and intestinal epithelial cell. Even though there have been drug discovery efforts for SMYD3, there are still no compounds that show promise.
  • each bond represented by a dotted line is an optional bond
  • Q is a moiety selected from formulas (A) or (B):
  • W 1 is CH, N, O, or S
  • W 2 , W 3 , andW 4 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 5 is CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W is C in Formula (B);
  • W 6 is CH, N, O or S when the bonds represented by the dotted lines between W 5 and
  • W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 6 is CH or N in Formula (B);
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • W 9 is CH or N
  • X ⁇ X 2 , X 3 and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 , or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is Z 2 is -NHC(O)- when W 6 is CH;
  • Z 3 is selected from -NCY 1 )- or -N ⁇ -Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, and q are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only S0 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • each bond represented by a dotted line is an optional bond
  • W 1 is CH, N, O, or S
  • W 2 , W , and W 4 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 5 is CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 5 is C when r is 1 ;
  • W 6 is CH, N, O or S when the bonds represented by the dotted lines between W 5 and
  • W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 6 is CH or N when r is 1 ;
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • X*, X 2 , X 3 , and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or Z 2 is optionally substituted C 1 -C 2 alkyl when W 5 is
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, q, and r are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only -S(0) 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, and a pharmaceutically acceptable excipient.
  • a compound disclosed herein, or a pharmaceutically form or prodrug thereof, or a composition disclosed herein for use in therapy is provided.
  • j is 0 or 1 ;
  • W ⁇ W 2 , W 3 , W 4 , W 8 , X 2 , Z 1 Z 3 , R 3 , R 4 , Q, n, m, are as defined above;
  • a polar aprotic solvent preferably N,N-dimethylformamide
  • a peptide coupling reagent preferably (1- [Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid
  • HATU hexafluorophosphate
  • j is 0 or 1 ;
  • W ⁇ W 2 , W 3 , W 4 , W 8 , X 2 , Z 1 Z 3 , R 3 , R 4 , Q, n, m, are as defined herein;
  • a reducing agent preferably sodium borohydride or
  • X 3 , X 4 , W 7 , R 1 , and R 2 are defined herein.
  • the compounds of the present disclosure may inhibit the SMYD3 protein effectively at low concentrations.
  • Pharmaceutical compositions comprising these compounds and the use for the preparation of a medicament for the prophylaxis or/and treatment of diseases linked to SMYD3 overexpression, de-regulation of histone methylation, MAP3K2 expression, other SMYD3 substrate methylation or Ras driven cancers may be provided.
  • the compounds of the present disclosure may offer a novel treatment to cancers including without limitation cancer types such as hepatocellular carcinoma, breast cancer, ovarian cancer, colorectal carcinoma cancer, lung cancer, pancreatic cancer, leukemia and other diseases linked to high SMYD3 expression.
  • the compounds of the present disclosure show high effectiveness in SMYD3 inhibition combined with a desirable excellent anti-proliferative activity.
  • the compounds of the present disclosure can further be processed well into formulation for further drug testing.
  • the compounds of the present disclosure may have a unique potency profile against the target protein.
  • the compounds may be modified to have different potencies against different targets for a variety of indications or applications.
  • the compounds of the present disclosure may be small molecule inhibitors. Small molecule inhibitors, unlike macromolecules such as polymers, proteins and DNA, may be less toxic and have fewer occurrences of adverse drug effects while maintaining a high level of activity.
  • the compounds of the present disclosure may have a siginificantly higher potency against the target protein compared to conventionally known compounds.
  • the compounds as defined above may have a significantly higher potency in inhibiting SMYD3.
  • the compounds of the present disclosure have demonstrated inhibitory activities against the methyl transferase activity of SMYD3 enzyme and anti-proliferative activities against a variety of human tumor cell lines.
  • the compounds of the present disclosure may demonstrate good drug-like properties, that is, in vitro metabolic stability, solubility and desirable lipophilicity. More advantageously, the compounds of the present disclosure may inhibit methyltransferase activity of SMYD3 in an MTase assay using MAP3K2 as a peptide substrate. Further advantageously, the compounds of the present disclosure may show antiproliferative activity. Further advantageously, the compounds may inhibit SMYD3 mediated methylation of MAP3K2 and inhibit anchorage independent growth in human cancer cells.
  • the group may be a terminal group or a bridging group. This is to signify that the use of the term is intended to encompass the situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
  • alkyl alkyl
  • alkylene alkylene
  • examples of acyl include acetyl, benzoyl and amino acid derived aminoacyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Aliphatic means non-aromatic, open chain, straight or branched organic compounds.
  • Alkenyl as a group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-12 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • Exemplary alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • Alkoxy refers to an alkyl-O- group in which alkyl is as defined herein.
  • the alkyloxy is a C 1 -C 6 alkyloxy. Examples include, but are not limited to methoxy and ethoxy.
  • the group may be a terminal group or a bridging group.
  • alkoxy may be used interchangeably with the term "alkyloxy”.
  • Alkyl or “alkylene” as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a C 1 -C 12 alkyl, more preferably a C 1 -C 10 alkyl, most preferably C 1 -C 6 unless otherwise noted.
  • suitable straight and branched C 1 -C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-12 carbon atoms, more preferably 2- 10 carbon atoms, more preferably 2-6 carbon atoms in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkylamino includes both mono-alkylamino and dialkylamino, unless specified.
  • Mono-alkylamino means an Alkyl-NH- group, in which alkyl is as defined herein.
  • Dialkylamino means a (alkyl) 2 N- group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxyalkyl refers to an alkyloxy-alkyl- group in which the alkyloxy and alkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Alkyloxyaryl refers to an alkyloxy-aryl- group in which the alkyloxy and aryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the aryl group.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but are not limited to, methoxy carbonyl and ethoxy carbonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the carbonyl carbon.
  • Alkyloxycycloalkyl refers to an alkyloxy-cycloalkyl- group in which the alkyloxy and cycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the cycloalkyl group.
  • Alkyloxyheteroaryl refers to an alkyloxy-heteroaryl- group in which the alkyloxy and heteroaryl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroaryl group.
  • Alkyloxyheterocycloalkyl refers to an alkyloxy-heterocycloalkyl- group in which the alkyloxy and heterocycloalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heterocycloalkyl group.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Alkynyloxy refers to an alkynyl-O- group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C 1 -C 6 alkynlyloxy groups.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Amino refers to groups of the form -NR a R b wherein R a and R b are individually selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.
  • Amino acid as a group or part of a group means having at least one primary, secondary, tertiary or quaternary amino group, and at least one acid group, wherein the acid group may be a carboxylic, sulfonic, or phosphonic acid, or mixtures thereof.
  • the amino groups may be "alpha", “beta”, “gamma” ... to “omega” with respect to the acid group(s).
  • the amino acid may be natural or synthetic, and may include their derivatives.
  • the backbone of the "amino acid” may be substituted with one or more groups selected from halogen, hydroxy, guanido, heterocyclic groups.
  • amino acids also includes within its scope glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, asparte, glutamine, lysine, arginine and histidine, taurine, betaine, N-methylalanine etc.
  • L and (D) forms of amino acids are included in the scope of this disclosure.
  • the amino acids suitable for use in the present disclosure may be derivatized to include amino acids that are hydroxylated, phosphorylated, sulfonated, acylated, and glycosylated, to name a few.
  • amino acid residue refers to amino acid structures that lack a hydrogen atom of the amino group (-NH-CHR-COOH), or the hydroxy moiety of the carboxygroup (NH2-CHR-CO- ), or both (-NH-CHR-CO-).
  • aminocarbonyl group and “carbonylamino” group can be used interchangeably and are used to describe a -CO-NR 2 group.
  • Aminoalkyl means an NH 2 -alkyl- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 6 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5 _ 7 cycloalkyl or C 5 _ 7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C 6 -C 18 aryl group.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as defined herein.
  • exemplary arylalkenyl groups include phenylallyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as defined herein. Preferred arylalkyl groups contain a C 1 _ 5 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl, 1-naphthalenemethyl and 2-naphthalenemethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Arylalkyloxy refers to an aryl-alkyl-0- group in which the alkyl and aryl are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono-arylamino means a group of formula arylNH-, in which aryl is as defined herein.
  • Di-arylamino means a group of formula (aryl) 2 N- where each aryl may be the same or different and are each as defined herein for aryl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Arylheteroalkyl means an aryl-heteroalkyl- group in which the aryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Aryloxy refers to an aryl-0- group in which the aryl is as defined herein.
  • the aryloxy is a C 6 -C 18 aryloxy, more preferably a C 6 -C 10 aryloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • azidoalkyl refers to an alkyl group in which alkyl is as defined herein and which is substituted by an -N 3 group.
  • the azidoalkyl is a C 1 -C 6 azidoalkyl. Examples include, but are not limited to azidomethyl and azidoethyl.
  • a “bond” is a linkage between atoms in a compound or molecule.
  • the bond may be a single bond, a double bond, or a triple bond, as valency permits.
  • Cycloaliphatic means non-aromatic, cyclic organic compounds.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups.
  • a cycloalkenyl group typically is a C 3 -C 12 alkenyl group. The group may be a terminal group or a bridging group.
  • Cycloalkyl refers to a saturated monocyclic or fused or bridged or spiro poly cyclic, carbocycle preferably containing from 3 to 9 carbon atoms per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.
  • a cycloalkyl group typically is a C 3 -C 12 alkyl group. The group may be a terminal group or a bridging group.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as defined herein.
  • Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Cycloalkylheteroalkyl means a cycloalkyl -heteroalkyl- group in which the cycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Cycloalkyloxy refers to a cycloalkyl-O- group in which cycloalkyl is as defined herein.
  • the cycloalkyloxy is a C 1 -C 6 cycloalkyloxy. Examples include, but are not limited to, cyclopropanoxy and cyclobutanoxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Cycloalkenyloxy refers to a cycloalkenyl-O- group in which the cycloalkenyl is as defined herein.
  • the cycloalkenyloxy is a C 1 -C 6 cycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Cycloamino refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one nitrogen atom in at least one ring. Each ring is preferably containing from 3 to 10 carbon atoms per ring, more preferably 4 to 7 carbon atoms per ring.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Haloalkyl refers to an alkylgroup in which alkyl is as defined herein and the alkyl is substitueted by at least one halogen.
  • the alkyl group is substituted by 1 to 5 halogen atoms.
  • the alkyloxy is a C 1 -C 6 haloalkyl. Examples include, but are not limited to chloromethyl, fluoromethyl and trifluoromethyl.
  • the group may be a terminal group or a bridging group.
  • Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, lH-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phen
  • a heteroaryl group is typically a C 1 - C 18 heteroaryl group.
  • a heteroaryl group may comprise 3 to 8 ring atoms.
  • a heteroaryl group may comprise 1 to 3 heteroatoms independently selected from the group consisting of N, O and S.
  • the group may be a terminal group or a bridging group.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms in the chain, one or more of which has been replaced by a heteroatom selected from S, O, P and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, amides, alkyl sulfides, and the like.
  • heteroalkyl also include hydroxy C 1 -C 6 alkyl, C 1 C- 6 alkyloxy C 1 C- 6 alkyl, amino C 1 - C 6 alkyl, C 1 -C 6 alkylamino C 1 -C 6 alkyl, and di( C 1 -C 6 alkyl)amino C 1 C- 6 alkyl.
  • the group may be a terminal group or a bridging group.
  • Heteroalkyloxy refers to a heteroalkyl-O- group in which heteroalkyl is as defined herein.
  • the heteroalkyloxy is a C 1 -C 6 heteroalkyloxy.
  • the group may be a terminal group or a bridging group.
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as defined herein. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridinylmethyl. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heteroarylheteroalkyl means a heteroaryl-heteroalkyl- group in which the heteroaryl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heteroarylamino refers to groups containing an aromatic ring (preferably 5 or 6 membered aromatic ring) having at least one nitrogen and at least another heteroatom as ring atoms in the aromatic ring, preferably from 1 to 3 heteroatoms in at least one ring. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • Arylamino and aryl is as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Heteroaryloxy refers to a heteroaryl-0- group in which the heteroaryl is as defined herein. Preferably the heteroaryloxy is a C 1 -C 18 heteroaryloxy. The group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocyclyl refers to saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom. Examples of heterocyclic moieties include heterocycloalkyl and heterocycloalkenyl.
  • Heterocycloalkenyl refers to a heterocycloalkyl as defined herein but containing at least one double bond.
  • a heterocycloalkenyl group typically is a C 2 -C 12 heterocycloalkenyl group.
  • the group may be a terminal group or a bridging group.
  • Heterocycloalkyl refers to a saturated monocyclic, fused or bridged or spiro polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4-oxathiapane.
  • a heterocycloalkyl group typically is a C 2 -C 12 heterocycloalkyl group.
  • a heterocycloalkyl group may comprise 3 to 9 ring atoms.
  • a heterocycloalkyl group may comprise 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The group may be a terminal group or a bridging group.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as defined herein.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuranyl)methyl, (2-tetrahydrothiofuranyl)methyl.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkyl group.
  • Heterocycloalkylalkenyl refers to a heterocycloalkyl-alkenyl- group in which the heterocycloalkyl and alkenyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the alkenyl group.
  • Heterocycloalkylheteroalkyl means a heterocycloalkyl-heteroalkyl- group in which the heterocycloalkyl and heteroalkyl moieties are as defined herein.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the heteroalkyl group.
  • Heterocycloalkyloxy refers to a heterocycloalkyl-O- group in which the heterocycloalkyl is as defined herein.
  • the heterocycloalkyloxy is a C 1 - C 6 heterocycloalkyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocycloalkenyloxy refers to a heterocycloalkenyl-O- group in which heterocycloalkenyl is as defined herein.
  • the heterocycloalkenyloxy is a C 1 C 6 heterocycloalkenyloxy.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the oxygen atom.
  • Heterocycloamino refers to a saturated monocyclic, bicyclic, or polycyclic ring containing at least one nitrogen atom and at least another heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • Hydroalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms have been replaced with an OH group.
  • a hydroxyalkyl group typically has the formula C n H (2n+ i- X) (OH) x
  • n is typically from 1 to 10, more preferably from 1 to 6, most preferably from 1 to 3.
  • x is typically from 1 to 6, more preferably from 1 to 4.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbon atoms such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or t-butyl).
  • the group may be a terminal group or a bridging group.
  • Patient refers to an animal, preferably a mammal, and most preferably a human.
  • Subject refers to a human or an animal.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group, it is bonded to the remainder of the molecule through the sulfur atom.
  • the group may be a terminal group or a bridging group. If the group is a terminal group it is bonded to the remainder of the molecule through the nitrogen atom.
  • isomeric forms including diastereomers, enantiomers, tautomers, and geometrical isomers in "E” or “Z” configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non- hydrated forms.
  • compounds of the invention may contain more than one asymmetric carbon atom.
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of the Formulas of the present disclosure may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present disclosure and specified formulae.
  • Prodrug means a compound that undergoes conversion to a compound of a formula of the present disclosure within a biological system, usually by metabolic means (e.g. by hydrolysis, reduction or oxidation).
  • metabolic means e.g. by hydrolysis, reduction or oxidation.
  • an ester prodrug of a compound of a formula of the present disclosure containing a hydroxyl group may be converted by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of a formula of the present disclosure containing a hydroxyl group are for example formates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ - hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates.
  • ester prodrug of a compound of a formula of the present disclosure containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987.
  • an acyl prodrug of a compound of a formula of the present disclosure containing an amino group may be converted by hydrolysis in vivo to the parent molecule.
  • prodrugs for these and other functional groups, including amines are described in Prodrugs: Challenges and Rewards (Parts 1 and 2); Ed V. Stella, R. Borchardt, M. Hageman, R.Oliyai, H. Maag and J Tilley; Springer, 2007).
  • terapéuticaally effective amount or “effective amount” is an amount sufficient to effect beneficial or desired clinical results.
  • An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
  • the term "functional equivalent” is intended to include variants of the specific protein lysine methyl transferase species described herein. It will be understood that the protein lysine methyl transferases may have isoforms, such that while the primary, secondary, tertiary or quaternary structure of a given protein lysine methyl transferase isoform is different to the prototypical protein lysine methyl transferase, the molecule maintains biological activity as a protein lysine methyl transferase. Isoforms may arise from normal allelic variation within a population and include mutations such as amino acid substitution, deletion, addition, truncation, or duplication. Also included within the term “functional equivalent” are variants generated at the level of transcription. Enzymes have isoforms that arise from transcript variation. Other functional equivalents include protein lysine methyl transferases having altered post- translational modification such as glycosylation.
  • reprogramming cells is intended to include erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development.
  • optionally substituted means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups independently selected from optionally substituted aryl, optionally substituted heteroarylyl, alkyl, including an alkylene bride representing two substitutents, alkenyl, alkynyl, thioalkyl, cycloalkyl, aminocycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkenyl, heterocycloalkyl, cycloalkylheteroalkyl, cycloalkyloxy, cycloalkylaminocarbonyl, cycloalkenyloxy, cycloamino, halo, carboxyl, haloalkyl, haloalkenyl, haloalkynyl, alkynyloxy, heteroalkyl, heteroalkyloxy, hydroxyl, hydroxyalkyl, alkylene bride representing two substituten
  • the number of carbon and hetero atoms in the groups of the optional substituents is as defined for the groups mentioned above e.g. every alkyl or alkylene moiety can be a C 1 -C 12 alkyl, methyl, ethyl, n-propyl, 2-propyl, etc. Accordingly a haloalkoxy group is for instance defined as an alkoxy group as referred to above which is substituted by at least one halogen atom. Where the optional substituents are themselves optionally substituted there substituents can be chosen from the list of optional substituents and such substituents are not further substituted.
  • Preferred optional substituents are defined as one to three groups selected from halogen, C 1 C- 3 -alkyl, or C 3 -C 7 -cycloalkyl, nitro, halogen, C 1 -C 4 haloalkyl having 1 to 5 halogen atoms, C 1 -C 4 hydroxyalkyl, optionally halogen substituted C 3 -C 7 -cycloalkyl, aminocarbonyl- C 1 C- 3 - alkyl, optionally C 1 C- 3 -alkyl substituted and/or halogen substituted heteroaryl having 5 to 6 ring members and 1 to two hetero atoms selected from N or O, or optionally halogen, C 1 C- 3 -alkyl, C 1 -C 4 hydroxyalkyl and/or azido C 1 C- 3 -alkyl substituted phenyl.
  • Preferred optional substituents are also two substituents forming an optionally C 1 C- 3 -alkyl substituted C
  • the term "about”, in the context of concentrations of components of the formulations, typically means ⁇ 10% of the stated value, more typically ⁇ 7.5% of the stated value, more typically ⁇ 5% of the stated value, more typically ⁇ 4% of the stated value, more typically ⁇ 3% of the stated value, more typically, ⁇ 2% of the stated value, even more typically ⁇ 1% of the stated value, and even more typically ⁇ 0.5% of the stated value.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • FIG. 1 is a series of dose response curves showing the effect of compounds of the present invention (D001, D006, D015, and D014) against Comparative Compound 1 of Comparative Example 1 on the methyltransferase activity of SMYD3 using MAP3K2 peptide as a substrate and refers to dose-response curves showing the effect of compounds on the methyltransferase activity of SMYD3 using MAP3K2 peptide as a substrate (Fig. 1A: Comparative Compound 1 ; Fig. IB: D001; Fig. 1C: D006; Fig. ID: D015; Fig. IE: D014).
  • FIG. 2 is a series of dose response curves showing that SMYD3 compounds inhibit the proliferation of hepatocellular carcinoma (Fig. 2A: PLC/PRF-5; Fig. 2C: Huh7) and human pancreatic carcinoma (Fig. 2B: MIAPaCa-2) cell lines.
  • Fig. 3 is a series of dose response curves showing that SMYD3 compounds inhibit the proliferation of hepatocellular carcinoma (Fig. 2A: PLC/PRF-5; Fig. 2C: Huh7) and human pancreatic carcinoma (Fig. 2B: MIAPaCa-2) cell lines.
  • Fig. 3 is a series of dose response curves showing that SMYD3 compounds inhibit the proliferation of hepatocellular carcinoma (Fig. 2A: PLC/PRF-5; Fig. 2C: Huh7) and human pancreatic carcinoma (Fig. 2B: MIAPaCa-2) cell lines.
  • Fig. 3 is a series of dose response curves showing that SMYD3 compounds inhibit the proliferation
  • FIG. 3 is a western blot showing SMYD3 target engagement and inhibition of MAP3K2 methylation following compound treatment in PLC/PRF-5 of compound DO 15 (Fig. 3 A) and Comparative Compound 1 (Fig. 3B).
  • FIG. 4 is a series of mass spectras showing the analysis of SMYD3 modification with comparative compound 1 (Fig. 4A), DOOl (Fig. 4B), and D015 (Fig. 4C).
  • FIG. 5 shows the X-ray crystal structure of SMYD3 protein with compound DOOl occupying the substrate pocket and a molecule of S-Adenosyl methionine.
  • the present disclosure relates to a compound having the following Formula (I);
  • each bond represented by a dotted line is an optional bond
  • Q is a moiety selected from formulas (A) or (B):
  • W 1 is CH, N, O, or S
  • W 2 , W 3 , W 4 and W 7 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 5 is CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W is C in Formula (B);
  • W 6 is CH, N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 6 is CH or N in Formula (B);
  • W 8 is -CX 1 , N, O or S;
  • W 9 is CH or N
  • X 1 X 2 , X 3 and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or optionally substituted C 1 C- 2 alkyl, or Z 2 is - NHC(O)- when W 6 is CH;
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, and q are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only S0 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • the present disclosure also provides a compound having the following Formula (IC);
  • each bond represented by a dotted line is an optional bond
  • W 1 is CH, N, O, or S
  • W 2 , W , W 4 and W 7 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 5 is CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 5 is C when r is 1 ;
  • W 6 is CH, N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 6 is CH or N when r is 1 ;
  • W 8 is -CX 1 , N, O or S;
  • X 1 X 2 , X 3 , and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or optionally substituted C 1 C- 2 alkyl;
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 1 together with R 2 , or R 3 together with R 4 , may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, q, and r are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only -S(0) 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • W 1 is CH, N, O, or S
  • W 2 , W 3 ,andW 4 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 5 is CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W is C in Formula (B);
  • W 6 is CH, N, O or S when the bonds represented by the dotted lines between W 5 and
  • W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 6 is CH or N in Formula (B);
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • W 9 is CH or N
  • X ⁇ X 2 , X and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 , or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is CH, or Z 2 is -NHC(O)- when W 6 is CH;
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, and q are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only S0 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A; or (iii) q is 0 when p is 0 only when (a) R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A; or (b) when R 1 together with R 2 taken together to form a bicyclic or tricyclic ring system with Ring C; or a pharmaceutically acceptable salt or prodrug thereof.
  • the present disclosure also relates to a compound having the following Formula (IC):
  • each bond represented by a dotted line is an optional bond
  • W 1 is CH, N, O, or S
  • W 2 , W , and W 4 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 5 is CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 5 is C when r is 1 ;
  • W 6 is CH, N, O or S when the bonds represented by the dotted lines between W 5 and
  • W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent, and W 6 is CH or N when r is 1 ;
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • X ⁇ X 2 , X 3 , and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, q, and r are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only -S(0) 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • Z 1 may be C(O)
  • Z 2 is C(O)
  • Y 1 may be hydrogen or optionally substituted alkyl
  • Y 2 may be optionally substituted alkyl.
  • p and q may be selected from the integers 0 or 1 and m is 1, the dotted lines between W 5 and W 6 are present, and R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 represent independently of one another hydrogen or alkyl or R 5 and R 6 form an alkylene bridge, thereby forming a bicyclic ring system with Ring B.
  • R 3 and R 4 may be taken together to form an optionally substituted bicyclic or tricyclic ring system with Ring A, wherein said bicyclic or tricyclic system comprises 1 to 3 heteroatoms selected from N or O, or the ring system comprising Ring A may be an optionally substituted 5- membered heteroaryl group comprising 1 to 3 hetero atoms selected from N and O.
  • the ring system comprising Ring A may be:
  • W 2 is O, or N
  • W 4 is C or N
  • X 2 is H or optionally substituted alkyl or cycloalkyl
  • W 8 is O or -CX 1 , wherein X 1 is H, or halogen;
  • W 10 is CH 2 , NH, or C(O);
  • W 11 is CH 2 , or C(O);
  • X 7 is H or Me
  • R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • X 2 may be hydrogen, methyl, ethyl, propyl, butyl, or cyclopropyl.
  • one of R 3 or R 4 may be -NHC(0)(CH 3 ).
  • optionally substituted oxoindolinyl optionally substituted indolinyl, optionally substituted benzimidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted pyrazolyl, optionally substituted thiazolyl, optionally substituted thiophenyl, optionally substituted benzo[d]imidazolyl, optionally substituted indolyl, optionally substituted isoindolyl, optionally substituted indazolyl, optionally substituted pyrrolyl, optionally substituted pyridinyl, optionally substituted benzo[d]dioxolyl, optionally substituted triazolyl, optionally substituted benzotriazolyl, optionally substituted benzoxazolyl, optionally substituted benzofuranyl, optionally substituted pyrazolopyridinyl, optionally substituted pyrrolopyrimidinyl, optionally substituted pyrrolopyri
  • the ring system comprising Ring A may represent optionally substituted 2-oxoindolin-5-yl, optionally substituted indolin-5-yl, optionally substituted 2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl, optionally substituted isoxazol-5-yl, optionally substituted lH-l,2,3-triazol-4-yl, optionally substituted quinolin-7-yl, optionally substituted phenyl, or optionally substituted oxadiazol-2-yl.
  • the ring system comprising Ring A may represent a 2-oxoindolin-5-yl, 6-chloro-2-oxoindolin-5-yl, N-methyl,2-oxoindolin-5-yl, 6-chloro-2- oxoindolin-5-yl, indolin-5-yl, 2-oxobenzoimidazol-5-yl, N-methyl,2-oxobenzoimidazol-5-yl, 3- cyclopropyl-isooxazol-5-yl, 4-chloro-quinolin-7-yl, 4-acetamido-2-chlorophenyl, 1-methyl- l,2,3-triazol-4-yl, l-cyclopropyl-l,2,3-triazol-4-yl, or 5-cyclopropyl-l,3,4-oxadiazol-2-yl group.
  • the optional substituents may be one to three groups selected from oxo, acetamido, halogen, C 1 -C 3 -alkyl, or C 3 -C 7 -cycloalkyl.
  • W 7 is C or N
  • R and R 2 are each independently H, halogen, C 1 _ 3 alkyl substituted with chloro, or nitro, wherein R 2 is absent when W 7 is N;
  • X 3 is H, or C 1-3 alkyl substituted with halogen
  • X 4 is H or halogen
  • X 5 is halogen
  • X 6 is H, halogen, optionally substituted alkyl, optionally substituted pyrrolidinyl, optionally substituted phenyl, optionally substituted cyclopropyl, optionally substituted pyrazolyl, or optionally substituted pyridinyl, or optionally substituted pyrrolyl.
  • W 7 is C or N
  • R 1 and R 2 are each independently H, chloro, C 1 _ 3 alkyl substituted with chloro, or nitro, wherein R 2 is absent when W 7 is N;
  • X 3 is H, or C3 1 - alkyl substituted with halogen
  • X 4 is H or halogen
  • X 5 is halogen
  • X 6 is H, halogen, optionally substituted alkyl, optionally substituted pyrrolidinyl, optionally substituted phenyl, optionally substituted cyclopropyl, optionally substituted pyrazolyl, or optionally substituted pyridinyl, or optionally substituted pyrrolyl.
  • X 3 may be selected from the group consisting of hydrogen and -CH 2 Cl.
  • X 4 may be selected from the group consisting of hydrogen and fluoro.
  • X 5 may be chloro.
  • X 6 may be selected from the group consisting of H; CI; methyl; pyrazolyl; pyrazolyl substituted with at least one of methyl, -CH 2 C(0)NH 2 , or oxetane; cyclopropyl; cyclopropyl substituted with at least one of fluoro or NH 2 ; pyrrolidinyl; pyrrolidinyl substituted with methyl; phenyl; phenyl substituted with at least one of - C(CH 3 ) 2 (OH), -C(H)(N 3 ), methyl, methoxy, -C(O), -C(CH 3 ) 2 (CH 2 )(NH 2 ), -C(CH 3 )(N(CH 3 ) 2 ), - C(CH 3 )(pyrrolidine), fluoro, -(CH 2 )(NH 2 ), or -(CH 2 )(N(CH 3 ) 2
  • phenyl may represent optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridinyl, optionally substituted phenanthryl, optionally substituted anthracenyl, optionally substituted tetrahydroacridinyl, optionally substituted acridinyl, optionally substituted quinolinyl, optionally substituted tetrahydroquinolinyl, optionally substituted isoquinolinyl, optionally substituted 4-H-quinolizinyl, optionally substituted naphthyridine, optionally substituted oxoindolinyl, or optionally substituted indolinyl.
  • the ring system comprising Ring C may be selected from substituted phenyl, optionally substituted quinolin-7-yl or optionally substituted 5,6,7,8- tetrahydroacridin-3-yl, optionally substituted indolin-5-yl, or substituted pyridin-5-yl.
  • the ring system comprising Ring C may be selected from 9-chloro-5,6,7,8-tetrahydroacridin-3-yl, optionally substituted 4-chloro-quinolin-7-yl, 2,4- dichloro-quinolin-7-yl, 2-methyl,4-chloroquinolin-7-yl or from chloromethyl-substituted and optionally further substituted phenyl.
  • the ring system comprising Ring C may be selected from 4-chloroquinolin-7-yl substituted with one or more substituents selected from 1 -methyl - pyrrol-3-yl, l-methyl-pyrazol-4-yl, 1 -methyl -pyrazol-3-yl, l-(oxetan-3-yl)-pyrazol-4-yl, cyclopropyl, pyrrol-3-yl, (2-amino-2-oxoethyl)-pyrazol-4-yl, 1-fluoro-cycloprop-l-yl, 4(2- hydroxypropan-2-yl)phenyl, phenyl, 4(azidomethyl)phenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 4-(l-Aminocyclopropyl)phenyl , 3-formyl-4-methoxyphenyl , 3-hydroxymethyl- 4-methoxyphen
  • the optional substituents may be one to three groups selected from nitro, halog en, C 1 -C 3 -alkyl, C 1 -C 4 -haloalkyl having 1 to 5 halogen atoms, C 1 -C 4 - hydroxyalkyl, optionally halogen substituted C 3 -C 7 -cycloalkyl, aminocarbonyl- C 1 -C 3 -alkyl, optionally C 1 -C 3 -alkyl substituted and/or halogen substituted heteroaryl having 5 to 6 ring members and 1 to two hetero atoms selected from N or O, or optionally halogen, C 1 -C 3 - alkyl, C 1 -C 4 -hydroxyalkyl, and/or azido- C 1 -C 3 -alkyl substituted phenyl.
  • X 1 may be hydrogen, fluorine or chlorine.
  • Q may be a moiety selected from formulas (Al) or (B):
  • W 5 is -CR 13 , N, O or S in Formula (Al), and W 5 is C in Formula (B);
  • W 6 is CH, N, O or S in Formula (Al), and W 6 is CH or N in Formula (B); and
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and W 9 are as defined above.
  • (a) may be wherein W 5 is -CR 13 or N; W 6 is CH or N; R 5 ,
  • R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently H, halogen, or optionally substituted alkyl; q is 0 or 1 ; and p is 0 or 1 ;
  • (b) may be W 5 is C; W 6 is N; W 9 is N; R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently H, halogen, or optionally substituted alkyl;
  • (c) may be selected from the group consisting of formulas (A2) to (A6):
  • W 5 and W 6 are independently CH or N;
  • R 10 is fluoro or methyl;
  • R 6 and R 13 are independently H or methyl; and
  • p and q are independently 0 or 1 ;
  • (d) may be selected from the group consisting of optionally substituted piperidinyl, optionally substituted azabicyclo[3.2.1]octan-3-yl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, optionally substituted diazaspiro[3.3]heptanyl, and optionally substituted imidazolidinyl;
  • (e) may be selected from the group consisting of optionally substituted piperidinyl, optionally substituted azabicyclo[3.2.1]octan-3-yl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, optionally substituted diazaspiro[3.3]heptanyl, and optionally substituted imidazolidinyl, wherein the optional substituents are preferably one to three groups selected from halogen and alkyl;
  • (f) may be selected from the group consisting of unsubstituted piperidinyl, piperidinyl substituted with one or more fluoro, piperidinyl substituted with one or more methyl, unsubstituted azabicyclo[3.2.1]octan-3-yl, unsubstituted piperazinyl, unsubstituted pyrrolidinyl, unsubstituted azetidinyl, unsubstituted diazaspiro[3.3]heptanyl, and unsubstituted imidazolidinyl; or
  • (g) may be selected from the group consisting of 1 -piperidinyl -4-yl, 3-fluoropiperidin-4-yl, 4- methylpiperidin-4-yl, 8-azabicyclo[3.2.1]octan-3-yl, 4-piperazinyl-l-yl, l -pyrrolidinyl-3-yl, 1- azetidinyl-3-yl, 2,6-diazaspiro[3.3]heptan-2yl-6yl, and 3-imidazolidinyl-l-yl.
  • Q is azetidinyl-3-yl, 2,6-diazaspiro[3.3]heptan-2yl-6yl, and 3-imidazolidinyl-l-yl.
  • (a) may be formula (A7): wherein W 5 is CH 2 ; W 6 is CH 2 or
  • R 5 , R 10 , R 11 , and R 12 are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • (b) may be formula (A8): wherein W 5 is CH 2 ; and W 6 is CH 2 or NH: or
  • W 1 is CH, N, O, or S
  • W 2 , W 3 ,andW 4 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S in Formula (Al), and W 5 is C in Formula (B);
  • W 6 is CH, N, O or S in Formula (Al), and W 6 is CH or N in Formula (B);
  • W 7 isCorN
  • W 8 is -CX 1 , N, O or S;
  • W 9 is CH orN
  • X 1 X 2 ,X 3 andX 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 , or Z 2 is optionally substituted C 1 -C 2 alkyl when W 5 is CH, or Z 2 is -NHC(O)- when W 6 is CH;
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )- Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; or R 1 together with R 2 , or R 3 together with R 4 , may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, and q are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only S0 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • the present disclosure also relates to a compound having the following Formula (IE):
  • each bond represented by a dotted line is an optional bond
  • W 1 is CH, N, O, or S
  • W 2 , W , and W 4 are independently selected from C, N, O, or S;
  • W 5 is -CR 13 , N, O or S, and W 5 is C when r is 1 ;
  • W 6 is CH, N, O or S, and W 6 is CH or N when r is 1 ;
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • X 1 X 2 , X 3 , and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, q, and r are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only -S(0) 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • each bond represented by a dotted line is an optional bond
  • W 1 is CH, N, O, or S
  • W 2 , W , and W 4 are independently selected from C, N, O, or S;
  • W 5 is CH 2 ;
  • W 6 is NH or CH 2 ;
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • W 9 is CH or N
  • X 1 X 2 , X and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 , or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is CH, or Z 2 is -NHC(O)- when W 6 is CH;
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, and optionally substituted heteroaryl;
  • R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, and q are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only S0 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • the present disclosure also relates to a compound having the following Formula (IG):
  • each bond represented by a dotted line is an optional bond; represents an aromatic ring system;
  • W 1 is CH, N, O, or S
  • W 2 , W , and W 4 are independently selected from C, N, O, or S;
  • W 5 is CH 2 , or W 5 is C when r is 1 ;
  • W 6 is NH or CH 2 , or W 6 is CH or N when r is 1 ;
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • X 1 , X 2 , X 3 , and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is
  • Z 3 is selected from -N(Y 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, q, and r are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only -S(0) 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • the present disclosure also relates to a compound having the following Formula (IH):
  • each bond represented by a dotted line is an optional bond
  • W 1 is CH, N, O, or S
  • W 2 , W , and W 4 are independently selected from C, N, O,
  • W 5 is CH 2 ;
  • W 6 is NH or CH 2 ;
  • W 7 is C or N
  • W 8 is -CX 1 , N, O or S;
  • X ⁇ X 2 , X 3 , and X 4 are independently selected from H, halogen, optionally substituted alkyl, or optionally substituted cycloalkyl;
  • Z 1 is selected from C(O) or optionally substituted alkyl
  • Z 2 is selected from C(O) or S(0) 2 or Z 2 is optionally substituted C 1 C- 2 alkyl when W 5 is
  • Z 3 is selected from -NCY 1 )- or -N(Y 1 )-Y 2 -;
  • Y 1 is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl;
  • Y 2 is optionally substituted alkyl
  • R 5 , R 6 , R 7 , R 12 and R 13 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 8 , R 9 , R 10 , and R 11 are absent or are independently selected from the group consisting of H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • any two of R 5 , R 6 , R 7 , and R 12 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B, or wherein any two of R 8 , R 9 , R 10 , and R 11 may be taken together to form an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring B;
  • R 1 is selected from the group consisting of H, halogen, cyano, nitro, unsubstituted alkyl, or alkyl substituted with chloro, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl, thereby forming a bicyclic ring system with Ring A or Ring C, respectively;
  • R 1 together with R 2 , or R 3 together with R 4 may independently be optionally taken together to form an optionally substituted cycloalkyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted cycloalkenyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heterocyclyl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted aryl fused with an in each case optionally substituted cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; or an optionally substituted heteroaryl fused with an in each case optionally substituted cycloalkyl, cycloal
  • n, m, p, and q are integers independently selected from 0 and 1 ;
  • W 5 is only N when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A, wherein the ring system contains at least 8 ring members;
  • Z 2 is only -S(0) 2 when R 3 together with R 4 are taken together to form a bicyclic or tricyclic ring system with Ring A;
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure further provides a method of inhibiting SMYD3 in a cell comprising administering to a cell a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, or a composition disclosed herein.
  • the inhibition of SMYD3 may further comprise the inhibition of cell proliferation.
  • the present disclosure further provides a method of treating a SMYD-3 -related disorder comprising administering to a subject in need of treatment a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, or a composition disclosed herein.
  • the disorder may be linked to SMYD3 overexpression, de-regulation of histone methylation, MAP3K2 expression or is a cancer.
  • the disorder may be a cancer selected from hepatocellular carcinoma cancer, breast cancer, ovarian cancer, colorectal carcinoma, lung cancer, pancreatic cancer or leukemia.
  • the method disclosed herein may further comprise the step of administering an additional therapeutic agent in the subject.
  • the present disclosure also provides a compound disclosed herein, or a pharmaceutically form or prodrug thereof, or a composition disclosed herein for use in therapy.
  • the present disclosure further provides a use of a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, or a composition disclosed herein, in the manufacture of a medicament for treatment of a SMYD3 -related disorder.
  • the disorder may be cancer.
  • the disorder may be a cancer selected from hepatocellular carcinoma cancer, breast cancer, ovarian cancer, colorectal carcinoma, lung cancer, pancreatic cancer or leukemia.
  • the medicament may be administered with an additional therapeutic agent, wherein said medicament may be administered in combination or alteration with the additional therapeutic agent.
  • the present disclosure further provides a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, or a composition disclosed herein, for use in the treatment of a SMYD3 -related disorder.
  • the disorder may be cancer.
  • the disorder may be a cancer selected from hepatocellular carcinoma cancer, breast cancer, ovarian cancer, colorectal carcinoma, lung cancer, pancreatic cancer or leukemia.
  • the compound may be administered with an additional therapeutic agent, wherein said medicament may be administered in combination or alteration with the additional therapeutic agent.
  • they may be administered in any form or mode which may make the compound bioavailable.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances.
  • compositions of this disclosure may include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene
  • compositions as defined above may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions as defined above may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions for parenteral injection may comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
  • the compounds may be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • compositions as defined above may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions as defined above may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations may be readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds as defined above may include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, poly oxy ethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers may include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions as defined above may also be administered by nasal aerosol or inhalation.
  • Such compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions as defined above may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions as defined above may be administered without food. In other embodiments, pharmaceutically acceptable compositions as defined above may be administered with food.
  • compositions may vary depending upon the host treated, the particular mode of administration.
  • the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.
  • a method of inhibiting SMYD3 in a cell may comprise administering to a cell a compound as disclosed above, or a pharmaceutically acceptable form or prodrug thereof, or a composition as disclosed above.
  • the activity of a compound as an inhibitor may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays may include assays that determine inhibition of either the methylation activity and/or the subsequent functional consequences, or methylation activity of one or both of histone H3 at lysine 4 (H3K4me3) and histone H4 at lysine 5 (H4K5me), or the methylation of a lysine residue on MAP3K2.
  • SMYD3 catalyzes the methylation of the MAP3K2 peptide substrate by transferring a methyl group from S-Adenosyl methionine (SAM) to MAP3K2 peptide and further converts the SAM to SAH.
  • SAM S-Adenosyl methionine
  • the SMYD3 methyltransferase activity is measured based on the amount of S-Adenosyl homocysteine (SAH) produced from the reaction through the use of coupling enzymes that convert the SAH to ATP.
  • the inhibition of SMYD3 further comprises the inhibition of cell proliferation.
  • the cell may be in vitro.
  • the cell may be from a cell line.
  • the cell line may be an immortalized cell line, a genetically modified cell line or a primary cell line.
  • the cell line may be selected from the group consisting of HepG2, HCT116, A549, HPAF-II, CFPAC-1, HuH7, SNU398, Hep3B, PLC/PRF/5, HuHl, Bel7404, HCCLM3, HLE, SK-HEP-1, Mahlavu, JHH1, JHH2, JHH4, JHH5, JHH7, SNU354, SNU368, SNU387, SNU423, SNU449, SNU739, SNU761, SNU886, MIA PaCa-2 and HEK293.
  • the cell may be from tissue of a subject.
  • the cell may be in a subject.
  • the disorder may be lymphoma, cutaneous T-cell lymphoma, follicular lymphoma, or Hodgkin lymphoma, cervical cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, gastric cancer, pancreatic cancer, sarcoma, hepatocellular carcinoma, leukemia or myeloma, retinal angiogenic disease, liver fibrosis, kidney fibrosis, or myelofibrosis.
  • the present disclosure further provides a process for synthesizing a compound disclosed herein, comprising the steps of:
  • j is 0 or 1 ;
  • W 1 W 2 , W 3 , W 4 , W 8 , X 2 , Z 1 Z 3 , Pv 3 , Pv 4 , Q, n, m are as defined above; in the presence of a polar aprotic solvent, preferably N,N-dimethylformamide, optionally in the presence of a peptide coupling reagent, preferably (1- [Bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b]pyridinium 3 -oxid
  • HATU hexafluorophosphate
  • the Formula (II) may be of Formula (Ila):
  • j may be 0 when W 6 is N or NH, or j is 1 when W 6 is CH;
  • m may be 0 or 1 ;
  • W 5 may be -CR 13 when m is 1, or W 5 is N when m is 0;
  • Z 1 may be -C(O);
  • Z 3 may be -NC(Y 1 )- or -NC(Y 1 )-(Y 2 )- when m is 1;
  • W 6 may be N or CH when the bonds represented by the dotted lines between W 5 and W 6 are present, or W 6 is NH or CH 2 when the bonds represented by the dotted lines between W 5 and W 6 are absent; and W 1 , W 2 , W 3 , W 4 , X 2 , Z 1 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, m, and p are as defined above.
  • Formula (II) may be of Formula (lib):
  • n 0;
  • Z 1 may be -C(O);
  • W 9 may be NH
  • W 6 may be N
  • W 1 , W 2 , W 3 , W 4 , W 8 , X 2 , Z 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , W 5 , n, and m may be as defined above.
  • the present disclosure also provides a process for synthesizing the compound defined above, comprising the steps of:
  • j is 0 or 1 ;
  • W 1 , W 2 , W 3 , W 4 , W 8 , X 2 , Z 1 Z 3 , R 3 , R 4 , Q, n, m are as defined above; in the presence of a reducing agent, preferably sodium borohydride or
  • X 3 , X 4 , W 7 , R 1 , and R 2 are defined above.
  • Non-limiting examples of the invention and a comparative example will be further described in greater detail by reference to specific Examples, which should not be construed as in any way limiting the scope of the invention.
  • a SMYD3 enzymatic assay was developed using Promega' s Methyltransferase-GloTM reagents.
  • SMYD3 catalyzes the methylation of the MAP3K2 peptide substrate by transferring a methyl group from SAM to MAP3K2 peptide and further converts the SAM to SAH.
  • the SMYD3 methyltransferase activity is measured based on the amount of SAH produced from the reaction through the use of coupling enzymes that convert the SAH to ATP.
  • the MTase-Glo detection solution then catalyzes the formation of light from ATP.
  • the compounds were incubated with 0.4 ⁇ of SMYD3 enzyme for 30 min in low volume 384 well plates. A final concentration of 1.0 ⁇ and 10 ⁇ SAM and MAP3K2 peptide were added and further incubated for 30 min at room temperature before adding the MTase Glo and detection reagent. Reaction signals were detected using microplate readers on luminescent mode (Safire Tecan). The IC 50 was determined by non-linear regression, using GraphPad Prism version, 5.03.
  • PLC/PRF-5 is cultured in DMEM (4500 mg/L glucose), 10% FBS, 20 mM L-glutamate and 1% penicillin/streptomycin.
  • Huh-7 is cultured in DMEM (1000 mg/L glucose), 10% FBS, 20 mM L-glutamate and 1% penicillin/streptomycin.
  • MIAPaCa-2 is cultured in DMEM (4500 mg/L glucose), 10% FBS, 1% L-glutamate and 1% penicillin/streptomycin. All cell lines were from ATCC. All cells were grown in a temperature controlled incubator at 37 °C and 5% C0 2 .
  • Cell proliferation assay was performed using CellTiter-Glo Luminescent Cell Viability Assay (Promega) following manufacturer's instructions.
  • the cell-line of interest was treated with compounds that were serial diluted in its respective media. Plates were incubated for 3 days at 37 °C in 5% C0 2 . After 3 days, an equal volume of Cell Titer Glo reagent was added. Plates were rocked on a rotator for 2 h. 100 ⁇ ⁇ of each well were transferred to a 96-well opaque plate, and luminescence emitted was measured with the Tecan Safire II.
  • the target engagement assay was performed in PLC/PRF-5.
  • the cells were seeded to reach 80% confluency by end of treatment in a 60 mm 2 dish. After 24 hours, the cells were treated with either 1% DMSO or final concentration of the desired compound. It was incubated for 24 hours. The cells were trypsinized and the lysate was extracted with RIPA buffer (Santa Cruz). The total protein concentration of lysate was quantified using the standard Bradford assay (Biorad protein assay, microplate standard assay). Western blot analysis
  • the membrane was probed with anti-SMYD3 (Protein Tec #12011-1-AP, 1 :2000 dilution) for PLC/PRF-5 cell lines.
  • the antibodies were diluted in PBS, 0.1% Tween 20 and 5% dry milk overnight at 4 °C, followed by three washes (15 minutes each wash) in PBS, 0.1% Tween 20 on the next day.
  • SMYD3 Recombinant full length SMYD3 was incubated with 50 ⁇ and 100 ⁇ of compound for 1 hour at room temperature.
  • the SMYD3 control samples were incubated with DMSO. All samples were then analyzed for the change in molecular weight on ESI-TOF on Agilent 6224 LCMS.
  • SMYD3 inhibitors were analyzed against a panel of methyltransferases (Mtase).
  • the SMYD2 protein was expressed and purified as described in the protocol below (Ferguson et al., Structural basis of substrate methylation and inhibition of SMYD2, Structure, 2011, 19, pages 1262-73).
  • the p53 peptide substrate (GSRAHSSHLK-SKKGQSTSRH) and H3 peptides were synthesized at GenScript.
  • Human SMYD1 (residues 2-490; GenBank Accession No. NM_198274) with a GST tag expressed in E.coli was purchased from Reaction Biology Corp.
  • SMYD2 Human full-length SMYD2 was expressed from a pET21b vector in Terrific Broth (TB) with 100 ⁇ g/mL of Ampicillin at 37 °C using Escherichia coli BL21 (DE3) cells.
  • IPTG isopropyl- -D-thiogalactopyranoside
  • the cells were harvested by centrifugation at 6000 rpm for 30 minutes at 4 °C.
  • the cell pellet from a 1.5 litres culture was lysed in lysis buffer containing 20 mM Tris pH 8.0, 0.5M NaCl, 10 mM Imidazole, 5% glycerol, 2 mM ⁇ - Mercaptoethanol and cOmpleteTM, Mini, EDTA-free Protease Inhibitor Cocktail (Sigma- Aldrich).
  • the lysate was sonicated on ice and pelleted by centrifugation at 20000 rpm for 30 minutes at 4 °C.
  • the supernatant containing the protein of interest was applied onto a HisTrap HP 5 ml column (GE Healthcare).
  • the His-tagged protein was subjected to wash buffer containing 20 mM Tris pH 8.0, 250 mM NaCl, 10 mM Imidazole and 2 mM ⁇ -Mercaptoethanol and eluted with 250 mM Imidazole.
  • the protein was further purified by ion exchange chromatography using Mono Q 4.6/100 PE (GE Healthcare) with a gradient of 1M NaCl in buffer containing 20 mM Tris pH 8.0.
  • Apo crystals of SMYD3 protein were grown at room temperature by hanging drop vapor diffusion by mixing SMYD3 protein concentrated to 11 mg/mL in a 1 : 1 equivolume ratio to reservoir solution containing 0.2 M magnesium acetate and 17% PEG-3350. The apo crystals grew to their optimum size in 2-3 days. The apo crystals were then soaked overnight in reservoir solution containing 10 mM of D001. Crystals were cryoprotected using 25% glycerol and flash frozen in liquid nitrogen. A 2.4 A dataset was collected using a home source Rigaku MicroMaxTM 007 HF. The dataset was indexed, integrated and scaled using HKL2000 software.
  • SMYD3 (PDB ID: 1MEK) after the removal of water molecules was used as the search model for molecular replacement using the PHENIX suite of programs.
  • the chemical structure of D001 was drawn using JSME molecule editor and prodrg software was used to generate the PDB and CIF files needed for geometry restraints for refinement.
  • the SMYD3-D001 co-crystal structure was refined to a final R free value of 25.7% using Phenix.refine.
  • Table 2 Summary of anti-proliferative activity of SMYD3 inhibitors (D001, D015, D014 and D006) in different cancer cell lines (PLC/PRF/5, MIAPaCa-2 and Huh7).
  • Example 4 - SMYD3 compounds Inhibit the SMYD3 Mediated Methylation of MAP3K2 in cells
  • SMYD3 target engagement with D015 was demonstrated in PLC/PRF-5 HCC cells using Western blot anaylsis as shown in Fig. 3.
  • Treatment of the cells with compound D015 at 1, 5 and 12.5 ⁇ led to reduction in SMYD3 protein levels ranging from -15-51% when compared to DMSO control. Additionally, a 25-58% reduction in methylation of MAP3K2 was observed at these concentrations respectively.
  • Comparative Compound 1 showed no significant reduction in SMYD3 protein levels even when tested at 50 ⁇ . At 25 ⁇ , Comparative Compound 1 showed a -19% reduction in methylation of MAP3K2.
  • Example 7a General procedure for the synthesis of intermediate compounds wherein the ring system comprising Ring C is of Formula C2 , wherein X 3 , X 4 , X s and X 6 are as defined herein:
  • Example 7b General procedure for the synthesis of compounds of Formula (II), wherein W 1 W 2 , W 3 , W 4 , W 8 , X 2 , Z 1 Z 3 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , W 5 , W 9 , n, m q, and p are as defined herein.
  • Example 7c General procedure for the synthesis of compounds with Formula (I), wherein W 1 , W 2 , W 3 , W 4 , W 8 , X 2 , Z 1 , Z 3 , Q, X 3 , X 4 , W 7 , R 1 , R 2 , Z 2 , n and m are as defined herein.
  • Step 2 Gen eral Procedure F
  • Example 7ciii Synthesis of compounds with Formula (I) where Z 2 is sulfonyl -S0 2 - using compounds S 13 which are commercially available.
  • Table 4 shows a list representing the exemplified compoimds of this disclosure, together with the biological activity data.
  • the ability of the exemplified compounds to inhibit the catalytic function of SMYD3 was tested using the MTase assay by using the MAP3K2 as a peptide substrate. The compounds were found to inhibit the methyltransferase activity of SMYD3.
  • Compound DOOl was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperdine (S6 and S7 in General Procedure C) and commercially available 9-chloro-5, 6,7,8- tetrahydroacridine-3-carboxylic acid (S10) as starting materials.
  • Compound D002 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and commercially available 4-chloroquinoline- 7-carboxylic acid (S10) as starting materials.
  • Compound D003 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and compound S5 as starting materials.
  • Compound D004 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and N-boc-exo- 3-aminotropapne (S6 and S7 General Procedure C) and commercially available 9-chloro- 5,6,7,8-tetrahydroacridine-3-carboxylic acid (S10) as starting materials.
  • Compound D005 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and N-boc-exo- 3-aminotropane (S6 and S7 General Procedure C) and commercially available 4- chloroquinoline-7-carboxylic acid (S10) as starting materials.
  • Compound D006 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1-methylpyrrol- 3-yl as starting materials.
  • Compound D007 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and N-boc- endo- 3-aminotropane (S6 and S7 General Procedure C) and commercially available 9-chloro- 5,6,7,8-tetrahydroacridine-3-carboxylic acid (S10) as starting materials.
  • Compound D008 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and N-boc- endo -3-aminotropane (S6 and S7 General Procedure C) and commercially available 4- chloroquinoline-7-carboxylic acid (S10) as starting materials.
  • Compound D009 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and commercially available 9-chloro-5, 6,7,8- tetrahydroacridine-3-carboxylic acid (S10) as starting materials.
  • Compound DOlO was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and commercially available 4-chloroquinoline-7- carboxylic acid (S10) as starting materials.
  • Compound D012 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and N-boc- endo-3-aminotropane (S6 and S7 General Procedure C), and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D013 was prepared using 2-oxo-5-indolinecarboxylic acid and N-boc-exo-3- aminotropane (S6 and S7 General Procedure C), and compound S3 where X 6 is 1-methylpyrrol- 3-yl.
  • Compound D014 was prepared using 2-oxo-5-indolinecarboxylic acid and N-boc-endo-3- aminotropane (S6 and S7 General Procedure C), and compound S3 where X 6 is 1-methylpyrrol- 3-yl.
  • Compound D015 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is l-methylpyrrol-3-yl.
  • Compound D016 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 1,3- propanediamine (S6 and S7 General Procedure C) and commercially available 9-chloro-5, 6,7,8- tetrahydroacridine-3-carboxylic acid (S10) as starting materials.
  • Compound D017 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C), and compound S5 followed by boronic acid S12 where X 6 is 1 -methyl- lH-pyrazol-4-yl (General Procedure F).
  • Compound D018 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C), and compound S5 followed by boronic acid S12 where X 6 is 1 -methyl- lH-pyrazol-3-yl (General Procedure F).
  • Compound D019 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C), and compound S5 followed by boronic acid S12 where X 6 is cyclopropyl (General Procedure F).
  • Compound D020 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C), and compound S5 followed by boronic acid S12 where X 6 is 3 -pyrrole (General Procedure F).
  • Compound D021 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C), and compound S5 followed by boronic acid S12 where X 6 is l-(2-amino-2-oxoethyl)-lH-pyrazol-4-yl (General Procedure F).
  • Compound D022 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C), and 4-(chloromethyl)benzoyl chloride (S10 General Procedure E).
  • Compound D023 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 1,3- propanediamine (S6 and S7 General Procedure C) and and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D024 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1-fluorocyclopropyl.
  • Compound D025 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and compound S5 followed by boronic acid S12 where X 6 is methyl (General Procedure F).
  • Compound D026 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and N-boc-exo- 3-aminotropane (S6 and S7 General Procedure C) and compound S5.
  • Compound D027 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and 4-(chloromethyl)benzoyl chloride (S10 General Procedure E).
  • Compound D028 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and 3-(chloromethyl)benzoyl chloride (S10 General Procedure E).
  • Compound D030 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-(N-boc- amino)piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D031 was prepared using 2-oxo-5-indolinecarboxylic acid and tert-butyl (3S,4R)-4- amino-3-fluoropiperidine-l-carboxylate (S6 and S7 General Procedure C) and compound S3 where X 6 is l-methylpyrrol-3-yl.
  • Compound D032 was prepared using 2-oxo-5 -indolinecarboxylic acid and l-boc-4- methylaminopiperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D033 was prepared using intermediate S9 synthesized by 6-chloro-2-oxo-5- indolinecarboxylic acid and 4-amino-l-boc-piperidine (S6 and S7 General Procedure C).
  • the resulting intermediate S9 (147 mg, 0.50 mmol) was mixed with 4-(chloromethyl)benzaldehyde (136 mg, 1.0 mmol, 2 equiv) in methanol (3 mL) at 0 °C.
  • sodium borohydride 57 mg, 1.5 mmol, 3 equiv was added. Another 2 portions of sodium borohydride were added to complete the reaction before water was added to quench.
  • Compound D034 was prepared using 2,3-dioxoindoline-5-carboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is l-methylpyrrol-3-yl.
  • Step 1 Intermediate S9 using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C).
  • Step 2 Compound S2 where X 6 is l-methylpyrrol-3-yl (300 mg, 0.5 mmol) was dissolved in tetrahydrofuran (4 mL) at -78 °C. A solution of diisobutylaluminum hydride in tetrahydrofuran (1.2 equiv) was added dropwise and the mixture was stirred for 1 h. Rochelle's salt solution was added slowly followed by ethyl acetate and the slurry was stirred for 1 h at room temperature. The organic layer was separated, dried under anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford (4-chloro-2-(l-methyl-lH-pyrrol-3-yl)quinolin-7-yl)methanol (250 mg, 92%).
  • Step 3 To the above intermediate from Step 2 (136 mg, 0.5 mmol) in dichloromethane (3 mL) was added methane sulfonyl chloride (45 ⁇ , 0.58 mmol, 1.2 equiv) and triethylamine (0.1 mL, 0.717 mmol, 1.4 equiv) at 0 °C. The mixture was quenched after 30 min by addition of saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted twice more with dichloromethane.
  • methane sulfonyl chloride 45 ⁇ , 0.58 mmol, 1.2 equiv
  • triethylamine 0.1 mL, 0.717 mmol, 1.4 equiv
  • Step 4 The above intermediate S9 from Step 1 (147 mg, 0.5 mmol) was dissolved in N,N- dimethylformamide (2 mL) and triethylamine (0.21 mL, 1.5 mmol, 3 equiv) and the solution was added to the intermediate from Step 3 (1 equiv). After heating at 60 °C for 2 h, the reaction was quenched by addition of water. The aqueous layer was extracted 5 times with dichloromethane and the combined organic layer was washed with saturated sodium bicarbonate and brine. The layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford D035 as an off-white solid (200 mg, 73%).
  • Compound D036 was prepared using 2-oxo-5-indolinecarboxylic acid and (R)-3 -amino- 1-N- boc-pyrrolidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D038 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and l-boc-4- (aminomethyl)piperidine (S6 and S7 General Procedure C) and 4-(chloromethyl)benzoyl chloride (S10 General Procedure E).
  • Compound D039 was prepared using 2-oxo-5-indolinecarboxylic acid and boc-piperazine (S6 and S7 General Procedure C) and and 4-(chloromethyl)benzoyl chloride (S10 General Procedure E).
  • Compound D040 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and l-boc-4- (aminomethyl)piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D042 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and compound S5 followed by boronic acid S12 where X 6 is methyl (General Procedure F).
  • Compound D043 was prepared using 2-oxo-5-indolinecarboxylic acid and l-boc-3- (amino)azetidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D044 was prepared using l-methyl-2-oxoindoline-5-carboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1-methylpyrrol- 3-yl.
  • Compound D045 was prepared using 6-fluoro-2-oxo-5-indolinecarboxylic acid and 4-amino-l - boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is 1-methylpyrrol- 3-yl.
  • Compound D046 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and 4-(chloromethyl)benzenesulfonyl chloride (SI 3 General Procedure E).
  • Compound D047 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and 4-(chloromethyl)-3-nitrobenzoic acid
  • Compound D048 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and 4-(chloromethyl)-2-fluoro-benzoic acid (S10).
  • Compound D049 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and 4-(chloromethyl)-3-fluorobenzoic acid (S10).
  • Compound D050 was prepared using 2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carboxylic acid and 4-amino-l -boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is l-methylpyrrol-3-yl.
  • Compound D051 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is phenyl.
  • Step 1 To a solution of the indoline-5-carboxylic acid (100 mg, 0.613 mmol) in dichloromethane (5 mL) and triethylamine (0.2 mL, 1.433 mmol, 2.3 equiv) at 0 °C was added di-tert-butyl dicarbonate (268 mg, 1.228 mmol, 2 equiv). The mixture was stirred for 30 min at room temperature before addition of saturated ammonium chloride. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. The crude l-(tert-butoxycarbonyl)indoline-5-carboxylic acid was used without further purification.
  • Step 2.1 To a solution of S3 where X 6 is l-methylpyrrol-3-yl (60 mg, 0.2093 mmol) and 4- (Boc-amino)piperidine (46.1 mg, 0.230 mmol, 1.1 equiv) in N,N-dimethylformamide (0.5 mL) and triethylamine (0.060 mL, 0.43 mmol, 2 equiv) at 0 °C was added 1- [bis(dimethylamino)methylene] - 1H- 1 ,2,3 -triazolo [4,5 -b) pyridinium 3 -oxid hexafluorophosphate, HATU (119 mg, 0.313 mmol, 1.5 equiv).
  • Step 2.2 To a solution of intermediate 2.1 (87.3 mg, 0.186 mmol) in dichloromethane (0.15 mL) was added trifluoroacetic acid (0.15 mL). After 10 min, the volatiles were removed under reduced pressure and the crude (4-aminopiperidin-l-yl)(4-chloro-2-(l-methyl-lH-pyrrol-3- yl)quinolin-7-yl)methanone was used without further purification.
  • Step 3 To a solution of intermediate from Step 2.2 (68.5 mg, 0.186 mmol) and Step 1 (49 mg, 0.186 mmol, 1 equiv) in N,N-dimethylformamide (0.6 mL) and triethylamine (0.1 mL, 0.717 mmol, 3.9 equiv) at 0 °C was added HATU (106 mg, 0.279 mmol, 1.5 equiv). After 20 min, the reaction was quenched by adding water (5 mL) and the mixture was transferred to a separating funnel with dichloromethane.
  • Step 4 To a solution of intermediate from Step 3 (64.1 mg, 0.1044 mmol) in dichloromethane (0.090 mL) was added trifluoroacetic acid (0.090 mL). After 10 min, the volatiles were removed under reduced pressure and the crude material was redissolved in dichloromethane (1 mL). The organic layer was washed with saturated bicarbonate, dried over anhydrous sodium sulfate, filtered and dried under reduced pressure. Compound D052 was obtained as an off-white solid (43.6 mg, 82%).
  • Compound D053 was prepared using l-methyl-2-oxo-2,3-dihydro-lH-l,3-benzodiazole-5- carboxylic acid and 4-amino-l-boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X 6 is l-methylpyrrol-3-yl.
  • Compound D055 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C) and 6-(chloromethyl)nicotinic acid (S10).
  • Compound D057 was synthesized using 4-amino-l-boc-piperidine and 3 -cyclopropyl-5 - isoxazolecarboxylic acid (S7 and S6 General Procedure C) and commercially available 4- chloroquinoline-7-carboxylic acid (S10).
  • Compound D060 was synthesized using 4-amino-l-boc-piperidine and l-cyclopropyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X 6 is 1- methylpyrrol-3-yl.
  • Compound D061 was synthesized using 4-amino-l -boc-piperidine and l-cyclopropyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and commercially available 4- chloroquinoline-7-carboxylic acid (S10).
  • Compound D062 was prepared using 6-chloro-2-oxo-5-indolinecarboxylic acid and 4-amino-l- boc-piperidine (S6 and S7 General Procedure C), compound S5 followed by boronic acid pinacol ester S12 where X 6 is 4-(azidomethyl)phenyl (General Procedure F).

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Abstract

La présente invention concerne des composés hétérocycliques de formule générale (I) dans laquelle W1, W2, W3, W4, W7, W8, R1, R2, R3, R4, X2, X3, X4, Z1, Z2, Z3, Q, n et m sont tels que définis dans la description, ou un sel pharmaceutiquement acceptable de celui-ci, le composé étant utile pour le traitement du cancer associé à SMYD3.
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CN116194108A (zh) * 2020-08-13 2023-05-30 韩美药品株式会社 新型二氧代异喹啉酮衍生物及其用途
EP3999183A4 (fr) * 2019-07-17 2023-11-15 Ono Pharmaceutical Co., Ltd. Composé présentant une activité inhibitrice de kdm5 et utilisation pharmaceutique associée
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EP3999183A4 (fr) * 2019-07-17 2023-11-15 Ono Pharmaceutical Co., Ltd. Composé présentant une activité inhibitrice de kdm5 et utilisation pharmaceutique associée
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