Description

Title of Invention: Compounds For Treatment Of Cancer and

Epigenetics

Technical Field

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.

Background Art

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. The oncogenic activity is associated with the overexpression of SMYD3 protein in breast, lung, pancreatic, colorectal and hepatocellular tumors.

SMYD3 also methylates non-histone substrates like the cytoplasmic protein substrate, MAP3K2. A primary mechanistic understanding of SMYD3s role in cancer progression was demonstrated in Ras driven lung and pancreatic adenocarcinoma. In these tumors, SMYD3 methylates MAP3K2 at K260 and it leads to the dissociation of the substrate from the PP2A phosphatase complex. This further activates the MEK/ERK signaling pathway.

Recently, it has been shown that 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.

There is therefore a need to provide compounds that overcome, or at least ameliorates, one or more of the disadvantages of the effects of protein lysine methyltransferases, such as SMYD3, described above.

Summary

According to one aspect of the present disclosure, there is provided a compound having the following Formula (I):

wherein each bond represented by a dotted line is an optional bond;

represents an aromatic ring system;

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;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, and q are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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 are taken together to form a bicyclic or tricyclic ring system with Ring C; or a pharmaceutically acceptable salt or prodrug thereof.

In another aspect of the invention, there is also provided a compound having the following Formula (IC):

wherein 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 -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

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, optionally substituted aryl and optionally substituted heteroaryl;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, q, and r are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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; 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 are taken together to form a bicyclic or tricyclic ring system with Ring C; or a pharmaceutically acceptable salt or prodrug thereof.

In a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable form or prodrug thereof, and a pharmaceutically acceptable excipient.

In another aspect of the present disclosure, there is provided a compound disclosed herein, or a pharmaceutically form or prodrug thereof, or a composition disclosed herein for use in therapy.

In a further aspect of the present disclosure, there is provided 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.

In another aspect of the present disclosure, there is provided a process for synthesizing a compound disclosed herein, comprising the steps of:

(a) reacting an amine of the following Formula (II)

wherein j is 0 or 1 ; and

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;

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

hexafluorophosphate) (HATU), optionally in the presence of a base, and optionally at reduced temperatures, with a compound of Formula (III):

wherein X ³ , X ⁴ , W ⁷ , R ¹ ,R ² Z ² are defined herein, and L is OH

In a further aspect of the present disclosure, there is provided a process for synthesizing a compound disclosed herein, comprising the steps of:

(a) reacting an amine of the following Formula (II)

wherein j is 0 or 1 ; and

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;

in the presence of a reducing agent, preferably sodium borohydride or

diisobutylaluminum hydride, with a compound of Formula (III):

wherein -Z ² -L is -C(0)H or -C(0)(CH ₃ ); and

X ³ , X ⁴ , W ⁷ , R ¹ , and R ² are defined herein.

Advantageously, 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. Advantageously, 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.

Advantageously, compared to known compounds of the prior art, 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.

Further advantageously, 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. More advantageously, 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.

Further advantageously, 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.

Advantageously, 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.

Definitions

The following words and terms used herein shall have the meaning indicated:

In the definitions of a number of substituents below it is stated that "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. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.

"Acyl" means an R-C(=0)- group in which the R group may be an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl group as defined herein. 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.

"Acylamino" means an R-C(=0)-NH- group in which the R group may be an alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group 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.

"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. Preferably 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. The term 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. Examples of 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.

"Alkylaminocarbonyl" refers to a group of the formula (Alkyl) _x (H) _y NC(=0)- in which alkyl is as defined herein, x is 1 or 2, and the sum of X+Y =2. 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.

"Alkyloxycarbonyl" refers to an alkyl-0-C(=0)- group in which alkyl is as defined herein. 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.

"Alkylsulfinyl" means an alkyl-S-(=0)- group in which alkyl is as defined herein. 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. "Alkylsulfonyl" refers to an alkyl-S(=0) ₂ - group in which alkyl is as defined above. 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. Thus the term "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. Additionally, 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-).

The terms "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. "Aminosulfonyl" means an NH ₂ -S(=0) ₂ - 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. Examples of 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. Typically 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. Preferably 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. "Arylsulfonyl" means an aryl-S(=0) ₂ - group in which the aryl 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 sulfur atom.

"Azidoalkyl" refers to an alkyl group in which alkyl is as defined herein and which is substituted by an -N ₃ group. Preferably 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. Preferably 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. Preferably 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" or "halo" 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. Preferably the alkyl group is substituted by 1 to 5 halogen atoms. Preferably 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. Examples of heteroaryl 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, phenoxazine, 2-, 3- or 4- pyridinyl, 2-, 3-, 4-, 5-, or 8- quinolinyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3-thiophenyl. 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. Examples of 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. Preferably 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. Examples of suitable 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. Preferably 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. Preferably 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.

"Hydroxyalkyl" 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 In groups of this type, 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," as used herein, refers to an animal, preferably a mammal, and most preferably a human.

"Subject" refers to a human or an animal.

"Sulfinyl" means an R-S(=0)- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group 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 sulfur atom.

"Sulfinylamino" means an R-S(=0)-NH- group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group 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.

"Sulfonyl" means an R-S(=0) ₂ - group in which the R group may be OH, alkyl, cycloalkyl, heterocycloalkyl; aryl or heteroaryl group 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 sulfur atom.

"Sulfonylamino" means an R-S(=0) ₂ -NH- 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.

It is understood that included in the family of compounds of the Formulas of the present disclosure are 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.

Additionally, the Formulas of the present disclosure are intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non- hydrated forms.

Further, it is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, 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.

The term "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). For example 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-β- hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, and quinates. As another example an 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. (Examples of ester prodrugs are those described by F.J. Leinweber, Drug Metab. Res., 18:379, 1987). Similarly, 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 (Many examples of 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).

The term "therapeutically 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.

The term "reprogramming cells" is intended to include erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development.

The term "optionally substituted" as used herein 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, alkoxy, alkoxyalkyl, alkyloxyalkyloxyalkyl, cycloalkylalkyloxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, halogen, amino, aminocarbonyl, aminocarbonylalkyl, azidoalkyl, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, alkylaminocarbonyl, dialkylamino, dialkylaminoalkyl, alkenylamine, alkylcarbonylamino, aminoalkyl, alkynylamino, acyl, oxo, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxycarbonyl, alkyloxycycloalkyl, alkyloxyheteroaryl, alkyloxyheterocycloalkyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocyclic, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylheteroalkyl, heterocycloalkyloxy, heterocycloalkenyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, aminosulfonyl, phosphorus- containing groups such as phosphono and phosphinyl, sulfinyl, sulfinylamino, sulfonyl, sulfonylamino, alkylsulfamoyl, aryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroalkyl, heteroarylamino, heteroaryloxy, arylalkenyl, arylalkyl, alkylaryl, alkylheteroaryl, aryloxy, arylsulfonyl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), and - C(0)N(alkyl) ₂ . 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 ₁ C- ₄ -alkylene bridge.

Unless specified otherwise, the terms "comprising" and "comprise", and grammatical variants thereof, are intended to represent "open" or "inclusive" language such that they include recited elements but also permit inclusion of additional, unrecited elements.

As used herein, 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.

Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in 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.

Certain embodiments may also be described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the embodiments with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Brief Description of Drawings

The accompanying drawings illustrate a disclosed embodiment and serves to explain the principles of the disclosed embodiment. It is to be understood, however, that the drawings are designed for purposes of illustration only, and not as a definition of the limits of the invention.

Fig.1

[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

[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

[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

[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

[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.

Detailed Description of Embodiments

The present disclosure relates to a compound having the following Formula (I);

wherein each bond represented by a dotted line is an optional bond;

represents an aromatic ring system;

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;

wherein any two of 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively;

n, m, p, and q are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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;

(in) q is 0 when p is 0 only when R ³ together with R ⁴ are taken together to form a bicyclic or tricyclic ring system with Ring A;

or a pharmaceutically acceptable salt or prodrug thereof.

The present disclosure also provides a compound having the following Formula (IC);

wherein 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 , 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;

wherein any two of 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively;

n, m, p, q, and r are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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;

(iii) q is 0 when p is 0 only when R ³ together with R ⁴ are taken together to form a bicyclic or tricyclic ring system with Ring A;

or a pharmaceutically acceptable salt or prodrug thereof.

The present disclosure further provides a compound of the following Formula (I):

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;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, and q are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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):

wherein 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 -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

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, optionally substituted aryl and optionally substituted heteroaryl;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, q, and r are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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; 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 are taken together to form a bicyclic or tricyclic ring system with Ring C; or a pharmaceutically acceptable salt or prodrug thereof.

In the above-mentioned formulas, Z ¹ may be C(O), Z ² is C(O), Z ³ -N(Y ¹ )- or -N(Y ¹ )-Y ² -, Y ¹ may be hydrogen or optionally substituted alkyl, and Y ² may be optionally substituted alkyl.

In the above-mentioned formulas, 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.

In the above-mentioned formulas, 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.

In the above-mentioned formulas, the ring system comprising Ring A may be:

wherein W ² is O, or N;

W ³ is 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; and

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;

In the above-mentioned formulas, X ² may be hydrogen, methyl, ethyl, propyl, butyl, or cyclopropyl.

In the above-mentioned formulas, one of R ³ or R ⁴ may be -NHC(0)(CH ₃ ).

In the above-mentioned formulas, the ring system comprising Ring A:

may represent 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 pyrrolopyridinyl, optionally substituted naphthyridinyl, optionally substituted pyrimidinyl, optionally substituted benzothiazolyl, optionally substituted quinoline, optionally substituted phenyl, or optionally substituted oxadiazolyl.

In the above-mentioned formulas, 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.

In the above-mentioned formulas, 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. In the above-mentioned formulas, 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.

In the above-mentioned formulas, the ring system comprising Ring C:

wherein 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; and

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.

In the above-mentioned formulas, the ring system comprising Ring C:

wherein 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; and

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.

In the above-mentioned formulas, X ³ may be selected from the group consisting of hydrogen and -CH ₂ Cl.

In the above-mentioned formulas, X ⁴ may be selected from the group consisting of hydrogen and fluoro. In the above-mentioned formulas, X ⁵ may be chloro.

In the above-mentioned formulas, 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 ); pyridinyl; pyrrolyl; and pyrrolyl substituted with methyl.

In the above-mentioned formulas, the ring system comprising Ring C:

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.

In the above-mentioned formulas, 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.

In the above-mentioned formulas, 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.

In the above-mentioned formulas, 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-methoxyphenyl, 4-( 1 -Amino-2-methylpropan-2-yl)phenyl, 4-( 1 -(dimethylamino)ethyl)phenyl, 4-( 1 -(pyrrolidin- 1 -yl)ethyl)phenyl, 3 -(Aminomethyl)-4-fluorophenyl, 3 -

((dimethylamino)methyl)-4-fluorophenyl, 3 -((dimethylamino)methyl)-4-methoxyphenyl, 3 - (Aminomethyl)-4-methoxyphenyl, or pyridin-3-yl.

In the above-mentioned formulas, 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.

In the above-mentioned formulas, X ¹ may be hydrogen, fluorine or chlorine.

In Formula (I), Q may be a moiety selected from formulas (Al) or (B):

wherein

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.

In Formula (I), Q:

(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):

wherein 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. In Formula (I), Q:

(a) may be formula (A7): wherein W ⁵ is CH ₂ ; W ⁶ is CH ₂ or

NH; q is 0 or 1; 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

(c) may be formula (A9):

The present disclosure also provides a compound of the following Formula (ID):

wherein each bond represented by a dotted line optional bond;

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;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, and q are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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 are 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 (IE):

wherein 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 -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

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, optionally substituted aryl and optionally substituted heteroaryl;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, q, and r are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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; 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 are taken together to form a bicyclic or tricyclic ring system with Ring C; or a pharmaceutically acceptable salt or prodrug thereof.

The present disclosure provides a compound of the following Formula (IF):

wherein each bond represented by a dotted line is an optional bond;

represents an aromatic ring system;

formula (A7):

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;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, and q are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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 are 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 (IG):

wherein 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

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, optionally substituted aryl and optionally substituted heteroaryl;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, q, and r are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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; 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 are 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 (IH):

wherein 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,

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

CH ;

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;

wherein 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;

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 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, cycloalkenyl, heterocyclyl, aryl or heteroaryl, thereby forming a tricyclic ring system with Ring A or Ring C, respectively; and

n, m, p, and q are integers independently selected from 0 and 1 ;

provided that, independently:

(i) 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;

(ii) 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; 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 are 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 provides 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. In using the compounds, 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.

The term "pharmaceutically acceptable excipient" may refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the 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 glycol or wool fat.

Compositions as defined above may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, 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.

Pharmaceutically acceptable 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. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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.

Pharmaceutical 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. Examples of 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.

These 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.

If desired, and for more effective distribution, 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.

Alternatively, pharmaceutically acceptable compositions as defined above may be administered in the form of suppositories for rectal administration. These 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. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable 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.

For topical applications, 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. Alternatively, 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.

For ophthalmic use, 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. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

Pharmaceutically acceptable 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.

Most preferably, pharmaceutically acceptable 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.

The amount of compound that may be combined with the carrier materials to produce a composition in a single dosage form may vary depending upon the host treated, the particular mode of administration. Preferably, 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.

It should also be understood that 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. In the in vitro assay, 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. 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:

(a) reacting an amine of the following Formula (II)

wherein j is 0 or 1 ; and

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

hexafluorophosphate) (HATU), optionally in the presence of a base, and optionally at reduced temperatures, with a compound of Formula (III):

wherein X ³ , X ⁴ , W ⁷ , R ¹ , R ² Z ² are defined as in statement 1, and L is OH or CI.

The Formula (II) may be of Formula (Ila):

In 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):

(lib)

In Formula (lib):

m may be 0;

Z ¹ may be -C(O);

W ⁹ may be NH;

W ⁶ may be N; and

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:

(a) reacting an amine of the following Formula (II)

wherein j is 0 or 1 ; and

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

diisobutylaluminum hydride, with a compound of Formula (III):

wherein -Z ² -L is -C(0)H or -C(0)(CH ₃ ); and

X ³ , X ⁴ , W ⁷ , R ¹ , and R ² are defined above.

Examples

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.

Example 1

Materials and Methods of the Biological Assays

SMYD3 Biochemical Assay

A SMYD3 enzymatic assay was developed using Promega' s Methyltransferase-Glo™ reagents. In the assay, 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.

For the IC ₅₀ determination, the compounds were incubated with 0.4 μΜ of SMYD3 enzyme for 30 min in low volume 384 well plates. A final concentration of 1.0 μΜ and 10 μΜ 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.

Cells and Reagents

The cell proliferation assays were tested in PLC/PRF-5, Huh-7 and MIAPaCa-2 cell lines. 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

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 μί _^ of each well were transferred to a 96-well opaque plate, and luminescence emitted was measured with the Tecan Safire II.

Target Engagement Assay

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

Western blot analysis was performed using antibody against SMYD3 in cell line treated with different compounds. 15.0 μg of cell lysate was diluted in 2 ^χ Laemmli sample buffer (Bio-Rad) and boiled at 100 °C on heat block for 5 minutes. Lysates were separated using NuPAGE ^® 4-12% Bis-Tris precast polyacrylamide gels (Lifetech) at 200 V, 400 A for 40 minutes. The electrophoresed protein was transferred onto the nitrocellulose membrane for 7 minutes using the iBlot 2 Dry Blotting System (Lifetech). After 1 hour incubation in blocking buffer [PBS (phosphate buffered saline) with 0.1% Tween 20 and 5% dry milk], 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. This was further continued with 1 hour incubation with peroxidase-conjugated secondary antibody (anti-mouse-HRP, NA9310V (GE)), 1 :5000 dilutions in PBS, 0.1% Tween 20 and 5% dry milk followed by three washes (15 minutes each wash) in PBS, 0.1% Tween 20. The nitrocellulose membrane was developed with Enhanced Chemiluminescence (ECL) mixture (Amersham, Aylesbury, UK), incubated for 5 minutes and exposed using FluorChem E System instrument (Protein Simple).

Western blot analysis for detecting methylated MAP3K2 was carried out using a customized Anti-me2/me3-Lys 260 MAP3K2 at 1 :500 and the total MAP3K2 was detected using Anti-MEKK2 (AB33918) using a 1 : 10,000 dilution.

Mass Spectrometry analysis of covalent binding of compounds to SMYD3

Recombinant full length SMYD3 was incubated with 50 μΜ and 100 μΜ 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 Selectivity Screen Assay

The selectivity of SMYD3 inhibitors were analyzed against a panel of methyltransferases (Mtase).

SMYDl and SMYD2 methyltransferase inhibition assay

For the IC ₅₀ determination, compounds with 3 -fold dilution ranging from (0 μΜ - 750 μΜ) were incubated with 0.1 μΜ SMYDl enzyme (HMT-11-304) or 0.5 μΜ SMYD2 for 30 minutes in assay buffer. A final concentration of 2.0 μΜ of SAM and 0.4 μΜ of Histone H3 recombinant protein (NEB M2507S) were added to SMYDl reaction (Sirinupong et al., Crystal Structure of Cardiac-specific Histone Methyltransferase SmyDl Reveals Unusual Active Site Architecture, J. Biol. Chem. , 2010, 285(52), pages 40635-44) and further incubated for 90 minutes at room temperature with shaking at 28rpm. For the SMYD2 reaction, 1.0 μΜ of SAM and 20.0 μΜ p53 peptide were added to the enzyme inhibitor mix and incubated for 30 minutes. The reaction was terminated by the addition of 1 of 0.4% trifluoroacetic acid (TFA).

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 expression and purification

Human full-length SMYD2 was expressed from a pET21b vector in Terrific Broth (TB) with 100 μg/mL of Ampicillin at 37 °C using Escherichia coli BL21 (DE3) cells. The bacterial cells were induced with 0.1 mM isopropyl- -D-thiogalactopyranoside (IPTG) at OD=3.0 and allowed to grow an additional 16-18 hours at 18 °C. 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 β- Mercaptoethanol and cOmplete™, 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 β-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.

Crystallization and data collection

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 MicroMax™ 007 HF. The dataset was indexed, integrated and scaled using HKL2000 software. The structure of 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.

Example 2 - SMYD3 Biochemical Assay

The ability of compounds to inhibit the catalytic function of SMYD3 was tested using the MTase assay by using the MAP3K2 as a peptide substrate. The effect of the compounds on the methyltransferase activity of SMYD3 using the MAP3K2 as a peptide substrate can be found in Fig. 1 (Comparative compound 1; D001; D006; D015; D014). The data has been summarized in Table 1 :

Table 1. Summary of biochemical IC ₅₀ of SMYD3 inhibitors.

Example 3 - Antiproliferative Activity of SMYD3 Compound In Different Cancer Cells

The anti-proliferative effects of SMYD3 inhibition were explored in different cancer cell lines. All compounds except comparative compound 1 showed anti-proliferative activity, summarized in Table 2.

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).

*ND: not determined

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 μΜ 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. In comparison, Comparative Compound 1 showed no significant reduction in SMYD3 protein levels even when tested at 50 μΜ. At 25 μΜ, Comparative Compound 1 showed a -19% reduction in methylation of MAP3K2.

Example 5 - Compounds Form a Covalent Bond With Recombinant SMYD3

An increase in the molecular weight of SMYD3 was observed when incubated with the covalent inhibitors DOOl and D015. This increase in molecular weight of 49828 Da and 49819 Da for DOOl and D015 corresponded to the addition of one molecule of compound to SMYD3. The 1% DMSO with SMYD3 served as a control in this analysis. As expected, Comparative Compound 1 was unable to form a covalent bond when incubated with SMYD3 (see Fig. 4).

Example 6 - SMYD3 Compounds Display Excellent Selectivity Against Other Methyltransferases

Selectivity screen assay against, SMYD2, SMYD 1 and PRDM9 were carried out (Table 3). The compounds were unable to inhibit the methyltransferase activity of the closely related SMYD1 and SMYD2. Table 3 - Summary of compoundsscreened against, SMYD2, SMYD1, PRDM9 using Promega'sMethyltransferaseGloTM reagents.

Example 7 - Synthesis

GeneralReactionSchemes

General Procedures. All reactions were performed using oven-dried round-bottomed flasks or reaction vessels. Where appropriate, reactions were carried out under an inert atmosphere of nitrogen with dry solvents, unless otherwise stated. Dry dichloromethane (DCM), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), toluene (PhMe), benzene (PhH), acetonitrile (MeCN) and methanol (MeOH) were purchased at the highest commercial quality. Yields refer to chromatographically and spectroscopically ( ¹ NMR) homogeneous materials, unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using ultraviolet light as visualizing agent and potassium permanganate and heat as developing agents. NMR spectra were recorded on a Bruker/Agilent 400 spectrometer and were calibrated using residual undeuterated solvent as an internal reference (CDC1 ₃ : ¹ H NMR = 7.26; DMSO-d ₆ ; ¹ H NMR = 2.50; CD ₃ OD ¹ :H NMR = 3.31). The following abbreviations or combinations thereof were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, sex = sextet, m = multiplet, br = broad. Liquid chromatography mass spectra (LCMS) were recorded on an Agilent or Shimadzu mass spectrometer using ESI-TOF (electrospray ionization-time of flight).

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 7ai. Synthesis of 2-substituted-4-chloroquinoline-7-carboxylic acid.

Step 1: General Procedure A

To a mixture of 2-amino-4-(methoxycarbonyl)benzoic acid (1 equiv) and ketone Sl/malonic acid (1.1-2.0 equiv) was added phosphorus oxychloride (6-10 equiv) dropwise. The resulting suspension was heated to reflux (110-120 °C) for 4-18 h. Upon cooling, the mixture was diluted with dichloromethane and neutralized to pH 7 using 6M aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted 4 more times with dichloromethane. The combined extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography to afford ester S2 or S4 as an off white solid (7-50%).

Step 2: General Procedure B

To a solution of S2 or S4 (1 equiv) in methanol (2 mL/mmol) and 1,4-dioxane (1 mL/mmol) was added an aqueous solution of lithium hydroxide (10 equiv) in water (2 mL/mmol). The mixture was heated to 50 °C for 1 h until all contents were soluble. The solution was cooled to room temperature before the mixture was acidified to pH 4 with 12 M aqueous hydrochloric acid. The organic solvent was removed under reduced pressure and the solid precipitated was collected via filtration. The residue was rinsed with copious amount of water and then dried under the vacuum oven at 50 °C for 2 h. Acid S3 or S5 was used without further purification.

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.

Step 1: General Procedure C

Compound wherein the ring system comprising Ring A where Z ¹ is carbonyl (S6, 1 equiv), amine comprising Ring B (S7/S7a, 1-2 equiv) and triethylamine (2-4 equiv) were dissolved in N,N-dimethylformamide (0.1 M) and the solution was cooled to 0 °C. HATU (1.5 equiv) was added and the reaction was quenched upon completion based on LCMS analysis (<1 h) by the addition of water. The aqueous layer was extracted 3-5 times with dichloromethane, and the combined organic layers were washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to afford compound S8/S8a. Step 2: General Procedure D

Compound S8/S8a was dissolved in 1 : 1 mixture of trifluoroacetic acid (10 equiv) and dichloromethane. After 10 min, the mixture was concentrated under reduced pressure to give compound S9/S9a which was used without further purification.

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.

Example 7ci Synthesis of compounds with Formula (I) where Z ² is carbonyl C=0 using compounds with Ring C which are commercially available.

Step 1.1: See General Procedure C if L = OH otherwise General Procedure E if L = CI (below)

Compound S9/S9a was dissolved N,N-dimethylformamide or tetrahydrofuran (0.1-0.5 M) and triethylamine (2-5 equiv) was added at 0 °C or room temperature. Compound S10 (1-2 equiv) was added and the mixture was allowed to stir at room temperature until the reaction was complete. Saturated sodium bicarbonate was added and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified to give compound with formula (I). Example 7cii - Synthesis of compounds of Formula (I) wherein the ring system comprising Ring C is Formula C2.

Step 1.2: see General Procedure C

Step 2 : Gen eral Procedure F

Intermediate Sll (1 equiv), boronic acid/derivative (1.1-1.3 equiv) and potassium phosphate tribasic (3-5 equiv) were added to a reaction vessel. A mixture of 1,4-dioxane/water (4: 1) was added (0.07 M) and the resulting mixture was degassed with nitrogen. [Ι, - Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.1 equiv) was added and the resulting mixture was heated to 100-120 °C (30 min to 12 h). Upon cooling, the mixture was filtered through a pad of Celite® with ethyl acetate, and the mixture was concentrated. The product was purified either with column chromatography or preparative HPLC to afford compounds with Formula (I).

Example 7ciii: Synthesis of compounds with Formula (I) where Z ² is sulfonyl -S0 ₂ - using compounds S 13 which are commercially available.

Step 1.3: See General Procedure E

General Procedure E but using S13 instead of S10.

Example 8 - Biological Activity

The following 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 List

Table 4. Table listing the structure and IC ₅₀ of the compounds disclosed

Compound Structure IC50 (μΜ)

Example 9 - Characterization Data

6-Chloro-N-(1-(9-chloro-5,6,7,8-tetrahydroacridine-3-carb onyl)piperidin-4-yl)-2- oxoindoline-5-carboxamide (D001)

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.

1H NMR (400 MHz. DMSO) δ 10.59 (s, 1 H). 8.31 (d, J = 7.7 Hz, 1 H), 8.20 (d. J = 8.6 Hz. 1 H), 7.88 (d, J = 1.0 Hz, 1 H), 7.62 (dd, J= 8.6, 1.4 Hz, 1 H), 7.26 (s, 1 H), 6.84 (s, 1 H), 4.39 (br s, 1 H), 4.03 (d, J = 7.3 Hz, 1 H), 3.57 (br s, 1 H), 3.50 (s, 2 H), 3.25-3.09 (m, 2 H), 3.06 (s, 2 H), 2.99 (s, 2 H), 1.90 (s, 4 H), 1.83 (br s, 2 H), 1.50 (br s, 2 H).

LCMS (ESI-TOF) m/z 537.1 [M + H ⁺ ] with a purity of >95%.

6-Chloro-iV-(l-(4-chloroquinoline-7-carbonyl)piperidin-4- yl)-2-oxoindoline-5-carboxamide (D002)

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.

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.92 (d, J = 4.7 Hz, 1 H), 8.35-8.25 (m, 2 H), 8.05 (d, J= 1.1 Hz, 1 H), 7.85 (d, J= 4.7 Hz, 1 H), 7.75 (dd, J= 8.6, 1.5 Hz, 1 H), 7.26 (s, 1 H), 6.83 (s, 1 H), 4.39 (br s, 1 H), 4.09-3.97 (m, 1 H), 3.57 (br s, 1 H), 3.50 (s, 2 H), 3.19 (br d, J = 47.5 Hz, 2 H), 1.88 (br d, J= 54.1 Hz, 2 H), 1.51 (br d, J= 34.6 Hz, 2 H).

LCMS (ESI-TOF) m/z 483.1 [M + H ⁺ ] with a purity of >99%.

6-Chloro-7V-(l-(2,4-dichloroquinoline-7-carbonyl)piperidi n-4-yl)-2-oxoindoline-5- carboxamide (D003)

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.

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.39-8.20 (m, 2 H), 8.05 (s, 1 H), 7.98 (s, 1 H),

7.78 (dd, J= 8.6, 1.2 Hz, 1 H), 7.26 (s, 1 H), 6.84 (s, 1 H), 4.38 (br d, J = 6.9 Hz, 1 H), 4.03 (d,

J = 7.2 Hz, 1 H), 3.53 (s, 1 H), 3.50 (s, 2 H), 3.18 (br d, J = 42.7 Hz, 2 H), 1.87 (br d, J = 61.7

Hz, 2 H), 1.50 (br d, J = 33.1 Hz, 2 H).

LCMS (ESI-TOF) m/z 519.0 [M + H ⁺ ] with a purity of >98%.

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.

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.20 (d, J= 8.6 Hz, 2 H), 7.98 (s, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.24 (s, 1 H), 6.83 (s, 1 H), 4.68 (s, 1 H), 4.38 (br s, 1 H), 4.01 (s, 1 H), 3.50 (s, 2 H), 3.05 (s, 2 H), 2.99 (s, 2 H), 2.04 (s, 2 H), 1.96-1.72 (m, 9 H), 1.61 (s, 1 H).

LCMS (ESI-TOF) m/z 563.1 [M + H ⁺ ] with a purity of >95%.

6-Chloro-7V-((1R,3s,5 S)-8-(4-chloroquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octan -3-yl)-2- oxoindoline-5-carboxamide (D005)

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.

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.92 (d, J = 4.7 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.19 (d, J= 8.1 Hz, 1 H), 8.14 (s, 1 H), 7.86 (d, J= 4.7 Hz, 1 H), 7.81 (dd, J= 8.6, 1.4 Hz, 1 H), 7.24 (s, 1 H), 6.83 (s, 1 H), 4.70 (s, 1 H), 4.38 (br s, 1 H), 4.03 (s, 1 H), 3.50 (s, 2 H), 2.16- 1.70 (m, 7 H), 1.61 (t, J= 11.5 Hz, 1 H).

LCMS (ESI-TOF) m/z 509.0 [M + H ⁺ ] with a purity of >99%.

6-Chloro-7V-(l-(4-chloro-2-(l-methyl-lH-pyrrol-3-yl)quino line-7-carbonyl)piperidin-4-yl)- 2-oxoindoline-5-carboxamide (D006)

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.

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.32 (d, J = 7.6 Hz, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.06 (s, 1 H), 7.84 (s, 1 H), 7.70 (s, 1 H), 7.54 (dd, J= 8.5, 1.3 Hz, 1 H), 7.27 (s, 1 H), 6.87- 6.77 (m, 3 H), 4.40 (br s, 1 H), 4.05 (br s, 1 H), 3.71 (s, 3 H), 3.63 (s, 1 H), 3.50 (s, 2 H), 3.27- 3.01 (m, 2 H), 2.06-1.67 (m, 2 H), 1.63-1.37 (m, 2 H).

LCMS (ESI-TOF) m/z 562.1 [M + H ⁺ ] with a purity of >95%.

6-Chloro- -8-(9-chloro-5,6,7,8-tetrahydroacridine-3-carbonyl)-8-

azabicyclo [3.2.1] octan-3-yl)-2-oxoindoline-5-carboxamide (D007)

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.

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.28 (d, J = 4.6 Hz, 1 H), 8.20 (d, J = 8.6 Hz, 1 H), 7.97 (s, 1 H), 7.70 (d, J= 8.6 Hz, 1 H), 7.24 (s, 1 H), 6.83 (s, 1 H), 4.65 (s, 1 H), 4.03 (d, J = 25.1 Hz, 1 H), 3.97 (s, 1 H), 3.51 (s, 2 H), 3.07 (s, 2 H), 2.99 (s, 2 H), 2.35-2.05 (m, 4 H), 2.04- 1.73 (m, 8 H).

LCMS (ESI-TOF) m/z 563.1 [M + H ⁺ ] with a purity of >95%.

6-Chloro -8-(4-chloroquinoline-7-carbonyl)-8-azabicyclo[3.2.1]octan-3 -yl)-2- oxoindoline-5-carboxamide (D008)

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.

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.93 (d, J = 4.7 Hz, 1 H), 8.30 (d, J = 6.4 Hz, 1 H), 8.28 (s, 1 H), 8.15 (s, 1 H), 7.86 (d, J= 4.8 Hz, 1 H), 7.84 (dd, J= 8.7, 1.5 Hz, 1 H), 7.24 (s, 1 H), 6.83 (s, 1 H), 4.67 (s, 1 H), 4.08 (s, 1 H), 3.98 (s, 1 H), 3.51 (s, 2 H), 2.35-2.06 (m, 4 H),

1.98 (s, 3 H), 1.83 (d, J= 13.8 Hz, 1 H).

LCMS (ESI-TOF) m/z 509.0 [M + H ⁺ ] with a purity of >96%.

7V-(l-(9-Chloro-5,6,7,8-tetrahydroacridine-3-carbonyl)pip eridin-4-yl)-2-oxoindoline-5- carboxamide (D009)

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.

1H NMR (400 MHz, DMSO) δ 10.61 (s, 1 H), 8.21 (d, J = 8.6 Hz, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 7.89 (s, 1 H), 7.76-7.71 (m, 2 H), 7.63 (d, J = 8.6 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 4.49 (br s, 1 H), 4.09 (br d, J= 6.8 Hz, 1 H), 3.59 (br s, 1 H), 3.53 (s, 2 H), 3.22 (br s, 1 H), 3.06 (s, 2 H), 2.99 (s, 2 H), 1.83 (d, J= 53.2 Hz, 7 H), 1.55 (br s, 2 H).

LCMS (ESI-TOF) m/z 503.1 [M + H ⁺ ] with a purity of >98%. iV-(l-(4-Chloroquinoline-7-carbonyl)piperidin-4-yl)-2-oxoind oline-5-carboxamide (DOlO)

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.

1H NMR (400 MHz, DMSO) δ 10.61 (s, 1 H), 8.92 (d, J = 4.7 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.15 (d, J = 7.7 Hz, 1 H), 8.06 (s, 1 H), 7.86 (d, J = 4.7 Hz, 1 H), 7.78-7.68 (m, 3 H), 6.85 (d, J= 8.6 Hz, 1 H), 4.50 (br s, 1 H), 4.09 (br d, J= 6.9 Hz, 1 H), 3.59 (br s, 1 H), 3.53 (s, 2 H), 3.24 (br s, 1 H), 3.03 (br s, 1 H), 1.85 (br d, J= 68.1 Hz, 2 H), 1.55 (br d, J= 26.6 Hz, 2 H). LCMS (ESI-TOF) m/z 449.1 [M + H ⁺ ] with a purity of >99%. 6-Chloro -8-(4-chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbonyl )-8-

azabicyclo [3.2.1] octan-3-yl -2-oxoindoline-5-carboxamide (D011)

Compound DOll was prepared using 6-chloro-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.

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.21 (d, J = 8.2 Hz, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.07 (s, 1 H), 7.94 (d, J= 1.2 Hz, 1 H), 7.69 (t, J= 1.8 Hz, 1 H), 7.60 (dd, J= 8.5, 1.6 Hz, 1 H), 7.25 (s, 1 H), 6.87-6.77 (m, 3 H), 4.69 (br s, 1 H), 4.39 (br s, 1 H), 4.07 (br s, 1 H), 3.70 (s, 3 H), 3.50 (s, 2 H), 2.16-1.70 (m, 7 H), 1.61 (t, J= 9.4 Hz, 1 H).

LCMS (ESI-TOF) m/z 588.1 [M + H ⁺ ] with a purity of >95%.

6-Chloro -8-(4-chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbonyl )-8-

azabicyclo [3.2.1] octan-3-yl -2-oxoindoline-5-carboxamide (D012)

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.

1H NMR (400 MHz, DMSO) δ 10.61 (s, 1 H), 8.31 (d, J = 4.7 Hz, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.09 (s, 1 H), 7.95 (d, J= 1.4 Hz, 1 H), 7.73 (t, J= 1.9 Hz, 1 H), 7.64 (dd, J= 8.5, 1.6 Hz, 1 H), 7.25 (s, 1 H), 6.90-6.78 (m, 3 H), 4.67 (s, 1 H), 4.08 (d, J= 5.1 Hz, 1 H), 4.02 (s, 1 H), 3.72 (s, 3 H), 3.52 (s, 2 H), 2.33-2.06 (m, 4 H), 1.98 (t, J= 19.4 Hz, 3 H), 1.85 (d, J= 13.8 Hz, 1 H). LCMS (ESI-TOF) m/z 588.1 [M + H ⁺ ] with a purity of >97%. )-8-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbony l)-8-

azabicyclo [3.2.1] octan-3-yl -2-oxoindoline-5-carboxamide (D013)

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.

1H NMR (400 MHz, DMSO) δ 10.63 (s, 1 H), 8.18 (d, J = 8.5 Hz, 1 H), 8.14 (d, J = 8.3 Hz, 1 H), 8.09 (s, 1 H), 7.99 (d, J = 1.3 Hz, 1 H), 7.76-7.70 (m, 3 H), 7.64 (dd, J = 8.5, 1.6 Hz, 1 H), 6.88-6.80 (m, 3 H), 4.71 (s, 1 H), 4.52-4.41 (m, 1 H), 4.08 (s, 1 H), 3.72 (s, 3 H), 3.55 (s, 2 H), 2.07 (s, 2 H), 1.96-1.65 (m, 6 H).

LCMS (ESI-TOF) m/z 554.1 [M + H ⁺ ] with a purity of >95%. -8-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbonyl )-8-

azabicyclo [3.2.1] octan-3-yl)-2-oxoindoline-5-carboxamide (D014)

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.

NMR (400 MHz, DMSO) δ 10.62 (s, 1 H), 8.16 (d, J= 8.5 Hz, 1 H), 8.09 (s, 1 H), 8.03 (d, J = 4.1 Hz, 1 H), 7.95 (d, J= 1.4 Hz, 1 H), 7.73 (t, J= 1.9 Hz, 1 H), 7.71-7.66 (m, 2 H), 7.65 (dd, J = 8.5, 1.6 Hz, 1 H), 6.89-6.81 (m, 3 H), 4.68 (s, 1 H), 4.09 (s, 1 H), 4.03 (s, 1 H), 3.72 (s, 3 H), 3.55 (s, 2 H), 2.35-1.98 (m, 7 H), 1.93 (d, J= 14.1 Hz, 1 H).

LCMS (ESI-TOF) m/z 554.1 [M + H ⁺ ] with a purity of >95%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-ca rbonyl)piperidin-4-yl)-2- oxoindoline-5-carboxamid

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. ¾ NMR (400 MHz, DMSO) δ 10.62 (s, 1 H), 8.19-8.14 (m, 2 H), 8.07 (s, 1 H), 7.85 (d, J= 1.3 Hz, 1 H), 7.74 (d, J = 6.1 Hz, 2 H), 7.71 (t, J = 1.9 Hz, 1 H), 7.55 (dd, J = 8.5, 1.6 Hz, 1 H), 6.87-6.78 (m, 3 H), 4.51 (br s, 1 H), 4.09 (dd, J= 7.3, 3.7 Hz, 1 H), 3.71 (s, 3 H), 3.64 (s, 1 H), 3.53 (s, 2 H), 3.23 (br s, 1 H), 3.01 (br s, 1 H), 1.86 (br d, J= 93.0 Hz, 2 H), 1.55 (br d, J= 48.0 Hz, 2 H).

LCMS (ESI-TOF) m/z 528.1 [M + H ⁺ ] with a purity of >96%.

9-Chloro-N- (3-(6-chloro-2-oxoindoline-5-carboxamido)propyl)-5,6,7,8-tet rahydroacridine- 3-carboxamide (D016)

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.

1H NMR (400 MHz, CDC1 ₃ ) δ 8.49 (s, 1 H), 8.26 (d, J = 8.8 Hz, 1 H), 8.08 (dd, J = 8.7, 1.6 Hz, 1 H), 7.85 (s, 1 H), 7.59 (s, 1 H), 7.47 (s, 1 H), 6.90 (s, 2 H), 3.66 (dt, J = 22.0, 6.4 Hz, 4 H), 3.50 (s, 2 H), 3.20 (s, 2 H), 3.07 (s, 2 H), 2.09-1.88 (m, 6 H).

LCMS (ESI-TOF) m/z 513.1 [M + H ⁺ ] with a purity of >93%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrazol-4-yl)quinoline-7-c arbonyl)piperidin-4-yl)-2- oxoindoline-5-carboxamide (D017)

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).

i NMR ^OO MHz, DMSO) δ 10.59 (s, 1 H), 8.53 (s, 1 H), 8.25-8.17 (m, 3 H), 8.14 (d, J= 7.7 Hz, 1 H), 7.91 (d, J = 1.1 Hz, 1 H), 7.77-7.70 (m, 2 H), 7.62 (dd, J = 8.5, 1.6 Hz, 1 H), 6.90- 6.81 (m, 1 H), 4.50 (br s, 1 H), 4.10 (d, J = 6.7 Hz, 1 H), 3.93 (s, 3 H), 3.63 (br s, 1 H), 3.53 (s, 2 H), 3.21 (s, 1 H), 3.04 (br s, 1 H), 1.87 (d, J= 50.2 Hz, 2 H), 1.59 (s, 2 H).

LCMS (ESI-TOF) m/z 529.1 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-(l-methyl-lH-pyrazol-3-yl)quinoline-7-carbo nyl)piperidin-4-yl)-2- oxoindoline-5-carboxam ide (D018)

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).

1H NMR (400 MHz, DMSO) δ 10.58 (s, 1 H), 8.30-8.24 (m, 2 H), 8.14 (d, J = 7.7 Hz, 1 H), 8.01 (d, J = 0.9 Hz, 1 H), 7.88 (d, J = 2.2 Hz, 1 H), 7.77-7.71 (m, 2 H), 7.69 (dd, J = 8.5, 1.4 Hz, 1 H), 7.01 (d, J = 2.2 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 4.52 (br s, 1 H), 4.10 (d, J = 7.2 Hz, 1 H), 3.98 (s, 3 H), 3.64 (br s, 1 H), 3.53 (s, 2 H), 3.24 (s, 1 H), 3.04 (br s, 1 H), 1.87 (br d, J = 57.5 Hz, 2 H), 1.58 (br s, 2 H).

LCMS (ESI-TOF) m/z 529.1 [M + H ⁺ ] with a purity of >99%. N-( l-(4-Chloro-2-cyclopropylquinoline-7-carbonyl)piperidin-4-yl )-2-oxoindoline-5- carboxamide (D019)

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).

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.19 (d, J = 8.5 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 7.84 (s, 1 H), 7.78 (s, 1 H), 7.76-7.70 (m, 2 H), 7.60 (dd, J = 8.5, 1.2 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 4.49 (br s, 1 H), 4.09 (d, J = 7.3 Hz, 1 H), 3.69-3.47 (m, 2 H), 3.53 (s, 2 H), 3.01 (br s, 1 H), 2.41-2.28 (m, 1 H), 1.85 (br d, J = 61.5 Hz, 2 H), 1.55 (br s, 2 H), 1.16-1.04 (m, 4 H).

LCMS (ESI-TOF) m/z 489.1 [M + H ⁺ ] with a purity of >95%. 7V-(l-(4-Chloro-2-(lH-pyrrol-3-yl)quinoline-7-carbonyl)piper idin-4-yl)-2-oxoindoline-5- carboxamide (D020)

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).

1H NMR (400 MHz, DMSO) δ 11.30 (s, 1 H), 10.58 (s, 1 H), 8.20-8.09 (m, 3 H), 7.87 (d, J = 1.1 Hz, 1 H), 7.75 (d, J= 1.8 Hz, 2 H), 7.73 (s, 1 H), 7.55 (dd, J= 8.5, 1.5 Hz, 1 H), 6.89 (d, J = 2.0 Hz, 1 H), 6.87-6.81 (m, 2 H), 4.50 (br s, 1 H), 4.10 (d, J = 7.5 Hz, 1 H), 3.65 (br s, 1 H), 3.53 (s, 2 H), 3.21 (s, 1 H), 3.03 (s, 1 H), 1.86 (br d, J= 46.6 Hz, 2 H), 1.56 (br s, 2 H).

LCMS (ESI-TOF) m/z 514.1 [M + H ⁺ ] with a purity of >97%. iV-(l-(2-(l-(2-Amino-2-oxoethyl)-lH-pyrazol-4-yl)-4-chloroqu inoline-7-carbonyl)piperidin- 4-yl)-2-oxoindoline-5-ca

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).

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.54 (s, 1 H), 8.26 (s, 1 H), 8.25-8.20 (m, 2 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.93 (d, J = 1.0 Hz, 1 H), 7.76-7.71 (m, 2 H), 7.63 (dd, J = 8.5, 1.4 Hz, 1 H), 7.60 (s, 1 H), 7.32 (s, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 4.87 (s, 2 H), 4.51 (br s, 1 H), 4.09 (br s, 1 H), 3.65 (br s, 1 H), 3.53 (s, 2 H), 3.25 (br s, 1 H), 3.02 (br s, 1 H), 1.86 (br d, J = 58.4 Hz, 2 H), 1.55 (s, 2 H).

LCMS (ESI-TOF) m/z 572.1 [M + H ⁺ ] with a purity of >99%. 6-Chloro-iV-(l-(4-(chloromethyl)benzoyl)piperidin-4-yl)-2-ox oindoline-5-carboxamide (D022)

D022

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).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.30 (d, J = 7.7 Hz, 1 H), 7.51 (d, J = 8.1 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 7.25 (s, 1 H), 6.83 (s, 1 H), 4.80 (s, 2 H), 4.32 (br s, 1 H), 4.08- 3.95 (m, 1 H), 3.54 (s, 1 H), 3.50 (s, 2 H), 3.11 (br d, J = 40.5 Hz, 2 H), 1.87 (s, 2 H), 1.44 (s, 2 H).

LCMS (ESI-TOF) m/z 446.0 [M + H ⁺ ] with a purity of >97%.

4-Chloro-iV-(3-(6-chloro-2-oxoindoline-5-carboxamido)prop yl)-2-(l-methyl-lH-pyrrol-3- yl)quinoline-7-carboxamid

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.

1H NMR (400 MHz, DMSO) δ 8.53 (s, 1 H), 8.22 (d, J= 8.5 Hz, 1 H), 8.02 (d, J= 8.6 Hz, 1 H), 7.77 (s, 1 H), 7.68-7.51 (m, 3 H), 7.43 (s, 1 H), 6.96 (s, 1 H), 6.86 (s, 1 H), 6.81 (s, 1 H), 6.72 (s, 1 H), 3.78 (s, 3 H), 3.67 (t, J= 12.1 Hz, 6 H), 3.50 (s, 2 H).

LCMS (ESI-TOF) m/z 536.0 [M + H ⁺ ] with a purity of >99%.

7V-(l-(4-Chloro-2-(l-fluorocyclopropyl)quinoline-7-carbon yl)piperidin-4-yl)-2-oxoindoline- 5-carboxamide (D024)

D024

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. ¹ H NMR (400 MHz, DMSO) δ 10.61 (s, 1 H), 8.29 (d, J = 8.6 Hz, 1 H), 8.14 (d, J = 7.7 Hz, 1 H), 7.98 (d, J= 1.4 Hz, 1 H), 7.91 (d, J= 1.2 Hz, 1 H), 7.78-7.66 (m, 3 H), 6.89-6.77 (m, 1 H), 4.49 (br s, 1 H), 4.09 (d, J = 7.2 Hz, 1 H), 3.59 (br s, 1 H), 3.53 (s, 2 H), 3.23 (br s, 1 H), 3.02 (br s, 1 H), 1.84 (br d, J= 68.7 Hz, 2 H), 1.74-1.43 (m, 6 H).

LCMS (ESI-TOF) m/z 507.1 [M + H ⁺ ] with a purity of >96%. N-(l-(4-Chloro-2-methylquinoline-7-carbonyl)piperidin-4-yl)- 2-oxoindoline-5- carboxamide (D025)

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).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.23 (d, J = 8.5 Hz, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 7.94 (d, J = 1.3 Hz, 1 H), 7.77 (s, 1 H), 7.76-7.70 (m, 2 H), 7.66 (dd, J = 8.5, 1.5 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 4.50 (br s, 1 H), 4.09 (d, J = 7.5 Hz, 1 H), 3.58 (br s, 1 H), 3.53 (s, 2 H), 3.22 (br s, 1 H), 3.03 (br s, 1H), 2.68 (s, 3 H), 1.86 (br d, J= 56.1 Hz, 2 H), 1.56 (br s, 2 H). LCMS (ESI-TOF) m/z 463.1 [M + H ⁺ ] with a purity of >96%.

6-Chloro- -8-(2,4-dichloroquinoline-7-carbonyl)-8-azabicyclo[3.2.1]oct an-3-

yl)-2-oxoindoline-5-carboxamide (D026)

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.

1H NMR (400 MHz, DMSO) δ 10.61 (s, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.18 (d, J = 8.3 Hz, 1 H), 8.07 (s, 1 H), 8.05 (d, J= 1.2 Hz, 1 H), 7.83 (dd, J= 8.6, 1.6 Hz, 1 H), 7.25 (s, 1 H), 6.83 (s, 1 H), 4.69 (br s, 1 H), 4.48-4.28 (m, 1 H), 4.00 (br s, 1 H), 3.50 (s, 2 H), 1.89 (dd, J = 75.7, 30.5 Hz, 7 H), 1.60 (t, J= 13.0 Hz, 1 H).

LCMS (ESI-TOF) m/z 540.9 [M + H ⁺ ] with a purity of >98%. N-(l-(4-(Chloromethyl)benzoyl)piperidin-4-yl)-2-oxoindoline- 5-carboxamide (D027)

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).

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 7.75-7.69 (m, 2 H), 7.52 (d, J= 8.2 Hz, 2 H), 7.39 (d, J= 8.2 Hz, 2 H), 6.89-6.79 (m, 1 H), 4.81 (s, 2 H), 4.44 (br s, 1 H), 4.15-3.99 (m, 1 H), 3.58 (br s, 1 H), 3.52 (s, 2 H), 3.17 (br s, 1 H), 2.95 (br s, 1 H), 1.82 (br d, J= 36.3 Hz, 2 H), 1.48 (s, 2 H).

LCMS (ESI-TOF) m/z All .1 [M + H ⁺ ] with a purity of >96%.

6-Chloro-iV-(l-(3-(chloromethyl)benzoyl)piperidin-4-yl)-2 -oxoindoline-5-carboxamide (D028)

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).

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.30 (d, J = 7.7 Hz, 1 H), 7.52 (d, J = 7.7 Hz, 1 H), 7.49-7.42 (m, 2 H), 7.33 (d, J= 7.5 Hz, 1 H), 7.25 (s, 1 H), 6.83 (s, 1 H), 4.81 (s, 2 H), 4.33 (br s, 1 H), 4.00 (dd, J = 10.8, 7.2 Hz, 1 H), 3.54 (br s, 1 H), 3.50 (s, 2 H), 3.22-2.95 (m, 2 H), 1.90 (br s, 2 H), 1.44 (br s, 2 H).

LCMS (ESI-TOF) m/z 446.0 [M + H ⁺ ] with a purity of >97%.

5-(4-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-car bonyl)piperazine-l- carbonyl)indolin-2-one (D029)

Compound D029 was prepared using 2-oxo-5-indolinecarboxylic acid and Boc-piperazine (S6 and S7 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl. ¹ H NMR (400 MHz, DMSO) δ 10.55 (s, 1 H), 8.16 (d, J= 8.4 Hz, 1 H), 8.08 (s, 1 H), 7.93 (s, 1 H), 7.71 (s, 1 H), 7.60 (d, J = 9.9 Hz, 1 H), 7.35-7.24 (m, 2 H), 6.92-6.76 (m, 3 H), 3.82-3.42 (m, 8 H), 3.72 (s, 3 H), 3.52 (s, 2 H).

LCMS (ESI-TOF) m/z 514.1 [M + H ⁺ ] with a purity of >99%.

4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)- N-(l-(2-oxoindoline-5-carbonyl)piperidin-4- yl)quinoline-7-carboxamide (D030)

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.

1H ΝΜΡν (400 MHz, DMSO) δ 10.54 (s, 1 H), 8.70 (d, J = 7.7 Hz, 1 H), 8.46 (d, J = 1.4 Hz, 1 H), 8.13 (d, J= 8.7 Hz, 1 H), 8.08 (s, 1 H), 7.99 (dd, J = 8.6, 1.7 Hz, 1 H), 7.71 (t, J= 1.8 Hz, 1 H), 7.28-7.19 (m, 2 H), 6.90-6.78 (m, 3 H), 4.50-3.79 (m, 3 H), 3.71 (s, 3 H), 3.53 (s, 2 H), 3.10 (br s, 2 H), 1.90 (d, J= 12.6 Hz, 2 H), 1.57 (d, J= 10.8 Hz, 2 H).

LCMS (ESI-TOF) m/z 528.1 [M + H ⁺ ] with a purity of >96%.

7V-((3^,4i?)-l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quino line-7-carbonyl)-3- fluoropiperidin-4-yl)-2-oxoindoline-5-carboxamide (D031)

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.

1H ΝΜΡν (400 MHz, DMSO) δ 10.62 (s, 1 H), 8.32 (d, J = 7.1 Hz, 1 H), 8.16 (d, J = 8.1 Hz, 1 H), 8.07 (s, 1 H), 7.86 (s, 1 H), 7.79 (s, 2 H), 7.71 (s, 1 H), 7.54 (dd, J= 8.5, 1.5 Hz, 1 H), 6.90- 6.76 (m, 3 H), 5.07-4.76 (m, 1 H), 4.68 (br s, 1 H), 4.42-4.16 (m, 1 H), 3.93 (br s, 1 H), 3.78- 3.56 (m, 4 H), 3.53 (s, 2 H), 3.11-2.92 (m, 1 H), 2.12-1.90 (m, 1 H), 1.88-1.53 (m, 1 H).

LCMS (ESI-TOF) m/z 546.1 [M + H ⁺ ] with a purity of >99%. 7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbo nyl)piperidin-4-yl)-7V- methyl-2-oxoindoline-5-carboxamide (D032)

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.

1H NMR (400 MHz, DMSO) δ 10.52 (s, 1 H), 8.14 (d, J= 8.5 Hz, 1 H), 8.06 (s, 1 H), 7.91 (s, 1 H), 7.70 (t, J = 1.7 Hz, 1 H), 7.58 (dd, J = 8.4, 1.2 Hz, 1 H), 7.27-7.19 (m, 2 H), 6.88-6.78 (m, 3 H), 4.65 (br s, 1 H), 3.79-3.58 (m, 4 H), 3.51 (s, 2 H), 3.28 (s, 1 H), 3.21-2.99 (m, 1 H), 2.94- 2.65 (m, 4 H), 1.80 (br s, 3 H), 1.61 (br s, 1 H).

LCMS (ESI-TOF) m/z 542.1 [M + H ⁺ ] with a purity of >97%.

6-Chloro-iV-(l-(4-(chloromethyl)benzyl)piperidin-4-yl)-2- oxoindoline-5-carboxamide (D033)

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. After 10 min, 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. The aqueous layer was extracted thrice with ethyl acetate and the organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography to afford D033 as a pale yellow solid (21.6 mg, 10%).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.30 (d, J= 8.0 Hz, 2 H), 7.22 (s, 1 H), 6.82 (s, 1 H), 4.75 (s, 2 H), 3.77-3.63 (m, 1 H), 3.49 (s, 2 H), 3.45 (s, 2 H), 2.76 (d, J = 11.6 Hz, 2 H), 2.02 (t, J = 10.7 Hz, 2 H), 1.77 (d, J = 10.1 Hz, 2 H), 1.49 (dd, J= 20.3, 11.2 Hz, 2 H).

LCMS (ESI-TOF) m/z 432 A [M + H ⁺ ] with a purity of >98%. 7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbo nyl)piperidin-4-yl)-2,3- dioxoindoline-5-carboxamide (D034)

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. ¾ NMR (400 MHz, DMSO) δ 11.30 (br s, 1 H), 8.38 (d, J= 7.6 Hz, 1 H), 8.16 (d, J= 8.5 Hz, 1 H), 8.10 (dd, J= 8.2, 1.8 Hz, 1 H), 8.07 (s, 1 H), 8.05 (d, J= 1.4 Hz, 1 H), 7.86 (s, 1 H), 7.71 (s, 1 H), 7.56 (dd, J = 8.5, 1.4 Hz, 1 H), 6.96 (d, J = 8.2 Hz, 1 H), 6.83 (dt, J = 4.3, 2.5 Hz, 2 H), 4.50 (br s, 1 H), 4.10 (d, J = 7.1 Hz, 1 H), 3.71 (s, 3 H), 3.63 (br s, 1 H), 3.26 (s, 1 H), 3.02 (br s, 1 H), 1.87 (br d, J = 56.6 Hz, 2 H), 1.55 (br s, 2 H).

LCMS (ESI-TOF) m/z 542.2 [M + H ⁺ ] with a purity of >99%.

6-Chloro-7V-(l-((4-chloro-2-(l-methyl-lH-pyrrol-3-yl)quin olin-7-yl)methyl)piperidin-4-yl)- 2-oxoindoline-5-carboxamide (D035)

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 μί, 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. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude (4-chloro-2-(l -methyl - lH-pyrrol-3-yl)quinolin-7-yl)methyl methane sulfonate.

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%).

1H NMR (400 MHz, DMSO) δ 10.58 (s, 1 H), 8.21 (d, J = 7.7 Hz, 1 H), 8.03 (d, J = 8.5 Hz, 1 H), 7.95 (s, 1 H), 7.82 (s, 1 H), 7.67 (s, 1 H), 7.55 (d, J= 10.0 Hz, 1 H), 7.23 (s, 1 H), 6.87-6.72 (m, 3 H), 3.81-3.61 (m, 6 H), 3.49 (s, 2 H), 2.84 (d, J = 11.8 Hz, 2 H), 2.13 (t, J = 10.9 Hz, 2 H), 1.80 (d, J= 10.3 Hz, 2 H), 1.65-1.45 (m, 2 H).

LCMS (ESI-TOF) m/z 548.1 [M + H ⁺ ] with a purity of >99%.

(i?)-7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline -7-carbonyl)pyrrolidin-3-yl)-2- oxoindoline-5-carboxamide (D036)

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.

1H NMR (400 MHz, DMSO, 80 °C) δ 10.37 (s, 1 H), 8.22 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 8.06-7.93 (m, 2 H), 7.71 (s, 2 H), 7.65 (d, J = 12.7 Hz, 2 H), 6.92-6.71 (m, 3 H), 4.50 (br s, 1 H), 4.01-3.38 (m, 9 H), 2.19 (s, 1 H), 2.01 (s, 1 H).

LCMS (ESI-TOF) m/z 514.1 [M + H ⁺ ] with a purity of >97%. (l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbonyl )pyrrolidin-3-yl)-2- oxoindoline-5-carboxamide (D037)

Compound D037 was prepared using 2-oxo-5-indolinecarboxylic acid and (S)-3 -amino- 1-N- boc-pyrrolidine (S6 and S7 General Procedure C) and compound S3 where X ⁶ is 1- methylpyrrol-3-yl.

1H NMR (400 MHz, DMSO, 80 °C) δ 10.37 (s, 1 H), 8.22 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 8.06-7.93 (m, 2 H), 7.71 (s, 2 H), 7.65 (d, J = 12.7 Hz, 2 H), 6.92-6.71 (m, 3 H), 4.50 (br s, 1 H), 4.01-3.38 (m, 9 H), 2.19 (s, 1 H), 2.01 (s, 1 H).

LCMS (ESI-TOF) m/z 514.1 [M + H ⁺ ] with a purity of >98%.

6-Chloro-7V-((l-(4-(chloromethyl)benzoyl)piperidin-4-yl)m ethyl)-2-oxoindoline-5- carboxamide (D038)

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).

1H NMR (400 MHz, DMSO) δ 10.58 (s, 1 H), 8.33 (t, J = 5.8 Hz, 1 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.38 (d, J= 8.1 Hz, 2 H), 7.25 (s, 1 H), 6.83 (s, 1 H), 4.80 (s, 2 H), 4.46 (br s, 1 H), 3.51 (br s, 1 H), 3.49 (s, 2 H), 3.13 (t, J= 5.7 Hz, 2 H), 3.02 (br s, 1 H), 2.78 (br s, 1 H), 1.88-1.50 (m, 3 H), 1.17 (s, 2 H).

LCMS (ESI-TOF) m/z 460.0 [M + H ⁺ ] with a purity of >96%. 5-(4-(4-(Chloromethyl)benzoyl)piperazine-l-carbonyl)indolin- 2-one (D039)

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).

1H NMR (400 MHz, DMSO) δ 10.54 (s, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.33-7.21 (m, 2 H), 6.84 (d, J= 7.9 Hz, 1 H), 4.80 (s, 2 H), 3.77-3.35 (m, 10 H).

LCMS (ESI-TOF) m/z 398.1 [M + H ⁺ ] with a purity of >96%. 6-Chloro-7V-((l-(4-chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoli ne-7-carbonyl)piperidin-4- yl)methyl)-2-oxoindoline-5-carboxamide (D040)

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.

1H NMR (400 MHz, DMSO) δ 10.58 (s, 1 H), 8.35 (t, J = 5.8 Hz, 1 H), 8.14 (d, J = 8.5 Hz, 1 H), 8.06 (s, 1 H), 7.85 (d, J= 1.1 Hz, 1 H), 7.70 (s, 1 H), 7.55 (dd, J= 8.5, 1.5 Hz, 1 H), 7.26 (s, 1 H), 6.92-6.76 (m, 3 H), 4.54 (br s, 1 H), 3.71 (s, 3 H), 3.61 (br s, 1H), 3.49 (s, 2 H), 3.16 (t, J = 6.0 Hz, 2 H), 3.08 (br s, 1 H), 2.84 (br s, 1 H), 1.92-1.55 (m, 3 H), 1.24 (s, 2 H).

LCMS (ESI-TOF) m/z 576.1 [M + H ⁺ ] with a purity of >98%.

7V-(l-(4-Chloro-2-(4-(2-hydroxypropan-2-yl)phenyl)quinoli ne-7-carbonyl)piperidin-4-yl)- 2-oxoindoline-5-carboxamide (D041)

Compound D041 was prepared using 2-oxo-5-indolinecarboxylic acid and 4-amino-l-boc- piperidine (S6 and S7 General Procedure C), compound S5 followed by boronic acid S12 where X ⁶ is 4-(2-hydroxy-2-propanyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 10.61 (s, 1 H), 8.46 (s, 1 H), 8.29 (d, J= 8.7 Hz, 1 H), 8.26 (d, J = 8.5 Hz, 2 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.07 (s, 1 H), 7.77-7.62 (m, 5 H), 6.85 (d, J = 8.6 Hz, 1 H), 5.14 (s, 1 H), 4.50 (br s, 1 H), 4.11 (br s, 1 H), 3.65 (br s, 1 H), 3.53 (s, 2 H), 3.26 (s, 1 H), 3.04 (br s, 1 H), 1.87 (br d, J= 55.4 Hz, 2 H), 1.59 (br s, 2 H), 1.48 (s, 6 H).

LCMS (ESI-TOF) m/z 583.1 [M + H ⁺ ] with a purity of >99%.

6-Chloro-7V-(l-(4-chloro-2-methylquinoline-7-carbonyl)pip eridin-4-yl)-2-oxoindoline-5- carboxamide (D042)

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).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.31 (d, J = 7.6 Hz, 1 H), 8.22 (d, J = 8.5 Hz, 1 H), 7.92 (d, J= 1.2 Hz, 1 H), 7.77 (s, 1 H), 7.66 (dd, J= 8.5, 1.5 Hz, 1 H), 7.26 (s, 1 H), 6.84 (s, 1 H), 4.39 (br s, 1 H), 4.03 (d, J = 7.6 Hz, 1 H), 3.56 (br s, 1 H), 3.50 (s, 2 H), 3.26-3.03 (m, 2 H), 2.68 (s, 3 H), 1.87 (br d, J= 55.3 Hz, 2 H), 1.53 (br s, 2 H).

LCMS (ESI-TOF) m/z 497.1 [M + H ⁺ ] with a purity of >98%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-ca rbonyl)azetidin-3-yl)-2- oxoindoline-5-carboxamide

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.

1H NMR (400 MHz, DMSO) δ 10.64 (s, 1 H), 8.91 (d, J = 6.5 Hz, 1 H), 8.15 (d, J = 8.6 Hz, 1 H), 8.10 (d, J= 8.4 Hz, 2 H), 7.85-7.66 (m, 4 H), 6.88 (d, J= 8.1 Hz, 1 H), 6.83 (d, J= 10.6 Hz, 2 H), 4.84-4.62 (m, 2 H), 4.48-4.24 (m, 2 H), 4.17-4.04 (m, 1 H), 3.71 (s, 3 H), 3.54 (s, 2 H). LCMS (ESI-TOF) m/z 500.1 [M + H ⁺ ] with a purity of >99%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-ca rbonyl)piperidin-4-yl)-l-methyl- 2-oxoindoline-5-carboxamide (D044)

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.

1H NMR (400 MHz, DMSO) δ 8.20 (d, J= 7.7 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 8.07 (s, 1 H), 7.89-7.81 (m, 2 H), 7.79 (s, 1 H), 7.70 (t, J= 1.8 Hz, 1 H), 7.56 (dd, J= 8.5, 1.6 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 1 H), 6.89-6.76 (m, 2 H), 4.51 (br s, 1 H), 4.27-4.02 (m, 1 H), 3.82-3.55 (m, 6 H), 3.24 (s, 1 H), 3.15 (s, 3 H), 3.03 (br s, 1 H), 1.88 (br d, J= 58.4 Hz, 2 H), 1.58 (s, 2 H). LCMS (ESI-TOF) m/z 542.2 [M + H ⁺ ] with a purity of >99%. -N-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbo nyl)piperidin-4-yl)-6-fluoro- 2-oxoindoline-5-carboxami

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.

1H NMR (400 MHz, DMSO) δ 10.69 (s, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.06 (s, 1 H), 8.02 (dd, J = 7.4, 2.5 Hz, 1 H), 7.85 (d, J = 1.1 Hz, 1 H), 7.70 (s, 1 H), 7.55 (dd, J = 8.5, 1.5 Hz, 1 H), 7.45 (d, J= 7.2 Hz, 1 H), 6.82 (dt, J= 4.4, 2.6 Hz, 2 H), 6.66 (d, J= 10.8 Hz, 1 H), 4.44 (br s, 1 H), 4.07 (br s, 1H), 3.71 (s, 3 H), 3.63 (br s, 1 H), 3.49 (s, 2 H), 3.25 (s, 1 H), 3.07 (br s, 1 H), 1.87 (br d, J= 53.7 Hz, 2 H), 1.57 (br s, 2 H).

LCMS (ESI-TOF) m/z 546.1 [M + H ⁺ ] with a purity of >98%.

6-Chloro-N-(l-((4-(chloromethyl)phenyl)sulfonyl)piperidin -4-yl)-2-oxoindoline-5- carboxamide (D046)

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).

1H NMR (400 MHz, DMSO) δ 10.58 (s, 1 H), 8.24 (d, J = 7.4 Hz, 1 H), 7.76 (d, J = 8.4 Hz, 2 H), 7.70 (d, J= 8.4 Hz, 2 H), 7.20 (s, 1 H), 6.80 (s, 1 H), 4.88 (s, 2 H), 3.74 (d, J= 7.4 Hz, 1 H), 3.50 (s, 1 H), 3.48 (s, 3 H), 2.59 (t, J = 10.0 Hz, 2 H), 1.86 (d, J = 9.9 Hz, 2 H), 1.55 (td, J = 13.8, 4.0 Hz, 2 H).

LCMS (ESI-TOF) m/z 482.0 [M + H ⁺ ] with a purity of >97%. 6-Chloro-N-(l-(4-(chloromethyl)-3-nitrobenzoyl)piperidin-4-y l)-2-oxoindoline-5- carboxamide (D047)

D047

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

(S10).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.31 (d, J = 7.6 Hz, 1 H), 8.05 (d, J = 1.6 Hz, 1 H), 7.86 (d, J= 7.9 Hz, 1 H), 7.78 (dd, J= 7.9, 1.6 Hz, 1 H), 7.25 (s, 1 H), 6.83 (s, 1 H), 5.07 (s, 2 H), 4.32 (br s, 1 H), 4.08-3.91 (m, 1 H), 3.50 (s, 3 H), 3.23 (br s, 1 H), 3.10 (br s, 1 H), 1.86 (br d, J= 31.3 Hz, 2 H), 1.47 (br s, 2 H).

LCMS (ESI-TOF) m/z 491.0 [M + H ⁺ ] with a purity of >95%.

6-Chloro-N-(l-(4-(chloromethyl)-2-fluorobenzoyl)piperidin -4-yl)-2-oxoindoline-5- carboxamide (D048)

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).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.31 (d, J = 7.5 Hz, 1 H), 7.44-7.33 (m, 3 H), 7.25 (s, 1 H), 6.83 (s, 1 H), 4.80 (s, 2 H), 4.36 (d, J = 13.4 Hz, 1 H), 4.01 (d, J = 6.9 Hz, 1 H), 3.49 (s, 2 H), 3.39 (d, J = 13.8 Hz, 1 H), 3.16 (t, J = 11.7 Hz, 1 H), 3.06 (t, J = 11.0 Hz, 1 H), 1.91 (d, J= 11.0 Hz, 1 H), 1.80 (d, J= 10.9 Hz, 1 H), 1.54-1.32 (m, 2 H).

LCMS (ESI-TOF) m/z 464.0 [M + H ⁺ ] with a purity of >95%.

6-Chloro-N-(l-(4-(chloromethyl)-3-fluorobenzoyl)piperidin -4-yl)-2-oxoindoline-5- carboxamide (D049)

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).

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.29 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 7.7 Hz, 1 H), 7.32-7.18 (m, 3 H), 6.83 (s, 1 H), 4.82 (s, 2 H), 4.30 (br s, 1 H), 4.01 (br s, 1 H), 3.50 (s, 3 H), 3.24-2.92 (m, 2 H), 1.85 (br d, J= 24.2 Hz, 2 H), 1.46 (br s, 2 H).

LCMS (ESI-TOF) m/z 464.0 [M + H ⁺ ] with a purity of >96%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-ca rbonyl)piperidin-4-yl)-2-oxo- 2,3-dihydro-lH-benzo [d] imidazole-5-carboxamide (D050)

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.

1H NMR (400 MHz, DMSO) δ 10.84 (d, J = 12.1 Hz, 2 H), 8.25-8.16 (m, 2 H), 8.13 (s, 1 H), 7.91 (s, 1 H), 7.78 (s, 1 H), 7.59 (d, J = 8.3 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.45 (s, 1 H), 6.95 (d, J= 8.1 Hz, 1 H), 6.87 (d, J= 10.5 Hz, 2 H), 4.51 (br s, 1 H), 4.09 (br s, 1 H), 3.97-3.45 (m, 4 H), 3.24 (br s, 1 H), 3.02 (br s, 1 H), 1.87 (br d, J= 55.1 Hz, 2 H), 1.57 (br s, 2 H).

LCMS (ESI-TOF) m/z 529.1 [M + H ⁺ ] with a purity of >95%.

6-Chloro-N-(l-(4-chloro-2-phenylquinoline-7-carbonyl)pipe ridin-4-yl)-2-oxoindoline-5- carboxamide (D051)

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.

1H NMR (400 MHz, DMSO) δ 10.59 (s, 1 H), 8.48 (s, 1 H), 8.37-8.24 (m, 4 H), 8.08 (s, 1 H), 7.72 (dd, J= 8.5, 1.5 Hz, 1 H), 7.62-7.51 (m, 3 H), 7.27 (s, 1 H), 6.84 (s, 1 H), 4.41 (br s, 1 H), 4.11-3.98 (m, 1 H), 3.62 (br s, 1 H), 3.50 (s, 2 H), 3.25 (br s, 1 H), 3.16 (br s, 1 H), 1.90 (br d, J = 50.2 Hz, 2 H), 1.54 (br s, 2 H).

LCMS (ESI-TOF) m/z 559.1 [M + H ⁺ ] with a purity of >97%. N-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)121uinolone-7-carb onyl)piperidin-4- yl)indoline-5-carboxamide (D052)

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). After 20 min, the reaction was quenched by adding water (5 mL) and the mixture was transferred to a separating funnel with dichloromethane. After extraction 5 times with dichloromethane, the combined organics were washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (0-4% methanol/dichloromethane) to afford tert-butyl (l-(4-chloro-2-(l -methyl- lH-pyrrol-3- yl)quinoline-7-carbonyl)piperidin-4-yl)carbamate as an off-white solid (87.3 mg, 89%).

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. After extraction 5 times with dichloromethane, the combined organics were washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (0-4% methanol/dichloromethane) to afford tert-butyl 5-((l-(4-chloro-2-(l-methyl-lH-pyrrol-3- yl)quinoline-7-carbonyl)piperidin-4-yl)carbamoyl)indoline-l- carboxylate as an off-white solid (64.1 mg, 56%).

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%).

1H NMR (400 MHz, DMSO) δ 8.17 (d, J= 8.5 Hz, 1 H), 8.08 (s, 1 H), 7.85 (d, J= 8.1 Hz, 2 H), 7.71 (s, 1 H), 7.59-7.53 (m, 2 H), 7.51 (d, J= 8.2 Hz, 1 H), 6.87-6.78 (m, 2 H), 6.45 (d, J= 8.2 Hz, 1 H), 6.00 (s, 1 H), 4.51 (br s, 1 H), 4.14-4.00 (m, 1 H), 3.65 (br s, 1 H), 3.72 (s, 3 H), 3.50 (t, J = 8.6 Hz, 2 H), 3.24 (s, 1 H), 3.07-2.91 (m, 3 H), 1.84 (br d, J = 62.0 Hz, 2 H), 1.58 (s, 2 H).

LCMS (ESI-TOF) m/z 516.1 [M + H ⁺ ] with a purity of >95%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-ca rbonyl)piperidin-4-yl)-l-methyl- 2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carboxamide (D053)

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.

1H NMR (400 MHz, CD ₃ OD) δ 8.26 (d, J = 8.5 Hz, 1 H), 8.02 (d, J = 1.1 Hz, 1 H), 7.95 (s, 1 H), 7.65 (dd, J = 8.3, 1.7 Hz, 1 H), 7.62-7.53 (m, 3 H), 7.16 (d, J = 8.3 Hz, 1 H), 6.80 (dt, J = 4.9, 2.7 Hz, 2 H), 4.75 (br s, 1 H), 4.29-4.13 (m, 1H), 3.81 (br s, 1 H), 3.76 (s, 3 H), 3.42 (s, 3 H), 3.35 (s, 1 H), 3.13 (br s, 1 H), 2.04 (br d, J= 65.3 Hz, 2 H), 1.72 (br s, 2 H).

LCMS (ESI-TOF) m/z 543.1 [M + H ⁺ ] with a purity of >96%. 4-Acetamido-2-chloro-iV-(l-(4-chloro-2-(l-methyl-lH-pyrrol-3 -yl)quinoline-7- carbonyl)piperidin-4-yl)benzamide (D054)

Compound D054 was prepared using 4-(Acetylamino)-2-chlorobenzoic acid and 4-amino-l - boc-piperidine (S6 and S7 General Procedure C) and compound S3 where X ⁶ is 1-methylpyrrol-

3-yl.

1H NMR (400 MHz, DMSO) δ 10.21 (s, 1 H), 8.36 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 8.07 (s, 1 H), 7.84 (dd, J= 9.3, 1.5 Hz, 2 H), 7.71 (d, J= 1.8 Hz, 1 H), 7.55 (dd, J= 8.5, 1.5 Hz, 1 H), 7.47 (dd, J = 8.4, 1.9 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 6.83 (dt, J = 4.5, 2.6 Hz, 2 H), 4.41 (br s, 1 H), 4.13-3.99 (m, 1 H), 3.71 (s, 3 H), 3.63 (br s, 1 H), 3.26 (br s, 1 H), 3.13 (br s, 1 H), 2.07 (s, 3 H), 1.90 (br d, J= 48.1 Hz, 2 H), 1.52 (s, 2 H).

LCMS (ESI-TOF) m/z 564.1 [M + H ⁺ ] with a purity of >97%.

6-Chloro-iV-(l-(6-(chloromethyl)nicotinoyl)piperidin-4-yl )-2-oxoindoline-5-carboxamide (D055)

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).

¾ NMR (400 MHz, DMSO) δ 10.60 (br s, 1 H), 8.58 (d, J= 1.6 Hz, 1 H), 8.33 (d, J= 7.6 Hz, 1

H), 7.88 (dd, J= 8.0, 2.2 Hz, 1 H), 7.64 (d, J= 7.9 Hz, 1 H), 7.26 (s, 1 H), 6.84 (s, 1 H), 4.83 (s,

2 H), 4.33 (br s, 1 H), 4.09-3.93 (m, 1 H), 3.60-3.46 (m, 4 H), 3.24 (br s, 1 H), 3.10 (br s, 1 H),

1.88 (br d, J= 29.1 Hz, 2 H), 1.47 (br s, 2 H).

LCMS (ESI-TOF) m/z 447.1 [M + H ⁺ ] with a purity of >97%. N-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbon yl)piperidin-4-yl)-3- cyclopropylisoxazole-5-carboxamide (D056)

Compound D056 was synthesized using 3 -cyclopropyl-5 -isoxazolecarboxylic acid and 4-amino- 1-boc-piperidine (S6 and S7 General Procedure C) and compound S3 where R ¹ is 1- methylpyrrol-3-yl.

1H NMR (400 MHz, DMSO) δ 8.77 (d, J= 7.9 Hz, 1 H), 8.15 (d, J = 8.5 Hz, 1 H), 8.07 (s, 1 H), 7.85 (d, J= 1.2 Hz, 1 H), 7.70 (t, J= 1.8 Hz, 1 H), 7.54 (dd, J= 8.5, 1.6 Hz, 1 H), 6.87-6.76 (m, 3 H), 4.50 (br s, 1 H), 4.14-4.00 (m, 1 H), 3.71 (s, 3 H), 3.63 (br s, 1 H), 3.24 (br s, 1 H), 3.00 (br s, 1 H), 2.13-2.02 (m, 1H), 1.83 (br d, J = 56.2 Hz, 2 H), 1.57 (br s, 2 H), 1.10-1.00 (m, 2 H), 0.85-0.71 (m, 2 H).

LCMS (ESI-TOF) m/z 504.1 [M + H ⁺ ] with a purity of >99%. iV-(l-(4-Chloroquinoline-7-carbonyl)piperidin-4-yl)-3-cyclop ropylisoxazole-5-carboxamide (D057)

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).

1H NMR (400 MHz, DMSO) δ 8.92 (d, J = 4.7 Hz, 1 H), 8.75 (d, J = 7.8 Hz, 1 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.05 (s, 1 H), 7.85 (d, J = 4.7 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 6.81 (s, 1 H), 4.51 (br s, 1 H), 4.20-3.97 (m, 1 H), 3.60 (br s, 1 H), 3.22 (br s, 1 H), 3.01 (br s, 1 H), 2.11-2.01 (m, 1 H), 1.84 (br d, J= 63.5 Hz, 2 H), 1.57 (br s, 2 H), 1.10-0.99 (m, 2H), 0.88-0.72 (m, 2H). LCMS (ESI-TOF) m/z 425.1 [M + H ⁺ ] with a purity of >98%. iV-(l-(4-(Chloromethyl)benzoyl)piperidin-4-yl)-3-cyclopropyl isoxazole-5-carboxamide (D058)

Compound D058 was synthesized using 4-amino-l-boc-piperidine and 3 -cyclopropyl-5 - isoxazolecarboxylic acid (S7 and S6 General Procedure C) and 4-(chloromethyl)benzoyl chloride (S10 General Procedure E). ¹ H NMR (400 MHz, DMSO) δ 8.74 (d, J = 7.9 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 6.81 (s, 1 H), 4.80 (s, 2 H), 4.43 (br s, 1 H), 4.12-3.95 (m, 1 H), 3.56 (br s, 1 H),

3.14 (br s, 1 H), 2.93 (br s, 1 H), 2.15-1.97 (m, 1 H), 1.80 (br d, J= 25.2 Hz, 2 H), 1.49 (br s, 2 H), 1.11-0.97 (m, 2 H), 0.91-0.71 (m, 2 H).

LCMS (ESI-TOF) m/z 388.1 [M + H ⁺ ] with a purity of >99%.

7V-(l-(4-(Chloromethyl)benzoyl)piperidin-4-yl)-l-cyclopro pyl-lH-l,2,3-triazole-4- carboxamide (D059)

Compound D059 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 4-(chloromethyl)benzoyl chloride (S10 General Procedure E).

1H NMR (400 MHz, DMSO) δ 8.58 (s, 1 H), 8.38 (d, J = 8.3 Hz, 1 H), 7.52 (d, J = 8.1 Hz, 2 H), 7.38 (d, J = 8.1 Hz, 2 H), 4.80 (s, 2 H), 4.45 (br s, 1 H), 4.18-3.96 (m, 2 H), 3.54 (br s, 1 H),

3.15 (br s, 1 H), 2.90 (br s, 1 H), 1.78 (br d, J= 39.6 Hz, 2 H), 1.58 (s, 2 H), 1.25-1.17 (m, 2 H), 1.17-1.07 (m, 2 H).

LCMS (ESI-TOF) m/z 388.1 [M + H ⁺ ] with a purity of >99%.

7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-ca rbonyl)piperidin-4-yl)-l- cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D060)

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.

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.41 (d, J= 8.3 Hz, 1 H), 8.15 (d, J= 8.5 Hz, 1 H), 8.06 (s, 1 H), 7.86 (d, J= 1.2 Hz, 1 H), 7.70 (t, J= 1.8 Hz, 1 H), 7.55 (dd, J = 8.5, 1.6 Hz, 1 H), 6.82 (dt, J= 4.5, 2.6 Hz, 2 H), 4.52 (br s, 1 H), 4.10 (br s, 1 H), 4.03 (ddd, J= 11.5, 7.5, 3.9 Hz, 1 H), 3.71 (s, 3 H), 3.60 (br s, 1 H), 3.21 (br s, 1 H), 2.97 (br s, 1 H), 1.87 (br s, 1 H), 1.67 (br s, 3 H), 1.29-1.18 (m, 2 H), 1.18-1.04 (m, 2 H). LCMS (ESI-TOF) m/z 504.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloroquinoline-7-carbonyl)piperidin-4-yl)-l-cyclopr opyl-lH-l,2,3-triazole-4- carboxamide (D061)

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).

1H NMR (400 MHz, DMSO) δ 8.92 (d, J= 4.7 Hz, 1 H), 8.59 (s, 1 H), 8.40 (d, J= 8.3 Hz, 1 H), 8.31 (d, J= 8.6 Hz, 1 H), 8.06 (s, 1 H), 7.85 (d, J= 4.7 Hz, 1 H), 7.75 (dd, J= 8.6, 1.3 Hz, 1 H), 4.52 (br s, 1 H), 4.16-4.08 (m, 1 H), 4.03 (ddd, J= 11.4, 7.6, 4.0 Hz, 1 H), 3.57 (br s, 1 H), 3.23 (br s, 1 H), 2.99 (br s, 1 H), 1.89 (br s, 1 H), 1.70 (br s, 3 H), 1.26-1.17 (m, 2 H), 1.17-1.05 (m, 2 H).

LCMS (ESI-TOF) m/z 425.1 [M + H ⁺ ] with a purity of >99%.

7V-(l-(2-(4-(Azidomethyl)phenyl)-4-chloroquinoline-7-carb onyl)piperidin-4-yl)-2- oxoindoline-5-carboxamide (D062)

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).

1H NMR (400 MHz, DMSO) δ 10.60 (s, 1 H), 8.51 (s, 1 H), 8.37 (d, J= 8.3 Hz, 2 H), 8.31 (d, J = 8.6 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 1.2 Hz, 1 H), 7.73 (dd, J = 9.5, 2.6 Hz, 3 H), 7.58 (d, J= 8.3 Hz, 2 H), 6.85 (d, J= 8.6 Hz, 1 H), 4.58 (s, 2 H), 4.53 (br s, 1 H), 4.10 (br s, 1 H), 3.65 (br s, 1 H), 3.53 (s, 2H), 3.26 (br s, 1 H), 3.04 (br s, 1 H), 1.86 (br d, J = 65.2 Hz, 2 H), 1.59 (br s, 2 H).

LCMS (ESI-TOF) m/z 580.2 [M + H ⁺ ] with a purity of >99%. N- (l-(4-Chloro-2-phenylquinoline-7-carbonyl)piperidin-4-yl)-l- cyclopropyl-lH-l,2,3- triazole-4-carboxamide (D06

Compound D063 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 phenyl.

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.48 (s, 1 H), 8.41 (d, J = 8.4 Hz, 1 H), 8.35-8.32 (m, 2 H), 8.30 (d, J = 8.5 Hz, 1 H), 8.10 (s, 1 H), 7.72 (dd, J = 8.6, 1.0 Hz, 1 H), 7.62-7.51 (m, 3 H), 4.53 (br s, 1 H), 4.12 (br s, 1 H), 4.04 (ddd, J = 11.3, 7.5, 3.9 Hz, 1 H), 3.62 (br s, 1 H), 3.25 (br s, 1 H), 2.99 (br s, 1 H), 1.91 (br s, 1 H), 1.70 (br s, 3 H), 1.29-1.17 (m, 2 H), 1.17-1.04 (m, 2 H).

LCMS (ESI-TOF) m/z 501.2 [M + H ⁺ ] with a purity of >99%.

7V-(l-(4-Chloro-2-(4-(2-hydroxypropan-2-yl)phenyl)quinoli ne-7-carbonyl)piperidin-4-yl)- l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D064)

Compound D064 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 S5 followed by boronic acid S12 where X ⁶ is 4-(2-hydroxy-2-propanyl)phenyl (General Procedure F).

¹ H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.45 (s, 1 H), 8.41 (d, J= 8.3 Hz, 1 H), 8.27 (t, J = 8.8 Hz, 3 H), 8.07 (d, J= 1.1 Hz, 1 H), 7.70 (dd, J= 8.5, 1.5 Hz, 1 H), 7.66 (d, J= 8.6 Hz, 2 H), 5.13 (s, 1 H), 4.55 (br s, 1 H), 4.12 (br s, 1 H), 4.03 (ddd, J= 11.5, 7.5, 4.0 Hz, 1 H), 3.63 (br s, 1 H), 3.25 (br s, 1 H), 2.99 (br s, 1 H), 1.91 (br s, 1 H), 1.70 (br s, 3 H), 1.48 (s, 6 H), 1.22 (dt, J = 8.1, 3.9 Hz, 2 H), 1.17-1.07 (m, 2 H).

LCMS (ESI-TOF) m/z 559.2 [M + H ⁺ ] with a purity of >96%. N-(l-(4-Chloro-2-(o-tolyl)quinoline-7-carbonyl)piperidin-4-y l)-l-cyclopropyl-lH-l,2,3- triazole-4-carboxamide (D06

Compound D065 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 S5 followed by boronic acid S12 where X ⁶ is 4-(2-methyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.40 (d, J= 8.3 Hz, 1 H), 8.33 (d, J= 8.6 Hz, 1 H), 8.06 (d, J= 1.2 Hz, 1 H), 8.03 (s, 1 H), 7.76 (dd, J= 8.6, 1.5 Hz, 1 H), 7.56 (d, J= 7.6 Hz, 1 H), 7.45-7.30 (m, 3 H), 4.55 (br s, 1 H), 4.12 (br s, 1 H), 4.03 (ddd, J= 11.4, 7.5, 3.9 Hz, 1 H), 3.62 (br s, 1 H), 3.25 (br s, 1 H), 3.01 (br s, 1 H), 2.42 (s, 3 H), 1.89 (br s, 1 H), 1.70 (br s, 3 H), 1.21 (td, J= 7.9, 3.7 Hz, 2 H), 1.17-1.06 (m, 2 H).

LCMS (ESI-TOF) m/z 515.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-(/n-tolyl)quinoline-7-carbonyl)piperidin-4- yl)-l-cyclopropyl-lH-l,2,3- triazole-4-carboxamide (D0

Compound D066 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 S5 followed by boronic acid S12 where X ⁶ is 4-(3-methyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.46 (s, 1 H), 8.41 (d, J= 8.4 Hz, 1 H), 8.29 (d, J = 8.5 Hz, 1 H), 8.17 (s, 1 H), 8.12 (d, J= 7.9 Hz, 1 H), 8.09 (d, J= 1.2 Hz, 1 H), 7.72 (dd, J= 8.5, 1.5 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 4.54 (br s, 1 H), 4.14 (br s, 1 H), 4.03 (ddd, J= 11.4, 7.5, 3.9 Hz, 1 H), 3.62 (br s, 1 H), 3.25 (br s, 1 H), 3.01 (br s, 1 H), 2.45 (s, 3 H), 1.90 (br s, 1 H), 1.70 (br s, 3 H), 1.21 (td, J= 8.0, 3.7 Hz, 2 H), 1.17-1.03 (m, 2 H). LCMS (ESI-TOF) m/z 515.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-(p-tolyl)quinoline-7-carbonyl)piperidin-4-y l)-l-cyclopropyl-lH-l,2,3- triazole-4-carboxamide (D0

Compound D067 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 S5 followed by boronic acid S12 where X ⁶ is 4-(4-methyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.45 (s, 1 H), 8.41 (d, J= 8.3 Hz, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 8.24 (d, J= 8.2 Hz, 2 H), 8.07 (d, J= 1.1 Hz, 1 H), 7.70 (dd, J= 8.5, 1.5 Hz, 1 H), 7.39 (d, J= 8.1 Hz, 2 H), 4.53 (br s, 1 H), 4.12 (br s, 1 H), 4.04 (dq, J= 11.4, 3.9 Hz, 1 H), 3.62 (br s, 1 H), 3.24 (br s, 1 H), 2.99 (br s, 1 H), 2.41 (s, 3 H), 1.91 (br s, 1 H), 1.70 (br s, 3 H), 1.21 (tt, J= 7.9, 3.8 Hz, 2 H), 1.18-1.01 (m, 2 H).

LCMS (ESI-TOF) m/z 515.2 [M + H ⁺ ] with a purity of >98%. N-(l-(4-Chloro-2-(pyridin-3-yl)quinoline-7-carbonyl)piperidi n-4-yl)-l-cyclopropyl-lH- l,2,3-triazole-4-carboxamide

Compound D068 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 S5 followed by boronic acid S12 where X ⁶ is pyridine-3-yl (General Procedure F).

¹ H NMR (400 MHz, DMSO) δ 9.49 (d, J = 1.7 Hz, 1 H), 8.74 (dd, J = 4.8, 1.5 Hz, 1 H), 8.71- 8.65 (m, 1 H), 8.59 (d, J= 1.3 Hz, 2 H), 8.41 (d, J= 8.3 Hz, 1 H), 8.32 (d, J= 8.5 Hz, 1 H), 8.13 (d, J= 1.2 Hz, 1 H), 7.76 (dd, J= 8.5, 1.5 Hz, 1 H), 7.61 (dd, J= 7.5, 4.8 Hz, 1 H), 4.53 (br s, 1 H), 4.13 (br s, 1 H), 4.03 (td, J= 7.3, 3.8 Hz, 1 H), 3.60 (br s, 1 H), 3.26 (br s, 1 H), 3.01 (br s, 1 H), 1.89 (br s, 1 H), 1.70 (br s, 3 H), 1.27-1.18 (m, 2 H), 1.18-1.07 (m, 2 H).

LCMS (ESI-TOF) m/z 502.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-cyclopropylquinoline-7-carbonyl)piperidin-4 -yl)-l-cyclopropyl-lH-l,2,3- triazole-4-carboxamide (D069

Compound D069 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 S5 followed by boronic acid S12 where X ⁶ is cyclopropyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.40 (d, J = 8.4 Hz, 1 H), 8.19 (d, J = 8.6 Hz, 1 H), 7.84 (d, J= 1.2 Hz, 1 H), 7.79 (s, 1 H), 7.60 (dd, J = 8.5, 1.5 Hz, 1 H), 4.49 (br s, 1 H), 4.11 (br s, 1 H), 4.04 (td, J = 7.4, 3.5 Hz, 1 H), 3.57 (br s, 1 H), 3.22 (br s, 1 H), 2.97 (br s, 1 H), 2.38- 2.29 (m, 1 H), 1.87 (br s, 1 H), 1.66 (br s, 3 H), 1.26-1.17 (m, 2 H), 1.12 (t, J = 7.0 Hz, 6 H). LCMS (ESI-TOF) m/z 465.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-phenylquinoline-7-carbonyl)piperidin-4-yl)- l-methyl-lH-l,2,3-triazole- 4-carboxamide (D070)

Compound D070 was synthesized using 4-amino-l-boc-piperidine and l-methyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X ⁶ is phenyl.

1H NMR (400 MHz, DMSO) δ 8.49 (d, J= 3.8 Hz, 2 H), 8.42 (d, J= 8.4 Hz, 1 H), 8.34 (dd, J = 7.8, 1.5 Hz, 2 H), 8.31 (d, J= 8.5 Hz, 1 H), 8.10 (d, J= 0.9 Hz, 1 H), 7.73 (dd, J= 8.5, 1.5 Hz, 1 H), 7.63-7.53 (m, 3 H), 4.56 (br s, 1 H), 4.12 (br s, 1 H), 4.09 (s, 3 H), 3.63 (br s, 1 H), 3.26 (br s, 1 H), 3.00 (br s, 1 H), 1.91 (br s, 1 H), 1.73 (br s, 3 H).

LCMS (ESI-TOF) m/z 475.1 [M + H ⁺ ] with a purity of >99%. N-(l-(9-Chloro-5,6,7,8-tetrahydroacridine-3-carbonyl)piperid in-4-yl)-l-cyclopropyl-lH- l,2,3-triazole-4-carboxamide (D071)

D071

Compound D071 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 9-chloro-5, 6,7,8- tetrahydroacridine-3-carboxylic acid (S10).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.40 (d, J= 8.2 Hz, 1 H), 8.21 (d, J= 8.6 Hz, 1 H), 7.90 (d, J = 1.1 Hz, 1 H), 7.63 (dd, J = 8.6, 1.4 Hz, 1 H), 4.52 (br s, 1 H), 4.17-4.08 (m, 1 H), 4.04 (ddd, J = 11.4, 7.5, 3.9 Hz, 1 H), 3.57 (br s, 1 H), 3.22 (br s, 1 H), 3.07 (s, 2 H), 2.99 (s, 3 H), 1.90 (s, 5 H), 1.67 (s, 3 H), 1.22 (td, J = 7.9, 3.7 Hz, 2 H), 1.18-1.07 (m, 2 H).

LCMS (ESI-TOF) m/z 479.2 [M + H ⁺ ] with a purity of >97%.

7V-(l-(4-Chloro-2-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)quinol ine-7-carbonyl)piperidin-4-yl)-l- cyclopropyl-lH-l,2,3-triazol

Compound D072 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 S5 followed by boronic acid pinacol ester S12 where X ⁶ is l-(3-oxetanyl)-lH-pyrazol-4-yl (General Procedure F).

¹ H NMR (400 MHz, DMSO) δ 8.78 (s, 1 H), 8.59 (s, 1 H), 8.41 (d, J = 8.5 Hz, 1 H), 8.39 (s, 1 H), 8.26 (s, 1 H), 8.22 (d, J= 8.5 Hz, 1 H), 7.94 (d, J= 1.1 Hz, 1 H), 7.64 (dd, J= 8.5, 1.5 Hz, 1 H), 5.73-5.62 (m, 1 H), 5.01-4.91 (m, 4 H), 4.60-4.40 (m, 1 H), 4.18-4.07 (m, 1 H), 4.07-3.98 (m, 1 H), 3.62 (br s, 1 H), 3.21 (br s, 1 H), 2.99 (br s, 1 H), 2.01-1.51 (m, 4 H), 1.34-1.05 (m, 4 H).

LCMS (ESI-TOF) m/z 547.2 [M + H ⁺ ] with a purity of >97%. N-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbon yl)-4-methylpiperidin-4-yl)- l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D073)

Compound D073 was synthesized using l-boc-4-amino-4-methylpiperidine and 1 -cyclopropyl - lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl.

1H NMR (400 MHz, DMSO) δ 8.57 (s, 1 H), 8.13 (d, J= 8.5 Hz, 1 H), 8.06 (s, 1 H), 7.88 (d, J = 1.1 Hz, 1 H), 7.70 (s, 2 H), 7.56 (dd, J = 8.5, 1.5 Hz, 1 H), 6.84 (t, J = 2.4 Hz, 1 H), 6.81-6.77 (m, 1 H), 4.16-3.96 (m, 2 H), 3.71 (s, 3 H), 3.40 (br s, 1 H), 2.44 (br s, 1 H), 2.25 (br s, 1 H), 1.63 (br s, 2 H), 1.43 (s, 3 H), 1.25-1.08 (m, 4 H).

LCMS (ESI-TOF) m/z 518.2 [M + H ⁺ ] with a purity of >98%. -8-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbonyl )-8- azabicyclo[3.2.1]octan-3-yl)-l-cyclopropyl-lH-l,2,3-triazole -4-carboxamide (D074)

Compound D074 was synthesized using -aminotropane and 1 -cyclopropyl- 1H- l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl.

1H NMR (400 MHz, DMSO) δ 8.62 (s, 1 H), 8.15 (d, J= 8.5 Hz, 1 H), 8.11-8.04 (m, 2 H), 7.94 (d, J = 0.9 Hz, 1 H), 7.72 (s, 1 H), 7.63 (dd, J = 8.5, 1.4 Hz, 1 H), 6.85 (t, J = 2.3 Hz, 1 H), 6.83-6.80 (m, 1 H), 4.69 (s, 1 H), 4.15 (d, J = 5.7 Hz, 1 H), 4.04 (tt, J = 7.4, 3.9 Hz, 2 H), 3.71 (s, 3 H), 2.29 (s, 1 H), 2.04 (s, 6 H), 1.90 (d, J= 14.3 Hz, 1 H), 1.29-1.05 (m, 4 H).

LCMS (ESI-TOF) m/z 530.2 [M + H ⁺ ] with a purity of >98%. iV-(l-(2-(4-(l-Aminocyclopropyl)phenyl)-4-chloroquinoline-7- carbonyl)piperidin-4-yl)-l- cyclopropyl-lH-l,2,3-triaz

Compound D075 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 4-(l-aminocyclopropyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.45 (s, 1 H), 8.41 (d, J= 8.3 Hz, 1 H), 8.27 (d, J = 8.6 Hz, 1 H), 8.24 (d, J= 8.5 Hz, 2 H), 8.07 (s, 1 H), 7.69 (dd, J= 8.5, 1.3 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 2 H), 4.53 (s, 1 H), 4.12 (d, J = 4.0 Hz, 1 H), 4.03 (tt, J = 7.5, 3.9 Hz, 1 H), 3.61 (s, 1 H), 3.25 (s, 1 H), 3.00 (s, 1 H), 2.39 (s, 2 H), 1.89 (s, 1 H), 1.70 (s, 3 H), 1.31-1.09 (m, 4 H), 1.09-0.91 (m, 4 H).

LCMS (ESI-TOF) m/z 556.2 [M + H ⁺ ] with a purity of >97%. N-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbon yl)-2-methylpiperidin-4-yl)- l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D076)

Compound D076 was synthesized using 4-amino-l-boc-2-methylpiperidine and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl.

1H NMR (400 MHz, DMSO) δ 8.60 (s, 1 H), 8.33 (d, J= 6.7 Hz, 1 H), 8.14 (d, J= 8.4 Hz, 1 H),

8.06 (s, 1 H), 7.85 (s, 1 H), 7.71 (s, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 6.83 (d, J = 14.5 Hz, 2 H), 4.34-3.97 (m, 3 H), 3.71 (s, 4 H), 1.92 (s, 3 H), 1.80 (s, 1 H), 1.30 (d, J = 6.6 Hz, 4 H), 1.26-

1.07 (m, 4 H).

LCMS (ESI-TOF) m/z 518.2 [M + H ⁺ ] with a purity of >98%. N-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbon yl)azetidin-3-yl)-l- cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D077)

Compound D077 was synthesized using l-boc-3-(amino)azetidine 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.

1H NMR (400 MHz, DMSO) δ 9.28 (d, J= 7.4 Hz, 1 H), 8.63 (s, 1 H), 8.15 (d, J= 8.5 Hz, 1 H), 8.09 (d, J = 6.3 Hz, 2 H), 7.78 (d, J = 8.7 Hz, 2 H), 7.72 (s, 1 H), 6.83 (d, J = 13.1 Hz, 2 H), 4.81 (s, 1 H), 4.66 (s, 1 H), 4.43 (s, 2 H), 4.09 (d, J = 38.2 Hz, 2 H), 3.71 (s, 3 H), 1.18 (d, J = 32.9 Hz, 4 H).

LCMS (ESI-TOF) m/z 476.2 [M + H ⁺ ] with a purity of >99%.

(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinolin-7-yl)(6-(l- cyclopropyl-lH-l,2,3-triazole-4- carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methanone (D078)

Compound D078 was synthesized using 2-N-boc-2,6-diazaspiro[3.3]heptane and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7a and S6 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl.

1H ΝΜΡν (400 MHz, DMSO) δ 8.61 (s, 1 H), 8.14 (d, J= 8.7 Hz, 1 H), 8.10 (d, J= 1.3 Hz, 1 H), 8.08 (s, 1 H), 7.78 (dd, J = 8.6, 1.6 Hz, 1 H), 7.71 (t, J= 1.9 Hz, 1 H), 6.85 (t, J = 2.4 Hz, 1 H), 6.83-6.78 (m, 1 H), 4.73 (s, 2 H), 4.61 (s, 2 H), 4.32 (s, 2 H), 4.24 (s, 2 H), 4.03 (ddd, J = 11.5, 7.5, 3.8 Hz, 1 H), 3.71 (s, 3 H), 1.29-1.04 (m, 4 H).

LCMS (ESI-TOF) m/z 502.2 [M + H ⁺ ] with a purity of >95%. 7V-(l-(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinoline-7-carbo nyl)piperidin-4-yl)-5- cyclopropyl-l,3,4-oxadiazole-2-carboxamide (D079)

Compound D079 was synthesized using 4-amino-l-boc-piperidine and 5-cyclopropyl- [l,3,4]oxadiazole-2-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl.

¹ H NMR (400 MHz, DMSO) δ 9.15 (d, J= 8.1 Hz, 1 H), 8.15 (d, J= 8.5 Hz, 1 H), 8.07 (s, 1 H), 7.85 (d, J = 1.3 Hz, 1 H), 7.70 (t, J = 1.8 Hz, 1 H), 7.54 (dd, J = 8.5, 1.6 Hz, 1 H), 6.85 (t, J = 2.4 Hz, 1 H), 6.82-6.74 (m, 1 H), 4.52 (br s, 1 H), 4.11 (br s, 1 H), 3.71 (s, 3 H), 3.64 (br s, 1 H), 3.24 (br s, 1 H), 3.00 (br s, 1 H), 2.31 (td, J = 8.4, 4.2 Hz, 1 H), 1.98-1.49 (m, 4 H), 1.30- 1.04 (m, 4 H).

LCMS (ESI-TOF) m/z 505.2 [M + H ⁺ ] with a purity of >99%.

7V-(l-(4-Chloro-2-(3-formyl-4-methoxyphenyl)quinoline-7-c arbonyl)piperidin-4-yl)-l- cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D080)

Compound D080 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 S5 followed by boronic acid S12 where X ⁶ is 3-formyl-4-methoxyphenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 10.44 (s, 1 H), 8.68 (d, J = 2.4 Hz, 1 H), 8.63 (dd, J = 8.8, 2.5 Hz, 1 H), 8.59 (s, 1 H), 8.51 (s, 1 H), 8.40 (d, J = 8.4 Hz, 1 H), 8.28 (d, J = 8.5 Hz, 1 H), 8.10 (d, J = 1.2 Hz, 1 H), 7.71 (dd, J = 8.5, 1.6 Hz, 1 H), 7.44 (d, J = 8.9 Hz, 1 H), 4.53 (br s, 1 H), 4.20-4.09 (m, 1 H), 4.09-3.97 (m, 4 H), 3.62 (br s, 1 H), 3.25 (br s, 1 H), 2.99 (br s, 1 H), 1.96- 1.59 (m, 4 H), 1.24-1.09 (m, 4 H).

LCMS (ESI-TOF) m/z 559.1 [M + H ⁺ ] with a purity of >96%. N-(l-(4-Chloro-2-(3-(hydroxymethyl)-4-methoxyphenyl)quinolin e-7-carbonyl)piperidin-4- yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D081)

Compound D081 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 S5 followed by boronic acid S12 where X ⁶ is 3-(hydroxymethyl)-4-methoxyphenyl (General Procedure F). ¾ NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.43-8.36 (m, 3 H), 8.26 (d, J= 8.5 Hz, 1 H), 8.21 (dd, J = 8.6, 2.4 Hz, 1 H), 8.05 (d, J = 1.2 Hz, 1 H), 7.67 (dd, J= 8.5, 1.6 Hz, 1 H), 7.13 (d, J = 8.7 Hz, 1 H), 5.17 (br s, 1 H), 4.59 (s, 2 H), 4.55 (br s, 1 H), 4.12 (br s, 1 H), 4.03 (ddd, J = 11.4, 7.5, 3.9 Hz, 1 H), 3.88 (s, 3 H), 3.62 (br s, 1 H), 3.25 (br s, 1 H), 2.99 (br s, 1 H), 2.00- 1.58 (m, 4 H), 1.31-1.06 (m, 4 H).

LCMS (ESI-TOF) m/z 561.2 [M + H ⁺ ] with a purity of >98%.

(4-Chloro-2-(l-methyl-lH-pyrrol-3-yl)quinolin-7-yl)(3-(l- cyclopropyl-lH-l,2,3-triazole-4- carbonyl)imidazolidin-l-yl)methanone (D082)

Compound D082 was synthesized using tert-butyl imidazolidine-l-carboxylate and 1- cyclopropyl-lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S3 where X ⁶ is l-methylpyrrol-3-yl.

1H NMR (400 MHz, DMSO) δ 8.72 (s, 1 H), 8.17 (dd, J= 8.4, 3.1 Hz, 1 H), 8.10 (s, 2 H), 7.75- 7.67 (m, 2 H), 6.85 (t, J= 2.4 Hz, 1 H), 6.82 (s, 1 H), 5.58 (br s, 1 H), 5.13 (br d, J= 44.4 Hz, 1 H), 4.27 (t, J = 6.7 Hz, 1 H), 3.99 (br d, J= 57.7 Hz, 2 H), 3.83 (s, 2 H), 3.71 (s, 3 H), 1.33-1.00 (m, 4H).

LCMS (ESI-TOF) m/z 476.2 [M + H ⁺ ] with a purity of >98%. N-(l-(2-(4-(l-Amino-2-methylpropan-2-yl)phenyl)-4-chloroquin oline-7- carbonyl)piperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-c arboxamide (D083)

Compound D083 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 4-(l-amino-2-methylpropan-2-yl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.44 (s, 1 H), 8.41 (d, J= 8.2 Hz, 1 H), 8.28 (d, J = 8.6 Hz, 1 H), 8.26 (d, J= 8.5 Hz, 2 H), 8.07 (d, J= 1.2 Hz, 1 H), 7.70 (dd, J= 8.5, 1.5 Hz, 1 H), 7.55 (s, 1 H), 7.53 (s, 1 H), 4.53 (br s, 1 H), 4.12 (br s, 1 H), 4.03 (ddd, J = 11.4, 7.5, 3.9 Hz, 1 H), 3.61 (br s, 1 H), 3.24 (br s, 1 H), 3.00 (br s, 1 H), 2.71 (s, 2 H), 2.02-1.57 (m, 4 H), 1.29 (s, 6 H), 1.26-1.00 (m, 4 H).

LCMS (ESI-TOF) m/z 572.2 [M + H ⁺ ] with a purity of >99%. iV-(l-(4-Chloro-2-(4-(l-(dimethylamino)ethyl)phenyl)quinolin e-7-carbonyl)piperidin-4-yl)- l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D084)

Compound D084 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 4-[l-(dimethylamino)ethyl]phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.46 (s, 1 H), 8.41 (d, J= 8.4 Hz, 1 H), 8.29 (d, J = 8.5 Hz, 1 H), 8.27 (d, J= 8.3 Hz, 2H), 8.07 (d, J= 1.1 Hz, 1 H), 7.71 (dd, J = 8.5, 1.5 Hz, 1 H), 7.49 (d, J= 8.3 Hz, 2 H), 4.53 (br s, 1 H), 4.11 (br s, 1 H), 4.03 (ddd, J= 11.3, 7.4, 3.9 Hz, 1 H), 3.62 (br s, 2 H), 3.24 (br s, 1 H), 3.00 (br s, 1 H), 2.14 (s, 6 H), 2.01-1.58 (m, 4 H), 1.32 (d, J = 6.7 Hz, 3 H), 1.28-1.08 (m, 4 H).

LCMS (ESI-TOF) m/z 572.1 [M + H ⁺ ] with a purity of >99%. N- (l-(4-Chloro-2-(4-(l-(pyrrolidin-l-yl)ethyl)phenyl)quinoline -7-carbonyl)piperidin-4-yl)- l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D085)

Compound D085 was synthesized 4-amino-l-boc-piperidine and l-cyclopropyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid S12 where X ⁶ is 4-(l-pyrrolidinoethyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.45 (s, 1 H), 8.41 (d, J= 8.4 Hz, 1 H), 8.29 (d, J =

8.6 Hz, 1 H), 8.26 (d, J= 8.4 Hz, 2 H), 8.07 (d, J= 1.1 Hz, 1 H), 7.71 (dd, J= 8.5, 1.6 Hz, 1 H),

7.51 (d, J = 8.3 Hz, 2 H), 4.52 (br s, 1 H), 4.13 (br s, 1 H), 4.07-3.99 (m, 1 H), 3.61 (br s, 2 H),

3.44 (br s, 2 H), 3.00 (br s, 1 H), 2.33 (d, J = 1.8 Hz, 2 H), 1.91 (br s, 1 H), 1.69 (s, 7 H), 1.35

(d, J= 6.6 Hz, 3 H), 1.29-1.02 (m, 4 H).

LCMS (ESI-TOF) m/z 598.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)quinoline- 7-carbonyl)-2- methylpiperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carb oxamide (D086)

Compound D086 was synthesized using 4-amino-l-boc-2-methylpiperidine and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid pinacol ester S12 where X ⁶ is l-(3-oxetanyl)-lH-pyrazol-4-yl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.78 (s, 1 H), 8.60 (s, 1 H), 8.39 (s, 1 H), 8.33 (d, J = 6.8 Hz, 1 H), 8.25 (s, 1 H), 8.21 (d, J= 8.5 Hz, 1 H), 7.94 (d, J= 1.2 Hz, 1 H), 7.65 (dd, J= 8.5, 1.5 Hz, 1 H), 5.68 (dd, J = 13.9, 6.4 Hz, 1 H), 4.96 (p, J = 6.6 Hz, 4 H), 4.33-4.19 (m, 1 H), 4.14 (t, J = 10.1 Hz, 1 H), 4.09-3.96 (m, 1 H), 3.71 (d, J= 8.8 Hz, 1 H), 3.48 (t, J= 8.7 Hz, 1 H), 2.04-1.70 (m, 4 H), 1.30 (d, J= 6.8 Hz, 3 H), 1.25-1.08 (m, 4 H).

LCMS (ESI-TOF) m/z 561.2 [M + H ⁺ ] with a purity of >98%. N- (l-(2-(4-(l-Amino-2-methylpropan-2-yl)phenyl)-4-chloroquinol ine-7-carbonyl)-2- methylpiperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carb oxamide (D087)

Compound D087 was synthesized using 4-amino-l-boc-2-methylpiperidine and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid hydrochloride S12 where X ⁶ is 4-(l-amino-2-methylpropan-2-yl) phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.60 (s, 1 H), 8.43 (s, 1 H), 8.33 (d, J= 6.8 Hz, 1 H), 8.27 (d, J = 8.4 Hz, 2 H), 8.26 (d, J= 8.5 Hz, 1 H), 8.07 (d, J= 1.2 Hz, 1 H), 7.71 (dd, J= 8.5, 1.5 Hz, 1 H), 7.54 (d, J= 8.5 Hz, 2 H), 4.26 (d, J= 6.3 Hz, 1 H), 4.14 (dd, J= 11.2, 5.7 Hz, 1 H), 4.03 (dt, J= 7.5, 3.8 Hz, 1 H), 3.72 (d, J = 10.8 Hz, 1 H), 3.57-3.43 (m, 2 H), 2.72 (s, 2 H), 2.03-1.72 (m, 5 H), 1.31 (d, J= 6.8 Hz, 3 H), 1.29 (s, 6 H), 1.25-1.09 (m, 4 H).

LCMS (ESI-TOF) m/z 586.3 [M + H ⁺ ] with a purity of >99%. N- (l-(4-Chloro-2-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)quinoline-7- carbonyl)azetidin-3-yl)-l- cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D088)

Compound D088 was synthesized using l-boc-3-(amino)azetidine and l-cyclopropyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid pinacol ester S12 where X ⁶ is l-(3-oxetanyl)-lH-pyrazol-4-yl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 9.29 (d, J = 7.1 Hz, 1 H), 8.79 (s, 1 H), 8.63 (s, 1 H), 8.40 (s, 1 H), 8.28 (s, 1 H), 8.22 (d, J = 8.7 Hz, 1 H), 8.18 (s, 1 H), 7.86 (d, J = 8.5 Hz, 1 H), 5.72-5.59 (m, 1 H), 4.97 (p, J = 6.7 Hz, 4 H), 4.80 (dd, J = 12.8, 5.1 Hz, 1 H), 4.66 (t, J = 8.9 Hz, 1 H), 4.49-4.33 (m, 2 H), 4.19-4.11 (m, 1 H), 4.04 (td, J= 7.4, 3.8 Hz, 1 H), 1.30-1.03 (m, 4 H). LCMS (ESI-TOF) m/z 519.2 [M + H ⁺ ] with a purity of >99%. N- (l-(4-Chloro-2-(4-(2-hydroxypropan-2-yl)phenyl)quinoline-7-c arbonyl)azetidin-3-yl)-l- cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D089)

Compound D089 was synthesized using l-boc-3-(amino)azetidine and l-cyclopropyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid S12 where X ⁶ is 4-(2-hydroxy-2-propanyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 9.29 (d, J = 7.3 Hz, 1 H), 8.63 (s, 1 H), 8.47 (s, 1 H), 8.32-8.23 (m, 4 H), 7.93 (d, J = 8.6 Hz, 1 H), 7.66 (d, J = 8.3 Hz, 2 H), 5.15 (s, 1 H), 4.81 (dt, J = 13.3, 6.7 Hz, 1 H), 4.69 (t, J= 8.0 Hz, 1 H), 4.52-4.36 (m, 2 H), 4.16 (dd, J= 10.0, 5.0 Hz, 1 H), 4.05 (tt, J= 7.6, 3.9 Hz, 1 H), 1.49 (s, 6 H), 1.26-1.05 (m, 4 H).

LCMS (ESI-TOF) m/z 531.2 [M + H ⁺ ] with a purity of >99%. N- (l-(4-Chloro-2-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)quinoline-7- carbonyl)-3- methylpiperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carb oxamide (D090)

Compound D090 was synthesized according using 4-amino-l-boc-3-methylpiperidine and 1- cyclopropyl-lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid pinacol ester S12 where X ⁶ is l-(3-oxetanyl)-lH- pyrazol-4-yl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.78 (d, J = 3.3 Hz, 1 H), 8.60 (d, J = 10.1 Hz, 1 H), 8.39 (s, 1 H), 8.26 (d, J = 1.1 Hz, 1 H), 8.22 (dd, J = 8.4, 3.3 Hz, 1 H), 7.96-7.90 (m, 1 H), 7.63 (dd, J = 8.5, 1.5 Hz, 1 H), 5.75-5.57 (m, 1 H), 4.96 (p, J = 6.8 Hz, 4 H), 4.26 (s, 1 H), 4.03 (ddd, J = 11.4, 7.5, 3.9 Hz, 1 H), 3.82 (br s, 1 H), 3.59 (br s, 1 H), 3.41 (br s, 2 H), 1.95-1.52 (m, 3 H), 1.28-1.04 (m, 4 H), 1.04-0.59 (m, 3 H).

LCMS (ESI-TOF) m/z 561.2 [M + H ⁺ ] with a purity of >97%. N- (l-(4-Chloro-2-(4-(2-hydroxypropan-2-yl)phenyl)quinoline-7-c arbonyl)-3- methylpiperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carb oxamide (D091)

Compound D091 was synthesized using 4-amino-l -boc-3-methylpiperidine and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid S12 where X ⁶ is 4-(2-hydroxy-2-propanyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.49 (d, J = 14.1 Hz, 1 H), 8.35 (s, 1 H), 8.27 (dd, J = 8.4, 2.0 Hz, 1 H), 8.22 (d, J = 8.4 Hz, 2 H), 8.08 and 7.88 (2 ^χ s, 1 H), 8.07 (s, 1 H), 7.68 (d, J = 9.9 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2 H), 4.87 (s, 1 H), 4.28 (br s, 1 H), 4.07-3.96 (m, 1 H), 3.82 (br s, 1 H), 3.38 (br s, 1 H), 2.79 (br s, 1 H), 2.16 (br s, 1 H), 1.96-1.59 (m, 3 H), 1.50 (s, 6 H), 1.28- 1.04 (m, 4 H), 0.86 (d, J= 13.3 Hz, 3 H).

LCMS (ESI-TOF) m/z 573.2 [M + H ⁺ ] with a purity of >97%. N- (l-(2-(4-(l-Amino-2-methylpropan-2-yl)phenyl)-4-chloroquinol ine-7-carbonyl)-3- methylpiperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carb oxamide (D092)

Compound D092 was synthesized using 4-amino-l -boc-3-methylpiperidine and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid hydrochloride S12 where X ⁶ is 4-(l-amino-2-methylpropan-2-yl) phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.48 (d, J = 14.0 Hz, 1 H), 8.33 (s, 1 H), 8.26 (d, J = 8.4 Hz, 1 H), 8.21 (d, J = 8.4 Hz, 2 H), 8.08 and 7.85 (2 ^χ s, 1 H), 8.06 (d, J = 4.3 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 7.54 (d, J = 8.3 Hz, 2 H), 4.27 (br s, 1 H), 4.06-3.96 (m, 1 H), 3.82 (br s, 1 H), 3.55-3.32 (m, 2 H), 2.74 (s, 2 H), 2.17 (br s, 1 H), 1.95-1.64 (m, 3 H), 1.30 (s, 6 H), 1.22 (s, 2 H), 1.18-1.02 (m, 4 H), 0.86 (d, J = 16.9 Hz, 3 H).

LCMS (ESI-TOF) m/z 586.3 [M + H ⁺ ] with a purity of >98%. N- (l-(4-Chloro-2-(4-(2-hydroxypropan-2-yl)phenyl)quinoline-7-c arbonyl)-2- methylpiperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carb oxamide (D093)

Compound D093 was synthesized using 4-amino-l-boc-2-methylpiperidine and 1-cyclopropyl- lH-l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid S12 where X ⁶ is 4-(2-hydroxy-2-propanyl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.60 (s, 1 H), 8.45 (s, 1 H), 8.33 (d, J= 6.8 Hz, 1 H), 8.27 (d, J = 8.5 Hz, 1 H), 8.26 (d, J= 8.6 Hz, 2 H), 8.08 (d, J= 1.2 Hz, 1 H), 7.71 (dd, J= 8.5, 1.6 Hz, 1 H), 7.66 (d, J = 8.6 Hz, 2 H), 4.26 (d, J = 5.0 Hz, 1 H), 4.14 (dd, J = 10.9, 5.7 Hz, 1 H), 4.07-3.97 (m, 1 H), 3.71 (s, 1 H), 3.51 (t, J = 11.0 Hz, 1 H), 2.05-1.84 (m, 3 H), 1.80 (s, 1 H), 1.48 (s, 7 H), 1.31 (d, J= 6.8 Hz, 3 H), 1.26-1.07 (m, 4 H).

LCMS (ESI-TOF) m/z 573.2 [M + H ⁺ ] with a purity of >99%. -8-(2-(4-(l-Amino-2-methylpropan-2-yl)phenyl)-4-chloroquinol ine-7-

carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-l-cyclopropyl-lH-l, 2,3-triazole-4-carboxamide

(D094)

Compound D094 was synthesized using N-boc-endo -3-aminotropane and 1-cyclopropyl-lH- l,2,3-triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid hydrochloride S12 where X ⁶ is 4-(l-amino-2-methylpropan-2-yl)phenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.62 (s, 1 H), 8.45 (s, 1 H), 8.28 (d, J= 8.5 Hz, 1 H), 8.26 (d, J = 8.5 Hz, 2 H), 8.15 (d, J= 1.1 Hz, 1 H), 8.09 (d, J= 5.9 Hz, 1 H), 7.78 (dd, J= 8.5, 1.5 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 2 H), 4.70 (s, 1 H), 4.17 (s, 1 H), 4.12-3.97 (m, 2 H), 2.71 (s, 2 H), 2.21- 1.82 (m, 7 H), 1.29 (s, 6 H), 1.23-1.07 (m, 5 H).

LCMS (ESI-TOF) m/z 598.2 [M + H ⁺ ] with a purity of >96%. N-(l-(2-(3-(Aminomethyl)-4-fluorophenyl)-4-chloroquinoline-7 -carbonyl)piperidin-4-yl)-l- cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D095)

D095

Compound D095 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 3-(aminomethyl)-4-fluorophenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.49 (s, 1 H), 8.46 (dd, J = 7.4, 2.3 Hz, 1 H), 8.41 (d, J = 8.3 Hz, 1 H), 8.29 (d, J = 8.5 Hz, 1 H), 8.27-8.21 (m, 1 H), 8.09 (d, J = 1.2 Hz, 1 H), 7.72 (dd, J = 8.5, 1.5 Hz, 1 H), 7.36-7.30 (m, 1 H), 4.55 (br s, 1 H), 4.20-4.06 (m, 1 H), 4.03 (td, J = 7.4, 3.8 Hz, 1 H), 3.86 (s, 2 H), 3.61 (br s, 1 H), 3.18 (br s, 1 H), 3.00 (br s, 1 H), 1.99- 1.58 (m, 4 H), 1.28-1.07 (m, 4 H).

LCMS (ESI-TOF) m/z 548.2 [M + H ⁺ ] with a purity of >99%. iV-(l-(4-Chloro-2-(3-((dimethylamino)methyl)-4-fluorophenyl) quinoline-7- carbonyl)piperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-c arboxamide (D096)

Compound D096 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 3-((dimethylamino)methyl)-4-fluorophenyl (General Procedure F).

LCMS (ESI-TOF) m/z 576.2 [M + H ⁺ ] with a purity of >99%. N-(l-(4-Chloro-2-(3-((dimethylamino)methyl)-4-methoxyphenyl) quinoline-7- carbonyl)piperidin-4-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-c arboxamide (D097)

Compound D097 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 3-((dimethylamino)methyl)-4-methoxyphenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.43-8.37 (m, 2 H), 8.28 (d, J= 2.3 Hz, 1 H), 8.26 (d, J = 8.5 Hz, 1 H), 8.22 (dd, J = 8.6, 2.4 Hz, 1 H), 8.05 (d, J= 1.2 Hz, 1 H), 7.67 (dd, J= 8.5, 1.5 Hz, 1 H), 7.16 (d, J= 8.7 Hz, 1 H), 4.53 (br s, 1 H), 4.12 (br s, 1 H), 4.03 (ddd, J= 11.4, 7.5, 3.9 Hz, 1 H), 3.88 (s, 3 H), 3.61 (br s, 1 H), 3.48 (s, 3 H), 2.99 (br s, 1 H), 2.21 (s, 6 H), 1.97- 1.58 (m, 4 H), 1.28-1.06 (m, 4 H).

LCMS (ESI-TOF) m/z 588.3 [M + H ⁺ ] with a purity of >99%. iV-(l-(2-(3-(Aminomethyl)-4-methoxyphenyl)-4-chloroquinoline -7-carbonyl)piperidin-4- yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D098)

Compound D098 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 S5 followed by boronic acid hydrochloride S12 where X ⁶ is 3-(aminomethyl)-4-methoxyphenyl (General Procedure F).

1H NMR (400 MHz, DMSO) δ 8.59 (s, 1 H), 8.44 (s, 1 H), 8.41 (d, J= 8.3 Hz, 1 H), 8.33 (d, J = 2.3 Hz, 1 H), 8.26 (d, J= 8.5 Hz, 1 H), 8.22 (dd, J = 8.6, 2.3 Hz, 1 H), 8.04 (s, 1 H), 7.67 (dd, J = 8.5, 1.5 Hz, 1 H), 7.13 (d, J = 8.7 Hz, 1 H), 4.53 (br s, 1 H), 4.11 (br s, 1 H), 4.03 (tt, J = 7.7, 3.9 Hz, 1 H), 3.89 (s, 3 H), 3.77 (s, 2 H), 3.64 (br s, 1 H), 3.00 (br s, 1 H), 2.09 (br s, 1 H), 1.98- 1.56 (m, 4 H), 1.24-1.05 (m, 4 H).

LCMS (ESI-TOF) m/z 560.2 [M + H ⁺ ] with a purity of >99%. N-(l-(2-(4-(l-Amino-2-methylpropan-2-yl)phenyl)-4-chloroquin oline-7-carbonyl)azetidin- 3-yl)-l-cyclopropyl-lH-l,2,3-triazole-4-carboxamide (D099)

Compound D099 was synthesized using 4-amino-l-boc-azetidine and l-cyclopropyl-lH-1,2,3- triazole-4-carboxylic acid (S7 and S6 General Procedure C) and compound S5 followed by boronic acid hydrochloride S12 where R ¹³ is 4-(l-amino-2-methylpropan-2-yl)phenyl (General Procedure F).

¹ H NMR (400 MHz, DMSO) δ 9.28 (d, J = 7.3 Hz, 1 H), 8.63 (s, 1 H), 8.46 (s, 1 H), 8.31-8.22 (m, 4 H), 7.92 (dd, J= 8.7, 1.5 Hz, 1 H), 7.54 (d, J= 8.5 Hz, 2 H), 4.87-4.76 (m, 1 H), 4.68 (t, J = 8.3 Hz, 1 H), 4.51-4.37 (m, 2 H), 4.19-4.11 (m, 1 H), 4.10-3.96 (m, 1 H), 2.72 (s, 2 H), 1.29 (s, 6 H), 1.25-1.18 (m, 2 H), 1.18-1.08 (m, 2 H).

LCMS (ESI-TOF) m/z 544.2 [M + H ⁺ ] with a purity of >99%.

Comparative Example 1

EPZ031686 (Comparative Compound 1) has an IC50 of 3 nM and in-cell western IC50 of 36 nM using MAP3K2 as substrate (Figure 1). However, upon testing by the inventors, Comparative Compound 1 failed to show any anti-proliferative activity against a panel of human cancer cell lines (Table 1, entry 1). These results do not correspond with early studies using SMYD3-small interfering RNA (SiRNA) in human cancer cells, where significant growth suppression was observed.

Phenotypes observed in a knockout model are not always predictive of what happens when small molecule inhibitors are used. In these KO models, by eliminating the protein entirely, complex protein-protein interactions that dominate certain phenotypes are also disrupted. Consequently, small molecules developed to inhibit the enzymatic activity by binding to a single ligand site might fail to reproduce the phenotype observed. Inhibition of enzymatic activity of SMYD3 alone is not sufficient to show anti-proliferative activity in cancer cells.

Industrial Applicability

The compounds as defined above may find a multiple number of applications in which their ability to inhibit protein lysine methyltransferases such as SMYD3. The compounds may also be used in treating or preventing a condition or disorder in a mammal in which inhibition of a protein methyl transferase and/or co-factor thereof and/or via an unspecified mechanism prevents, inhibits or ameliorates apathology or a symptomology of the condition. The condition or disorder may be cancer, angiogenic disorder or pathological angiogenesis, fibrosis and inflammatory conditions. The compounds may be particularly useful in treating cancer such as breast, gastric, pancreatic, colorectal, lung cancer and hepatocellular carcinoma and other hypervascular tumors as well as angiogenic diseases.

It will be apparent that various other modifications and adaptations of the invention will be apparent to the person skilled in the art after reading the foregoing disclosure without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.