Compounds, compositions and methods for attenuation of mammalian translation of c-MYC or n-MYC proteins

Abstract

A method of modulating c-MYC activity is disclosed. The method includes administering an effective amount of a compound of Formula (I).

Description

Attorney Docket No.: 01317-0001-00PCT COMPOUNDS, COMPOSITIONS AND METHODS FOR ATTENUATION OF MAMMALIAN TRANSLATION OF C-MYC OR N-MYC PROTEINS OF THE MYC PROTO-ONCOGENE FAMILY OF BHLH TRANSCRIPTION FACTORS Field

[0001] The present disclosure provides compounds that are inhibitors of c-MYC or n-MYC translation and are therefore useful for the treatment of cancers. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. Background

[0002] The expression level of c-MYC or n-MYC proteins are dysregulated in most tumor types and are key drivers of cancer progression and maintenance (e.g. in non-small-cell lung carcinoma, triple-negative breast cancer, and glioblastoma). Either c-MYC or n-MYC are known to be aberrantly expressed in up to 70 % of human cancers. Both c-MYC and n- MYC are generally considered undruggable by small molecules due to their lack of a defined ligand binding sites, intrinsically disordered structure and nuclear localization. Multiple in vivo studies (Souchek 2008; Felsher 2010; Danasekaran 2020) have demonstrated that transient c-MYC inhibition results in sustained tumor regression by promoting proliferative arrest, differentiation, apoptosis, and cellular senescence in cancer cells while having minimal effects on normal tissue which are reversible. Thus targeting c-MYC presents an exciting opportunity for anti-cancer therapy.

[0003] The present disclosure is based in part on the discovery of a new approach to targeting MYC that directly circumvents these issues above. In this approach translation stallers target a cytosolic nascent chain / ribosome complex instead of a fully translated protein. Translation can be tuned to deliver partial inhibition and thus impact the therapeutic index. There are currently no effective approaches to target either c-MYC n-MYC with small molecule inhibitors and the medical opportunity is enormous with >100K deaths a year in the US attributed to c-MYC or n-MYC dysregulation.

[0004] Substituted amides have been suggested for the mediation of PCSK9 and diseases including coronary artery disease (e.g., US2014 / 0315928; WO2018 / 192493; and | https: / / doi.org / 10.1371 / journal.pbio.2001882 “Selective stalling of human translation throughAttorney Docket No.: 01317-0001-00PCT small-molecule engagement of the ribosome nascent chain” Nathanael Lintner et al. March 212017). Summary

[0005] The following embodiments are provided.

[0006] Provided herein are methods of modulating c-MYC activity comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein * denotes a stereocenter; M is C1-9heteroaryl, C1-9heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; Rcis absent, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10 arylene, C3-9 heteroarylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, or C1-9heterocyclylene, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH- aryl, NH-heteroaryl, and cyano;Attorney Docket No.: 01317-0001-00PCT Z is a bond, -O-, S, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, -N(Rb)(C1-3alkylene), where Rbis H, or C1-3 alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C2-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH- heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond.

[0007] In another embodiment, provided herein are methods of treating a condition associated with MYC activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, as defined above, or a pharmaceutically acceptable salt thereof,

[0008] In another embodiment, provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, as defined above, or a pharmaceutically acceptable salt thereof.

[0009] In still other embodiments, provided herein are compounds of Formula (Ia), (Ib), (Ic), or a pharmaceutically acceptable salt thereof:Attorney Docket No.: 01317-0001-00PCTwherein * denotes a stereocenter; M is pyrrolo[2,3-c] pyridinyl, pyrrolo[3,2-c] pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[2,3- c]pyridinyl, thieno[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, quinolinyl-2-one, 1,6- naphthyridinyl, 1,6-naphthyridinyl, pyridinyl, 2-pyrazinyl, thiazolo[5,4-c]pyridinyl, or thiazolyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; V is N, or CH; Rdis absent, halo, cyano, C1-3alkyl, or C1-3alkyloxy; Rcis H, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; X3is CH2 (or CH if bonded to T through Z), NH (or N if bonded to T through Z); Reis H or C1-3alkyl; Z2is a bond or C1-3 alkylene; and Z is a bond, C1-3 alkylene, -(CH2)2C(O)NH-, -N(Rb)-, where Rbis H, or C1-3 alkyl; and T is [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, pyrrolidinyl, isoxazolyl, isoindolyl, piperidinyl, oxetanyl, thiophenyl, morpholino, thiazolyl, pyridinyl-2-one, pyrazinyl-2-one, indazolyl, 4,5,6,7-Attorney Docket No.: 01317-0001-00PCT tetrahydro-indazolyl, isoindolinyl-1,3-dione, 1,3,4-oxadiazolyl, 1,3,4-oxadiazolyl-2-one, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,3-dihydro- 2H-imidazolyl-2-one, phthalazinyl, isoquinolinyl, 2λ5-quinolinyl-2-one, 6,7-dihydro-4H- [1,2,3]triazolo[5,1-c][1,4]oxazinyl, 2,3-dihydro-4λ2-pyrido[3,2-b][1,4]oxazinyl, thiazolo[5,4- c]pyridinyl, or quinazolinyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH-heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when the compound is of Formula (Ia) then i) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is 3-chloropyridin-2-yl or 3- methylpyridin-2-yl, then T is not unsubstituted pyrazolo[2,3-a]pyrimidinyl; methyl substituted pyrazolo[2,3-a]pyrimidinyl; unsubstituted [1,2,3]triazolo[4,5-b]pyridinyl; methyl substituted [1,2,3]triazolo[4,5-b]pyridinyl; or pyrazolyl substituted with a methyl group, a substituted carboxyl group, a substituted or unsubstituted tetrazolyl group, or a substituted or unsubstituted 1,3,4-oxadiazolyl-2-one group; or ii) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is unsubstituted isoquinolinyl or methyl substituted pyrrolo[2,3-c]pyridinyl, then T is not a pyrazolyl substituted with methyl, substituted carboxyl or both methyl and substituted carboxyl; or iii) when M is phenyl or pyridinyl, and Z is a bond, then T is not 5,5-dimethylisoxazolyl- 4(5H)-one or 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl. Detailed Description

[0010] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. I. Definitions AbbreviationsAttorney Docket No.: 01317-0001-00PCT

[0011] BHLH. Basic helix–loop–helix.

[0012] EC50. “Effective concentration”, as defined below.

[0013] pEC50. Negative logarithm base 10 of the EC50.

[0014] IC50. “Inhibitory concentration 50” as defined below.

[0015] pIC50. Negative logarithm base 10 of the IC50.

[0016] DNA. Deoxyribonucleic acid.

[0017] RNA. Ribonucleic acid.

[0018] mRNA. Messenger RNA. This is typically comprised of the following elements in order starting from the 5’ end of the mRNA: mRNA CAP, 5’-untranslated region, initiation codon, “open reading frame”, stop codon, and 3’ untranslated region.

[0019] 5’-mRNA CAP: A specially altered nucleotide on the 5’ end of an mRNA molecule, which consists of a guanine nucleotide connected to mRNA via a 5’ to 5’ triphosphate linkage.

[0020] LC. Liquid chromatography.

[0021] LLOQ. Lower limit of quantification, as described below.

[0022] MAX. The protein encoded by this gene is a member of the basic helix-loop-helix leucine zipper (bHLHZ) family of transcription factors. It is able to form homodimers and heterodimers with other family members, which include Mad, Mxi1 and Myc. The underlying gene structure is further described here: https: / / www.ncbi.nlm.nih.gov / gene / 4149.

[0023] MS. Mass spectrometry.

[0024] MYC. The family of proto-oncogenes comprised of c-MYC, n-MYC and l-MYC, as defined and described below.

[0025] C-MYC. The c-MYC gene is a protooncogene whose dysregulation due to rearrangement, copy number amplification and other forms of dysregulation (i.e. mutations in the Wnt pathway the result in upregulation of c-MYC) are correlated with many forms of cancer. The underlying gene structure is further described here: https: / / www.ncbi.nlm.nih.gov / gene / 4609.

[0026] N-MYC. The n-MYC gene is a protooncogene whose dysregulation due to rearrangement, copy number amplification and other forms of dysregulation are correlated with many forms of cancer, notably neuroblastoma. The underlying gene structure is further described here: https: / / www.ncbi.nlm.nih.gov / gene / 4613

[0027] L-MYC. The l-MYC gene is a protooncogene whose dysregulation due to rearrangement, copy number amplification and other forms of dysregulation are correlatedAttorney Docket No.: 01317-0001-00PCT with many forms of cancer, notably neuroblastoma. The underlying gene structure is further described here: https: / / www.ncbi.nlm.nih.gov / gene / 4610.

[0028] MM. Multiple myeloma.

[0029] TMT. Tandem Mass Tag.

[0030] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0031] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through a line in a Formula indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0032] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0033] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In certain embodiments, the term “about” includes the indicated amount ± 5%. In certain embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0034] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 12 carbon atoms (i.e., C1-12 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 4 carbon atoms (i.e., C1-4alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl”Attorney Docket No.: 01317-0001-00PCT includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., - CH2CH(CH3)2) and tert-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0035] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group, “alkylenyl” group, or an “alkenyl” group, an “arylene” group or an “arylenyl” group, respectively. In another example, a trivalent group such as a trivalent “alkyl” group may also be referred to as an “alkylyne” group, “alkylynyl” group or “alkynyl” group. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0036] “Alkoxy” refers to the group “alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy and 1,2-dimethylbutoxy.

[0037] “Alkoxycarbonyl” refers to the group “alkyl-O-C(O)”.

[0038] “Amide” or “amido” refers to the group “R-C(O)NRR”.

[0039] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0040] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 18 carbon ring atoms (i.e., C6- 18 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl.

[0041] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20cycloalkyl), 3 to 15 ring carbon atoms (i.e., C3-15 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Cycloalkyl alsoAttorney Docket No.: 01317-0001-00PCT includes “spiro cycloalkyl” when there are two positions for substitution on the same carbon atom. Monocyclic radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the term cycloalkyl is intended to encompass any non-aromatic ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule.

[0042] “Carboxylic acid” and “hydroxycarbonyl” each refer to the group “R-COOH”.

[0043] “Cyano” or “Carbonitrile” refers to a -CN group.

[0044] “Ester” refers to the group “R-C(O)O-R”.

[0045] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

[0046] “Haloalkyl” refers to an alkyl group as defined herein wherein one ore more of the hydrogen atoms of the alkyl group are replace by a halogen group.

[0047] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include -CH2OCH3, -CH2SCH3, and -CH2NRCH3, where R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0048] “Heteroaryl” refers to an aromatic group (e.g., a 5-14 membered ring system) having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-20heteroaryl), 1 to 13 ring carbon atoms (i.e., C3-12heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12heteroaryl) or 3 to 8 carbon ring atoms (i.e., C3-8 heteroaryl); and 1 to 6 heteroatoms, 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groupsAttorney Docket No.: 01317-0001-00PCT include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl (i.e., thienyl). Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0049] “Heterocyclyl” refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro- heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more oxo (C=O) or N-oxide (N-O-) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass any non- aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-10 heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-8heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-12Attorney Docket No.: 01317-0001-00PCT heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-8heterocyclyl) or 3 to 6 ring carbon atoms (i.e., C3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo- thiomorpholinyl. Examples of the spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1- azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0050] “Thioether” refers to the group “R-S-R”.

[0051] “Cyclic organic radical” refers to a cyclic organic moiety which may be for example an aryl, heteroaryl, cycloalkyl or heterocyclyl moiety or one or more of said cyclic moieties bonded, spiro-linked or fused together, any of which may be optionally substituted with one or more substituents which optional substituents may also be optionally substituted.

[0052] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen. As used herein unless otherwise indicated an optionally substituted group may have 0, 1, 2, or 3 hydrogen atoms replaced by another group.

[0053] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methylAttorney Docket No.: 01317-0001-00PCT substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted. For example, in certain embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxy, halo, alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl. In certain embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is substituted. In certain embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is unsubstituted.

[0054] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds of the present disclosure containing an asymmetrically substituted atom may be isolated in optically active, optically enriched, optically pure, or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of materials. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0055] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and / or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof can exist as tautomers and / or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof, are within the scope of this disclosure. For example, pyrazole tautomers as shown below are equivalent structures. The depiction of one such structure is intended to both structures.Attorney Docket No.: 01317-0001-00PCT

[0056] In some embodiments the compounds of Formula (I) may present in two or more rotamer forms, for example around the central tertiary amide bond. In some embodiments of compounds of Formula (I) with a sterically hindered substitution on the amide in Formula (I), for example compounds of Formula (I) with the 8-position substitution on an isoquinoline Mand / or with substitution on the L group, show more than one set of signals in either NMR and / or HPLC.

[0057] Any compound or Formula given herein, such as the compounds of Formula I, is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0058] The disclosure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0059] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F,3H,11C labeled compound may be useful for PETAttorney Docket No.: 01317-0001-00PCT or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0060] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0061] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0062] Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, stereoisomers and prodrugs of the compounds described herein, such as the compounds of Formula I, and are included within the term “compounds”. “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0063] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloricAttorney Docket No.: 01317-0001-00PCT acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

[0064] Certain compounds of the present invention or combination agents may exist in more than one crystal form (generally referred to as “polymorphs”). Polymorphs may be prepared by crystallization under various conditions, for example, using different solvents or different solvent mixtures for recrystallization; crystallization at different temperatures; and / or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast colling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

[0065] The term “hydrate” refers to the complex formed by the combining of a compound described herein and water.

[0066] A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure. Examples of solvents that form solvates include, but areAttorney Docket No.: 01317-0001-00PCT not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine.

[0067] The compounds disclosed herein, such as the compounds of Formula I, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0068] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0069] “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0070] “Rotamers” are conformational isomers that differ by rotation about only a single sigma bond.

[0071] “Prodrugs” means any compound which releases an active parent drug according to a Formula described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerateAttorney Docket No.: 01317-0001-00PCT the free hydroxy, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0072] The phrase “pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0073] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0074] As used herein, the terms “administering” and “administered” refer to the delivery of a composition into a subject by a method or route that results in at least partial localization of the composition at a desired site. A composition can be administered by any appropriate route that results in effective treatment in the subject, i.e., administration results in delivery to a desired location in the subject where at least a portion of the composition is delivered to the desired site for a period of time. Modes of administration include injection, infusion, instillation, or ingestion. “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebrospinal, and intrasternal injection and infusion. In some examples, the route is intravenous.

[0075] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more ofAttorney Docket No.: 01317-0001-00PCT the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life and / or prolonging survival).

[0076] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in certain embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0077] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0078] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, prodrug, stereoisomer or a mixture of stereoisomers thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of as described herein. The therapeutically effective amount may vary depending on the subject and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0079] As defined herein “Inhibition of Translation” refers to inhibition of the rate of translational elongation of an mRNA to a corresponding polypeptide by the ribosome. This mode of inhibition may include a compound inducing the action of processes collectively known as Ribosomal Quality Control in a compound- and mRNA-dependent manner. This mode of inhibition contrasts with inhibition of initiation of translation at a “start codon” and termination of translation at a “stop codon”. This mode of inhibition is also in contrast toAttorney Docket No.: 01317-0001-00PCT inhibition of gene expression at an “upstream” step such as transcription of DNA to RNA or splicing of pre-mRNA to mRNA. Direct inhibition may be determined by the “In Vitro Single Point Translation Screening Assay” provided herein (Example 1). This “In Vitro Translation Single Point Screening Assay” is specific to the production of protein from mRNA and therefore detects inhibitors of this translational process rather than other mechanisms by which protein accumulation may be reduced. Any compound that presents an IC50(µM) below about 50 µM in the “In Vitro Translation Single Point Screening Assay” is considered as inhibiting translation. In some embodiments, the IC50 of the compound is less than about 30 µM, or the IC50 of the compound is less than about 20 µM.

[0080] As used herein “modulating, modulate or modulated” refers to modulation of protein accumulation in either an in vitro or in a cellular context. Modulation may be measured in an in vitro biochemical assay using the In Vitro Single Point Translation Screening Assay provided herein or by direct proteomic assays such as Western blots, alpha screen or mass spec analysis. Modulation may also be measured in a cellular context using Western blots, alpha screen, or other proteomic assay methods such as mass spec analysis. Any compound that modulates the accumulation of c-MYC or n-MYC protein in a cellular context will indirectly modulate the expression level of downstream genes that are controlled by the respective c-MYC or n-MYC transcription factors. The c-MYC or n-MYC oncoproteins potentially regulate the transcription of at least 15% of the entire genome (Chen 2018).

[0081] A biomarker is a measurable indicator of the severity or presence of some disease state as well as an indicator of the mechanism of action of a drug of interest. More generally a biomarker is anything that can be used as an indicator of a particular disease state or some other physiological state of an organism. According to the WHO, the indicator may be chemical, physical, or biological in nature - and the measurement may be functional, physiological, biochemical, cellular, or molecular. A biomarker can be a substance whose detection indicates a particular disease state or a substance for which a change in expression or state of a protein correlates with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment. Biomarkers can be characteristic biological properties or molecules that can be detected and measured in parts of the body like the blood or tissue. They may indicate either normal or diseased processes in the body. Biomarkers can be specific cells, molecules, gene rearrangements (as with Burkitt’s lymphoma), gene products, enzymes, or hormones. Biomarkers are useful in a number of ways, including mechanism of action of the drug of interest, measuring the progress of disease, evaluating theAttorney Docket No.: 01317-0001-00PCT most effective therapeutic regimes for a particular cancer type, and establishing long-term susceptibility to cancer or its recurrence. Biomarkers play roles in medicinal biology and help in early diagnosis, disease prevention, drug target identification, drug response etc. As used herein the phrase “biomarker that predicts anti-MYC activity” refers to a biomarker as described above associated with modulation of translation of c-MYC or n-MYC.

[0082] As used herein, “effective concentration50 (EC50)” refers to the concentration at which a given compound exerts 50% of the maximum effect observed for that compound. This concentration is typically estimated using Prism Graphpad or an equivalent software tool that infers the EC50 from a multi-point dose response curve. In a typical EC50 estimation there is region at the low concentration end of the dose response curve showing no significant change relative to the DMSO control. This is the so-called “top” of the dose response curve. At high concentrations, there is a “top” where the effect is observed to plateau to a maximum value. The maximum value for inhibition is often defined using a known inhibitor of the pathway dosed at a concentration that is 10x or move above the EC50 for the known inhibitor. The EC50 refers to the concentration that is mathematically inferred by a software program such as Prism Graphpad to give a 50% of maximum effect. As used herein the phrase “activates c-MYC or n-MYC activity” refers to direct activation versus, for example, upstream activation. Direct activation is determined in some instances by the In Vitro Multiple Point Translation Screening Assay. Any compound that results in at least 2x increased expression of MYC relative to the DMSO control and presents an Effective Concentration (EC50) below about 50 µM in the In Vitro Multiple Point Translation Screening Assay is considered as activating translation. In some embodiments, the EC50 of the compound is less than about 30 µM, or the EC50 of the compound is less than about 20 µM.

[0083] As used herein the phrase “condition associated with c-MYC or n-MYC activity” refers to at least those conditions disclosed herein, especially in the methods section, and any other conditions known to be mediated, caused, moderated or associated with c-MYC or n- MYC activity, for example the GeneCards Summary for c-MYC Gene indicates that diseases associated with MYC include Burkitt Lymphoma and High-Grade B-Cell Lymphoma Double-Hit / Triple-Hit.

[0084] In some embodiments, the compound “selectively” inhibits translation of mRNA to protein. The terms “selective” or “selectively” are defined as “significant inhibition” of translation of less than 10 percentage of proteins in a typical “Global Proteomic Assay”. As used herein, “Global Proteomic Assay” refers to an assay wherein the expression level of allAttorney Docket No.: 01317-0001-00PCT proteins is assessed without utilizing a protein-specific detection method such as is used in Western blots, alpha screen assays or ELISA assays. In contrast to protein-specific proteomic methods, a Global proteomic Assay is designed to quantitatively measure the levels of all proteins that are observed above the Lower Limit of Quantification (LLOQ) of the detection method used in the protocol. The LLOQ is the lowest value of a signal (or concentration, activity, response, etc….) that can be quantified with acceptable precision and accuracy in an assay of interest.

[0085] A typical Global Proteomic Assay utilizes liquid chromatography of trypsinized whole cellular extracts, together with mass spectrometry to assess the relative abundance of all tryptic peptides that are present within the Limit of Quantification for the particular instruments used in the assay. A typical Global Proteomic Assay uses Tandem Mass Tags (TMT) and is described in Rauniyar N. et al. 2014 and Deracinois B. et al. 2013. It is preferred that the level is below about 1% of proteins and especially preferred that the level is below about 0.5% or 0.1 % of proteins. Typically, in a standard assay the 1% level equates to about 40 non-target proteins out of about 4000 proteins for which statistically significant measurements can be made. “Significant inhibition” of a particular protein in a Global Proteomic Assay is defined as a decrease in protein expression in the Global Proteomic Assay to below about 50% of its starting level relative to vehicle. This definition of “inhibition related to the Global Proteomic Assay” is not to be confused with the previous definition of inhibition related to the In Vitro Single Point Translation Screening Assay or the In Vitro Multiple Point Translation Screening Assay.

[0086] As used herein, Ribosome Profiling Assay is an assay in which one measures the relative abundance of sequences of mRNA present in cellular extracts prepared under specified conditions that are protected from nuclease digestion due to occupancy by ribosomes. A typical Ribosome Profiling Assay is described here: https: / / ribomaps.com / services. In a typical application, cells are treated with either vehicle or vehicle plus compound of interest at a concentration known to have measurable cellular effects and extracts are prepared at a specified time point where measurable activity is expected. The extracts are subjected to Ribosome Profiling, an analysis wherein the sequencing results are used to infer the locations on mRNA of ribosomes in the cellular extracts at the specified timepoints with the specified treatments. The data can be used to infer the locations on mRNA of compound-dependent translationally stalling.Attorney Docket No.: 01317-0001-00PCT II. Compounds

[0087] Provided herein are compounds of Formula I, or a pharmaceutically acceptable salt thereof,wherein * denotes a stereocenter; M is C1-9heteroaryl, C1-9heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; Rcis absent, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10 arylene, C3-9 heteroarylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, or C1-9heterocyclylene, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH- aryl, NH-heteroaryl, and cyano; Z is a bond, -O-, S, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, -N(Rb)(C1-3alkylene), where Rbis H, or C1-3 alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C2-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano,Attorney Docket No.: 01317-0001-00PCT substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH- heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond.

[0088] In some embodiments, pyrrolo[2,3-c] pyridinyl, pyrrolo[3,2-c] pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, quinolinyl-2-one, 1,6-naphthyridinyl, 1,6-naphthyridinyl, pyridinyl, or 2- pyrazinyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, ester, carboxylic acid, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents.

[0089] In some embodiments, M is; wherein each R1is independently absent halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted ester, substituted or unsubstituted acetyl, carboxylic acid, substituted or unsubstituted alkoxycarbonyl, substitutedAttorney Docket No.: 01317-0001-00PCT or unsubstituted amido, substituted or unsubstituted carbamate; substituted or unsubstituted alkoxy, substituted or unsubstituted thioether, substituted or unsubstituted amino, cyano, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, wherein each substituted group has 1, 2 or 3 substituents; n* is 0, 1, 2 or 3; R2is absent, halo, alkyl, alkenyl, alkynyl, aryl heteroaryl or cyano; R1*is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2*is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl; and each W, X, and Y are independently -CH, -N, -NH, N-alkyl, O, or S; R2#is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl or C-heteroaryl; Y2is CH or N; R2^is absent, alkyl, alkenyl, alkynyl, cyano or halo; and R3is absent, alkyl, alkenyl, alkynyl, halo, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, alkoxy, thioether, or amino; and ---- is a bond that is a double bond or a single bond. In some M is, or ; wherein each R1is independently absent, cyano; chloro; bromo; fluoro; acetyl; amido; carbamate; alkylcarbamate; pyrazinyl; tetrazolyl; hydroxycarbonyl; alkoxycarbonyl; pyridinyl-2-one; C1-6 alkoxy; C1-6 haloalkyl; C1-6 cycloalkyl; C1-6 alkyl optionally substituted with OH, pyridinyl, amido, or phenyl; C2-6 alkenyl optionally substituted with amido, OH, pyrazolyl, pyridinyl, isoxazolyl, thiophenyl, alkyl substituted amido, hydroxyalkylamido, arylalkylamido, alkoxycarbonyl, or hydroxycarbonyl; C2-6 alkynyl optionally substituted with OH; phenyl optionally substituted with OH, halo, hydroxyalkyl, sulfonyl, or alkylsulfonyl; pyrazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, or acetamide; pyridinyl optionally substituted with amino; triazolyl optionally substituted with C1-6hydroxyalkyl; thiazolylAttorney Docket No.: 01317-0001-00PCT optionally substituted with C1-6alkyl; or 1,3,4-thiadiazolyl optionally substituted with C1-6alkyl; n* is 0, 1 or 2; R2is absent, halo, or C1-6alkyl, or cyano.

[0091] In some embodiments, M is; wherein Y2is CH or N; R1*is absent; chloro; cyano; amido; alkylamido; allyl; alkoxycarbonyl; pyrazolyl; methylpyrazolyl; hydroxyethylpyrazolyl; isoxazolyl; 2,5-dihydro-pyrrolyl; thiophenyl; thieno[3,2-c]pyridinyl; C1-6 alkyl; C2-6 alkenyl optionally substituted with OH; or C2-6 alkynyl optionally substituted with OH; R2*is absent; C1-6alkyl; halo; pyrazolyl; C2-6alkenyl optionally substituted with phenyl, methylpyrazolyl, or pyridinyl. In some M isor ; wherein R1is absent, bromo, fluoro; chloro; amido; alkyl substituted amido; cyano; C1-6cycloalkyl; C1-6alkyl optionally substituted with phenyl or pyridinyl; C2-6alkenyl optionally substituted with OH, amido, alkyl substituted amido, or alkoxycarbonyl; C2-6 alkynyl optionally substituted with OH, alkyl substituted amido, or pyridinyl; phenyl optionally substituted with one, two or three groups chosen from halo, OH, hydroxyalkyl, halohydroxyalkyl, cyano, CH3O-, carboxyl, amino, amido, amidoalkyl, amidoalkoxy, alkyl substituted amido, phenyl substituted amido, hydroxyalkylamido, acetamido, aldehyde, acetyl, hydroxyalkylamido, sulfonylamino, alkylsulfonyl, isoxazolyl, pyrazolyl, and thiourea; pyridinyl optionally substituted with one or two groups chosen from C1-6 alkyl, halo, amino, cyano, cyanoalkyl, haloalkyl, and alkoxy; 1,2,3-triazolyl optionally substituted with C1-6 alkyl; thiazolyl optionally substituted with C1-6alkyl, hydroxyalkyl, alkoxycarbonyl, or hydroxycarbonyl; pyrazolyl optionally substituted with C1-6alkyl, hydroxyalkyl, pyridinyl, methylpyridinyl, orAttorney Docket No.: 01317-0001-00PCT acetamido; benzo[d]isoxazolyl optionally substituted with amino; thiophenyl optionally substituted with hydroxyalkyl, cyano, or amido; pyrimidinyl optionally substituted with amino or alkylamino; pyridylcarbonyl; [1,2,4]triazolo[1,5-a]pyridinyl; pyrazinyl; pyridazinyl; pyridinyl-2-one; isoindolinyl-1-one; indolinyl; indolinyl-2-one; 1,3-dihydro-2H- benzo[d]imidazolyl-2-one; or indazolyl, wherein each substituted group has 1, 2 or 3 substituents.

[0093] In some embodiments, M is; wherein X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl or C-heteroaryl; R2#is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amido, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2^is absent, alkyl, alkenyl, alkynyl, cyano or halo; and R3is H, alkyl, alkenyl, alkynyl, halo, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, alkoxy, thioether, or amino.

[0094] In some embodiments, L is a bond, phenylene, pyridinylene, piperidinylene, or piperazinylene, each optionally substituted with 1 or 2 substituents chosen from halo, C1-3alkyl, C1-3alkyloxy and combinations thereof, or -NRa-, where Rais H or C1-3alkyl. In some embodiments, L is a bond. In some embodiments, L is phenylene, pyridinylene, piperidinylene, or piperazinylene, each optionally substituted with 1 or 2 substituents chosen from halo, C1-3alkyl, C1-3alkyloxy and combinations thereof. In some embodiments, L is chosen from phenylene, fluorophenylene, chlorophenylene, methoxyphenylene, methylphenylene, ethylphenylene, pyridinylene, piperidinylene, and piperazinylene.

[0095] In some embodiments, Z is a bond. In some embodiments, Z is C1-3alkylene. In some embodiments, Z is methylene. In some embodiments, Z is -NH. In some embodiments, Z is - N(CH3)-.

[0096] In some embodiments, T is a substituted or unsubstituted group chosen from [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, pyrrolidinyl, isoxazolyl, isoindolyl, piperidinyl, oxetanyl,Attorney Docket No.: 01317-0001-00PCT thiophenyl, morpholino, thiazolyl, pyridinyl-2-one, pyrazinyl-2-one, indazolyl, 4,5,6,7- tetrahydro-indazolyl, isoindolinyl-1,3-dione, 1,3,4-oxadiazolyl, 1,3,4-oxadiazolyl-2-one, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,3-dihydro- 2H-imidazolyl-2-one, phthalazinyl, isoquinolinyl, 2λ5-quinolinyl-2-one, 6,7-dihydro-4H- [1,2,3]triazolo[5,1-c][1,4]oxazinyl, 2,3-dihydro-4λ2-pyrido[3,2-b][1,4]oxazinyl, thiazolo[5,4- c]pyridinyl, and quinazolinyl. In some embodiments T is not 5,5-dimethylisoxazolyl-4(5H)- one. In some embodiments, T is not a substituted 5,5-dimethylisoxazolyl-4(5H)-one. In some embodiments T is not 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl. In some embodiments T is not a substituted 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl.

[0097] In some embodiments, T is [1,2,3]triazolo[4,5-b]pyridinyl optionally substituted with halo, haloalkyl, cyano, methyl, methoxy, ethyl, pyrazolyl, alkoxycarbonyl, hydroxycarbonyl, amido, or phenyl; 5,6-dihydropyrrolo[2,3-d]pyrimidinyl optionally substituted with methyl; isoxazolyl optionally substituted with methyl, haloalkyl, alkyoxycarbonyl, or amido; thiazolyl optionally substituted with methyl; pyrazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, C1-6 alkoxyalkyl, amino, phenyl, hydroxycarbonyl or any combination of two or three thereof; pyrimidinyl optionally substituted with amido, amino, or one or two methyl groups; 1,2,3-triazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, halo, or any combination of two or three thereof; 1,2,4-triazolyl optionally substituted with methyl; phenyl optionally substituted with OH, pyrazolyl, pyridinyl, cyano, indazolyl, amidoindazolyl, methoxy, benzyloxy, C2-6alkynyl, or any combination of two or three thereof, and wherein the C2-6alkynyl is further substituted by OH, oxo, alkoxy, isoindolinyl-1,3-dione, morpholino, amino, hydroxyalkyl substituted amino, pyrrolidinyl substituted amino, hydroxypyrrolidinyl substituted amino, pyridinyl substituted amino, pyridinylmethyl substituted amino, or any combination of two or three thereof; pyridinyl optionally substituted with halo, methyl, amino pyridinyl or any combination of two or three thereof; pyrazolo[3,4-d]pyrimidinyl optionally substituted with phenoxyphenyl; imidazolyl optionally substituted phenyl, methyl, amino, or any combination of two or three thereof; pyrazinyl optionally substituted with OH, halo, cyano, amino, substituted amino, C1-6 alkoxycarbonyl, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-8 cycloalkyl, substituted C1-8cycloalkyl, C1-3alkyl substituted with cycloalkyl, C1-3alkyl substituted with substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, C1-3alkyl substituted with heterocyclyl, C1-3 alkyl substituted with substituted heterocyclyl, heteroaryl, substituted heteroaryl, C1-3 alkyl substituted with heteroaryl, C1-3 alkyl substituted with substituted heteroaryl, aryl, substituted aryl, C1-3alkyl substituted with aryl, C1-3alkyl substituted with substituted aryl, C2-6alkenyl,Attorney Docket No.: 01317-0001-00PCT C2-6hydroxyalkenyl, C2-6alkoxyalkenyl, C2-6alkynyl, C2-6hydroxyalkynyl, C2-6alkoxyalkynyl or any combination of two or three thereof; tetrazolyl optionally substituted with methyl, ethyl, or haloalkyl; 1,3,4-oxadiazolyl optionally substituted with C1-6 alkyl, C3-6 cycloalkyl; 1,3,4-thiadiazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, C3-6 cycloalkyl, CD3, OH; pyridinyl-2-one optionally substituted with methyl; 1,3-dihydro-2H-imidazolyl-2-one optionally substituted with methyl; 1,3,4-oxadiazolyl-2-one optionally substituted with methyl; pyrrolidinyl optionally substituted with methyl; benzo[d]isothiazolyl optionally substituted with methyl; 1,2,4-oxadiazolyl optionally substituted with C1-6 alkyl, cyclopropyl or phenyl; morpholino optionally substituted with 1 or 2 C1-6alkyl groups; or pyridazinyl optionally substituted with halo, wherein each substituted group has 1, 2 or 3 substituents. In some embodiments, T is not 5,5- dimethylisoxazolyl-4(5H)-one or 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl.

[0098] In some embodiments, the * stereocenter is in the (R) configuration. In some embodiments, the * stereocenter is in the (S) configuration.

[0099] In some embodiments, the compound is of Formula (Ia), (Ib), (Ic), or a pharmaceutically acceptable salt thereof:wherein * denotes a stereocenter; M is pyrrolo[2,3-c] pyridinyl, pyrrolo[3,2-c] pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[2,3- c]pyridinyl, thieno[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, quinolinyl-2-one, 1,6- naphthyridinyl, 1,6-naphthyridinyl, pyridinyl, 2-pyrazinyl, thiazolo[5,4-c]pyridinyl, orAttorney Docket No.: 01317-0001-00PCT thiazolyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; V is N, or CH; Rdis absent, halo, cyano, C1-3alkyl, or C1-3alkyloxy; Rcis absent, H, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; X3is CH2(or CH if bonded to T through Z), NH (or N if bonded to T through Z); Reis H or C1-3 alkyl; Z2is a bond or C1-3 alkylene; and Z is a bond, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, where Rbis H, or C1-3alkyl; and T is [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, pyrrolidinyl, isoxazolyl, isoindolyl, piperidinyl, oxetanyl, thiophenyl, morpholino, thiazolyl, pyridinyl-2-one, pyrazinyl-2-one, indazolyl, 4,5,6,7- tetrahydro-indazolyl, isoindolinyl-1,3-dione, 1,3,4-oxadiazolyl, 1,3,4-oxadiazolyl-2-one, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,3-dihydro- 2H-imidazolyl-2-one, phthalazinyl, isoquinolinyl, 2λ5-quinolinyl-2-one, 6,7-dihydro-4H- [1,2,3]triazolo[5,1-c][1,4]oxazinyl, 2,3-dihydro-4λ2-pyrido[3,2-b][1,4]oxazinyl, thiazolo[5,4- c]pyridinyl, or quinazolinyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstitutedAttorney Docket No.: 01317-0001-00PCT thioether, substituted or unsubstituted amino, NH-aryl, and NH-heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when the compound is of Formula (Ia) then i) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is 3-chloropyridin-2-yl or 3- methylpyridin-2-yl, then T is not unsubstituted pyrazolo[2,3-a]pyrimidinyl; methyl substituted pyrazolo[2,3-a]pyrimidinyl; unsubstituted [1,2,3]triazolo[4,5-b]pyridinyl; methyl substituted [1,2,3]triazolo[4,5-b]pyridinyl; or pyrazolyl substituted with a methyl group, a substituted carboxyl group, a substituted or unsubstituted tetrazolyl group, or a substituted or unsubstituted 1,3,4-oxadiazolyl-2-one group; or ii) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is unsubstituted isoquinolinyl or methyl substituted pyrrolo[2,3-c]pyridinyl, then T is not a pyrazolyl substituted with methyl, substituted carboxyl or both methyl and substituted carboxyl; or iii) when M is phenyl or pyridinyl, and Z is a bond, then T is not 5,5-dimethylisoxazolyl- 4(5H)-one or 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl.

[0100] In some embodiments, Rcis absent, methyl, ethyl, OH, NH2, or fluoro and Z is a bond, methylene, -NH- or -N(CH3)-.

[0101] In some embodiments, when the compound is of Formula (I), (Ia), (Ib), (Ic), or a pharmaceutically acceptable salt thereof and Z is bond and T is pyrazinyl, the pyrazinyl groups is not further substituted with a substituted or unsubstituted group chosen from cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0102] In some embodiments, provided herein is a compound of Formula Ia, and pharmaceutically acceptable salts thereof,wherein * denotes a stereocenter with (R) configuration; wherein M is isoquinolinyl or a 9 membered fused bicyclic heteroaryl ring having 2 heteroatoms selected independently from nitrogen and sulfur, the isoquinolinyl or 9 membered ring optionally substituted with 1 to 2 substituents independently selected fromAttorney Docket No.: 01317-0001-00PCT pyridinyl, C1-3alkyl, C1-3alkoxy, fluoro or chloro; V is CH; n is 1; Rcis absent; Rdis absent, C1-3 alkyl, C1-3 alkoxy, fluoro or chloro; Z is a bond; and T is a 5 membered heteroaryl or a 9 membered fused bicyclic ring each 5 or 9 membered ring having 3-4 heteroatoms selected independently from nitrogen and sulfur and each 5 or 9 membered ring optionally substituted with 1 to 2 substituents selected independently from C1-3 alkyl, C(D)3, C1-3 alkoxy, or fluoro.

[0103] In some embodiments, M is thieno[3,2-c]pyridinyl or isoquinolinyl substituted with 1 to 2 substituents independently selected from pyridinyl, methyl, fluoro or chloro; T is a 9 membered fused bicyclic ring having 4 nitrogens and is optionally substituted with 1 to 2 substituents selected independently from fluoro, C1-3 alkyl, C(D)3.

[0104] In some embodiments, M is thieno[3,2-c]pyridinyl or isoquinolinyl substituted with 1 to 2 substituents independently selected from pyridinyl, methyl fluoro, or chloro; and T is a 5 membered heteroaryl having 3 heteroatoms selected independently from nitrogen and sulfur optionally substituted with 1 substituent selected independently from fluoro, C1-3 alkyl, C(D)3.

[0105] In some embodiments, M is thieno[3,2-c]pyridin-4-yl or isoquinolin-1-yl substituted with 1 to 2 substituents independently selected from pyridinyl, methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, fluoro or chloro; Z is a bond; and T is [1,2,3]triazolo[4,5- b]pyridin-3-yl, thieno[3,2-c]pyridinyl, 1,2,3-triazol-4-yl or 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

[0106] In some embodiments, M is thieno[3,2-c]pyridin-4-yl substituted with pyridinyl, methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, fluoro or chloro; Z is a bond; and T is [1,2,3]triazolo[4,5-b]pyridin-3-yl, thieno[3,2-c]pyridinyl, 1,2,3-triazol-4-yl or 1,3,4- thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

[0107] In some embodiments, M is thieno[3,2-c]pyridin-4-yl substituted with pyridinyl or methyl; n is 1; Rcis absent; V is CH, Rdis fluoro or chloro; Z is a bond; and T is [1,2,3]triazolo[4,5-b]pyridin-3-yl, thieno[3,2-c]pyridinyl, or 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.Attorney Docket No.: 01317-0001-00PCT

[0108] In some embodiments, provided herein is a compound of Formula Iawherein * denotes a stereocenter with (R) configuration; M is isoquinolinyl substituted with 1 to 2 substituents independently selected from C1-3 alkyl, C1-3alkoxy, fluoro or chloro; n is 1; Rcis absent; V is CH, Rdis absent, C1-3alkyl, C1-3alkoxy, fluoro or chloro; Z is a bond; and T is a 5 membered heteroaryl having 3 heteroatoms selected independently from nitrogen and sulfur optionally substituted with 1 to 2 substituents selected independently from C1-3alkyl, C(D)3, C1-3alkoxy, or fluoro; and further wherein T is not a pyrazolyl substituted with methyl, substituted carboxyl or both methyl and substituted carboxyl.

[0109] In some embodiments, M is isoquinolinyl substituted with 1 to 2 substituents independently selected from methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, methyl, fluoro or chloro; Z is a bond; and T is a 5 membered heteroaryl having 3 heteroatoms selected independently from nitrogen and sulfur optionally substituted with 1 substituent selected independently from methyl, C(D)3, or fluoro.

[0110] In some embodiments, M is isoquinolin-1-yl substituted with 1 to 2 substituents independently selected from methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, fluoro or chloro; Z is a bond; and T is 1,2,3-triazol-4-yl or 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

[0111] In some embodiments, the compound is of (Ib), or a pharmaceutically acceptable salt thereof:Attorney Docket No.: 01317-0001-00PCTwherein * denotes a stereocenter with (R) configuration; X3is CH2(or CH if bonded to T through Z), NH (or N if bonded to T through Z); Rcis H, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; n is 1; and Z is a bond, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, where Rbis H, or C1-3alkyl.

[0112] In some embodiments, X is CH2 (or CH if bonded to T through Z). In some embodiments, X is NH (or N if bonded to T through Z). In some embodiments, Z is Z is a bond, methylene, -(CH2)2C(O)NH-, -NH- or -N(CH3)-.

[0113] In some embodiments, the compound is of Formula (Ic), or a pharmaceutically acceptable salt thereof:wherein * denotes a stereocenter with (R) configuration; Reis H or C1-3alkyl; and Z2is a bond or C1-3alkylene.

[0114] In some embodiments, Reis H, methyl, or isopropyl. In some embodiments, Z2is a bond. In some embodiments, Z2is methylene.

[0115] In some embodiments, the compound is selected from those of Table 1. The chemical names used herein are generated using the MarvinSketch Version 6.1.6 (ChemAxon) or the ChemDraw Ultra Version 13.0 software naming programs.Attorney Docket No.: 01317-0001-00PCT Table 1Attorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTmethylisoquinolin-1-yl)benzamide (S)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3- yl)-N-(8-methylisoquinolin-1-yl)-N- (pyrrolidin-3-yl)benzamideAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 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[0116] In some embodiments, one or more hydrogen atoms attached to carbon atoms of the compound of Formula (I) are replaced by deuterium atoms. General Synthetic Methods

[0117] The compounds described herein can be made using conventional organic syntheses and commercially available starting materials, or the methods provided herein. By way of example and not limitation, compounds of Formula I can be prepared as outlined in Schemes 1-12, as well as in the examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired products.

[0118] Furthermore, all compounds of Formula I or any other Formula or compound as described herein which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the disclosure can be converted to their free base or acid form by standard techniques.

[0119] It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this disclosure may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the disclosure which are pharmacologically active. Such derivatives may therefore be described as “prodrugs.” All prodrugs of compounds of this disclosure are included within the scope of the disclosure. Further, the above general scheme can be applied to any other Formula or compound as described herein.

[0120] When enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be used as described in the Examples. It will also be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino,Attorney Docket No.: 01317-0001-00PCT mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include C(O) R” (where R” is alkyl, aryl or arylalkyl), p methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (2006), 4th Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin. Scheme 1.

[0121] Scheme 1 above, wherein R1is H, halogen, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxyl, thioether, amino, CN, heteroaryl, cycloalkyl, or heterocyclyl, and R2is H, halogen, alkyl, alkenyl, alkynyl, aryl heteroaryl, or CN provides exemplary methods for making embodiments of ring M in formula (I).

[0122] The isoquinoline building blocks 1 and 2 can be prepared according to the route illustrated in Scheme 1. Readily available isoquinolines A-1 or A-4 are converted into the corresponding N-oxide intermediate A-2 or A-5 first via treatment with an oxidant such as m- CPBA, ozone, hydrogen peroxides or KMnO4, in a reaction medium such as THF, DCM, MeCN or acetone. Subsequently, A-2 or A-5 are converted to the corresponding isoquinolone intermediate A-3 or A-6 upon treatment of acetic anhydride with heating followed by hydrolysis with an aq. inorganic base such as NaOH, KOH or LiOH. Finally,Attorney Docket No.: 01317-0001-00PCT treating A-3 or A-6 with POCl3and i-PrNEt2in an organic solvent such as MeCN, DCM or DCE with heating affords the corresponding 1-chloroisoquinoline compound 1 and compound 2. Scheme 2.

[0123] Scheme 2, above, wherein W, X, and Y are each independently CH, N, NH, N- alkyl, O, or S, and R2^is H, alkyl, alkenyl, alkynyl, cyano, or halo,provides methods of making embodiments of ring M in formula (I).

[0124] The 5,6-fused aryl building blocks 3, 4, 5, or 6 can be synthesized by utilizing two approaches as described in Scheme 2. The 5,6-fused aromatic precursors B-1 or B-2 are converted to the corresponding chloropyridine compound 3 or compound 5 upon treatment of POCl3 or other chlorination reagents (Step A). Alternatively, the corresponding triflate building blocks compound 4 and compound 6 are prepared from precursors B-1 or B-2 by treatment of triflate anhydride in the presence of an organic base such as 4,6-lutidine, pyridine, DBU, or Et3N, in a solvent such as DCM or THF (Step B). When W, X, or Z is NH, a suitable protecting group such as t-Boc, ester, carbamate, tetrahydropyranyl ethers (THP), sulfonyl, trimethylsilylethoxymethyl (SEM), or silyl group, are used prior to the transformation to the triflate.Attorney Docket No.: 01317-0001-00PCT Scheme 3.

[0125] Scheme 3, above, wherein X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl, or C-heteroaryl; R2^is described above; R2#is halo, H, alkyl, alkenyl, alkynyl, cyano; and R3is H, alkyl, alkenyl, alkynyl, halogen, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, ether, thioether, or amino, provides exemplary methods for making embodiments of ring M in formula (I).

[0126] The corresponding 5,6-fused aryl building blocks 7, 7b and 8 can be prepared according to Scheme 3. The pyrimidinone precursor B-3 is converted into compound 7 upon the treatment of POCl3(Step A). Subsequent halogenation of compound 7 (Step B) with reagents such as NIS, NBS or NCS affords compound 8, wherein R3 is halogen. This halogen in compound 8 can be further converted into other functional groups defined by R3 above by known transformations. Alternatively, the corresponding triflate intermediate 7b can be prepared by treating B-3 with triflate anhydride as described for the preparation of compounds 4 and 6 in Scheme 2. Scheme 4.

[0127] Scheme 4 above, wherein R1*is H, halogen, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxyl, thioether, cyano, heteroaryl, cycloalkyl, or heterocyclyl; R2*Attorney Docket No.: 01317-0001-00PCT is H, halogen, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxyl, thioether, cyano, heteroaryl, cycloalkyl, or heterocyclyl; Rcis H, C1-C6 alkyl, OH, NH2, fluoro, or gem- difluoro; and R4is ester, t-Boc, CBz, Fmoc, or other carbamate protecting groups provides methods for making intermediate compounds useful for making compounds of Formula (I).

[0128] Compound 9 can be prepared according to the route described in Scheme 4. Precursor 2-chloropyridine C-1 is either commercially available or prepared through installations of the corresponding functional groups from commercially available precursors, such as aryl halides, by cross-coupling reactions or nucleophilic displacement reactions. Amine C-2, such as piperidine or its corresponding pyrrolidine or azepine (n = 0, 1, or 2), is commercially available or is prepared from the corresponding commercially available starting materials. Coupling of C-1 and C-2 (Step A) under heating in the presence of a base such as DEA, i-PrNEt2, K2CO3, or Cs2CO3 provides amino compound 9. Alternatively, metal- catalyzed reactions of C-1 and C-2 in the presence of a catalyst such as Pd affords amino compound 9. Scheme 5.

[0129] Scheme 5, above, wherein R1*, R2*, and Rcare described above and R4is ester, t- Boc, CBz, Fmoc, or other carbamate protecting groups, provides methods for making intermediate compounds useful for making compounds of Formula (I).

[0130] Alternative to Scheme 4, compound 9 can be prepared in two other routes as described in Scheme 5. Precursor C-1 is converted into the N-oxide intermediate D-1 by treating with an oxidizing reagent such as m-CPBA, ozone, hydrogen peroxide, or KMnO4, in a reaction medium such as THF, DCM, MeCN, or acetone (Step A). N-oxide D-1 is thenAttorney Docket No.: 01317-0001-00PCT reacted with amine building block C-2 in peptide coupling conditions, for example, with PyBop and i-PrNEt2 in a solvent such as DMF or THF, to afford amine 9 (Step B). Alternatively, primary amine building block C-2 is converted to secondary amine D-2 via reaction at ambient temperature or with heating in a solvent such as THF, MeCN, or DMF (Step C). Subsequently, reductive conversion of the N-oxide in D-2 is achieved with a metal catalyst such as Pd or Pt with a hydrogen source or hypodiboric acid in MeCN to afford amine 9 (Step D).

[0131] Similarly, bicyclic isoquinolines in the forms of compounds 4 and 6, or the 5,6- bicyclic fused hetero building blocks in the forms of compounds 7 and 8, can be substituted for compound C-1 in Scheme 5 to provide amine products with the ring M corresponding to the starting compounds. Scheme 6

[0132] In Scheme 6 above, G is CH2, CH-alkyl, NH, N-alkyl, or O; R1*,R2*, Rcare and R4defined above; R5is aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, amino, cyano, carboxylic acid, ester, or amide; R6is H, halogen, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxyl, thioether, amino, cyano, heteroaryl, cycloalkyl, or heterocyclyl; and indicates that the bond can be either a single or double bond.

[0133] Compounds 10 and 11 can be prepared according to the route described in Scheme 6. Precursor amino compound 9 is reacted with phosgene or an equivalent to provide carbamoyl chloride intermediate E-1 (Step A). Coupling of E-1 with either amine E-2 or E-3Attorney Docket No.: 01317-0001-00PCT provides the corresponding amide intermediate E-4 or E-5 (Step B). Finally, cleavage of R4in E-4 and E-5 (Step C) affords compound 10 or compound 11, respectively. Scheme 7

[0134] Scheme 7 above, wherein R1, R2, Rc, R4, R5, and R6are defined above, provide methods of preparing compounds of Formula (I) and intermediates useful for preparing compounds of Formula (I).

[0135] Compounds 12–14 can be prepared from precursor 2-chloroisoquinoline 1 according to the route described in Scheme 7. Compound 12 is prepared by conjugating compound 1 and amine C-2 (Step A) via procedures similar to those as shown in the preparation of compound 9 in either Scheme 4 or Scheme 5. Conversion of compound 12 into carbamoyl chloride F-1 is performed according to the procedure described for E-1 in Scheme 6. Coupling of F-1 and the corresponding amine E-2 or E-3 in Step C provides compounds F-2 or F-3, respectively. Finally, removal of the protecting group R4in F-2 or F- 3 affords the products compound 13 and compound 14, respectively.Attorney Docket No.: 01317-0001-00PCT Scheme 8

[0136] In Scheme 8, above, R1, R2, Rcand R4are defined above; A and B are each CH2, O, or NH; W1is CH2, O, or NH; X1and Y1are each CH or N; R5*is halogen, cyano, amide, alkenyl, alkynyl, aryl, heteroaryl, alkoxylaryl (aryl ether), alkoxylheteroaryl (heteroaryl ether), NH-aryl, or NH-heteroaryl; and indicates that the bond can be either a single or double bond.

[0137] Compounds 15–19 can be prepared from precursor 2-chloroisoquinoline 12 according to the route described in Scheme 8. Coupling reaction between compound 12 and the corresponding carboxylic acid building blocks G-1, G-2, G-3, or G-4, or their activated carboxylic acids or converted acyl chlorides, under common amide formation conditions yield the four respective intermediates (G-5, G-6, G-7, or G-8) in Step A. Removal of the protecting group R4in these intermediates afford the corresponding final products compounds 15, 16, 17, or 18 (Step B).Attorney Docket No.: 01317-0001-00PCT Scheme 9

[0138] In Scheme 9 R2^, X, W, Y, Rc, R4, A, B, W1, X1, Y1, and R5*are defined above; and indicates that the bond can be either a single or double bond.

[0139] Compounds 20, 21, 22, and 23 can be prepared from precursor compound 3 (R = Cl) or compound 4 (R = OTf) and the corresponding carboxylic acids (G-1, G-2, G-3, or G- 4) according to the route described in Scheme 9. Reacting the precursor compound 3 with the respective carboxylic acid (G-1, G-2, G-3, or G-4) via processes similar to those described for the preparation of compounds 15, 16, 17, or 18 in Scheme 8 affords compounds 20, 21, 22, and 23.Attorney Docket No.: 01317-0001-00PCT Scheme 10

[0140] In Scheme 10, R1*, R2*, Rc, R4, R5*, A, B, W1, X1and Y1are as defined above.

[0141] Compounds 24, 25, 26, and 27 can be prepared from precursor 9 and the corresponding carboxylic acids (G-1, G-2, G-3, and G-4) according to the route in Scheme 10. Reacting the precursor compound 9 with the respective carboxylic acid (G-1, G-2, G-3, or G-4) via processes similar to those described for the preparation of compounds 15, 16, 17, or 18 in Scheme 8 affords compounds 24, 25, 26, and 27.Attorney Docket No.: 01317-0001-00PCT Scheme 11

[0142] In Scheme 9, above R1, R2, Rc, R4, X1, and Y1are defined above. W2is H, I, Br, Cl, or OTf; and R7is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; and R8is H, alkyl, aryl, heteroaryl, or heterocyclyl.

[0143] Compounds 28 and 29 can be synthesized according to Scheme 11. Precursor H-1 prepared according to Scheme 8 by conversion into intermediate H-2 via a cross coupling reaction with a substrate such as boronic acid or ester reagent (Suzuki reaction), tin reagentAttorney Docket No.: 01317-0001-00PCT (Stille reaction), zinc reagent (Neigishi reaction), alkynyl substrate (Sonogashira reaction), or vinyl substrate (Heck reaction) in Step A. Subsequent removal of the protecting group R4in H-2 affords the final product 28 (Step B).

[0144] Alternatively, precursor H-1 is converted into the amine intermediate H-3 by treating with amine (H2NR8) in the presence of a catalyst such as Pd or Cu (Step C). Removal of the R4protecting group in intermediate H-3 (Step D) affords final product 29.

[0145] Alternatively, precursor H-1 is converted into the boronic ester intermediate H-4 by boronylation (Step E) upon treating with bis(pinacolacto)diboron or pinacolborane in the presence of a Pd catalyst (for W2= I, Br, Cl, or OTf) or Ir catalyst (W2= H). Subsequently, intermediate H-4 is converted to intermediate H-2 via a Suzuki coupling reaction with an aryl or alkenyl halide (Step F), followed by deprotection of the amine (Step B) to afford compound 28. To afford compound 29, Boronic ester intermediate H-4 is converted to intermediate H-3 via Chan-Lam-Evans reaction with an amine (H2NR8) and a Cu catalyst in the presence of an organic base such as pyridine or lutidine. Cleavage of the protecting group R4of intermediate H-3 (Step D) then affords the final product 29. Scheme 12

[0146] In Scheme 12, R2^, R4, R5*, R7, X1, Y1, W, Y, and Rcare defined above; E is I, Br, Cl, or OTf;; and the in this scheme indicates that the bond can be either a single or double bond provided in this embodiment the five-membered ring is aromatic.

[0147] Compound 30 can be synthesized from compound 20 following procedures as described in Scheme 12. Precursor compound 20 is converted into intermediate I-1 via a cross-coupling reaction with a reagent such as boronic acid or ester reagent (Suzuki reaction), tin reagent (Stille reaction), zinc reagent (Neigishi reaction), alkynyl substrate (Sonogashira reaction), or vinyl substrate (Heck reaction) in Step A. Removal of the protecting group R4in intermediate I-1 affords the final product compound 30 (Step B).

[0148] “Compounds of Formula I may be isolated as racemates, enantiomers or diastereoisomers using well-known techniques such as crystallization, chiral chromatography,Attorney Docket No.: 01317-0001-00PCT or supercritical fluid chromatography. These techniques may be applied at the appropriate point in the synthesis. The Formula I compound diastereomers / enantiomers can be prepared as racemic mixtures followed by appropriate chiral separation as described herein or by for example reaction with the desired chiral starting compound.Optically active forms of the compounds can be prepared using any method known in the art, including but not limited to by resolution of the racemic form by recrystallization techniques, by synthesis from optically- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

[0149] Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) cocrystallization: a technique whereby the individual enantiomers are crystallized together from a solution of the racemate; iv) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; v) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; vi) chemical asymmetric synthesis: a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved using chiral catalysts or chiral auxiliaries; vii) diastereomer separations: a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; viii) first- and second-order asymmetric transformations: a technique wherebyAttorney Docket No.: 01317-0001-00PCT diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; ix) kinetic resolutions: this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; x) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; xi) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xii) chiral gas chromatography: a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xiii) extraction with chiral solvents: a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiv) transport across chiral membranes: a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. III. Compositions

[0150] For the purposes of administration, the compounds of the present disclosure may be administered as a raw chemical or may be formulated as pharmaceutical compositions.Attorney Docket No.: 01317-0001-00PCT Pharmaceutical compositions of the present disclosure comprise a compound of Formula I and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, different embodiments are directed to pharmaceutical compositions comprising any one or more of the foregoing compounds of Formula I or a pharmaceutically acceptable salt, prodrug, stereoisomer or a mixture of stereoisomers thereof and a pharmaceutically acceptable carrier, diluent or excipient are also provided in various embodiments.

[0151] The pharmaceutical compositions of the present disclosure may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension or sustained-release formulation; topical application, for example, as a cream, ointment or a controlled-release patch or spray applied to the skin; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly; transdermally; or nasally, pulmonary and to other mucosal surfaces.

[0152] Provided herein are pharmaceutical compositions comprising a compound and / or a pharmaceutically acceptable salt or prodrug of the compounds of Formula (I) and a pharmaceutically acceptable excipient.

[0153] Also provided herein are compounds of Formula (I) for use as a medicament. In some embodiments, the compounds of Formula (I) are used in the manufacture of a medicament for treating a disease in a subject in which MYC contributes to the pathology and / or symptoms of the disease. IV. Methods Methods of Treating, Administration, and Pharmaceutical Compositions

[0154] Provided herein are methods of modulating c-MYC activity comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:Attorney Docket No.: 01317-0001-00PCTwherein * denotes a stereocenter; M is C1-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; Rcis absent, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10arylene, C3-9heteroarylene, C3-10cycloalkylene, C3-10cycloalkenylene, or C1-9 heterocyclylene, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH- aryl, NH-heteroaryl, and cyano; Z is a bond, -O-, S, C1-3 alkylene, -(CH2)2C(O)NH-, -N(Rb)-, -N(Rb)(C1-3 alkylene), where Rbis H, or C1-3alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C2-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted orAttorney Docket No.: 01317-0001-00PCT unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH- heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond.

[0155] In some embodiments, the method of modulating c-MYC activity comprises administering an effective amount of any of the compounds described herein.

[0156] In some embodiments, the MYC activity is modulated in a cell. In some embodiments, the MYC activity is modulated in a cellular assay. In some embodiments, MYC activity is modulated in an In Vitro Multiple Point Translation Screening Assay.

[0157] In some embodiments, the MYC activity is modulated in a subject in need thereof, wherein the subject is a model animal or a human. In some embodiments, the MYC activity modulates transcriptional regulation of a gene that is a biomarker. In some embodiments, the MYC activity modulates transcriptional regulation of a gene that is a biomarker that predicts anti-MYC activity.

[0158] In some embodiments, the compound of Formula I inhibits MYC activity. In some embodiments, the compound of Formula I activates MYC activity.

[0159] Also provided herein are methods of treating a condition associated with MYC activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, as defined herein or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the method of treating a condition associated with MYC activity in a subject in need thereof comprises administering an effective amount of any of the compounds described herein.

[0161] In some embodiments, the condition associated with MYC activity is cancer. In some embodiments, the cancer is chosen from solid and hematopoietic cancers such as breast, prostate, pancreatic, hepatocellular, renal, multiple myeloma, lymphoma, lung, skin, oral squamous, haemopoietic, and neuroblastoma. In some embodiments, the cancer is derived from breast, colon, lung or hematopoietic lineages.

[0162] In some embodiments, the method further comprises administering to the subject an effective amount of a second anti-cancer agent. In some embodiments, the second anti-cancer agent is chosen from PARP inhibitors, immune oncology (I / O) drugs, tyrosine kinase inhibitors, CHK1 inhibitor, GLS inhibitor, SAE1 / 2 modulators, BUD31 modulators, TRRAP modulators and BRD4 modulators. In some embodiments, the second anti-cancer agent isAttorney Docket No.: 01317-0001-00PCT chosen from Olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula), nivolumab (Opdivo), atezolizumab (Tecentriq), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi) and cemiplimab-rwlc (Libtayo), axitinib (Inlyta) dasatinib (Sprycel), erlotinib (Tarceva), imatinib (Glivec), nilotinib (Tasigna), pazopanib (Votrient), sunitinib (Sutent).

[0163] In some embodiments, the method comprises treating cancer by administering to a patient in need thereof a therapeutically effective amount of a compound that selectively inhibits the translation of c-MYC mRNA to c-MYC protein. In some embodiments, translation stalls by targeting a cytosolic nascent chain / ribosome complex. In some embodiments, a ternary complex between small molecule, ribosome and nascent c-MYC polypeptide is visible by Cryo-electron microscopy. In some embodiments, translation is stalled to deliver 50% partial inhibition of translation. In some embodiments, translation is stalled resulting in 90% partial inhibition of translation.

[0164] In some embodiments, the compound of Formula (I) has an IC50 below about 50 µM in an In Vitro Multiple Point Translation Screening Assay In some embodiments, the compound has an IC50 below about 5 µM in an In Vitro Multiple Point Translation Screening Assay. In some embodiments, the selective inhibition of MYC is such that less than 1% of non-MYC proteins are inhibited in a Global Proteomic Assay. In some embodiments, the selective inhibition of MYC is such that less than 0.1% of non-MYC proteins are inhibited in a Global Proteomic Assay.

[0165] Also provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, as defined herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is chosen from solid and hematopoietic cancers such as breast, prostate, pancreatic, hepatocellular, renal, multiple myeloma, lymphoma, lung, skin, oral squamous, haemopoietic, and neuroblastoma. In some embodiments, the cancer is derived from breast, colon, lung or hematopoietic lineages.

[0166] In general, the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. In one embodiment, the dosage level will be about 0.1 to about 250 mg / kg per day. In another embodiment the dosage level will be about 0.5 to about 100 mg / kg per day. A suitable dosage level may be about 0.01 to about 250 mg / kg perAttorney Docket No.: 01317-0001-00PCT day, about 0.05 to about 100 mg / kg per day, or about 0.1 to about 50 mg / kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg / kg per day. For oral administration, the compositions may be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound of this disclosure, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.

[0167] In general, compounds of this disclosure will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

[0168] Pharmaceutical compositions can be formulated using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries. The formulation can be modified depending upon the route of administration chosen. The pharmaceutical compositions can also include the compounds described herein in a free base form or a pharmaceutically acceptable salt or prodrug form.

[0169] Methods for formulation of the pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compositions described herein can be lyophilized or in powder form for re-constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug-delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.Attorney Docket No.: 01317-0001-00PCT

[0170] The pharmaceutical compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through sterile filtration.

[0171] The pharmaceutical compositions described herein can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include a sterile suspension, solution, or emulsion in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. Injections can be formulated for bolus injection or continuous infusion.

[0172] For parenteral administration, the compounds can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently nontoxic, and non-therapeutic. A vehicle can be water, saline, Ringer’s solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as fixed oils and ethyl oleate can also be used. Liposomes can be used as carriers. The vehicle can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0173] Sustained-release preparations can also be prepared. Examples of sustained- release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTM(i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(–)-3-hydroxybutyric acid.

[0174] Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing a compound with a pharmaceutically acceptable carrier, excipient, and / or a stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be nontoxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and / or non-ionic surfactants or polyethylene glycol.Attorney Docket No.: 01317-0001-00PCT

[0175] The compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subject such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non-domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit. In preferred embodiments, compounds, pharmaceutical compositions, and methods of the present disclosure are used for treating a human.

[0176] The compounds, pharmaceutical compositions, and methods described herein can be useful as a therapeutic, for example a treatment that can be administered to a subject in need thereof. A therapeutic effect can be obtained in a subject by reduction, suppression, remission, or eradication of a disease state, including, but not limited to, a symptom thereof. A therapeutic effect in a subject having a disease or condition, or pre-disposed to have or is beginning to have the disease or condition, can be obtained by a reduction, a suppression, a prevention, a remission, or an eradication of the condition or disease, or pre-condition or pre- disease state.

[0177] In practicing the methods described herein, therapeutically effective amounts of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and / or preventing a condition or progression thereof. A pharmaceutical composition can affect the physiology of the subject, such as the immune system, inflammatory response, or other physiologic affect. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.

[0178] Treat and / or treating can refer to any indicia of success in the treatment or amelioration of the disease or condition. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treat can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0179] Prevent, preventing, and the like can refer to the prevention of the disease or condition in the patient. For example, if an individual at risk of contracting a disease is treated with the methods of the present disclosure and does not later contract the disease, then the disease has been prevented, at least over a period of time, in that individual.Attorney Docket No.: 01317-0001-00PCT

[0180] A therapeutically effective amount can be the amount of a compound or pharmaceutical composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered. A therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment and can be ascertainable by one skilled in the art using known techniques.

[0181] The compounds or pharmaceutical compositions described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder to be treated, the condition of the individual patient, the site of delivery of the compound or pharmaceutical composition, the method of administration and other factors known to practitioners. The compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein.

[0182] One of ordinary skill in the art would understand that the amount, duration, and frequency of administration of a pharmaceutical composition or compound described herein to a subject in need thereof depends on several factors including, for example but not limited to, the health of the subject, the specific disease or condition of the patient, the grade or level of a specific disease or condition of the patient, the additional therapeutics the subject is being or has been administered, and the like.

[0183] The methods, compounds, and pharmaceutical compositions described herein can be for administration to a subject in need thereof. Often, administration of the compounds or pharmaceutical compositions can include routes of administration, non-limiting examples of administration routes include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or intraperitoneally. Additionally, a pharmaceutical composition or compound can be administered to a subject by additional routes of administration, for example, by inhalation, oral, dermal, intranasal, or intrathecal administration.

[0184] Pharmaceutical compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations. The one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks, or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof less than 21 days, or less than 14 days, less than 10 days, less than 7 days, lessAttorney Docket No.: 01317-0001-00PCT than 4 days or less than 1 day after the first administration. The one or more administrations can occur more than once per day, more than once per week, or more than once per month. The compounds or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days, or daily over a period of one to seven days.

[0185] The MYC gene family is a family of proto-oncogenes that encode three nuclear phosphoproteins that play critical roles in cell cycle progression, apoptosis and cellular transformation, as defined and referenced above. The encoded c-MYC protein forms a heterodimer with the related transcription factor MAX. This complex binds to the E box DNA consensus sequence and regulates the transcription of specific target genes. Amplification of this gene is frequently observed in numerous human cancers. Translocations involving this gene are associated with Burkitt lymphoma and multiple myeloma in human patients. There is evidence to show that translation initiates both from an upstream, in-frame non-AUG (CUG) and a downstream AUG start site, resulting in the production of two isoforms with distinct N-termini. Another target of interest in the MYC family is N-MYC as defined and referenced above. Despite numerous attempts (reviewed in Liombart 2022), it has proven technically challenging to discover potent drug-like inhibitors of c-MYC or n- MYC and no c-MYC or n-MYC inhibitors have advanced into phase 2 human clinical testing or beyond.

[0186] The present disclosure is based in part on the discovery of a new approach to targeting c-MYC or n-MYC that directly circumvents these issues above. In this approach translation stallers target a cytosolic nascent chain / ribosome complex instead of a fully translated protein. Translation can be tuned to deliver partial inhibition and thus impact the therapeutic index. Accordingly, one aspect described herein provides a method of treating cancers, the method comprising administering to a subject in need thereof an effective amount of an agent that modulates c-MYC or n-MYC.

[0187] Another aspect described herein provides a method of inhibiting c-MYC or n-MYC, the method comprising administering to a subject in need thereof an effective amount of an agent that modulates c-MYC or n-MYC.

[0188] Dysregulation of c-MYC in human cancer. Literature evidence supports the hypothesis that inhibitors of c-MYC translation or n-MYC translation will have utility for treatment of various cancersAttorney Docket No.: 01317-0001-00PCT

[0189] In another aspect, described herein are methods of treating cancer, the method comprising administering to a subject in need thereof an effective amount of an agent that modulates MYC.

[0190] In some embodiments the cancer is chosen from breast, prostate, pancreatic, hepatocellular, renal, multiple myeloma, lymphoma, lung, skin, oral squamous, haemopoietic, and neuroblastoma.

[0191] The oncogenes c-MYC and n-MYC are dysregulated in a variety of cancers and are known to promote cancer growth. The MYC family of transcription factors are master regulators of gene expression. Notably, c-MYC is believed to modulate the expression of up to 15% of all expressed human genes. Genetic aberrations such as chromosomal translocations, gene amplification or aberrant transcriptional regulation of the c-MYC gene or stabilization of the c-MYC protein are among the most common causes of cancer in human (Reviewed in Dang 2012; Dhanashekaran 2022) and implicated in up to 70% of all cancers. In a number of cancer types, c-MYC is frequently amplified in the extrachromosomal DNA during tumor evolution (Turner 2017). Pharmacological or genetic inhibition of c-MYC or n- MYC in cellular and animal models have shown that this is a viable strategy for treatment of cancer and is considered to be an attractive target for cancer drug discovery (Madden 2021, Dhanashekaran 2020, Chen 2018).

[0192] c-MYC over-expression implicated in dysregulation of many cancer cell lines

[0193] There is extensive evidence to support the hypothesis that overexpression of c- MYC and / or n-MYC play causative roles in dysregulated growth of diverse human cancers. Exemplary literature reports are given in Table 2 and the supporting explanatory text below. Table 2. Human cancer lines for which there is literature evidence that overexpression of c- MYC and / or n-MYC play a causative role.Oral squamous ORL-136TAttorney Docket No.: 01317-0001-00PCTNeuroblastoma SK-N-BE2, IMR32 Breast cancer.

[0194] Knockdown of c-MYC expression by RNAi inhibits MCF-7 tumor cells in vitro and in vivo (Wang Y 2004). Inhibition of c-MYC expression with the CDK inhibitor Dinaciclib results in apoptosis and tumor volume particularly in MDA-MB-231 cells (Horiuchi 2015). Combination of c-MYC inhibitors with the PARP inhibitor Niraparib is synergistic (Carey 2018). Knockdown of c-MYC using siRNA directed to c-MYC results in a drop in cell viability particularly in MDA-MB-231 and SUM149 (Carey 2018).

[0195] Small molecule GSPT1 / 2 degraders inhibit c-MYC driven cancers in vivo (Monte Rosa WO2021 / 069705 A1) with MDA-MB-231 cells and CAL51 cells. Prostate cancer.

[0196] Honokiol, a natural product, shows significant anti-cancer activity against prostate cancer cell lines PC-3 and 22 Rv1. It results in a marked decrease in levels of total and / or phosphorylated c-MYC protein as well as its mRNA expression (Hahm 2016). Han et al (2020) discovered a series of small molecule c-MYC inhibitors that engage c-MYC inside cells, disrupt c-MYC / MAX dimers, and impair c-MYC-driven gene expression. The compounds enhance c-MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated c-MYC degradation. The initial lead, c-MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice. Pancreatic.

[0197] Silencing of c-MYC using si-RNA inhibits proliferation of pancreatic cancer and enhances the activity of the cardiotonic steroid Bufalin (Liu 2020). Hepatocellular carcinoma.

[0198] Anti-sense oligonucleotides (ASO) directed to c-MYC suppress c-MYC-driven tumorigenesis in vivo in autochthonous transgenic mouse models of c-MYC-driven HCC and RCC, and in a Hep-G2 xenograft model of human liver cancer (Danasekharan 2020). Renal cell carcinoma.

[0199] Stauprimide is a staurosporine analogue that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the c-MYC transcription factor NME2, which in turn results in downregulation of c-MYC transcription and inhibition of renal cancer cells RXF393, CAKI-1 in vitro and in vivo (Bouvard 2017).Attorney Docket No.: 01317-0001-00PCT Multiple myeloma.

[0200] Using precise genome-engineering approaches, Steinberger (2019) et al developed a phenotypic screen capable of identifying c-MYC expression modulators. They found that a number of Na / K ATPase inhibitors such as Bufalin, Ouabain etc inhibit c-MYC expression and inhibit cell viability of multiple myeloma cells such as JJN-3, OPM-2, OPM-1, HP29, KMS-11, MM.1S.

[0201] Using a selective small molecule bromodomain inhibitor, JQ1, Delmore et al (2011) identify BET bromodomain proteins as regulatory factors for c-MYC. BET inhibition by JQ1 downregulates MYC transcription, followed by genome-wide downregulation of c- MYC-dependent target genes. JQ1 is efficacious in three murine models of MM. Establishing the therapeutic rationale for inhibiting pathologic activation of c-MYC. Felsenstein report a novel G4-binding small molecule that inhibits c-MYC expression in cell models. The compound induced G1 arrest and was selectively toxic to c-MYC driven cancer cell lines containing the G4 in the promoter but had minimal effects in peripheral blood mononucleocytes or a cell line lacking the G4 in its c-MYC promoter (Felsenstein, 2016). Lymphoma.

[0202] AZD9150, an antisense oligonucleotide (ASO), decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma (SUP- M2) and lung cancer models (Hong 2015). AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase I dose escalation study. In this same study another derivative showed a concentration-dependent decrease in both c-MYC mRNA and protein levels in K562 cells (human erythroleukemia cells). Lung cancer.

[0203] Inhibition of STAT3 a known activator of c-MYC by antisense oligonucleotide AZD9150 (Hong 2015) or STX-0119 (Kang 2019) inhibit survival of lung cancer cells in vitro and in vivo.

[0204] Sriratanaska (2020) show that a novel c-MYC–targeting compound, N, N-bis (5- ethyl-2-hydroxybenzyl) methylamine (EMD) exhibited strong cytotoxicity toward various human lung cancer cell lines (H23 and H292), as well as chemotherapeutic-resistant patient- derived lung cancer cells, through apoptosis induction. EMD strongly induced the ubiquitination of c-MYC and promoted protein degradation.Attorney Docket No.: 01317-0001-00PCT Skin cancer.

[0205] Inhibition of STAT3 a known activator of c-MYC by antisense oligonucleotide AZD9150 (Hong 2015) inhibits survival of A431 epidermis cancer cells in vitro and in vivo. C-MYC overexpression is known to drive melanoma metastasis Lin (2017). Oral squamous cells carcinoma.

[0206] knockdown of c-MYC in ORL-136T resulted in a significant decrease in the cell viability and c-MYC protein synthesis. Furthermore, caspase-3 was shown to be upregulated leading to apoptosis via the intrinsic pathway (Sabit 2021). Haemopoietic cancers.

[0207] K562 cells treated with antisense oligodeoxynucleotides (ASOs) designed to bind to and inhibit a target mRNA showed a concentration-dependent decrease in both c-MYC mRNA and protein levels, with a maximal 65% inhibition of protein expression and inhibited cell growth by 70 % (Coulis 2000). Small molecule c-MYC inhibitor 10058-F4 reduced viability in acute promyelocytic leukemia (APL)-derived NB4 cells (with wild-type PTEN) and acute lymphoblastic leukemia (ALL)-derived Nalm-6 cells (with down-regulated PTEN). In the presence of a PI3K inhibitor BKM120, 10058-F4 had significantly increased potency (Bashash 2019). Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cell (Maniwa 2015). Inhibition of STAT3, a known activator of c-MYC, by antisense oligonucleotide AZD9150 inhibits survival of SUP-M2 tumor mice models (Hong 2015). Neuroblastoma.

[0208] CSNK1e is synthetic lethal with n-MYC in neuroblastomas. Using RNAi and small-molecule inhibitors, they confirmed that inhibition of CSNK1e halted growth of n- MYC-amplified neuroblastoma xenografts (Toyoshima 2012). These authors further show that CSNK1e expression was also associated with c-MYC in other tumor settings such as colon, lung, and breast cancer. An independently derived link between c-MYC and CSNK1e was obtained through the genome-wide identification of modifiers of transcription factor activity through the MINDy algorithm, where CSNK1e scored as modifier of c-MYC target gene expression (Wang 2009)

[0209] Taken together, these and other studies support the hypothesis that overexpression of c-MYC or n-MYC can play a causative role in many human cancers and that smallAttorney Docket No.: 01317-0001-00PCT molecule agents that block translation of c-MYC or n-MYC can be expected to provide therapeutic benefit.

[0210] c-MYC translation inhibitors may synergize with other known anti-cancer drugs.

[0211] In another aspect, described herein are methods of treating cancer, the method comprising administering to a subject in need thereof an effective amount of an agent that modulates c-MYC and a second anti-cancer agent.

[0212] In some embodiments, the second anti-cancer agent is chosen from Quizartinib, Gilteritinib, Venetoclax, Osimertinib, Crizotinib, Irinotecan, and Olaparib.

[0213] Synergy with PARP inhibitors

[0214] In some embodiments the second anti-cancer agent is chosen from PARP inhibitors., immune oncology (I / O) drugs, and tyrosine kinase inhibitors.

[0215] A number of lines of evidence show that c-MYC expression and nuclear poly(ADP-ribose)polymerase (PARP) activity are closely related suggesting that c-MYC inhibitors could potentially work synergistically with PARP inhibitors. Fekete et al (2012) show that the human PARP-1 protein participates in the regulation of the c-MYC gene expression through its interaction with the Guanine-Quadruplex (GQ) structure of the human c-MYC gene promoter in vitro and in vivo. The c-MYC / MAX heterodimer binds directly to the PARP1 promoter and mediates transcription; high c-MYC expression correlates to PARPi sensitivity in multiple myeloma (MM) (Caraciollo 2021) Burkitt lymphoma (Muvarak 2015) and neuroblastomas (Colicchia 2017).

[0216] Caraciollo et al (2021) show that high c-MYC expression correlates with sensitivity to PARP inhibitors in multiple myeloma. They found a significant correlation between higher PARP1 mRNA expression and poor prognosis of MM patients. PARP1 knockdown or its pharmacological inhibition by olaparib impaired MM cell viability in vitro and was effective against in vivo xenografts of human MM. They identified c-MYC as a promoter of PARP1-mediated repair in MM and demonstrated that cytotoxic effects induced by PARP inhibition are mostly detectable in c-MYC-proficient MM cells. Their findings show that c-MYC-driven MM cells are addicted to PARP1 alternative non-homologous end joining repair (Alt NHEJ).

[0217] Leukemias expressing the constitutively activated tyrosine kinases (TKs) BCR- ABL1 and FLT3 / ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSBs) and error- prone repair. In TK-activated-leukemia Mavurak et al (2015) show that c-MYC expressionAttorney Docket No.: 01317-0001-00PCT leads to genomic instability via augmented expression of an alternative form of NHEJ (ALT- NHEJ), evidenced by increased expression of DNA ligase IIIα (LIG3) and poly (ADP-ribose) polymerase (PARP1).

[0218] In c-MYC driven B-cell lymphomas Galindo Campos et al (2022) show that selective PARP-2 inhibition prevents lymphoma progression, potentially representing a new therapeutic approach for the treatment of c-MYC–driven tumors.

[0219] c-MYC translation inhibitors may synergize with immune oncology (I / O) drugs

[0220] Dhanasekaran et al (2022) review evidence that c-MYC pathways not only govern cancer cell pathophysiology, but also play a key role in suppressing the ability of the host immune system to attack cancer cells. Among these mechanisms is the governance of PDL1 expression outlined below.

[0221] Han et al (2019) using small molecule MYC / MAX / DNA inhibitors (MYCi) show that it induces immunogenic cell death (ICD) in tumor cells and allows increased T cell infiltration and subsequent upregulation of PD-L1 in the tumor microenvironment. Accordingly, MYCi treatment sensitized otherwise refractory tumors to immune checkpoint blockade. A possible treatment regimen is one in which a c-MYC inhibitor is given to patients for a limited period of time prior to, concurrently with or followed by immune checkpoint blockade, thus avoiding potential toxicities to normal tissues that may arise from prolonged c-MYC inhibition.

[0222] Immunotherapy using anti-PD-1 / PD-L1 antibodies has been shown to be effective for many types of malignancies however its activity has been limited in Human pancreatic ductal adenocarcinoma (PDAC). Pan et al (2019) have shown using several PDAC cell lines a significant correlation between the expression of PD-L1 and c-MYC. Further they show that JQ1, an inhibitor of the c-MYC pathway (acting via BRD4) inhibited PD-L1 expression and tumor growth. Using xenograft models, Pan et al demonstrated that the combination of JQ1 and anti-PD-L1 antibody exerted synergistic inhibition of PDAC growth. This is further supported by the work of Casey et al (2018) who provide evidence that c-MYC regulates expression of PD-L1 and that c-MYC translation inhibitors should therefore lower PD-L1 levels in tumors and may provide clinical benefit by augmenting I / O therapeutic regimens.

[0223] Taken together, this literature suggests that treatment of patients with c-MYC translation inhibitors may reverse cancerous growth and may augment or restore host anti- tumor immune response in patients with c-MYC-driven cancers (Dhanasekaran et al, 2022).Attorney Docket No.: 01317-0001-00PCT

[0224] c-MYC translation inhibitors may synergize with tyrosine kinase inhibitors

[0225] Overexpression of c-MYC has been hypothesized to drive tyrosine kinase resistance. For example, Iyer (2022) show that in c-MYC-amplified patient-derived cell line and xenograft (LUAD-0006) c-MYC overexpression induces broad ROS1-TKI resistance. Pharmacologic inhibition of ROS1 combined with c-MYC knockdown were essential to completely suppress LUAD-0006 cell proliferation compared with either treatment alone.

[0226] Simertinib (AZD9291 or TAGRISSO™) is a promising and approved third- generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for treating patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR- activating mutations or the resistant T790M mutation. Zhu et al (2021) show that the mechanism of action of Osimertinib appears to be mediated via rapid and sustained decrease of c-MYC levels primarily via enhancing protein degradation in EGFR-mutant (EGFRm) NSCLC cell lines and xenograft tumors. In fact, c-MYC levels were substantially elevated in different EGFRm NSCLC cell lines with acquired resistance to osimertinib in comparison with their corresponding parental cell lines and could not be reduced any further by osimertinib. Thus, c-MYC translation inhibitors may well provide clinical benefit in combination with these EGFR inhibitors.

[0227] ALK tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced ALK-positive NSCLC. Nevertheless, drug resistance inevitably occurs. Minari et al (2022) show the case of a patient with metastatic ALK positive lung adenocarcinoma with resistance to sequential treatment with ALK TKIs (7 months of crizotinib, brigatinib and lorlatinib) mediated by YES1 and c-MYC amplification.

[0228] Synthetic lethal interactions with c-MYC suggest other combination therapies

[0229] A phenomenon of c-MYC mediated synthetic lethality has been observed with various targets, including CDK1 cyclin-dependent kinase 1, CHK1 checkpoint kinase 1, GLS glutaminase (Chen 2018). Inhibitors of any of these targets could work in concert with inhibition of c-MYC translation.

[0230] Genome-wide RNA interference screens to search for c-MYC–synthetic lethal genes uncovered a role for the SUMO-activating enzyme (SAE1 / 2). In vitro and in vivo data (Kessler 2012) in SUM159 and MDA-MB-231 show that loss of SAE1 / 2 enzymatic activity drives synthetic lethality with c-MYC.Attorney Docket No.: 01317-0001-00PCT

[0231] Hsu et al (2015) identify BUD31, a component of the core spliceosome, as a c- MYC-synthetic lethal gene. Core splice-osomal factors (SF3B1, U2AF1, and others) associated with BUD31 are also required to tolerate oncogenic c-MYC. Notably, c-MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. Genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of c- MYC-dependent breast cancers.

[0232] Toyoshima et al (2012) identified synthetic lethal interactions with c-MYC overexpression (MYC-SL) in a collection of ∼3,300 druggable genes, using high-throughput siRNA screening. Among 49 genes selected for follow-up, 48 were confirmed by independent retesting and approximately one-third selectively induced accumulation of DNA damage, consistent with enrichment in DNA-repair genes by functional annotation. In addition, genes involved in histone acetylation and transcriptional elongation, such as TRRAP and BRD4, were identified, indicating that the screen revealed known c-MYC- associated pathways.

[0233] Taken together, these studies support a rationale for combining inhibitors of c- MYC translation with inhibitors of one or more of the pathways given in Table 3. Table 3. Genes and pathways for which there is evidence of synthetic lethality with c-MYCtyrosine kinase resistance Iyer et al (2022)Attorney Docket No.: 01317-0001-00PCT

[0234] It is well known that c-MYC genes are artificially amplified in copy number due to the encoding genes being present on aberrant extrachromosomal elements that occur in elevated copy number in the affected cancer cells. Cancer patients for whom extrachromosomal amplification of c-MYC-encoding DNA is confirmed may be preferred patients for treatment with c-MYC inhibitors and the presence of such extrachromosomal elements may provide the basis for selecting patients for therapy. Diagnostics for circular extrachromosomal elements encoding c-MYC may also serve as an informative biomarker. There are well established methods for enriching for circular DNA relative to linear genomic DNA. For example, Moller et al (2016) report genome-wide methods for selectively purifying and amplifying circular eukaryotic DNA.

[0235] Biomarkers for c-MYC inhibition

[0236] c-MYC drives the transcriptional regulation of a number of genes, some of which could be used as biomarkers for on-target activity or as predictors of anti-c-MYC activity. Zeller et al (2003) report a database of genes responsive to the c-MYC oncogenic transcription factor. The database c-MYC Target Gene prioritizes candidate target genes according to experimental evidence and clusters responsive genes into functional groups. Using mRNA profiling, Perna et al (2012) identify close to 300 c-MYC-dependent serum response (MDSR) genes, which are induced by serum in a c-MYC-dependent manner in mouse fibroblasts. MDSR gene products were involved in a variety of processes, including nucleotide biosynthesis, ribosome biogenesis, DNA replication and RNA control. To delineate the molecular program regulated downstream of c-MYC, Watson et al (2002) used a cDNA microarray approach and identified 52 putative targets out of >6000 cDNAs analyzed. The list was further narrowed down to c-MYC specific target genes (see table below) rather than genes regulated in response to mitogenic or apoptosis events.Attorney Docket No.: 01317-0001-00PCTV. References 1. Bashash D. et al (2019) IJBCB, 108: 7. 2. Bouvard C. et al (2017) PNAS, 114(13): 3497. 3. Caracciolo D. et al (2021) Haematologica, 106(1): 185. 4. Carey J. P. W. et al (2018) Cancer Res., 78(3): 742 5. Casey et al (2018) Blood, 131: 2007. 6. Chen H et al (2018) Signal Transduction and Targeted Therapy, 3: 5. 7. Colicchia V. et al (2017) Oncogene, 4682. 8. Coulis C. M. et al (2000) Mol Phmarcol, 57: 485. 9. Dang C. V. et al (2012) Cell, 149(1): 22. 10. Delmore J. E. (2011) Cell, 146(6): 904. 11. Deracinois B. et al. (2013) Proteomes, 1, 180-218. 12. Dhanasekaran R et al (2020) Molecular Therapy: Nucleic Acids, 21: 850. 13. Dhanasekaran R et al (2022) Nature Reviews, 19: 23. 14. Fekete A. et al (2012) PlosOne, 7(8): e42690. 15. Felsenstein K. M. et al (2016) ACS Chemical Biology, 11: 139. 16. Felsher D. W. and Bishop M. (1999) Molecular Cell, 4: 199. 17. Felsher D. W. (2010) Genes and Cancer, 1(6): 597. 18. Galindo-Campos et al (2022) Blood, 139(2): 228. 19. Hahm E. (2016) Cell Cycle, 15(17): 2309. 20. Han H. (2019) Cancer Cell, 36(5): 483. 21. Hong D. et al (2015) Sci Transl Med., 7(314). 22. Horiuchi D. et al (2015) J Expt Med., 209(4): 679.Attorney Docket No.: 01317-0001-00PCT 23. Hsu T. Y. (2015) Nature, 525(7569): 384. 24. Iyer S. R. (2022) Mol Cancer Res, 20(5): 722. 25. Kang J. et al (2019) Laboratory Animal Research, 35: 30. 26. Kessler J. D. et al (2012) Science, 335: 348. 27. Lin X. et al (2017) J Mol Med, 95: 53. 28. Liombart et al (2022) The Lancet, 75: 103756. 29. Liu X. et al (2020) Frontiers in Pharmacology, 11(495). 30. Madden S. K. et al (2021) Molecular Cancer, 20: 3. 31. Maniwa Y. et al (2015) Int J Oncology, 47: 473. 32. Mikami S. et al (2010) in Chapter 5 of “Cell Free Protein Production”, Humana Press New York: 43. 33. Minara R. et al (2022) JTO Clinical and Res Reports, 3(2): 100278. 34. Moller H. D. et al (2016) J Vis Exp. 110: 54239. 35. Muvarak N. et al (2015) Mol Cancer Res, 13(4): 699. 36. Pan Y. et al (2019) Oncoimmunology, 8(5): e1581529. 37. Perna D. et al (2012) Oncogene, 31: 1695. 38. Raunivar N. et al. (2014) J Proteome Research, 13, 5293−5309. 39. Sabit H. et al (2021) IJMCM, 20(1): 45. 40. Schumacher M. et al (1999) Current Biology, 9: 1255. 41. Shachaf C. M. (2004) Nature, 431: 1112. 42. Shroff E. H. (2015) PNAS, 112(21): 6539. 43. Soucek L. (2008) Nature, 455: 679. 44. Sriratanasak N (2020) Mol Pharmacol, 98: 130. 45. Steinberger J. et al (2019) Cell Chemical Biology, 26: 699. 46. Toyoshima M. et al (2012) PNAS, 109(24): 9545. 47. Turner K. M. et al (2017) Nature, 543(7643): 122. 48. Wang Y. et al (2004) Breast Cancer Research, 7(2): R220. 49. Wang K. et al (2009) Nat Biotechnol, 27(9): 829. 50. Watson J. D. (2002) J Biol Chem, 277(4): 36921. 51. Zhu L. et al (2021) Cancer Res, 81(18): 4822. 52. Zeller K. I. (2003) Genome Biology, 4: R69.

[0237] Taken together, the literature cited above supports the utility of embodiments disclosed herein, in addition to, but not limited to, kits to measure protein or mRNA levels inAttorney Docket No.: 01317-0001-00PCT the noted pathways as either diagnostics to select patients for therapy or as companion diagnostics to assess efficacy of c-MYC translation inhibitors in a clinical setting.

[0238] The disclosure further provides any compounds disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy may be by any mechanism disclosed herein, such as inhibiting, reducing, or reducing progression of the diseases disclosed herein. The disclosure further provides any compound disclosed herein for prevention or treatment of any condition disclosed herein. The disclosure also provides any compound or pharmaceutical composition thereof disclosed herein for obtaining any clinical outcome disclosed herein for any condition disclosed herein. The disclosure also provides use of any compound disclosed herein in the manufacture of a medicament for preventing or treating any disease or condition disclosed herein. VI. Embodiments

[0239] Provided herein are various embodiments of the invention. The following embodiments provide additional non-limiting examples of the present invention.

[0240] Embodiment A1 is a method of modulating c-MYC activity comprising administering an effective amount of a compound of Formula Iwherein M is C1-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents chosen from halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, amino, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl, heterocyclyl, and combinations thereof; Rcis H, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10arylene, C3-9heteroarylene, C3-10cycloalkylene, or C1-9heterocyclylene, each optionally substituted with 1, 2 or 3 substituents chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH-heteroaryl, and cyano;Attorney Docket No.: 01317-0001-00PCT Z is a bond, -O-, C1-3alkylene, -N(Rb)-, where Rbis H, or C1-3alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C3-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH-heteroaryl, and cyano; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond; or a pharmaceutically acceptable salt thereof.

[0241] Embodiment A2 is the method of Embodiment A1, wherein the MYC activity is modulated in a cell.

[0242] Embodiment A3 is the method of Embodiment A1, wherein the MYC activity is modulated in a cellular assay.

[0243] Embodiment A4 is the method of Embodiment A1, wherein the MYC activity is modulated in an In Vitro Multiple Point Translation Screening Assay.

[0244] Embodiment A5 is the method of Embodiment A1, wherein the MYC activity is modulated in a subject in need thereof, wherein the subject is a model animal or a human.

[0245] Embodiment A6 is the method of Embodiment A1, wherein the MYC activity modulates transcriptional regulation of a gene that is a biomarker.

[0246] Embodiment A7 is the method of Embodiment A1, wherein the MYC activity modulates transcriptional regulation of a gene that is a biomarker that predicts anti-MYC activity.

[0247] Embodiment A8 is the method of anyone of Embodiments A1-7, wherein the compound of Formula I inhibits MYC activity.

[0248] Embodiment A9 is the method of any one of Embodiments A1 to 7, wherein the compound of Formula I activates MYC activity.

[0249] Embodiment A10 is a method of treating a condition associated with MYC activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula IAttorney Docket No.: 01317-0001-00PCT wherein M is C1-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents chosen from halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, amino, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl, heterocyclyl, and combinations thereof; n is 0, 1 or 2; Rcis H, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; L is a bond, C6-10arylene, C3-9heteroarylene, C3-10cycloalkylene, or C1-9heterocyclylene, each optionally substituted with 1, 2 or 3 substituents chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH-heteroaryl, and cyano; Z is a bond, -O-, C1-3alkylene, -N(Rb)-, where Rbis H, or C1-3alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C3-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH-heteroaryl, and cyano; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond; or a pharmaceutically acceptable salt thereof.

[0250] Embodiment A11 is the method of any one of Embodiments A1 to 10, wherein the condition associated with MYC activity is cancer.

[0251] Embodiment A12 is the method of Embodiment A11, wherein the cancer is chosen from solid and hematopoietic cancers such as breast, prostate, pancreatic, hepatocellular, renal, multiple myeloma, lymphoma, lung, skin, oral squamous, haemopoietic, and neuroblastoma.

[0252] Embodiment A13 is the method of Embodiment A11, wherein the cancer is derived from breast, colon, lung or hematopoietic lineages.

[0253] Embodiment A14 is the method of any one of Embodiments A11 to 13, wherein the method further comprises administering to the subject an effective amount of a second anti- cancer agent.

[0254] Embodiment A15 is the method of Embodiment A14, wherein the second anti-cancer agent is chosen from PARP inhibitors, immune oncology (I / O) drugs, tyrosine kinase inhibitors, CHK1 inhibitor, GLS inhibitor, SAE1 / 2 modulators, BUD31 modulators, TRRAP modulators and BRD4 modulators.

[0255] Embodiment A16 is the method of Embodiment A14, wherein the second anti-cancer agent is chosen from Olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula),Attorney Docket No.: 01317-0001-00PCT nivolumab (Opdivo), atezolizumab (Tecentriq), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi) and cemiplimab-rwlc (Libtayo), axitinib (Inlyta) dasatinib (Sprycel), erlotinib (Tarceva), imatinib (Glivec), nilotinib (Tasigna), pazopanib (Votrient), sunitinib (Sutent).

[0256] Embodiment A17 is the method of any one of Embodiments A1 to 16, wherein M is pyrrolo[2,3-c] pyridinyl, pyrrolo[3,2-c] pyridinyl, quinolinyl, isoquinolinyl, pyridinyl, or 2- pyrazinyl, each optionally substituted with 1 or 2 substituents chosen from halo, C1-2alkyl and combinations thereof.

[0257] Embodiment A18 is the method of any one of Embodiments A1 to 17, wherein M is chosen from 1-methyl-3H-pyrrolo[2,3-c]pyridin-7-yl, 1-methyl-3H-pyrrolo[2,3-c]pyridin-5- yl, 1-methyl-3H-pyrrolo[3,2-c]pyridin-6-yl, quinolin-2-yl, isoquinolinyl, isoquinolin-3-yl, 8- methylisoquinolinyl, pyridin-2-yl, 3-chloropyridin-2-yl, 3-methylpyridin-2-yl, and 2- methylpyrazin-3-yl.

[0258] Embodiment A19 is the method of any one of Embodiments A1 to 16, wherein M is or ; wherein R1is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2is H, halo, alkyl, alkenyl, alkynyl, aryl heteroaryl or cyano; R1*is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2*is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl;and each W, X, and Y are independently -CH, -N, -NH, N-alkyl, O, or S; R2#is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl or C-heteroaryl;Attorney Docket No.: 01317-0001-00PCT R2^is H, alkyl, alkenyl, alkynyl, cyano or halo; and R3 is H, alkyl, alkenyl, alkynyl, halo, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, alkoxy, thioether, or amino; and ---- is a bond that is a double bond or a single bond. Embodiment A20 is the method of any one of Embodiments A1 to 16, wherein M is, or ; wherein R1is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; and R2is H, halo, alkyl, alkenyl, alkynyl, aryl heteroaryl or cyano.

[0260] Embodiment A21 is the method of any one of Embodiments A1 to 16, wherein M is; wherein R1*is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl; and R2*is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl.

[0261] Embodiment A22 is the method of any one of Embodiments A1 to 16, wherein M isor ; wherein each W, X, and Y are independently -CH, -N, -NH, N-alkyl, O, or S; R2^is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; and ---- is a bond that is a double bond or a single bond.Attorney Docket No.: 01317-0001-00PCT

[0262] Embodiment A23 is the method of any one of Embodiments A1 to 16, wherein M is; wherein X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl or C-heteroaryl; R2#is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2^is H, alkyl, alkenyl, alkynyl, cyano or halo; and R3is H, alkyl, alkenyl, alkynyl, halo, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, alkoxy, thioether, or amino.

[0263] Embodiment A24 is the method of any one of Embodiments A1 to 23, wherein L is a bond, phenylene, pyridinylene, piperidinylene, or piperazinylene, each optionally substituted with 1 or 2 substituents chosen from halo, C1-3 alkyl, C1-3 alkyloxy and combinations thereof, or -NRa-, where Rais H or C1-3 alkyl.

[0264] Embodiment A25 is the method of any one of Embodiments A1 to 23, wherein L is a bond.

[0265] Embodiment A26 is the method of any one of Embodiments A1 to 23, wherein L is phenylene, pyridinylene, piperidinylene, or piperazinylene, each optionally substituted with 1 or 2 substituents chosen from halo, C1-3alkyl, C1-3alkyloxy and combinations thereof.

[0266] Embodiment A27 is the method of any one of Embodiments A1 to 23, wherein L is chosen from phenylene, fluorophenylene, chlorophenylene, methoxyphenylene, methylphenylene, ethylphenylene, pyridinylene, piperidinylene, and piperazinylene.

[0267] Embodiment A28 is the method of any one of Embodiments A1 to 23, wherein L is - NRa-, where Rais H or C1-3 alkyl.

[0268] Embodiment A29 is the method of any one of Embodiments A1 to 23, wherein L is - NRa-, where Rais H, isopropyl, or methyl.

[0269] Embodiment A30 is the method of any one of Embodiments A1 to 29, wherein Z is a bond.

[0270] Embodiment A31 is the method of any one of Embodiments A1 to 29, wherein Z is C1-3 alkylene.

[0271] Embodiment A32 is the method of any one of Embodiments A1 to 29, wherein Z is methylene.Attorney Docket No.: 01317-0001-00PCT

[0272] Embodiment A33 is the method of any one of Embodiments A1 to 29, wherein Z is - NRb-, where Rbis H, or C1-3 alkyl.

[0273] Embodiment A34 is the method of any one of Embodiments A1 to 29, wherein Z is - NRb-, where Rbis H or methyl.

[0274] Embodiment A35 is the method of any one of Embodiments A1 to 34, wherein T is [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyridinyl, pyrazolyl, tetrazolyl, 1,2,4- triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, isoxazolyl, isoindolyl, piperidinyl, or oxetanyl each optionally substituted with 1 or 2 substituents chosen from Cl, F, cyano, C1-3alkyl, C1-3alkyloxy and combinations thereof.

[0275] Embodiment A36 is the method of any one of Embodiments A1 to 34, wherein T is chosen from [1,2,3]triazolo[4,5-b]pyridin-3-yl, 5-methyl-1H-[1,2,3]triazolo[4,5-b]pyridin-3- yl, 1H-[1,2,3]triazolo[4,5-c]pyridin-4-yl, pyrazolo[2,3-a]pyrimidin-3-yl, 5,6-dihydro-1H- pyrrolo[2,3-d]pyrimidin-4-yl, phenyl, 2-cyanophenyl, 3-cyanophenyl, 3-cyano-6-fluoro- phenyl, 4-cyanophenyl, 4-methoxyphenyl, purin-6-yl, pyrimidin-2-yl, pyrimidin-5-yl, 4- cyanopyrimidin-2-yl, 2-chloropyridin-6-yl, 4-chloropyridin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-cyanopyrazin-6-yl, 1-methyl-1H-pyrazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 5- methyl-1H-pyrazolyl, tetrazol-2-yl, 4H-1,2,4-triazol-4-yl, 1H-1,2,3-triazolyl, 1H-1,2,3- triazol-2-yl, 1H-imidazolyl, 2-methyl-benzo[d]imidazolyl, pyrrolyl, isoxazol-5-yl, 3- methylisoxazol-5-yl, 5-cyano-1H-isoindol-2-yl, 1-methylpiperidin-4-yl, and oxetan-3-yl.

[0276] Embodiment A37 is the method of any one of Embodiments A1 to 23, wherein ring L, Z and T are, , , , , or wherein G is CH2, CH-alkyl, NH, N-alkyl; R5is aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, amino, cyano, carboxylic acid, ester or amide; R6is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; A and B are each independently CH2, O or NH; W1is -CH2, O or NH;Attorney Docket No.: 01317-0001-00PCT X1and Y1are each independently CH or N; R5*is halo, cyano, amide, alkenyl, alkynyl, aryl, heteroaryl, alkoxyaryl, alkoxyheteroaryl, NH-aryl, or NH-heteroaryl; R7is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; R8is H, alkyl, aryl, heteroaryl, or heterocyclyl; and ---- is a bond that is a double bond or a single bond.

[0277] Embodiment A38 is the method of any one of Embodiments A1 to 23, wherein ring L, Z and T are, or wherein G is CH2, CH-alkyl, NH, N-alkyl; R5is aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkoxy, amino, cyano, carboxylic acid, ester or amide; R6is H, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; and ---- is a bond that is a double bond or a single bond.

[0278] Embodiment A39 is the method of any one of Embodiments A1 to 23, wherein ring L, Z and T together arewherein A and B are each independently CH2, O or NH; and R5*is halo, cyano, amide, alkenyl, alkynyl, aryl, heteroaryl, alkoxyaryl, alkoxyheteroaryl, NH-aryl, or NH-heteroaryl.

[0279] Embodiment A40 is the method of any one of Embodiments A1 to 23, wherein ring L, Z and T are, orAttorney Docket No.: 01317-0001-00PCT wherein W1is -CH2, O or NH; R5*is halo, cyano, amide, alkenyl, alkynyl, aryl, heteroaryl, alkoxyaryl, alkoxyheteroaryl, NH-aryl, or NH-heteroaryl; and ---- is a bond that is a double bond or a single bond.

[0280] Embodiment A41 is the method of any one of Embodiments A1 to 23, wherein ring L, Z and T are, , or wherein X1and Y1are each independently CH or N; R5*is halo, cyano, amide, alkenyl, alkynyl, aryl, heteroaryl, alkoxyaryl, alkoxyheteroaryl, NH-aryl, or NH-heteroaryl; R7is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; and R8is H, alkyl, aryl, heteroaryl, or heterocyclyl.

[0281] Embodiment A42 is the method of any one of Embodiments A1 to 41, wherein the compound is selected from Table 1, and / or a pharmaceutically acceptable.

[0282] Embodiment A43 is the method of any one of Embodiments A1 to 42, wherein the compound of Formula (I) is provided in a pharmaceutical composition comprising a compound and / or or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0283] Embodiment A44is a method of treating cancer by administering to a patient in need thereof a therapeutically effective amount of a compound that selectively inhibits the translation of c-MYC mRNA to c-MYC protein.

[0284] Embodiment A45 is the method of Embodiment A44, wherein translation stalls by targeting a cytosolic nascent chain / ribosome complex.

[0285] Embodiment A46 is the method of Embodiment A45, wherein a ternary complex between small molecule, ribosome and nascent c-MYC polypeptide is visible by Cryo- electron microscopy.

[0286] Embodiment A47 is the method of Embodiment A44, wherein translation is stalled to deliver 50% partial inhibition of translation.Attorney Docket No.: 01317-0001-00PCT

[0287] Embodiment A48 is the method of Embodiment A45, wherein translation is stalled resulting in 90% partial inhibition of translation

[0288] Embodiment A49 is the method of Embodiment A44, wherein the compound has an IC50 below about 50 µM in an In Vitro Multiple Point Translation Screening Assay.

[0289] Embodiment A50 is the method of Embodiment A44, wherein the compound has an IC50 below about 5 µM in an In Vitro Multiple Point Translation Screening Assay.

[0290] Embodiment A51 is the method of Embodiment A44, wherein the selective inhibition of MYC is such that less than 1% of non-MYC proteins are inhibited in a Global Proteomic Assay.

[0291] Embodiment A52 is the method of Embodiment A44, wherein the selective inhibition of MYC is such that less than 0.1% of non-MYC proteins are inhibited in a Global Proteomic Assay.

[0292] Embodiment A53 is the method of Embodiment A43, wherein the compound is administered by oral administration.

[0293] Embodiment A54 is the method of Embodiment A43, wherein the compound has a MW of about 300 to about 600 Da.

[0294] Embodiment A55 is a compound of Formula (Ia)wherein M is pyrrolo[3,2-c]pyridinyl, quinolinyl, or 2-pyrazinyl, each optionally substituted with 1 or 2 substituents chosen from halo, C1-2alkyl and combinations thereof; Rdis halo, C1-3 alkyl, or C1-3 alkyloxy; Z is a bond, C1-3 alkylene, -N(Rb)-, where Rbis H, or C1-3 alkyl; and T is 5,6-dihydropyrrolo[2,3-d]pyrimidinyl, purinyl, pyrimidinyl, pyridinyl, pyridinyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, isoxazolyl, isoindolyl, piperidinyl, or oxetanyl each optionally substituted with 1 or 2 substituents chosen from Cl, F, cyano, C1-3alkyl, C1-3alkyloxy and combinations thereof; or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 01317-0001-00PCT

[0295] Embodiment A56 is the compound of Embodiment A34, wherein Rdis Cl, F, CH3, or OCH3.

[0296] Embodiment A57 is a compound of Formula (Ib)wherein M is pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, quinolinyl, or 2-pyrazinyl, each optionally substituted with 1 or 2 substituents chosen from halo, C1-2alkyl and combinations thereof; X3is CH2 (or CH if bonded to T through Z), NH (or N if bonded to T through Z); Z is a bond, C1-3 alkylene, -N(Rb)-, where Rbis H, or C1-3 alkyl; and T is [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyridinyl, pyrazolyl, tetrazolyl, 1,2,4- triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, isoxazolyl, isoindolyl, piperidinyl, or oxetanyl each optionally substituted with 1 or 2 substituents chosen from Cl, F, cyano, C1-3 alkyl, C1-3 alkyloxy and combinations thereof; or a pharmaceutically acceptable salt thereof.

[0297] Embodiment A58 is the compound of Embodiment A36, wherein X is CH2(or CH if bonded to T through Z).

[0298] Embodiment A59 is the compound of Embodiment A36, wherein X is NH (or N if bonded to T through Z).

[0299] Embodiment A60 is the compound of any one of Embodiments A34 to 38, wherein Z is a bond or methylene.Attorney Docket No.: 01317-0001-00PCT

[0300] Embodiment A61 is a compound of Formula (Ic)wherein M is pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, pyridinyl, or 2-pyrazinyl, each optionally substituted with 1 or 2 substituents chosen from halo, C1-2 alkyl and combinations thereof; Reis H or C1-3alkyl; Z2is a bond or C1-3alkylene; and T is [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyridinyl, pyrazolyl, tetrazolyl, 1,2,4- triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, isoxazolyl, isoindolyl, piperidinyl, or oxetanyl each optionally substituted with 1 or 2 substituents chosen from Cl, F, cyano, C1-3 alkyl, C1-3 alkyloxy and combinations thereof; or a pharmaceutically acceptable salt thereof.

[0301] Embodiment A62 is the compound of Embodiment A40, wherein Reis H, methyl, or isopropyl.

[0302] Embodiment A63 is the compound of Embodiment A40 or 41, wherein Z2is a bond.

[0303] Embodiment A64 is the compound of Embodiment A40 or 41, wherein Z2is methylene.

[0304] Embodiment A65 is a compound selected from Table 1, and / or pharmaceutically acceptable salts thereof.

[0305] Embodiment A66 is a compound of any one of Embodiments A55 to 65, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.

[0306] Embodiment A67 is a pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt or prodrug of any one of Embodiments A55 to 65 and a pharmaceutically acceptable excipient.Attorney Docket No.: 01317-0001-00PCT

[0307] Embodiment A68 is a compound of any one of Embodiments A55 to 65 for use as a medicament.

[0308] Embodiment A69 is the compound of Embodiment A68, wherein the compound is for use in treating a cancer associated with MYC activity.

[0309] Embodiment A70 is the use of a compound of any one of Embodiments A55 to 65 in the manufacture of a medicament for treating a disease in a subject in which MYC contributes to the pathology and / or symptoms of the disease. EXAMPLES

[0310] In order that the invention described herein can be more fully understood, the following examples are set forth. It should be understood that these examples are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure and are not to be construed as limiting the invention in any manner. Reasonable variations, such as those that occur to a reasonable artisan, can be made herein without departing from the scope of the present disclosure.

[0311] All chemicals, reagents, and solvents were purchased from commercial sources and used without further purification. Suzuki and Buchwald couplings were performed under an atmosphere of nitrogen. Nuclear magnetic resonance spectra (1H NMR) were recorded with a 400 MHz Bruker spectrometer. Chemical shifts are expressed in parts per million downfield from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet. Due to differences in solvents used in sample preparation and, in some cases, amount of water present, not all exchangeable protons were observable. Liquid chromatograph-mass spectrometry (LC-MS) was performed on an Agilent 1200 HPLC / 6100Series MSD / SEDEX 85 ELSD using an electron scatter ionization (ESI) source. Silica gel chromatography was performed using a medium pressure ISCO system using columns prepackaged by various commercial vendors including ISCO. Merck precoated silica gel plates (400 μm) were used for analytical TLC. 1.1 Experimental details for intermediate synthesis: Synthesis of 6 Het-Cl: General procedure for preparation of compound WA004Attorney Docket No.: 01317-0001-00PCT

[0312] WA004_2 (87.5 g, 832 mmol) was added to a solution of compound WA004_1 (100 g, 832 mmol, 96.1 mL) in toluene (500 mL). The reaction mixture was stirred at 130 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used in the next step without further purification. Compound WA004_3 (120 g, 89%) was obtained as a pale yellow oil.

[0313] P(OMe)3(92.4 g, 744 mmol,) and compound WA004_4 (84.7 g, 620 mmol,) were added to a solution of compound WA004_3 (100 g, 620 mmol) in THF (300 mL). The reaction mixture was stirred at 0 °C for 16 h. Then, H2SO4 (20 mL) was added at 0 °C, and the mixture was stirred at 70 °C for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layer waswas washed with NaHCO3 (3x50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1). Compound WA004_5 (25 g, 65%) was obtained as a yellow solid.

[0314] To a solution of compound WA004_5 (15.0 g, 105 mmol) in dichloromethane (500 mL) was added m-CPBA (42.5 g, 209 mmol, 85% purity). The mixture was stirred at 60 °C for 6 h. After quenching by Na2SO3(3 eq), the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layer was washed with NaHCO3 (3x50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / MeOH=20 / 1 to 10 / 1). Compound WA004_6 (15.0 g, 89.9%) was obtained as a brown solid.

[0315] A solution of compound WA004_6 (15.0 g, 94.2 mmol) in Ac2O (30 mL) was stirred at 140 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. Compound WA004_7 (16.0 g, 84.4%) was obtained as a brown solid.Attorney Docket No.: 01317-0001-00PCT

[0316] To a solution of compound WA004_7 acetate (16.0 g, 79.5 mmol) in MeOH (200 mL) was added NaOH (4.77 g, 119 mmol). The mixture was stirred at 20 °C for 6 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound WA004_8 (12.0 g, 94.8%) was obtained as a brown solid.

[0317] A solution of compound WA004_8 (12.0 g, 75.4 mmol) in POCl3 (100 mL) was stirred at 100 °C for 4 h. The reaction mixture was quenched by the addition of Na2HCO3(500mL) at 0 °C, and then diluted with water (100 mL) and extracted with EtOAc (2x100 mL). The combined organic layer was washed with water (2x100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1). Compound WA004 (8.00 g, 59.7%) was obtained as a brown solid.1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.41 - 7.22 (m, 1H), 3.00 (s, 3H). General for of WA005Step 1:

[0318] To a solution of compound WA005_1 (45.0 g, 313 mmol) in 10% aq. HCl (1350 mL) was added NaNO2 (43.2 g, 627 mmol). The mixture was stirred at 20 °C for 4 h. The reaction mixture was concentrated under reduced pressure at 45 °C. The crude product was used in the next step without further purification. Compound WA005_2 (77 g, crude, HCl salt) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 8.30 - 8.34 (m, 1H), 7.90 (br d, J=5.50 Hz, 1H).

[0319] To a solution of compound WA005_2 (55.0 g, 356 mmol) in THF (800 mL) was added LiHMDS dropwise (1 M, 534 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, MeI (303 g, 2.14 mol) was added dropwise at 20 °C, and the mixture was stirred at 20 °C for 16 h under N2atmosphere. The reaction mixture was a yellow solution. The reaction mixture was quenched by pouring into H2O (1000 mL) at 0 °C, and the mixture was stirred for 1 h. The reaction solution was concentrated under reduced pressure to remove THF, and then filtered to give a residue. The H2O layer was extracted with dichloromethaneAttorney Docket No.: 01317-0001-00PCT (3x3000 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~50% Ethyl acetate / Petroleum ether). Compound WA005 (20.0 g, 33.3%) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 - 8.35 (m, 1H), 8.11 (d, J=5.75 Hz, 1H), 4.56 (s, 3H).Step 1

[0320] To a solution of compound WA006_1 (20.0 g, 104 mmol) in dichloromethane (300 mL) was added triethylamine (13.6 g, 135 mmol, 18.7 mL) and methanamine hydrochloride salt (9.80 g, 145.09 mmol). The mixture was stirred at 45 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1). Compound WA006_2 (15.0 g, 77.2%) was obtained as a yellow solid. Step 2:

[0321] To a solution of compound WA006_2 (10.0 g, 53.3 mmol) in H2O (100 mL) and THF (100 mL) was added Fe (14.9 g, 267 mmol) and NH4Cl (14.3 g, 266 mmol). The mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layer was washed with NaHCO3(3x50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound WA006_3 (7.00 g, 83.3%) was obtained as a yellow solid. Step 3:

[0322] To a solution of compound WA006_3 (7.00 g, 44.4 mmol, 1.00 eq) in 10% aq. HCl (200 mL) was added NaNO2 (4.60 g, 66.6 mmol). The mixture was stirred at 0 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used into the next step without further purification. Compound WA006 (6 g, 80%) was obtained as a yellow solid.Attorney Docket No.: 01317-0001-00PCT

[0323] To a solution of compound WA007_1 (3.00 g, 19.7 mmol) in THF (30 mL) was added NaH (1.18 g, 29.5 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then, MeI (3.35 g, 23.6 mmol) was added to the solution. The reaction was stirred at 20 °C for 2 h. The reaction mixture was quenched by the addition of saturated NH4Cl (50 mL) at 25 °C and then diluted with H2O (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~40% Ethyl acetate / Petroleum ether). Compound WA007 (2.50 g, 76.3%) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.61 (s, 1H), 7.63 (s, 1H), 7.48 (d, J=3.25 Hz, 1H), 6.62 (dd, J=3.13, 0.63 Hz, 1H), 3.80 (s, 3H).

[0324] To a solution of compound WA008_1 (3.00 g, 19.7 mmol) in THF (30 mL) was added NaH (1.18 g, 29.5 mmol, 60% purity) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then, MeI (3.35 g, 23.6 mmol) was added to the solution. The reaction was stirred at 20 °C for 2 h. The reaction mixture was quenched by the addition of saturated NH4Cl (50 mL) at 25 °C and then diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~40% Ethyl acetate / Petroleum ether). Compound WA008 (2.80 g, 68.4%, 80% purity) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (s, 1H), 7.54 - 7.73 (m, 2H), 6.48 (d, J=2.88 Hz, 1H), 3.85 - 3.96 (m, 3H).Attorney Docket No.: 01317-0001-00PCT

[0325] DAST (2.74 mL, 20.8 mmol) was added to dichloromethane (100 mL), cooled to - 70 °C, and treated dropwise with a solution of compound WA012_1 (2.50 g, 17.3 mmol) in dichloromethane (40 mL) under argon. The resulting mixture was allowed to warm to 20 °C and stirred for 3 h. The reaction was quenched by adding water (100 mL), and the solution was extracted with dichloromethane (2x100 mL). The combined organic layer was dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum ether). WA012 (3.00 g, 50.9%) was obtained as a white solid. NMR (400 MHz, CDCl3) δ ppm 8.57 (br s, 1H), 8.37 - 8.44 (m, 1H), 5.51 - 5.74 (m, 2H). Synthesis of 14 Acid BBs: Part I: General WB006Step 1:

[0326] To a solution of compound WB006_2 (23.0 g, 161mmol) in dioxane (200 mL) was added TsOH (56.0 g, 294 mmol) and compound WB006_1 (24.3 g, 147 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used for next step directly without further purification. Compound WB006_3 (20.0g, 47.3%) was obtained as a brown solid. Step 2:Attorney Docket No.: 01317-0001-00PCT

[0327] To a solution of compound WB006_3 (20.0 g, 69.6 mmol) in H2O (100 mL) and THF (100 mL) was added Fe (19.4 g, 348 mmol) and NH4Cl (18.6 g, 348mmol). The mixture was stirred at 70 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give a filter liquor. The filter liquor was further concentrated under reduced pressure. The crude product was used into the next step without further purification. Compound WB006_4 (15.00 g, 83.7%) was obtained as a black solid. Step 3:

[0328] To a solution of compound WB006_4 (15.0 g, 58.3 mmol) in 10% aq. HCl (500 mL) was added NaNO2 (6.03 g, 87.4 mmol). The mixture was stirred at 0 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound WB006_5 (9.00g, 57.5%) was obtained as a brown solid. Step 4:

[0329] To a solution of compound WB006_5 (9.00 g, 33.6 mmol) in MeOH (100 mL) was added NaOH (2.68 g, 67.1 mmol). The mixture was stirred at 60 °C for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1). Compound WB006 (8.00 g, 93.8%) was obtained as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.92 (dd, J = 1.3, 4.4 Hz, 1H), 8.75 (dd, J = 1.3, 8.4 Hz, 1H), 8.27 (brs, 1H), 8.24 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 4.6, 8.3 Hz, 1H), 2.82 - 2.64 (m, 3H).Step 1: To a solution of compound WB007_5 (25.0 g, 96.1 mmol) and potassium vinyltrifluoroborate (14.2 g, 105.8 mmol) in water (20.0 mL) and dioxane (100 mL) wasAttorney Docket No.: 01317-0001-00PCT added Cs2CO3(62.7 g, 192 mmol) and Pd-118 (1.25 g, 1.92 mmol). The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / 1 to 5 / 1). Compound WB007_6 (18.0 g, 90.4%) was obtained as a brown solid. Step 2:

[0330] To a solution of WB007_6 (18.0 g, 86.9 mmol, 1.00 eq) in MeOH (150 mL) and EtOAc (150 mL) was added Pd / C (5.00 g, 10wt%) under N2. The suspension was degassed and purged with H2 several times. The mixture was stirred under H2 (50 psi) at 30 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure at 40 °C to afford crude product. The crude product was used in the next step directly without further purification. Compound WB007_1 (12.0 g, 77.1%) was obtained as a yellow solid. Steps 3 – 6: WB007 was prepared according to the procedure described for WB006 by substituting methyl 4-amino-2-methylbenzoate with methyl 4-amino-2-ethylbenzoate, provided the desired product as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 1.4, 4.5 Hz, 1H), 8.77 (dd, J = 1.4, 8.4 Hz, 1H), 8.31 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 4.5, 8.4 Hz, 1H), 3.30 - 3.08 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H). General WB008WB008 was prepared according to the procedure described for WB006 by substituting methyl 4-amino-2-methylbenzoate with methyl 4-amino-2-fluorobenzoate, provided the desired product as a solid. %)1H NMR (400 MHz, DMSO-d6) δ ppm 12.16 - 14.11 (m, 1H), 8.91 - 9.01 (m, 1H), 8.76 - 8.81 (m, 1H), 8.31 - 8.47 (m, 2H), 8.16 - 8.27 (m, 1H), 7.64 - 7.76 (m, 1H). General WB009Attorney Docket No.: 01317-0001-00PCT WB009 was prepared according to the procedure described for WB006 by substituting methyl 4-amino-2-methylbenzoate with methyl 4-amino-2-chlorobenzoate, provided the desired product as a solid.

[0331] 1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 1.3, 4.5 Hz, 1H), 8.77 (dd, J = 1.1, 8.4 Hz, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.41 (dd, J = 1.9, 8.6 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.68 (dd, J = 4.5, 8.4 Hz, 1H). General WB010WB010 was prepared according to the procedure described for WB006 by substituting methyl 4-amino-2-methylbenzoate with methyl 4-amino-2-methoxybenzoate, provided the desired product as a solid.

[0332] 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br s, 1H)1H), 8.88 (dd, J=4.50, 1.38 Hz, 1H)1H), 8.72 (dd, J=8.32, 1.31 Hz, 1H)1H), 8.05 (d, J=1.50 Hz, 1H)1H), 7.92 - 8.00 (m, 2H), 7.63 (dd, J=8.38, 4.50 Hz, 1H)1H), 3.96 (s, 3H). General WB011WB011 was prepared according to the procedure described for WB006 by substituting methyl 4-amino-2-methylbenzoate with methyl 4-aminobenzoate, provided the desired product as a solid.

[0333] 1H NMR (400 MHz, DMSO-d6) δ 13.24 (br s, 1H), 8.90 (dd, J = 1.2, 4.4 Hz, 1H), 8.74 (dd, J = 1.3, 8.4 Hz, 1H), 8.50 - 8.43 (m, J = 8.6 Hz, 2H), 8.26 - 8.21 (m, J = 8.8 Hz, 2H), 7.66 (dd, J = 4.5, 8.4 Hz, 1H). Part Ⅱ: General procedure for preparation of compound WB013Attorney Docket No.: 01317-0001-00PCTStep 1:

[0334] To a solution of compound WB013_1 (5.00 g, 19.8mmol), Na2CO3 (4.19 g, 39.5 mmol) and compound WB013_2 (3.91 g, 21.7 mmol) in H2O (20 mL) and dioxane (100 mL) was added Pd-118 (644 mg, 988 μmol) under N2. The reaction was stirred at 90 °C for 3 h. The mixture was concentrated under reduced pressure at 50 °C. The residue was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (3x100 mL). The combined organic phase was washed with brine (2x100 mL), dried with anhydrous MgSO4, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® SilicaFlash Column, eluent of 0-10% EtOAc / PE) to afford desired product. WB013_3 (5.26 g, 86.4%) was obtained as a brown solid. Step 2:

[0335] To a solution of compound WB013_3 (5.26 g, 17.1 mmol) in THF (100 mL) and H2O (50 mL) was added LiOH.H2O (1.43 g, 34.1 mmol). The reaction was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (3x100 mL). The organic phase was discarded. The aqueous phase was adjusted to pH 4-5 by 1N aq. HCl. The precipitate was collected and dried. to afford Compound WB013 (2.09 g, 41.6%) was obtained as a white solid.

[0336] 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1H), 8.27 (d, J=8.25 Hz, 2H), 8.11 – 8.16 (m, 1H), 7.98 – 8.03 (m, 1H), 7.70 – 7.78 (m, 3H).Attorney Docket No.: 01317-0001-00PCT

[0337]

[0339] General procedure for preparation of compound WB014

[0340] To a solution of compound WB014-1 (5.00 g, 27.5 mmol), Cs2CO3(17.9 g, 54.9 mmol), and compound WB014-2(5.01 g, 30.2 mmol) in dioxane (100 mL) and H2O (20 mL) was added Pd-118 (895 mg, 1.37 mmol) under N2. The reaction was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~10% THF / MEOH). Compound WB014 (4.00 g, 65.2%) was obtained as a brown solid.

[0341] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.17 – 8.20 (m, 1H), 8.03 – 8.08 (m, 1H), 7.99 (d, J=8.25 Hz, 2H), 7.81 – 7.87 (m, 1H), 7.74 (d, J=8.38 Hz, 2H), 7.65 – 7.70 (m, 1H). General WB015Step 1:

[0342] A mixture of compound WB015_1 (4.50 g, 17.8 mmol), compound WB015_2 (3.84 g, 21.3 mmol), Na2CO3(3.77 g, 35.6 mmol) in dioxane (100 mL), and H2O (25 mL) was degassed and purged with N2 thrice, and then Pd-118 (1.03 g, 889 μmol) was added to the mixture. The mixture was stirred at 90 °C for 3 h under N2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum ether, gradient). Compound WB015_3 (4.50 g, 82%) was obtained as a yellow solid.Attorney Docket No.: 01317-0001-00PCT

[0343] 1H NMR (400 MHz, CDCl3) δ ppm 8.04 - 8.14 (m, 4H), 7.68 - 7.78 (m, 2H), 7.59 - 7.67 (m, 2H), 3.88 (s, 3H). Step 2:

[0344] To a solution of compound WB015_3 (4.50 g, 14.6 mmol) in THF (45 mL) and H2O (15 mL) was added LiOH.H2O (1.23 g, 29.2 mmol). The mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure. After adjusting to pH 3 with HCl (2 M, 20 mL). The precipitate was collected and dried to afford Compound WB015 (2.4 g, 55.88%) as a white solid.

[0345] 1H NMR (400 MHz, CDCl3) δ ppm 8.23 (dd, J=13.20, 8.19 Hz, 4H), 7.64 - 7.93 (m, 4H). General WB017Step 1:

[0346] To a solution of compound WB017_1 (10.0 g, 70.6 mmol) in dichloromethane (100 mL) was chilled to 0 °C in an ice / water bath was added dropwise TMSCF3 (12.1 g, 84.8 mmol, 1.20 eq) and followed by the dropwise addition of TBAF (1 M, 1.06 mL). The reaction was allowed to warm to 20 °C, stirred for 2 h, and then additional TBAF (1 M, 35.3 mL) was slowly added. The reaction mixture was stirred at 20 °C for 1 h. The reaction was diluted with EtOAc (500 mL), washed with 0.1N aq. HCl (200 mL) and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. Compound WB017_2 (15.0 g, crude) was obtained as a brown solid.

[0347] 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (t, J=7.82 Hz, 1H), 7.32 (dd, J=15.01, 7.75 Hz, 2H), 4.89 – 5.06 (m, 1H), 4.69 (br d, J=9.38 Hz, 1H),. Step 2:

[0348] To a solution of compound WB017_2 (15.0 g, 70.9 mmol) in dichloromethane (150 mL) was added Dess-Martin periodinane (36.1 g, 85.1 mmol). The reaction was stirred at 20 °C for 16 h. The reaction was then diluted with dichloromethane (250 mL), washed with saturated NaHCO3solution (2 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4,Attorney Docket No.: 01317-0001-00PCT filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~50% Ethyl acetate / Petroleum ether). Compound WB017_3 (6.00 g, 40.4%) was obtained as a yellow oil.

[0349] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 - 8.09 (m, 1H), 7.76 (s, 1H), 7.59 (d, J=7.88 Hz, 1H). Step 3:

[0350] To a solution of compound WB017-3 (5.63 g, 26.8 mmol), Na2CO3(5.69 g, 53.7 mmol) and compound WB017-4 (5.31 g, 29.5 mmol) in H2O (20 mL) and dioxane (100 mL) was added Pd-118 (875 mg, 1.34 mmol) under N2. The reaction was stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3x100 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous MgSO4, filtered, and concentrated in vacuum. The residue was purified by flash silica gel chromatography (Eluent of 0~35% Ethyl acetate / THF) to afford desired product. Compound WB017-5 (5.74 g, 69 %) was obtained as a brown solid. Step 4:

[0351] To a solution of compound WB017-5 (2.87 g, 9.28 mol, 1. THF (50 mL) and H2O (25 mL) was added LiOH.H2O (779 mg, 18.6 mmol). The reaction was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and then the residue was poured into water (100 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (3x100mL). The organic phase was discarded. The aqueous phase was adjusted to pH 4-5 with 1N aq. HCl. The precipitate was collected and dried to afford Compound WB017 (2.22 g, 81.03%) as a white solid.

[0352] 1H NMR (400 MHz, CDCl3) δ ppm 8.15 - 8.22 (m, 3H), 7.93 - 8.11 (m, 3H), 7.84 - 7.90 (m, 1H), 7.76 (d, J=7.75 Hz, 1H).Attorney Docket No.: 01317-0001-00PCT

[0353] Compound WB018_3 was synthesized according to the procedure described for Compound WB017 by substituting 6-chloropicolinaldehyde with 2-chloroisonicotinaldehyde, provided the title compound as a white solid.

[0354] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.80 (d, J=5.00 Hz, 1H), 8.17 - 8.21 (m, 2H), 8.10 (t, J=8.51 Hz, 3H), 8.00 (br s, 2H), 7.61 (d, J=5.00 Hz, 1H). General WB019

[0355] Compound WB015was synthesized according to the procedure described for Compound WB017 by substituting 1-(4-bromophenyl)-2,2,2-trifluoroethan-1-one with 6- chloropyrazine-2-carbonitrile, provided the title compound as a white solid.

[0356] 1H NMR (400 MHz, DMSO-d6) δ ppm 12.54 (br s, 1H), 8.62 (s, 1H), 7.77 - 7.90 (m, 2H), 7.60 (d, J=8.76 Hz, 2H), 2.95 (s, 6H). General WB035Step 1:

[0357] To a solution of compound WB035_1 (20.0 g, 121 mmol) in THF (200 mL) was added compound WB035_2 (39.1 g, 363 mmol). The mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (Eluent of 0~25% THF / Petroleum etherCompound WB035_3 (3.60 g, 12.6%) was obtained as a white solid.

[0358] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 - 8.73 (m, 1H), 7.83 (d, J=8.88 Hz, 2H) 7.60 - 7.66 (m, 2H) 4.27 (q, J=7.17 Hz, 2H) 2.86 - 3.03 (m, 6H) 1.27 - 1.35 (m, 3H).Attorney Docket No.: 01317-0001-00PCT Step 2:

[0359] To a solution of compound WB035_3 (3.60 g, 15.2 mmol) in THF (50 mL) and H2O (50 mL) was added LiOH.H2O (1.28 g, 30.5 mmol). The reaction mixture was stirred at 20°C for 16 h. The reaction was concentrated under reduced pressure. The mixture was poured into water (50 mL), and the solution was adjusted to pH 4-5 by 1N aq. HCl. The precipitate was collected and dried to afford Compound WB035 (2.00 g, 63.0%) as a white solid.

[0360] 1H NMR (400 MHz, DMSO-d6) δ ppm 12.54 (br s, 1H), 8.62 (s, 1H), 7.77 - 7.90 (m, 2H), 7.60 (d, J=8.76 Hz, 2H), 2.95 (s, 6H). 1.2 Experimental details for final compound synthesis using the procedures in 1.1 Procedure W1Step 1

[0361] t-BuONa (30 mmol, 3.0 eq) was added to a solution of WAi (10 mmol, 1.0 eq) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (15 mmol, 3 g, 1.5 eq) in t-AmOH (60 mL) was added. Then, BINAP (0.5mmol, 0.05 eq) and Pd(OAc)2 (0.5mmol, 0.05 eq) were added to the above reaction mixture under N2. The reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAi_1, which was purified by preparative TLC. Step 2

[0362] To a solution of WBi (100 μmol, 2.0 eq) in SOCl2 (500 μL) was added two drops of DMF. The reaction mixture was shaken at 60 °C for 16 h and then concentrated under reduced pressure to give WBi_1, which was used without further purification. LiHMDS (150 μmol, 1.0 M in THF, 3.0 eq) or NaH (150 μmol, 3.0 eq) was added to a solution of WAi_1 (50 μmol, 1.0 eq) in THF (200 μL) and stirred at 0 °C for 15 mins. A solution of crude acidAttorney Docket No.: 01317-0001-00PCT chloride WBi_1 in THF (0.3 mL) was added to the above solution, and the reaction was stirred at 30 °C for 16 h. The reaction was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAiBi_1, which was used in the next step directly without further purification. Step 3

[0363] WAiBi _1 (50 μmol, 1.0 eq) was dissolved in a solution (1.0 mL) of dichloromethane / TFA (v / v = 5 / 1), and the reaction was shaken at 30 °C for 2 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to obtain the final product. Procedure W2Step 1

[0364] t-BuONa (30 mmol, 3.0 eq) was added to a solution of WAi (10 mmol, 1.0 eq) and (R)-benzyl 3-aminopiperidine-1-carboxylate in t-AmOH (60 mL). Then BINAP (0.5mmol, 0.05 eq) and Pd(AcO)2(0.5mmol, 0.05 eq) were added to the above reaction mixture under N2. The reaction mixture was stirred at 110°C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAi_1, which was purified by preparative TLC. Step 2

[0365] To a solution of WBi (100 μmol, 2.0 eq) and WAi_1 (50 μmol, 1.0 eq) in dioxane (500 μL) was added T3P (150 μL. 50% wt in ethyl acetate) and triethylamine (150 μmol, 3.0 eq) under N2. The reaction mixture was shaken at 110 °C for 16 h, after which the reaction was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAiBi_1, which was used in the next step directly. Step 3Attorney Docket No.: 01317-0001-00PCT

[0366] WAiBi _1 (50 μmol, 1.0 eq) was dissolved in a solution of dichloromethaneand MeOH (1.6 mL, v:v = 1:1). Triethylsilane (200 μL) and triethylamine (500 μmol, 10.0 eq) were then added to the above solution. Finally, Pd(AcO)2 (5 μmol, 1.0 eq) was added to the reaction mixture. The reaction mixture was stirred at 30 °C for 2 h, after which it was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the final product. Procedure W3Step 1

[0367] To a solution of WBi (150 μmol, 1.0 eq) and (R)-tert-butyl 3-aminopiperidine-1- carboxylate (100 μmol, 1.0 eq) in DMSO (0.5 mL) was added a solution of HOPO (120 μmol, 1.2 eq) and EDCI (120 μmol, 1.2 eq) in DMSO (0.5 mL). The reaction mixture was shaken at 50 °C for 16 h, after which the reaction mixture was concentrated under reduced pressure. The residue WAiBi_1 was purified by preparative TLC. Step 2

[0368] The following series of reactions were completed in a glove box. To a solution of WAiBi _1 (50 μmol, 1.0 eq) in dichloromethane (500 μL) was added 2, 6-lutidine (110 μmol, 2.2 eq). The reaction mixture was shaken at -30 °C for 0.5 h. Then, Tf2O (55 μmol, 1.1 eq) was added to the reaction mixture, and the reaction mixture was shaken at -20 °C for 1 h. Next, a solution of Ai_1 (60 μmol, 1.2 eq) was added to the reaction, and the reaction mixture was shaken at 30 °C for 16 h. After 16 h, the reaction was concentrated under reduced pressure. The residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAiBi_1, which was used in the next step directly. Step 3

[0369] WAiBi _1 (50 μmol, 1.0 eq) was dissolved in a solution (1.0 mL) of dichloromethane / TFA (v / v = 5 / 1). The reaction mixture was shaken at 30 °C for 2 h, after which it was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the final product.Attorney Docket No.: 01317-0001-00PCT Procedure W4

[0370] To a solution of WAi_1 (200 μmol, 1.0 eq) in dichloromethane (1 mL) was added a solution of m-CPBA (300 μmol, 1.5 eq) in dichloromethane (1 mL). The reaction mixture was shaken at 30 °C for 3 h, after which it was concentrated under reduced pressure to remove solvent. The residue was quenched with a saturated solution of NaHSO3 and extracted with dichloromethane (1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAi_2, which was purified by preparative TLC. Step 2

[0371] To a solution WAi_2 (100 μmol, 1.0 eq) and Bi (110 μmol, 1.1 eq) in dichloromethane (0.5 mL) was added DIEA (300 μmol, 3.0 eq). Then, a solution of HOPO (110 μmol, 1.1 eq) and EDCI (110 μmol, 1.1 eq) in dichloromethane (0.5 mL) was added to the reaction mixture. The reaction mixture was shaken at 50 °C for 16 h, after which the reaction was concentrated under reduced pressure. The residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAiBi_1, which was used in the next step directly. Step 3

[0372] To a solution of WAiBi _1 (50 μmol, 1.0 eq) in EtOH (0.8 mL) was added NH4Cl (500 μmol, 10.0 eq) and activated Zn (300 μmol, 6.0 eq). The reaction mixture was shaken at 80 °C for 2 h, after which it was filtered and concentrated under reduced pressure. The residue was used in the next step directly. Step 4

[0373] WAiBi _2 (50 μmol, 1.0 eq) was dissolved in a solution (1.0 mL) of dichloromethane andTFA (v:v = 5 : 1). The reaction mixture was shaken at 30 °C for 2 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to obtain the final product.Attorney Docket No.: 01317-0001-00PCT 2.1 Experimental information for intermediate synthesis: for intermediate :Step 1:

[0374] Compound W1_1 (3.94 g, 24.97 mmol), tert-butyl (3R)-3-aminopiperidine-1- carboxylate (5 g, 24.97 mmol, specific optical rotation = -35oat 20oC (concentration = 5 in MeOH)), t-BuONa (4.80 g, 49.93 mmol), Xantphos (0.7223 g, 1.25 mmol), and Pd(OAc)2 (0.2825 g, 1.25 mmol) were dissolved in toluene (300 mL), purged with N2for 2 minutes, and then heated at 90 °C for 10 h under N2. The reaction mixture was poured into H2O (100 mL) and extracted with ethyl acetate (3x100 mL). Thecombined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 30% Ethyl acetate / Petroleum ether) to give compound W1_2 (3.2 g, 46%) as a white solid. Step 2:

[0375] A solution of compound W1_2 (1.5 g, 5.41 mmol) in THF (30 mL) was cooled to -65 °C, and then triethylamine (3.28 g, 32.45 mmol) and triphosgene (4.95 g, 16.68 mmol) were added to the cooled solution. The mixture was allowed to slowly warm to 25°C, and then stirred at 25 °C for 18 h. The mixture was then filtered. The filtrate was quenched with saturated aq. NH4Cl (30 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 20% Ethyl acetate / Petroleum ether) to give WA001_1 (1.27 g, 57%) as a colorless oil.

[0376] 1H NMR (400 MHz, CD3OD) δ ppm 8.58 (dd, J=1.3, 4.9 Hz, 1H), 8.00 (dt, J=1.9, 7.7 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.46 (d, J=7.9 Hz, 1H), 4.39 (td, J=2.1, 12.7 Hz, 1H), 4.20 (tt, J=4.0, 11.4 Hz, 1H), 3.95 (br d, J=12.1 Hz, 1H), 2.93 (br s, 1H), 2.55 (br s, 1H), 2.07 (br s, 1H), 1.74 - 1.64 (m, 1H), 1.59 - 1.41 (m, 11H).Attorney Docket No.: 01317-0001-00PCT for intermediate :Step 1:

[0377] Compound W2_1 (2.45 g, 14.98 mmol), tert-butyl (3R)-3-aminopiperidine-1- carboxylate (3.0 g, 14.98 mmol, specific optical rotation = -35oat 20oC (concentration = 5 in MeOH)), t-BuONa (2.88 g, 29.96 mmol), BINAP (1.37 g, 1.50 mmol) and Pd2(dba)3(1.87 g, 3.00 mmol) were dissolved in toluene (50 mL), purged with N2 for 2 min, and then heated at 90 °C for 16 h under N2. The reaction mixture was poured into H2O (50 mL) and extracted with ethyl acetate (3x50 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Eluent of 30% Ethyl acetate / Petroleum ether) to give compound W1_2 (3.0 g, 61%) as a yellow solid.

[0378] 1H NMR (400 MHz, CD3OD) δ ppm 8.81 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.63 - 7.55 (m, 1H), 7.54 - 7.48 (m, 1H), 7.23 (t, J=7.5 Hz, 1H), 6.74 (s, 1H), 3.71 (s, 1H), 3.36 - 3.29 (m, 4H), 2.10 (s, 1H), 1.83 (s, 1H), 1.62 (dt, J=4.4, 8.8 Hz, 2H), 1.54 - 1.29 (m, 9H). Step 2:

[0379] A solution of compound W1_2 (1.5 g, 4.58 mmol) in THF (30 mL) was cooled to -65 °C, and then triethylamine (2.78 g, 27.49 mmol,) and triphosgene (4.08 g, 13.74 mmol) were added to the cooled solution. The mixture was slowly allowed to warm to 25 °C, and then stirred at 25 °C for 18 h. The mixture was then filtered. The filtrate was quenched with saturated aq. NH4Cl (30 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 30% Ethyl acetate / Petroleum ether) to give WA002_1 (1.02 g, 57%) as a white solid.

[0380] 1H NMR (400 MHz, CD3OD) δ ppm 9.28 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.91 (s, 1H), 7.90 - 7.86 (m, 1H), 7.84 - 7.78 (m, 1H), 4.46 (td, J=2.0, 12.7 Hz, 1H), 4.29 (tt, J=4.0, 11.2 Hz, 1H), 3.93 (br d, J=13.2 Hz, 1H), 2.97 (br s, 1H), 2.54 (br s, 1H), 2.13 (d, J=10.6 Hz, 1H), 1.75 - 1.65 (m, 1H), 1.60 - 1.40 (m, 11H).Attorney Docket No.: 01317-0001-00PCT for intermediate :Step 1:

[0381] To a solution of compound W3_1 (5 g, 30.56 mmol) and tert-butyl (3R)-3- aminopiperidine-1-carboxylate (6.12 g, 32.56 mmol, specific optical rotation = -35oat 20oC (concentration = 5 in MeOH)) in dioxane (150 mL) were added Cs2CO3 (19.92 g, 61.12 mmol), Pd(OAc)2(686.13 mg, 3.06 mmol) and BINAP (1.90 g, 3.06 mmol). The mixture was stirred at 100 °C for 16 h under N2. The mixture was brown and muddy. After 16 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was diluted with EtOAc (100mL), and the organic layer was washed with water (3x100mL). The aqueous layer was extracted with EtOAc (3x100mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~15% Ethyl acetate / Petroleum ether) to give compound W3_2 (5.6 g, 56%) as a yellow solid.

[0382] 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=9.0 Hz, 1H), 7.60 (dd, J=8.1, 13.4 Hz, 2H), 7.52-7.41 (m, 1H), 7.24-7.09 (m, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.06 (dd, J=3.8, 7.5 Hz, 1H), 3.98-3.37 (m, 2H), 3.31-2.67 (m, 2H), 2.20-1.98 (m, 1H), 1.83 (s, 1H), 1.72-1.53 (m, 2H), 1.52-1.16 (m, 9H). Step 2:

[0383] A solution of compound W3_2 (4 g, 12.22 mmol) in THF (100 mL) was cooled to -78 °C under N2, and then triethylamine (7.42 g, 73.30 mmol) and triphosgene (10.88 g, 36.65 mmol) were added. The mixture was stirred at 25 ℃ for 16 h. The mixture was yellow and muddy. The mixture was poured into ice water (30 mL) and extracted with EtOAc (4x100 mL). The combined organic layer was washed with saturated NaHCO3(50 mL), brine (50 mL), and then dried over Na2SO4 and filtered, concentrated. The crude product was purified by flash silica gel chromatography (Eluent of 0~15% EtOAc / PE) to give compound WA003_1 (1 g, 21%) as a white solid.

[0384] 1H NMR (400 MHz, CD3OD) δ ppm 8.49 (d, J=8.5 Hz, 1H), 8.06 (dd, J=8.3, 13.8 Hz, 2H), 7.91-7.83 (m, 1H), 7.76-7.68 (m, 1H), 7.54 (d, J=8.5 Hz, 1H), 4.46 (td, J=2.0, 12.7Attorney Docket No.: 01317-0001-00PCT Hz, 1H), 4.28 (tt, J=3.9, 11.1 Hz, 1H), 3.92 (d, J=13.3 Hz, 1H), 3.24-2.87 (m, 1H), 2.64-2.45 (m, 1H), 2.19-2.04 (m, 1H), 1.72-1.35 (m, 12H). for intermediate :Step 1:

[0385] A solution of compound W4_1 (510 mg, 2.87 mmol), tert-butyl (3R)-3- aminopiperidine-1-carboxylate (862.53 mg, 4.32 mmol), t-BuONa (827.85 mg, 8.61 mmol) and BrettPhos Pd G3 (182.19 mg, 200.97 μmol) in THF (18 mL) was purged with N2and then heated to 80 °C for 2 h under N2. The reaction mixture was poured into H2O (60 mL). The mixture was extracted with ethyl acetate (3x60 mL), and the combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 5% THF / Petroleum ether) to give compound W4_2 (964 mg, 98%) as a yellow oil. Step 2:

[0386] A solution of compound W4_2 (964 mg, 2.82 mmol) in THF (14 mL) was cooled to -65 °C, and then triethylamine (1.71 g, 16.94 mmol) and triphosgene (2.80 g, 9.44 mmol) were added. The mixture was allowed to slowly warm to 25 °C, and then stirred at 25 °C for 16 h. The mixture was filtered. The filtrate was quenched with saturated NH4Cl (200 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 5% THF / Petroleum ether) to give key intermediate WA004_1 (790 mg, 69%) as a white solid. for intermediate :Attorney Docket No.: 01317-0001-00PCT Step1:

[0387] To a solution of compound W6_1 (880 mg, 5.20 mmol) in t-AmOH (28 mL) was added tert-butyl (3R)-3-aminopiperidine-1-carboxylate (1.57g, 7.84 mmol), t-BuONa (3.31 g, 34.44 mmol), BINAP (227.52 mg, 365.40 μmol), and Pd(Oac)2(82.04 mg, 365.40 μmol) under N2. The reaction was heated to 100 °C for 16 h under N2. The mixture was poured onto saturated aq. NH4Cl (200 mL), and the product was extracted with EtOAc (180 mL). The organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 35% THF / Petroleum ether) to give W6_2 (847 mg, 49%) as a oil. Step 2:

[0388] A solution of compound W6_2 (847 mg, 2.55 mmol) in THF (12 mL) was cooled to -65 °C, and then triethylamine (1.55 g, 15.29 mmol) and triphosgene (2.00 g, 6.74 mmol) were added. The mixture was allowed to slowly warm to 25°C, and then stirred at 25 °C for 16 h. The mixture was filtered. The filtrate was quenched with saturated aq. NH4Cl (200 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 35% THF / Petroleum ether) to give key intermediate WA006_1 (370 mg, 37%) as a white solid. for intermediate :Step 1:

[0389] A mixture of compound W7_1 (2.69 g, 16.15 mmol), tert-butyl (3R)-3- aminopiperidine-1-carboxylate (6.47 g, 32.29 mmol), t-BuONa (3.10 g, 32.29 mmol) in dioxane (100 mL) was purged with N2for 2 minutes. Then BrettPhos Pd G3(439.08 mg, 484.37 mmol) was added under N2. The resulting mixture was stirred at 105 °C for 5 h. Water (50 mL) was added to the mixture, and the product was extracted with EtOAc (2x100 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~80% Tetrahydrofuran / Petroleum ether) to give compound W7_2 (5 g, 91%) as a yellow oil.Attorney Docket No.: 01317-0001-00PCT

[0390] 1H NMR (400 MHz, CD3OD) δ ppm 8.24 (s, 1H), 7.27 (d, J=2.9 Hz, 1H), 6.72 (d, J=0.6 Hz, 1H), 6.26 (d, J=2.8 Hz, 1H), 3.81 (s, 3H), 3.63-3.52 (m, 1H), 3.26-3.00 (m, 2H), 2.79 (t, J=11.2 Hz, 1H), 2.58 (br s, 1H), 2.07-2.06 (m, 1H), 1.99-1.89 (m, 1H), 1.81-1.79 (m, 1H), 1.48-1.47 (m, 10H). Step 2:

[0391] A solution of compound W7_2 (2 g, 6.05 mmol) in THF (80 mL) was cooled to - 65 °C under N2, and then triethylamine (3.67 g, 36.32 mmol) was added. The mixture was stirred at -65 ℃ for 30 min. Then triphosgene (6 g, 20.22 mmol) was added to the mixture. The mixture was allowed to warm to 25 °C and then stirred for 16 h. The mixture was poured onto ice water (40 mL) and extracted with EtOAc (200 mL). The organic layer was combined, washed with saturated NaHCO3(50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (Eluent of 0~60% EtOAc / dichloromethane) to give key intermediate WA007_1 (381 mg, 14%) as a yellow oil.

[0392] 1H NMR (400 MHz, CD3OD) δ ppm 8.72 (s, 1H), 7.63-7.56 (m, 2H), 6.66 (d, J=3.0 Hz, 1H), 4.45-4.42 (m, 1H), 4.30-4.18 (m, 1H), 4.01 (s, 3H), 3.97-3.89 (m, 1H), 2.86 (br s, 1H), 2.52 (br s, 1H), 2.12-2.09 (m, 1H), 1.76-1.62 (m, 2H), 1.53-1.48 (m, 10H). for intermediate :Step 1:

[0393] A solution of compound W8_1 (5 g, 32.77 mmol) in THF (30 mL) was cooled to 0 °C under N2 and then NaH (1.57 g, 39.32 mmol, 60% purity) was added in portions. The mixture was stirred at 0 °C for 30 min. Then, MeI (5.12 g, 36.05 mmol, 2.24 mL) was added dropwise. After the addition, the mixture was stirred at 25 °C for 2 h. The mixture was poured onto saturated NH4Cl (25 mL) and extracted with EtOAc (3x20). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Compound W8_2 (5.92 g, 98%) was obtained as a solid. The product was used without further purification. Step 2:Attorney Docket No.: 01317-0001-00PCT

[0394] Pd2(dba)3(742 mg, 810.29 μmol), t-BuONa (3.11 g, 32.41 mmol), and JohnPhos (241.79 mg, 810.29 μmol) were added to a solution of compound W8_2 (3 g, 16.21 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (3.57 g, 17.83 mmol) in dioxane (30 mL). The reaction mixture was stirred at 120 °C for 16 h under N2. The mixture was poured onto ice water (20 mL) and extracted with EtOAc (2x15 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 40% Ethyl acetate / Petroleum ether) to give compound W8_3 (1.5 g, 26%) as a brown oil. Step 3:

[0395] A mixture of compound W8_3 (1.45 g, 4.39 mmol) and triethylamine (2.66 g, 26.33 mmol) in THF (20 mL) was cooled to 0 °C, and then triphosgene (5.11 g, 17.22 mmol) was added. The mixture was stirred at 25 °C for 2 h under N2. The mixture was poured onto saturated aq. NaHCO3 (100 mL) and the product was extracted with EtOAc (2x100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 35% THF / Petroleum ether) to give compound WA008_1 (1.1 g, 61%) as a yellow solid.

[0396] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1H), 7.66 (s, 1H), 7.57 (d, J=3.1 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.29 (br d, J=10.5 Hz, 1H), 4.18 - 4.06 (m, 1H), 3.86 (s, 3H), 3.79 (br d, J=13.0 Hz, 1H), 2.44 (br s, 2H), 2.06 - 1.98 (m, 1H), 1.59 (br d, J=12.6 Hz, 1H), 1.47 - 1.33 (m, 11H). for intermediate :Step 1:

[0397] t-BuONa (5.59 g, 58.13 mmol), Xantphos (840.91 mg, 1.45 mmol), and Pd(OAc)2 (326.28 mg, 1.45 mmol) were added to a solution of W9_1 (5 g, 29.07 mmol) and tert-butyl (3R)-3-aminopiperidine-1-carboxylate (5.82 g, 29.07 mmol) in toluene (100 mL). The resulting mixture was purged with N22 times, and then stirred at 100 °C for 6 h. The mixture was cooled to 25 °C and diluted with water (80 mL). The aqueous layer was extracted withAttorney Docket No.: 01317-0001-00PCT EtOAc (3x50 mL). The combined organic layer was washed with brine (2x50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~23% Ethyl acetate / Petroleum ether) to give Compound W9_2 (5.34 g, 63%) as a yellow solid.

[0398] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.87 (dd, J=1.4, 5.0 Hz, 1H), 7.31-7.13 (m, 1H), 6.47 (dd, J=5.0, 7.0 Hz, 1H), 5.37 (brs, 1H), 4.05-3.66 (m, 3H), 2.99-2.66 (m, 2H), 2.04 (s, 3H), 1.96-1.87 (m, 1H), 1.77-1.66 (m, 1H), 1.56 (s, 1H), 1.46-1.23 (m, 10H). Step 2:

[0399] A solution of W9_2 (1 g, 3.43 mmol) in THF (10 mL) was cooled to -65 °C and triethylamine (2.08 g, 20.59 mmol) and triphosgene (3.00 g, 10.11 mmol) were added to the solution. The yellow mixture was allowed to slowly warm to 25 °C and then stirred at 25 °C for 18 h. The mixture was poured onto ice water (200 mL) and extracted with EtOAc (3x100 mL). The combined organic layer was washed with saturated aq. NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~27% Ethyl acetate / Petroleum ether) to give the key intermediate WA009_1 (0.92 g, 73%) as a light yellow solid.

[0400] 1H NMR (400 MHz, CD3OD) δ ppm 8.41 (br d, J=4.4 Hz, 1H), 7.86 (m, 1H), 7.44 (br d, J=7.5 Hz, 1H), 4.62-4.26 (m, 1H), 4.22-3.84 (m, 2H), 3.16 (s, 1H), 2.73-2.46 (m, 1H), 2.40 (d, J=8.3 Hz, 3H), 1.91 (bs, 1H), 1.78-1.59 (m, 1H), 1.58-1.52 (m, 1H), 1.48 (d, J=16.5 Hz, 10H). for intermediate :Step 1:

[0401] Compound W10-1 (5 g, 39 mmol) and tert-butyl (3R)-3-aminopiperidine-1- carboxylate (11.7 g, 58.3 mmol) were dissolved in THF (100 mL), and t-BuONa (11.2 g, 116.7 mmol) and BrettPhos Pd G3 (1.76 g, 1.94 mmol) were added. The reaction was purged with N2for 2 minutes and then heated to 80 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gelAttorney Docket No.: 01317-0001-00PCT chromatography (Eluent of 30% Ethyl acetate / Petroleum ether) to give compound W10-2 (9 g, 79.2%) as a brown oil. Step 2:

[0402] NaH (3.69 g, 92.4 mmol, 60% purity) was added to a solution of compound W10- 2 (9 g, 30.8 mmol) in THF (100 mL) under N2. The reaction mixture was stirred at 25°C for 0.5 h. Then, triphosgene (10.81 g, 36.43 mmol) in toluene (30 mL) was slowly added, after which the reaction mixture was stirred at 60 °C for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate (200mL) and extracted with EtOAc (3x200 mL). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 40% Ethyl acetate / Petroleum ether) to give WA010_1 (2.6 g, 24%) as a yellow oil.

[0403] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73-8.64 (m, 1H), 8.54 (s, 1H), 5.75 (s, 1H), 4.38-3.93 (m, 2H), 3.92-3.59 (m, 1H), 2.56 (br s, 3H), 2.09-1.82 (m, 1H), 1.80-1.50 (m, 2H), 1.38 (d, J = 18.8 Hz, 11H). for intermediate :Step 1:

[0404] To a solution of compound W11-1 (5.0 g, 34.59 mmol) and tert-butyl (3R)-3- aminopiperidine-1-carboxylate (8.31 g, 41.51 mmol) in THF (70 mL) was added t-BuONa (9.97 g, 103.76 mmol) and BrettPhos Pd G3 (1.57 g, 1.73 mmol). The reaction mixture was purged with N2 for 2 minutes and then heated to 80 °C for 2 h under N2. The reaction mixture was filtered, and the organic layer was concentrated under reduced pressure. The crude product was poured onto H2O (150 mL) and extracted with ethyl acetate (3x150 mL). The combined organic layer was dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 18% Ethyl acetate / Petroleum ether) to give W11-3 (10 g, 84.4%) as yellow oil. Step 2:

[0405] NaH (1.63 g, 40.9 mmol, 60% purity) was added to a solution of compound W11- 3 (10 g, 29.2 mmol) in THF (100 mL) at 25°C under N2. The mixture was stirred at 25°C forAttorney Docket No.: 01317-0001-00PCT 0.5 h. Then bis(trichloromethyl) carbonate (6.91 g, 23.29 mmol) in toluene (30 mL) was slowly added to the reaction mixture, which was then stirred at 60 °C for 8 h. LC-MS showed that ~40 % of compound W11-3 remained, so another batch of NaH (1.63 g, 40.87 mmol, 60% purity) was added to the reaction mixture. The mixture was stirred at 25°C for 0.5 h, and then bis(trichloromethyl) carbonate (8.0 g, 26.97 mmol) in toluene (30 mL) was slowly added. The reaction mixture was stirred at 60 °C for another 2 h, after which LC-MS showed that the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (300mL) and extracted with ethyl acetate (3x250 mL). The combined organic layer was dried over Mg2SO4 and concentrated. The residue was purified by flash silica gel chromatography (ISCO®; 120g SepaFlash® Silica Flash Column, Eluent of 2% Ethyl acetate / dichloromethane gradient @ 100 mL / min) to give WA011_1 (3.5 g, 8.12 mmol, 27.81%, 86% purity) as a colorless oil.

[0406] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 4.27-4.06 (m, 2H), 4.01 (s, 3H), 3.83-3.66 (m, 1H), 3.03-2.58 (m, 1H), 2.11-1.80 (m, 1H), 1.74-1.52 (m, 2H), 1.39 (br s, 10H), 1.28-1.06 (m, 1H). Experimental for intermediate (WA012_1):Step 1:

[0407] t-BuONa (8.14 g, 84.65 mmol) and BrettPhos Pd G3 (3.07 g, 3.39 mmol) were added to a solution of compound W12-1 (6.5 g, 42.33 mmol) and compound W12-2 (9.32 g, 46.56 mmol) in THF (80 mL) under N2. Then the reaction mixture was stirred at 80 °C for 2 h under N2, after which it was diluted with water (200 mL) and extracted with EtOAc (3x200 mL). The combined organic layer was washed with saturated NaCl (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 30% THF / Petroleum ether) to give compound W12-3 (13.00 g, 75%) as a black solid. Step 2:Attorney Docket No.: 01317-0001-00PCT

[0408] A solution of compound W12-3 (8 g, 19.66 mmol) and triethylamine (11.94 g, 117.96 mmol) in THF (140 mL) was cooled to 0 °C, and triphosgene (17.11 g, 57.66 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h under N2. The mixture was filtered and washed with EtOAc (2x20 mL). The filtrate was diluted with saturated NH4Cl (150 mL) and extracted with EtOAc (3x150 mL). The combined organic layer was washed with saturated aq. NaHCO3 (200 mL), brine (200mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 43% THF / Petroleum ether) to give WA012_1 (3.75 g, 44%) as a yellow solid.

[0409] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.78 (d, J=4.8 Hz, 1H), 8.30 (d, J=0.8 Hz, 1H), 7.97 - 7.85 (m, 2H), 4.30 (br d, J=11.8 Hz, 1H), 4.18 (br t, J=10.9 Hz, 1H), 3.75 (br d, J=11.0 Hz, 1H), 3.39 (br s, 2H), 1.98 (br d, J=15.1 Hz, 1H), 1.67 - 1.53 (m, 1H), 1.38 (s, 10H), 1.36 (s, 1H). 2.2 details for final the in 2.1Procedure W5 Step 1

[0410] DIEA (150 μmol, 3.0 eq) was added to a solution of WBi (60 μmol, 1.2 eq) and WAi_1 (18.7 mg, 50 μmol, 1.0 eq) in dichloromethane (100 μL). The reaction vial was capped and shaken at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give WAiBi_1, which was used in the next step directly. Step 2:

[0411] WAiBi _1 (~50 μmol, 1.0 eq) was dissolved in a mixed solution (1.0 mL) of dichloromethane:TFA (v / v = 5:1). The reaction mixture was shaken at 30 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to obtain the final product.Attorney Docket No.: 01317-0001-00PCT 3.1 details for intermediateStep 1:

[0412] A solution of compound Z1_1 (25 g, 130 mmol), tert-butyl (3R)-3- aminopiperidine-1-carboxylate (26.0 g, 130 mmol), t-BuONa (24.9 g, 260 mmol), Xantphos (3.76 g, 6.50 mmol), and Pd(Oac)2 (1.46 g, 6.50 mmol) in toluene (300 mL) was purged with N2for 2 min and then heated at 100 °C for 10 h under N2. The reaction mixture was poured into H2O (800 mL) and extracted with ethyl acetate (3x800 mL). The combined organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 18% Ethyl acetate / Petroleum ether) to give compound Z1_2 (35 g, 106 mmol, 82.1%, 95% purity) as a white solid.

[0413] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (dd, J=4.88, 1.50 Hz, 1H), 7.61 (dd, J=7.63, 1.50 Hz, 1H), 6.59 (dd, J=7.63, 4.88 Hz, 1H), 5.89 (br s, 1H), 3.87 – 3.99 (m, 1H), 3.40 – 3.85 (m, 2H), 2.74 – 3.25 (m, 2H), 1.82 – 1.92 (m, 1H), 1.66 (br dd, J=10.44, 3.19 Hz, 2H), 1.23 – 1.45 (m, 10 H). Step 2:

[0414] A solution of compound Z1_2 (12 g, 38.5 mmol) in THF (150 mL) was cooled to -65 °C, and then triethylamine (23.3 g, 231 mmol) and triphosgene (34.2 g, 115 mmol) were added. Then the reaction mixture was allowed to slowly warm to 25 °C and subsequently stirred at 25 °C for 18 h. The reaction mixture was filtered, and the filtrate was quenched with saturated NH4Cl (300 mL) and extracted with ethyl acetate (3x300 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 20% Ethyl acetate / Petroleum ether) to give key intermediate Z1 (11.5 g, 75.8%) as a colorless oil.

[0415] 1H NMR: (400 MHz, CDCl3) δ ppm 8.12 (d, J=5.38 Hz, 1H), 7.58 (d, J=5.25 Hz, 1H), 6.57 (d, J=3.00 Hz, 1H), 4.66 (br d, J=12.26 Hz, 1H), 4.18 – 4.36 (m, 1H), 3.91 – 4.05 (m, 4H), 3.33 (br t, J=11.13 Hz, 1H), 2.46 (br s, 1H), 1.65 – 1.81 (m, 1H), 1.48 (br s, 9H).Attorney Docket No.: 01317-0001-00PCTStep 1:

[0416] To a solution of compound Z2_1 (25.0 g, 164 mmol) in THF (200 mL) was added NaH (7.86 g, 196 mmol, 60% purity) in portions at 0 °C under N2. The reaction mixture was stirred at 0 °C for 30 min. Then MeI (25.6 g, 180 mmol) was added dropwise. After the addition, the reaction mixture was stirred at 25 °C for 2 h. The reaction was poured into saturated NH4Cl (200 mL) and extracted with EtOAc (200 mL). The organic layer was washed with brine (3x50 mL), dried over Na2SO4, filtered, and concentrated to give compound Z2_2 (26 g, 95%) as a yellow solid. The product was used without further purification.

[0417] 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (d, J=5.38 Hz, 1H), 7.41 (d, J=5.38 Hz, 1H), 7.16 (d, J=3.13 Hz, 1H), 6.48 (d, J=3.13 Hz, 1H), 4.15 (s, 3H). Step 2:

[0418] A mixture of compound Z2_2 (15.0 g, 90.0 mmol), tert-butyl (3R)-3- aminopiperidine-1-carboxylate (19.8 g, 99.0 mmol), and t-BuONa (17.3 g, 180 mmol) in dioxane (300 mL) was purged with N2 for 2 minutes. Then, BrettPhos Pd G3 (2.45 g, 2.70 mmol) was added under N2. The resulting mixture was stirred at 105 °C for 4 h. The reaction mixture was poured into ice water (500 mL) and extracted with EtOAc (3x200 mL). The combined organic layer was washed with brine (3x100 mL), dried over Na2SO4, filtered, and concentrated to give compound Z2_3 (29 g, 97%) as a yellow solid. The product was used without further purification.

[0419] 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (d, J=5.77 Hz, 1H), 6.92 (d, J=3.01 Hz, 1H), 6.88 (d, J=5.77 Hz, 1H), 6.32 (d, J=3.01 Hz, 1H)), 4.37 (br s, 1H), 4.08 (s, 3H), 3.85 – 3.95 (m, 1H), 3.77 – 3.84 (m, 1H), 3.70 (s, 3H), 3.42 (br d, J=13.30 Hz, 1H), 3.06 – 3.17 (m, 1H), 1.89 (br s, 1H), 1.61 (br s, 1H), 1.45 (s, 9H). Step 3:

[0420] To a solution of compound Z2_3 (10 g, 30.2 mmol) in THF (150 mL) was added NaH (1.57 g, 39.3 mmol, 60% purity) under N2at 0 °C. The mixture was stirred at 25 °C for 30 min. Then a solution of triphosgene (6.44 g, 21.70 mmol) in toluene (20 mL) was added dropwise. The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture wasAttorney Docket No.: 01317-0001-00PCT poured into ice water (200 mL) and extracted with EtOAc (100 mL). The combined organic layer was washed with saturated aq. NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (Eluent of 0~20% Ethyl acetate / Petroleum ether) to give key intermediate Z2 (5.2 g, 41%) as a yellow gum.

[0421] 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (d, J=5.38 Hz, 1H), 7.58 (d, J=5.25 Hz, 1H), 7.21 (d, J=2.88 Hz, 1H), 6.57 (d, J=3.00 Hz, 1H), 4.66 (br d, J=12.26 Hz, 1H), 4.18 – 4.36 (m, 1H), 3.91 – 4.05 (m, 4H), 3.33 (br t, J=11.13 Hz, 1H), 2.46 (br s, 1H), 1.65 – 1.81 (m, 1H), 1.48 (br s, 9H), 1.00 – 1.20 (m, 1H), 0.78 – 0.94 (m, 2H). General procedure for preparation of compound ZB002Step 1:

[0422] DIEA (1.75 g, 13.5 mmol) and N-Boc piperazine (1.26 g, 6.76 mmol) were added to a solution of compound ZB002_1 (1.00 g, 6.76 mmol) in DMA (20.0 mL). The reaction mixture was stirred at 170 °C for 6 h, after which it was poured into saturated NaHCO3(50 mL) and extracted with EtOAc (3x50 mL). The combined organic layer was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 47% THF / petrolem ether) to give compound ZB002_2 (240 mg, 14%) as a yellow oil.

[0423] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br s, 1H). 8.18 (s, 1H). 3.40 (br s, 4H). 3.25 (m, 4H). 1.41 (s, 9H). Step 2:

[0424] HCl / dioxane (4.00 M, 5.00 mL) was added to a solution of compound ZB002_2 (240 mg, 947 μmol) in dioxane (2.00 mL). The reaction mixture was stirred at 25 °C for 1 h. The reaction was then concentrated in vacuo to give compound ZB002 hydrochloride salt (167 mg, 92.9%) as a yellow solid, which was directly used in the next step without further purification.Attorney Docket No.: 01317-0001-00PCT

[0425] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.65 (br s, 2H). 8.52 (s, 1H). 3.74 (br d, J=4.52 Hz, 4H). 3.21 (br s, 4H). General ZB011

[0426] Triethylamine (2.36 g, 23.3 mmol, 3.25 mL) was added to a solution of Z11_1 (1 g, 7.78 mmol) and Z11_2 (670 mg, 7.78 mmol) in i-PrOH (10 mL). The reaction mixture was stirred at 100 °C for 18 h, after which it was filtered and concentrated in vacuo. The crude product was used in the next step directly. Compound ZB011 (800 mg, crude) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (s, 1H). 7.70 (s, 1H). 3.68 (m, 1H). 3.44 (m, 4H). 2.77 (dd, J=5.93, 4.22 Hz, 4H). 2.29 (s, 3H). General procedure for preparation of compound Z14Step 1:

[0427] DIEA (1.51 g, 11.7 mmol, 2.03 mL) was added to a solution of compound Z14-1 (500 mg, 3.89 mmol) and tert-butyl piperazine-1-carboxylate (869 mg, 4.67 mmol) in i-PrOH (10.0 mL). The reaction mixture was stirred at 25 °C for 2 h, after which it was poured into water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layer was concentrated in vacuo to give compound Z14-2 (500 mg, crude) as a white residue which was used without further purification. Step 2:

[0428] To a solution of compound Z14-2 (453 mg, 1.63 mmol) in dioxane (3.00 mL) was added HCl / dioxane (4 M, 406.96 μL). The reaction mixture was stirred at 25 °C for 12 h.Attorney Docket No.: 01317-0001-00PCT The mixture was then concentrated in vacuo to give compound ZB014 hydrochloride salt (330 mg) as a gray solid which was used without further purification.

[0429] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.30 (d, J=5.1 Hz, 1H), 6.71 (d, J=5.1 Hz, 1H), 4.05 – 3.97 (m, 4H), 3.34 (br s, 1H), 3.17 – 3.10 (m, 4H), 2.38 – 2.33 (m, 3H), 1.33 – 1.29 (m, 1H). General procedure for preparation of compound ZB021Step1:

[0430] To a solution of compound ZB021_1 (340 mg, 2.44 mmol) and compound ZB021_2 (453 mg, 2.44 mmol) in i-PrOH (5.00 mL) was added DIEA (629 mg, 4.87 mmol). The reaction mixture was stirred at 100 °C for 16 h, after which it was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~50% Ethyl acetate / Petroleum ether, gradient). Compound ZB021_3 (700 mg, 99.3%) was obtained as a yellow solid. The product was used without further purification.

[0431] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (d, J = 4.6 Hz, 1H), 7.19 (d, J = 4.6 Hz, 1H), 3.76 – 3.70 (m, 4H), 3.45 – 3.39 (m, 4H), 1.43 (s, 9H). Step 2:

[0432] To a solution of compound ZB021_3 (300 mg, 1.04 mmol) in dioxane (2.00 mL) was added HCl / dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 2 h, after which it was concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound ZB021 hydrochloride salt (1.26 g, crude) was obtained as a yellow solid.

[0433] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 – 9.31 (m, 3H), 8.73 (d, J = 4.6 Hz, 1H), 7.29 (d, J = 4.8 Hz, 1H), 4.03 – 3.95 (m, 4H), 3.16 (br s, 5H).Attorney Docket No.: 01317-0001-00PCT General of compound ZB023

[0434] Triethylamine (1.98 g, 19.5 mmol) and piperazine (729 mg, 8.47 mmol) were added to a solution of compound ZB023_1 (1.00 g, 6.51 mmol) in i-PrOH (15 mL). The reaction mixture was stirred at 100 °C for 2 h, after which it was filtrated and concentrated. The crude residue was triturated with EtOAc (20 mL) at 25 °C for 1 h and then filtered. The filter cake was dried to give compound ZB023 (293 mg, 22%) as a white solid. This compound was used without further purification.

[0435] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (br s, 1H). 8.15 (m, 1H). 7.19 (br s, 1H). 6.63 (m, 1H). 3.86 (br s, 2H). 3.47 (m, 4H). 2.91 (br s, 3H). LC-MS+= 204.2.Step 1:

[0436] Carbonyldiimidazole (8.68 g, 53.5 mmol) was added to a solution of compound WB025_1 (5.00 g, 44.6 mmol) in MeCN (100 mL). The reaction mixture was stirred at 70 °C for 3 h. Then 2,2-dimethoxyethanamine (4.69 g, 44.6 mmol) was added to the reaction. The reaction was stirred at 70 °C for 2 h, after which the solvent was removed by evaporation. The residue was dissolved in EtOAc (200 mL), washed with aqueous 1N aq. HCl solution (3x50 mL), and the organic layer was concentrated. The crude product was triturated with EtOAc (50 mL) and filtered, and the filter cake was dried to give compoundAttorney Docket No.: 01317-0001-00PCT ZB025_2 hydrochloride salt (7.48 g, 84.2%) as a white solid. This compound was used without further purification.

[0437] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.24 (br s, 1H). 7.98 (br s, 1H). 7.81 (s, 1H). 6.63 (s, 1H). 4.51 (br t, J=5.40 Hz, 1H). 3.35 (br s, 1H). 3.32 (br s, 1H). 3.27 (s, 7H). Step 2:

[0438] A solution of compound ZB025_2 (2.00 g, 10.0 mmol) in HCl (5 M, 20.0 mL) was stirred at 25 °C for 3 h. The reaction mixture was filtered, washed with EtOH (10 mL), and concentrated in vacuo to give a compound ZB025_3 (1.00 g, 65.0 %) as a white solid. The product was used in the next step without further purification. Step 3:

[0439] HCl (12.0 M, 8.00 mL) was added to a solution of compound ZB025_3 (1.80 g, 11.8 mmol) in dioxane (8 mL). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was poured into saturated aq. NaHCO3 (15 mL) and extracted with EtOAc (3x10 mL). The combined organic layer was concentrated in vacuo to give compound ZB025_4 (2.05 g, crude) as a yellow solid, which was directly used in the next step without further purification. Step 4:

[0440] PyBOP (4.62 g, 8.88 mmol) and triethylamine (899 mg, 8.88 mmol) were added to a solution of compound ZB025_4 (1.00 g, 7.40 mmol) in DMF (20.0 mL). The mixture was stirred at 25 °C for 30 min, after which N-Boc piperazine (1.79 g, 9.62 mmol) was added. The reaction mixture was then stirred at 25 °C for 3 h. LC-MS showed that the starting material remained, so the reaction was stirred for an additional 17 h at 80 °C. The residue was poured into saturated aq. NaHCO3 (50 mL) and extracted with EtOAc (3x25 mL). The combined organic layer was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 10% THF / petroleum ether) to give compound ZB025_5 (995 mg, 44.3%) as a yellow oil. Step 5:

[0441] A solution of HCl in dioxane (4 M, 15.0 mL) was added to a solution of compound ZB025_5 (995 mg, 3.28 mmol) in MeOH (5 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to give compound ZB025 (670 mg, 85.2%, HCl salt) as a yellow solid. The product was used without further purification.

[0442] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (br s, 2H), 8.28 (d, J=5.02 Hz, 1H), 8.14 (d, J=2.51 Hz, 1H), 7.41 (d, J=5.02 Hz, 1H), 7.26 (s, 1H), 4.02 (m, 4H), 3.27 (br s, 4H).Attorney Docket No.: 01317-0001-00PCT General of compound ZB026

[0443] Compound ZB026_1 (500 mg, 1.63 mmol) was added to a solution of HCl in dioxane (4 M, 6 mL), and the reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was used in the next step without further purification. Compound ZB026 (430 mg, crude, HCl salt) was obtained as a white solid.

[0444] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (br s, 2H), 8.40 (d, J = 1.2 Hz, 1H), 8.24 (br d, J = 8.8 Hz, 1H), 7.35 (br d, J = 8.4 Hz, 1H), 4.02 (br s, 4H), 3.31 – 3.23 (m, 1H), 3.27 (br s, 3H). General Z27Step 1:

[0445] Triethylamine (4.08 g, 40.2 mmol) was added to a solution of compound Z27_1 (3 g, 20.1 mmol) andcompound Z27_2 (3.75 g, 20.1 mmol) in DMF (30 mL). The reaction mixture was stirred at 25 °C for 2 h, after which it was poured into water (100 mL) and stirred for 5 min. The solid was collected by filtration and dried to give compound Z27_3 (4 g, 6.5%) as a yellow solid. The product was used without further purification. Step 2:

[0446] Hydrazine hydrochloride (1.38 g, 20.1 mmol) was added to a solution of compound Z27_3 (4 g, 13.4 mmol) and triethylamine (4.06 g, 40.1 mmol) in dioxane (40 mL). The reaction mixture was stirred at 120 °C for 18 h. LC-MS showed that starting material remained, so the reaction mixture was stirred at 120 °C for another 24 h. The reaction mixture was cooled and filtered, and the filtrate was concentrated in vacuo to giveAttorney Docket No.: 01317-0001-00PCT compound Z27_4 (3 g, 76.1%) as a yellow solid. The product was used without further purification. Step 3:

[0447] A solution of compound Z27_4 (800 mg, 2.72 mmol) in CH(OEt)3(10 mL) was stirred at 140 °C for 2 h. The mixture was cooled and filtered, and the filter cake was dried to give compound Z27_5 (550 mg, 66%) as a yellow solid. The product was used without further purification.

[0448] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (s, 1H), 8.56 (br d, J=7.70 Hz, 1H), 6.88 (br d, J=7.70 Hz, 1H), 3.72 (br s, 4H), 3.44 (br s, 4H), 1.43 (s, 9H). Step 4:

[0449] A solution of compound Z27_5 (500 mg, 1.64 mmol) in a solution of HCl in dioxane (4 M, 10 mL, 24.35 eq) was stirred at 25 °C for 2 h. The mixture was concentrated to give compound ZB027 (380 mg, 96%, HCl salt) as a yellow solid. The product was used without further purification.

[0450] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (br s, 2H), 9.16 (s, 1H), 8.86 (d, J=8.00 Hz, 1H), 7.38 (d, J=7.88 Hz, 1H), 4.15 (br s, 4H), 3.25 (br s, 4H). General of compound ZB028

[0451] A mixture of 6-chloro-7H-purine (500 mg, 3.24 mmol), piperazine (278 mg, 3.24 mmol), and triethylamine (982 mg, 9.71 mmol) in i-PrOH (10 mL) was stirred at 100 °C for 18 h. The precipitate was collected and dried to give compound ZB028 (600 mg, 90.8%) as a yellow solid. The product was used without further purification.

[0452] 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.20 (s, 1H), 4.44 (br s, 4H), 3.19 (br s, 4H).Attorney Docket No.: 01317-0001-00PCT General compound ZB029

[0453] DIEA (836 mg, 6.47 mmol, 1.13 mL) and piperazine (306 mg, 3.56 mmol) were added to a solution of compound Z29-1 (500 mg, 3.24 mmol) in i-PrOH (1 mL). The reaction mixture was stirred at 100 °C for 12 h, after which the mixture was filtered. The filter cake was dried under reduced pressure to give compound ZB029 (600 mg, crude) as a gray solid which was used in the next step without further purification.

[0454] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.35 – 9.30 (m, 1H), 8.00 – 7.93 (m, 1H), 7.40 (d, J=4.5 Hz, 1H), 4.54 – 4.35 (m, 4H), 3.31 – 3.18 (m, 4H), 1.04 (d, J=6.1 Hz, 1H). General procedure for preparation of compound ZB037

[0455] Triethylamine (6.97 g, 68.8 mmol, 9.59 mL), picoline borane (11.0 g, 103 mmol), and compound ZB037_2 (2.79 g, 41.3 mmol, HCl salt) were added to a solution of compound ZB037_1 (5.00 g, 34.4 mmol) in MeOH (50.0 mL) and AcOH (5.00 mL). The reaction mixture was stirred at 50 °C for 16 h, after which it was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~100% THF / Petroleum ether). Compound ZB037 (1.68 g, 30%) was obtained as a white solid.

[0456] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.42 (br d, J = 6.3 Hz, 3H), 3.76 (q, J = 6.8 Hz, 1H), 2.13 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H).Attorney Docket No.: 01317-0001-00PCT General procedure for preparation of compound Z41Step 1:

[0457] BPO (5.92 g, 24.4 mmol) and NBS (4.35 g, 24.4 mmol) were added to a solution of compound Z41_1 (3 g, 22.2 mmol) in CCl4 (50 mL). The mixture was stirred at 80 °C for 3 h. The mixture was cooled to 0 °C, and a white solid precipitated. The suspension was filtered, and the filtrate was concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~10% Ethyl acetate / Petroleum ether) to give compound Z41_2 (2.5 g, 52.6%) as a white solid.

[0458] 1H NMR (400 MHz, CDCl3) δ ppm 7.75 (dd, J=6.85, 2.08 Hz, 1H), 7.63 (ddd, J=8.56, 4.71, 2.14 Hz, 1H), 7.19 (t, J=8.93 Hz, 1H), 4.48 (s, 2H). Step 2:

[0459] MeNH2.HCl (265 mg, 3.92 mmol) and triethylamine (993 mg, 9.81 mmol) were added to a solution of compound Z41_2 (700 mg, 3.27 mmol) in THF (5 mL). The mixture was stirred at 25 °C for 1 h. The mixture was filtered and concentrated to give compound ZB041 (480 mg, 89.4%) as a yellow solid, which was used without further purification.

[0460] Benzoyl benzenecarboperoxoate (11.3 g, 46.6 mmol) and NBS (8.29 g, 46.6 mmol) were added to a solution of compound Z42_1 (5 g, 42.3 mmol) in CCl4(50 mL). The reaction mixture was stirred at 70 °C for 4 h, after which it was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 20% Ethyl acetate / Petroleum ether). Compound Z42_2 (2.2 g, 23.7%) was obtained as a brown solid.Attorney Docket No.: 01317-0001-00PCT

[0461] 1H NMR (400 MHz, CDCl3) δ ppm 8.63 (d, J=5.0 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H), 7.47 (dd, J=1.7, 4.9 Hz, 1H), 4.36 (s, 2H).

[0462] Triethylamine (308 mg, 3.05 mmol) and compound Z42_2 (0.6 g, 3.05 mmol) were added to a solution of MeNH2 (472 mg, 7.00 mmolHCl salt) in THF (5 mL). The reaction mixture was stirred at 25 °C for 1 h, after which it was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 80% Ethyl acetate / Petroleum ether). Compound ZB042 (0.18 g, 36.2%) was obtained as a brown solid.

[0463] 1H NMR (400 MHz, CDCl3) δ ppm 8.66 (d, J=5.0 Hz, 1H), 7.75 (d, J=0.7 Hz, 1H), 7.53 (td, J=0.8, 5.0 Hz, 1H), 3.87 (s, 2H), 2.48 (s, 4H). General ZB044

[0464] Na2CO3(685 mg, 6.47 mmol) and Pd-118 (105 mg, 161 μmol) were added to a solution of Z44_2 (1 g, 3.23 mmol) and Z44_1 (588 mg, 3.23 mmol) in dioxane (10 mL) and H2O (3 mL) under N2. The reaction mixture was stirred at 80 °C for 2 h, after which it was poured into water (20 mL) and extracted with EtOAc (2x30mL). The combined organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum ether). Compound Z44_3 (800 mg, 86.9%) was obtained as a yellow oil.

[0465] Pd / C (50 mg, 2.81 mmol, 10% wt) was added to a solution of Z44_3 (800 mg, 2.81 mmol) in MeOH (20 mL) under H2. The reaction mixture was stirred at 25 °C for 18 h, after which it was filtered and concentrated in vacuo. The crude product was used in the next step directly. Compound Z44_4 (670 mg, crude) was obtained as a colorless oil.

[0466] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.74 (s, 1H), 7.67 (dt, J=7.58, 1.34 Hz, 1H), 7.62 (m, 1H), 7.51 (m, 1H), 4.08 (br d, J=10.64 Hz, 2H), 2.77 (m, 3H), 1.75 (br d, J=12.59 Hz, 2H), 1.53 (m, 2H), 1.42 (s, 9H).Attorney Docket No.: 01317-0001-00PCT

[0467] A solution of Z44_4 (400 mg, 1.40 mmol) in a solution of HCl in dioxane (20 mL) was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo, and the crude product was used in the next step directly without further purification. Compound ZB044 (370 mg, crude, HCl salt) was obtained as a white solid.

[0468] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (br s, 2H), 7.62 (m, 4H), 3.33 (br d, J=12.23 Hz, 2H), 2.97 (m, 3H), 1.95 (m, 4H). General Z45

[0469] A solution of compound Z45_1 (2 g, 9.38 mmol) and compound Z45_2 (1.01 g, 9.38 mmol) in CHCl3(100 mL) and EtOH (0.1 mL) was cooled to 0 °C, after which TFA (3.21 g, 28.1 mmol) was added dropwise. The mixture was then stirred at 50 °C for 18 h. The mixture was poured into saturated NaHCO3 (100 mL), and the separated organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give compound Z45_3 (2.66 g, 99.1%) as a brown solid.

[0470] 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1H), 7.67 (d, J=7.58 Hz, 1H), 7.35 – 7.42 (m, 2H), 7.26 – 7.31 (m, 1H), 3.93 – 4.08 (m, 2H), 3.49 (ddd, J=13.72, 9.87, 3.55 Hz, 2H), 1.81 (ddd, J=13.69, 9.66, 4.03 Hz, 2H), 1.66 (dt, J=13.66, 4.29 Hz, 2H), 1.51 (s, 9H). Step 2:

[0471] A solution of compound Z45_3 (800 mg, 2.79 mmol) in HCl / dioxane (4 M, 8.00 mL) was stirred at 25 °C for 2 h. The reaction mixture was concentrated to give compound ZB045 (610 mg, 98.04%, HCl salt) as a yellow solid. The compound was used without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 9.46 – 9.75 (m, 2H), 8.96 (br s, 1H), 7.62 (br d, J=6.78 Hz, 1H), 7.34 – 7.47 (m, 3H), 3.36 – 3.45 (m, 4H), 2.21 – 2.36 (m, 2H), 1.62 (br d, J=14.05 Hz, 2H). General procedure for preparation of compound Z50_2Attorney Docket No.: 01317-0001-00PCT

[0472] To a solution of compound Z50_1 (1.50 g, 5.37 mmol) and 2H-triazole (407 mg, 5.91 mmol) in MeCN (15 mL) was added Cs2CO3 (3.50 g, 10.7 mmol). The reaction mixture was stirred at 90 °C for 15 h, after which it was partitioned between water (200 mL) and ethyl acetate (3x300 mL). The combined organic layer was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0-45% THF / Petroleum ether). Compound Z50_2 (0.70 g, 49.1%) was obtained as a white solid.

[0473] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (s, 2H), 4.74 (tt, J=4.1, 11.0 Hz, 1H), 3.97 (br d, J=12.8 Hz, 2H), 3.01 (br s, 2H), 2.16 – 2.04 (m, 2H), 1.84 (dq, J=4.3, 11.9 Hz, 2H), 1.42 (s, 9H).

[0474] To a solution of compound Z50_2 (700 mg, 2.77 mmol) in dioxane (4 mL) was added a solution of HCl in dioxane (4M, 4 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound ZB050 (390 mg, crude, HCl salt) as a yellow residue which was used in the next step without further purification.

[0475] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 - 9.19 (m, 2H), 7.83 (s, 2H), 4.93 - 4.83 (m, 1H), 3.33 (br d, J=12.9 Hz, 2H), 3.11 (br s, 2H), 2.33 - 2.19 (m, 4H). General procedure for preparation of compound Z54_2

[0476] To a solution of 2H-tetrazole (4 M, 4.03 mL) in DMF (15.0 mL) was added Cs2CO3 (3.50 g, 10.7 mmol) and compound Z54_1 (1.50 g, 5.37 mmol). The reaction mixture was stirred at 90 °C for 15 h, after which it was partitioned between water (200 mL) and ethyl acetate (3x300 mL). The combined organic layer was washed with brine (200 mL),Attorney Docket No.: 01317-0001-00PCT dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 50% THF / Petroleum ether, gradient). Compound Z54_2 (0.60 g, 41.9%) was obtained as a white solid.

[0477] 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (s, 1H), 5.04 - 4.87 (m, 1H), 4.20 (br d, J=13.5 Hz, 2H), 3.07 (ddd, J=3.1, 11.0, 13.8 Hz, 2H), 2.35 - 2.14 (m, 4H), 1.53 - 1.48 (m, 9H).

[0478] To a solution of HCl in dioxane (4 M, 2.47 mL) was added to a solution of compound Z54_2 (0.50 g, 1.97 mmol) in dioxane (3 mL). The reaction was stirred at 25 °C for 2 h, and a white solid formed. The reaction mixture was concentrated under reduced pressure, and the residue was used in the next step without further purification. Compound ZB054 (0.37 g, 93.9%, HCl salt) was obtained as a white solid.

[0479] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.47 - 9.10 (m, 2H), 9.04 (s, 1H), 5.31 - 5.19 (m, 1H), 3.45 - 3.30 (m, 2H), 3.15 (br d, J=12.3 Hz, 2H), 2.41 - 2.27 (m, 4H). General Z59_3

[0480] Triethylamine (4.41 g, 43.6 mmol, 6.07 mL) was added to a solution of Z59_1 (5 g, 21.8 mmol) and Z59_2 (2.77 g, 28.3 mmol, HCl salt) in DMF (40 mL). The reaction was allowed to stir for 10 min, after which HOBt (3.83 g, 28.3 mmol) and EDCI (5.43 g, 28.3 mmol) were added. The mixture was stirred at 20 °C for 18 h. The mixture was poured onto water (60 mL) and extracted with EtOAc (3x80 mL). The combined organic layer was washed with brine (3x200 mL), dried with MgSO4, filtered, and concentrated. The crude product was used in the next step directly without further purification. Compound Z59_3 (6.1 g, crude) was obtained as a colorless oil.

[0481] 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (br d, J=11.86 Hz, 2H), 3.69 (s, 3H), 3.33 (br s, 1H), 3.10 (s, 3H), 2.83 (m, 4H), 1.64 (br d, J=11.00 Hz, 2H), 1.40 (s, 9H).

[0482] A solution of Z59_4 (1.07 g, 14.6 mmol, 1.19 mL) in THF (26 mL) was cooled to 0 °C and then a solution of n-BuLi (2.5 M, 11.7 mL) was added dropwise over 5 min. The reaction was stirred for 30 min, and then a solution of Z59_3 (2 g, 7.34 mmol) in THF (20 mL) was added dropwise to the reaction mixture over 20 min. The reaction was stirred for 30Attorney Docket No.: 01317-0001-00PCT min, after which it was poured into a solution of H2SO4(3.60 g, 36.7 mmol) in THF and water (v:v=4:1, 6 mL) and refluxed for 1 h. The mixture was carefully neutralized with NaHCO3, and then water was added to dissolve the salts. The mixture was extracted with EtOAc (3x80 mL), and the combined organic layer was washed with brine, dried with MgSO4, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 0~25% THF / petroleum ether). Compound Z59_5 (1.6 g, 81.80%) was obtained as a colorless oil.

[0483] 1H NMR (400 MHz, DMSO-d6) δ ppm 6.14 (s, 1H), 3.95 (br d, J=12.96 Hz, 2H), 2.95 (m, 3H), 2.19 (s, 3H), 1.91 (m, 2H), 1.45 (m, 2H), 1.40 (s, 9H).

[0484] A solution of Z59_5 (1.1 g, 4.13 mmol) in a solution of HCl in dioxane (20 mL) was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to give a white solid. The crude product was used in the next step directly without further purification. Compound ZB059 (700 mg, HCl salt) was obtained as a white solid.

[0485] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (m, 1H), 9.26 (m, 2H), 6.19 (s, 1H), 3.27 (br d, J=12.84 Hz, 2H), 3.13 (tt, J=11.34, 3.58 Hz, 1H), 2.99 (m, 2H), 2.20 (s, 3H), 2.08 1.85 .General procedure for preparation of compound ZB062 Step 1:

[0486] Isopentyl nitrite (5.11 g, 43.6 mmol) was added to a solution of compound ZB062_1 (2.00 g, 12.1 mmol), CH2I2 (16.2 g, 60.6 mmol), and CuI (2.31 g, 12.1 mmol) in THF (21 mL). The reaction mixture was stirred at 80 °C for 1 h, after which it was poured into saturated NaCl (20 mL) and extracted with EtOAc (3x20 mL). The combined organic layer was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 9% Ethyl acetate / Petroleum ether) to give compound ZB062_2 (2.12 g, 83.4%) as a yellow solid. Step 2:

[0487] To a solution of compound ZB062_2 (500 mg, 2.38 mmol) and compound ZA (957 mg, 3.10 mmol) in dioxane (10 mL) and H2O (2 mL) was added Na2CO3(505 mg, 4.76Attorney Docket No.: 01317-0001-00PCT mmol) and Pd-118 (77.6 mg, 119 μmol) under N2. The reaction mixture was stirred at 80 °C for 3 h under N2. The residue was poured into water (15 mL), extracted with EtOAc (3x10 mL), and the combined organic layer was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Eluent of 10% Ethyl acetate / Petroleum ether) to give compound ZB062_3 (400 mg, 63.3%) as a yellow solid. Step 3:

[0488] To a solution of compound ZB062_3 (400 mg, 1.51 mmol) in MeOH (6.00 mL) was added Pd / C (1.51 mmol, 1.00 mL, 10% wt) under H2. The reaction mixture was stirred at 25 °C for 2 h under H2. The mixture was filtered and concentrated in vacuo to give compound ZB062_4 (400 mg, crude) as a white solid, which was used directly in the next step without further purification. Step 4:

[0489] To a solution of compound ZB062_4 (400 mg, 1.50 mmol) in MeOH (2 mL) was added a solution of HCl in dioxane (4 M, 7 mL). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give compound ZB062 (295 mg, 96.8%, HCl salt) as a white solid, which was used directly in the next step without further purification.

[0490] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.30 (m, 2H), 4.32 (s, 2H), 4.31 (m, 1H), 3.27 (m, 3H), 3.04 (m, 2H), 2.14 (br dd, J=13.88, 2.75 Hz, 2H), 1.97 (m, 2H). General ZB063Step 1:

[0491] To a solution of compound ZB063_1 (1.00 g, 10.4 mmol) in THF (10.0 mL) was added n-BuLi (2.5 M, 4.58 mL) dropwise at -78 °C under N2. The reaction mixture was stirred at -78 °C for 1 h. Then a solution of compound ZB063_2 (3.45 g, 10.4 mmol) in THF (10.0 mL) was added dropwise at -78 °C. After the addition, the reaction mixture was allowed to warm to 25 °C slowly. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated aq. NH4Cl (30.0 mL) and extracted with EtOAc (30 mL).Attorney Docket No.: 01317-0001-00PCT The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~50% Ethyl acetate / Petroleum ether). Compound ZB063_3 (700 mg, 24.2%) was obtained as a brown oil.

[0492] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 - 7.37 (m, 1H), 6.20 (d, J = 1.8 Hz, 1H), 5.88 (br s, 1H), 4.16 - 4.06 (m, 2H), 4.00 (br s, 2H), 3.57 - 3.44 (m, 2H), 2.39 - 2.23 (m, 2H), 1.43 (s, 9H), 1.35 - 1.29 (m, 3H). Step 2:

[0493] To a solution of compound ZB063_3 (700 mg, 2.52 mmol) in MeOH (3 mL) was added Pd / C (500 mg, 2.52 mmol). The reaction mixture was stirred at 25 °C for 48 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound ZB063_4 (650 mg, crude) was obtained as a yellow solid. Step 3:

[0494] To a solution of compound ZB063_4 (600 mg, 2.15 mmol) in dioxane (5 mL) was added a solution of HCl in dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound ZB063 (296 mg, HCl salt) was obtained as a yellow oil.

[0495] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.68 - 9.20 (m, 2H), 7.57 - 7.46 (m, 1H), 6.24 - 6.09 (m, 1H), 5.41 - 5.24 (m, 2H), 4.16 (q, J = 7.4 Hz, 2H), 3.28 (br d, J = 12.0 Hz, 2H), 1.97 - 1.77 (m, 4H), 1.33 (t, J = 7.2 Hz, 3H). General

[0496] To a solution of compound Z64_1 (4.00 g, 17.6 mmol) in dichloromethane (40 mL) was added triethylamine (3.56 g, 35.2 mmol, 4.90 mL) and methyl sulfonyl methane sulfonate (6.13 g, 35.2 mmol). The mixture was stirred at 25 °C for 10 h. The reaction was partitioned between water (400 mL) and dichloromethane (600 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The product was used in the next step without further purification. CompoundAttorney Docket No.: 01317-0001-00PCT Z64_2, which is a mixture of cis and trans stereoisomers, (5.00 g, 93.0%) was obtained as a yellow oil.

[0497] 1H NMR (400 MHz, DMSO-d6) δ ppm 5.03 - 4.90 (m, 1H), 4.10 (br s, 1H), 3.24 - 3.13 (m, 3H), 2.06 (br s, 2H), 1.97 - 1.79 (m, 4H), 1.77 - 1.68 (m, 1H), 1.77 - 1.56 (m, 2H), 1.41 (d, J=6.1 Hz, 9H).

[0498] To a solution of compound Z64_2 (0.60 g, 1.96 mmol) in DMF (6 mL) was added Cs2CO3 (638.61 mg, 1.96 mmol) and 1H-pyrazole (200 mg, 2.94 mmol). The mixture was stirred at 90 °C for 15 h. The reaction was partitioned between water (200 mL) and ethyl acetate (3x300 mL). The combined organic layer was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 50% THF / Petroleum ether). Compound Z65_1, which is a mixture of cis and trans stereoisomers, (0.45 g, 78.6%) was obtained as a white solid.

[0499] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (d, J=2.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 6.29 (t, J=2.0 Hz, 1H), 4.47 - 4.28 (m, 1H), 4.09 (br s, 2H), 2.56 (br d, J=14.1 Hz, 2H), 2.33 - 2.17 (m, 2H), 1.75 - 1.63 (m, 2H), 1.44 (s, 11H).

[0500] To a solution of compound Z65_1 (0.45 g, 1.62 mmol) in dioxane (2 mL) was added a solution of HCl in dioxane (2 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound ZB065, which is a mixture of cis and trans stereoisomers, (295 mg, HCl salt), a white solid which was used in the next step without further purification.

[0501] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br s, 2H), 8.05 (d, J=2.1 Hz, 1H), 7.50 (d, J=1.4 Hz, 1H), 6.35 (t, J=1.9 Hz, 1H), 4.49 - 4.45 (m, 2H), 3.98 (br s, 2H), 3.39 (s, 1H), 2.87 (br d, J=15.8 Hz, 2H), 1.86 - 1.75 (m, 2H), 1.60 - 1.52 (m, 2H), 1.39 - 1.14 (m, 3H), 0.90 - 0.71 (m, 1H). General procedure for preparation of compound Z64-3Attorney Docket No.: 01317-0001-00PCT

[0502] To a solution of compound Z64_2 (800 mg, 2.62 mmol) in DMF (8.00 mL) was added Cs2CO3 (2.56 g, 7.86 mmol) and imidazole (713 mg, 10.5 mmol). The mixture was stirred at 90 °C for 5 h. The reaction mixture was poured into water (50 mL), and the product was extracted with ethyl acetate (50 mL). The combined organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum ether) to give compound Z64-3, which is a mixture of cis and trans stereoisomers, (290 mg, 37.9%) as a white solid.

[0503] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (s, 1H), 7.36 (s, 1H), 6.91 (s, 1H), 4.20 - 4.08 (m, 3H), 2.41 - 2.29 (m, 2H), 2.11 (br dd, J=4.3, 14.3 Hz, 2H), 1.80 (br s, 2H), 1.53 (br d, J=7.3 Hz, 2H), 1.43 (s, 9H).To a solution of compound Z64-3 (290 mg, 1.05 mmol) in dioxane (2.00 mL) was added a solution of HCl in dioxane (4M, 2 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give compound ZB064, which is a mixture of cis and trans stereoisomers, (260 mg, crude, HCl salt) as a white residue which was used in the next step without further purification.

[0504] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.60 - 9.34 (m, 3H), 8.09 (s, 1H), 7.82 (s, 1H), 4.67 (br s, 1H), 4.03 (br s, 2H), 2.70 (br s, 4H), 1.98 - 1.86 (m, 2H), 1.45 (br d, J=8.5 Hz, 2H). General ZB066Step 1:

[0505] To a solution of ZB066_1 (6.95 g, 27.0 mmol) in EtOH (100 mL) was added N2H4.H2O (6.90 g, 135 mmol). The mixture was stirred at 95 °C for 16 h. The solvent was removed under reduced pressure to give compound ZB066_2 (6.50 g, crude) as a white solid which was used in the next step without further purification. Step 2:Attorney Docket No.: 01317-0001-00PCT

[0506] To a solution of ZB066_2 (1.70 g, 6.99 mmol) in DMF (20.0 mL) was added 1,1- dimethoxy-N,N-dimethyl-methanamine (832 mg, 6.99 mmol). The mixture was stirred at 100 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give compound ZB066_3 (1.8 g, crude) as a colorless residue which was used in the next step without further purification. Step 3:

[0507] To a solution of compound Z66_3 (2 g, 6.70 mmol) in AcOH (15 mL) was added ethanamine (3.02 g, 67.03 mmol) dropwise at 0 °C. The mixture was stirred at 100 °C for 3 h. The mixture was concentrated to give a yellow residue. The residue was dissolved in EtOAc (100 mL), washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was used directly in the next step without further purification. Compound Z66_4 (1.8 g, 67.1%) was obtained as a yellow solid.

[0508] 1H NMR (400 MHz, CDCl3) δ ppm 8.17 (s, 1H), 4.02 - 4.29 (m, 3H), 3.96 (q, J=7.34 Hz, 2H), 3.21 - 3.36 (m, 1H), 1.79 - 1.93 (m, 4H), 1.67 - 1.79 (m, 2H), 1.43 - 1.50 (m, 12H). Step 4:

[0509] A solution of compound Z66_4 (1.8 g, 4.49 mmol, ) in a solution of HCl in dioxane (4 M, 30 mL) was stirred at 25 °C for 1 h. The mixture was concentrated to give a white solid. The solid was directly used in the next step without further purification. Compound ZB066 (1.3 g, 93.4%, HCl salt) was obtained as a white solid. General Z67_1 and Z68_1

[0510] To a solution of compound Z64_2 (3.00 g, 9.82 mmol) in DMF (30 mL) was added Cs2CO3(3.20 g, 9.82 mmol) and 2H-triazole (1.02 g, 14.7 mmol). The mixture was stirred at 100 °C for 2 h. The reaction was partitioned between water (300 mL) and ethyl acetate (3x300 mL). The combined organic layer was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 10-60% THF / Petroleum ether, gradient). Compound Z68_1 (0.65 g, 22.6%) was obtained as a white solid.Attorney Docket No.: 01317-0001-00PCT Compound Z68_1 (0.35 g, 1.19 mmol, 12.2%, 95% purity) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.60 (s, 2H), 5.03 (tt, J=5.7, 11.7 Hz, 1H), 4.40 (br s, 2H), 2.43 - 2.19 (m, 2H), 2.15 - 1.99 (m, 4H), 1.87 - 1.75 (m, 2H), 1.51 (s, 9H). Compound Z67_1 (0.90 g, 3.07 mmol, 31.3%) was obtained as a white solid.1H NMR (400 MHz, CDCl3) δ ppm 7.79 (s, 1H), 7.72 (s, 1H), 4.63 (quin, J=5.0 Hz, 1H), 4.42 (br s, 1H), 4.33 (br s, 2H), 2.65 - 2.46 (m, 5H), 2.14 (td, J=2.9, 10.6 Hz, 2H), 1.89 (dq, J=3.0, 5.3 Hz, 2H), 1.60 - 1.54 (m, 2H), 1.51 (s, 13H).

[0511] To a solution of compound Z67_1 (0.90 g, 3.23 mmol) in dioxane (10 mL) was added a solution of HCl in dioxane (4 M, 4.85 mL). The mixture was stirred at 25 °C for 2 h. White solid was formed. The reaction mixture was concentrated under reduced pressure. The residue was used in the next step without further purification. Compound ZB067, which is a mixture of cis and trans stereoisomers, (0.69 g, 99.4%, HCl salt) was obtained as a white solid.

[0512] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 - 9.41 (m, 4H), 8.57 - 8.16 (m, 1H), 7.92 - 7.65 (m, 1H), 5.21 - 4.66 (m, 1H), 4.20 - 3.93 (m, 2H), 2.98 - 2.79 (m, 1H), 2.68 (ddd, J=3.3, 6.2, 16.2 Hz, 1H), 2.27 - 2.16 (m, 1H), 2.06 (s, 2H), 1.87 - 1.76 (m, 1H), 1.49 - 1.37 (m, 1H). General ZB068

[0513] To a solution of compound Z68_1 (0.65 g, 2.34 mmol) in dioxane (10 mL) was added a solution of HCl in dioxane (4 M, 3.50 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was used in the next step without further purification. Compound ZB068, which is a mixture of cis and trans stereoisomers, (0.50 g, 99.7%, HCl salt) was obtained as a white solid.

[0514] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (br s, 2H), 8.01 - 7.80 (m, 2H), 4.72 (t, J=6.1 Hz, 1H), 4.02 (br s, 2H), 3.07 (br d, J=15.8 Hz, 2H), 2.78 - 2.56 (m, 2H), 1.87 - 1.68 (m, 2H), 1.42 - 1.19 (m, 2H). General procedure for preparation of compound Z69_1Attorney Docket No.: 01317-0001-00PCT

[0515] To a solution of compound Z64_2 (1.50 g, 4.91 mmol) in DMF (15 mL) was added Cs2CO3 (2.40 g, 7.37 mmol) and 1H-1,2,4-triazole (1.02 g, 14.7 mmol). The mixture was stirred at 100 °C for 2 h. The reaction was partitioned between water (200 mL) and ethyl acetate (3x300 mL). The combined organic layer was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 50% THF / Petroleum ether). Compound Z69_1, which is a mixture of cis and trans stereoisomers, (0.50 g, 34.7%) was obtained as a white solid.

[0516] 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (s, 1H), 7.92 (s, 1H), 4.39 (quin, J=5.2 Hz, 1H), 4.25 (br s, 2H), 2.39 (br s, 4H), 1.91 - 1.79 (m, 2H), 1.47 (br d, J=7.6 Hz, 2H), 1.42 (s, 9H).

[0517] To a solution of compound Z69_1 (0.50 g, 1.80 mmol) in dioxane (4 mL) was added a solution of HCl in dioxane (4 M, 2.69 mL). The mixture was stirred at 25 °C for 10 h. The reaction mixture was concentrated under reduced pressure. The residue was used in the next step without further purification. Compound ZB069, which is a mixture of cis and trans stereoisomers, (0.38 g, 98.5%, HCl salt) was obtained as a white solid.

[0518] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.41 (br s, 2H), 9.12 (s, 1H), 8.21 (s, 1H), 4.62 (br t, J=6.3 Hz, 1H), 4.02 - 3.99 (m, 2H), 2.85 - 2.75 (m, 2H), 2.66 - 2.57 (m, 2H), 1.88 - 1.77 , 1.55 - 1.43 .General procedure for preparation of compound Z71 Step 1:

[0519] To a solution of compound Z71_2 (1 g, 12.0 mmol) in THF (20 mL) was added n- BuLi (2.5 M, 5.30 mL) dropwise at -78 °C under N2. The mixture was stirred at -78 °C forAttorney Docket No.: 01317-0001-00PCT 0.5 h. Then a solution of compound Z71_1 (2.40 g, 12.0 mmol) in THF (10 mL) was added dropwise at -78 °C. After the addition, the mixture was allowed to slowly warm to 25 °C. The mixture was stirred at 25 °C for 1.5 h. The mixture was poured into saturated aq. NaH4Cl (30 mL) and extracted with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a yellow residue. The residue was purified by flash silica gel chromatography (Eluent of 0~60% Ethyl acetate / Petroleum ether) to give compound Z71_3 (3.2 g, 94.2%) as a yellow solid.

[0520] 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (s, 1H), 5.76 (s, 1H), 3.98 (s, 3H), 3.69 (br d, J=13.05 Hz, 2H), 3.22 (br d, J=2.01 Hz, 2H), 1.86 - 1.98 (m, 2H), 1.78 - 1.85 (m, 2H), 1.40 (s, 9H). Step 2:

[0521] A solution of compound Z71_3 (700 mg, 2.48 mmol) in a solution of HCl in dioxane (4 M, 10 mL) was stirred at 25 °C for 2 h. The mixture was concentrated to give compound ZB071 (540 mg, 99.6%, HCl salt) as a yellow solid, which was used without further purification.1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 - 9.37 (m, 2H), 7.87 (s, 1H), 3.99 (s, 3H), 3.16 (br s, 3H), 3.10 - 3.22 (m, 1H), 2.20 - 2.34 (m, 2H), 2.05 (br d, J=13.76 Hz, 1H), 1.95 - 2.12 .General procedure for preparation of compound Z77 Step 1:

[0522] To a solution of compound Z77_1 (1 g, 4.03 mmol) in THF (15 mL) was added triethylamine (1.22 g, 12.1 mmol) and methoxycarbonyl methyl carbonate (591 mg, 4.43 mmol, 475 μL). The mixture was stirred at 25 °C for 18 h. The mixture was diluted with EtOAc (30 mL), washed with saturated aq. NaHCO3 (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash silica gel chromatography (Eluent of 0~50% Ethyl acetate / Petroleum ether) to give compound Z77_2 (330 mg, 26.7%) as a white solid.Attorney Docket No.: 01317-0001-00PCT1H NMR (400 MHz, DMSO-d6) δ ppm 8.87 (s, 1H), 7.06 - 7.26 (m, 2H), 6.98 (br d, J=7.50 Hz, 1H), 4.48 (br s, 2H), 3.64 (s, 3H), 3.51 (br t, J=5.88 Hz, 2H), 2.64 (br t, J=5.82 Hz, 2H), 1.42 (s, 9H)Step 1:

[0523] A solution of compound Z72_1 (5 g, 26.99 mmol) in DMF-DMA (17.9 g, 150 mmol) was stirred at 80 °C for 2 h. The mixture was then concentrated to give a yellow solid, which was used directly in the next step without further purification. Compound Z72_2 (6.49 g, crude) was obtained as a yellow solid. Step 2:

[0524] To a solution of 2-methylisothiourea; sulfuric acid (6.95 g, 24.9 mmol) in EtOH (200 mL) was added NaOEt (1.70 g, 24.9 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h. Then compound Z72_2 (6 g, 24.97 mmol) was added in batches. The resulting mixture was stirred at 80 °C for 18 h. The mixture was concentrated, and the residue was partitioned between EtOAc (200 mL) and brine (200 mL). The organic layer was separated and concentrated to give a yellow residue. The residue was purified by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum ether) to give compound Z72_3 (1.1 g, 16.5%) as a yellow solid. Step 3:

[0525] To a solution of compound Z72_3 (1 g, 3.74 mmol) in dichloromethane (30 mL) was added m-CPBA (1.52 g, 7.48 mmol, 85% purity). The mixture was stirred at 25 °C for 16 h. The reaction mixture was washed with saturated aqueous Na2SO3(50 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~40% Ethyl acetate / Petroleum ether) to give compound Z72_4 (900 mg, 80.4%) as a yellow solid.Attorney Docket No.: 01317-0001-00PCT Step 4:

[0526] To a solution of compound Z72_4 (700 mg, 2.34 mmol) in DMF (7 mL) was added KCN (228 mg, 3.51 mmol) at 25 °C. The mixture was stirred at 25 °C for 2.5 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Eluent of 0~30% Ethyl acetate / Petroleum ether) to give compound Z72_5 (440 mg, 76%), which was obtained as a white solid. Step 5:

[0527] A solution of compound Z72_5 (500 mg, 1.42 mmol) in a solution of HCl in dioxane (4 M, 10 mL) was stirred at 25 °C for 20 min. The mixture was concentrated to give a white solid. The solid was directly used in the next step without further purification. Compound ZB072 (250 mg, 96.3%, HCl salt) was obtained as a white solid. 3.2 details for final the in 3.1Procedure Z1 Step 1

[0528] To a solution of ZBi (60 μmol, 1.2 eq) and ZA001 (18.7 mg, 50 μmol, 1.0 eq) in dichloromethane (100 μL) was added DIEA (150 μmol, 3.0 eq). The reaction vials were capped and shaken at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give ZA001Bi_1, which was used in the next step directly. Step 2

[0529] To a solution of ZA001Bi _1 (50 μmol, 1.0 eq) was added a solution (1.0 mL) of dichloromethane and TFA (v / v = 5 / 1). The reaction mixture was shaken at 30 °C for 2 h, after which it was concentrated under reduced pressure to give a residue, which was then purified by preparative HPLC to obtain the final product.Attorney Docket No.: 01317-0001-00PCTProcedure Z2 Step 1

[0530] To a solution of ZBi (60 μmol) and ZA002 (19.6 mg, 50 μmol) in dichloromethane (100 μL) was added DIEA (150 μmol). The reaction vials were capped and shaken at 50 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H2O (1.0 mL) and extracted with dichloromethane (3x1.5 mL). The combined organic layer was concentrated under reduced pressure to give a residue ZA002Bi_1, which was used in the next step directly. Step 2

[0531] To a solution of ZA002Bi _1 (50 μmol, 1.0 eq) was added a solution (1.0 mL) of dichloromethane and TFA (v / v = 5 / 1). The reaction mixture was shaken at 30 °C for 2 h, after which it was concentrated under reduced pressure to give a residue, which was then purified by preparative HPLC to obtain the final product. 4.1 Experimental details for intermediate synthesis:Attorney Docket No.: 01317-0001-00PCT Procedures for step 1 Condition Q1.1

[0532] To a solution of Q2Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added 200 μL of Cs2CO3(1.5 M in H2O, 300 μmol, 3.0 eq) and XPhos Pd G3 (10 μmol, 0.1 eq) under N2. The mixture was shaken at 80 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q3AiBi, which was used in the next step directly. Condition Q1.2

[0533] To a solution of Q2Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added 200 μL of Cs2CO3 (1.5 M in H2O, 300 μmol, 3.0 eq) and XPhos Pd G3 (10 μmol, 0.1 eq) under N2. The mixture was shaken at 80 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q3AiBi, which was used in the next step directly. Condition Q1.3

[0534] To a solution of Q2Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added 100 μL of K3PO4(1.0 M in H2O, 300 μmol, 2.0 eq) and Pd 118 (10 μmol, 0.1 eq) under N2. The mixture was shaken at 80 °C for 4 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q3AiBi, which was used in the next step directly. Condition Q1.4

[0535] To a solution of Q2Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added Pd(PPh3)2Cl2 (10 μmol, 0.1 eq) under N2. The mixture was shaken at 90 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q3AiBi, which was used in the next step directly.Attorney Docket No.: 01317-0001-00PCT Condition Q1.5

[0536] To a solution of Q5Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added Cs2CO3 (300 μmol, 3.0 eq,) and RuPhos Pd G4 (10 μmol, 0.1 eq) in dichloroethane (30 μL) under N2. The mixture was shaken at 100 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q6AiBi, which was used in the next step directly. Condition Q1.6

[0537] To a solution of Q5Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added t-BuONa (300 μmol, 3.0 eq,) and RuPhos Pd G4 (10 μmol, 0.1 eq) in dichloroethane (30 μL) under N2. The mixture was shaken at 100 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q6AiBi, which was used in the next step directly. Condition Q1.7

[0538] To a solution of Q5Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added Cs2CO3 (300 μmol, 3.0 eq,) and BrettPhos Pd G3 (10 μmol, 0.1 eq) in dichloroethane (30 μL) under N2. The mixture was shaken at 120 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q6AiBi, which was used in the next step directly. Condition Q1.8

[0539] To a solution of Q5Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added Cs2CO3(300 μmol, 3.0 eq) and RuPhos Pd G4 (10 μmol, 0.1 eq) in dichloroethane (30 μL) under N2. The mixture was shaken at 150 °C under N2 for 2 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q6AiBi, which was used in the next step directly.Attorney Docket No.: 01317-0001-00PCT Condition Q1.9

[0540] To a solution of Q5Bi (150 μmol, 1.5 eq) and Q1Ai (100 μmol, 1.0 eq) in dioxane (1.0 mL) was added K2CO3 (300 μmol, 3.0 eq) and BrettPhos Pd G3 (10 μmol, 0.1 eq) in dichloroethane (30 μL) under N2. The mixture was shaken at 120 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with H2O (1.0 mL) and extracted with ethyl acetate (3x1.5 mL). The combined organic layer was combined and concentrated in vacuo to give crude Q6AiBi, which was used in the next step directly. Procedures for step 2 Condition Q2.1

[0541] 1.0 mL of a solution of dichloromethane and TFA (v / v = 3 / 1) was added to Q3AiBi or Q6AiBi (80 μmol, 1.0 eq). The reaction mixture was shaken at 30 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with 2.0 mL of MeOH and adjusted to a pH of 8 ~ 9 with NH3.H2O. The residue was then purified by preparative HPLC to obtain the final product. Condition Q2.2

[0542] To a solution of Q3AiBi or Q6AiBi (80 μmol, 1.0 eq) in 1 mL of dichloromethane was added 0.5 mL of HCl-dioxane (4.0 M). The reaction mixture was shaken at 30 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to obtain the final product. Condition Q2.3

[0543] To a solution of Q3AiBi or Q6AiBi (80 μmol, 1.0 eq) was added CF3CH2OH (1 mL) and HBF4 (30 μL, 50% of purity). The reaction mixture was shaken at 30 °C for 2 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative. HPLC to obtain the final product.

[0544] Table 4 below provides a list of compounds made using the procedures describe above. The Ex No. is the Example Number for each exemplified compound.Attorney Docket No.: 01317-0001-00PCT

[0545] Table 4Attorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTpp yAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCTAttorney Docket No.: 01317-0001-00PCT

[0546] Synthesis of (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(6-(1- 1H- 4- 1- -N- 3- benzamide

[0547] 6-Bromo-1-chloroisoquinoline (1.00 g, 4.151 mmol) and tert-butyl (R)-3- aminopiperidine-1-carboxylate (4.10 g, 20.75 mmol, specific optical rotation = –35oat 20oCAttorney Docket No.: 01317-0001-00PCT (c = 5 in MeOH)) were placed in a sealed tube, and the reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was allowed to cool and concentrated. The residue was purified by Combi-flash using 100% EtOAc to afford tert-butyl (R)-3-((6-bromoisoquinolin- 1-yl)amino)piperidine-1-carboxylate (250 mg, 16%) as a thick oil. Step 2:

[0548] To a solution of tert-butyl (R)-3-((6-bromoisoquinolin-1-yl)amino)piperidine-1- carboxylate (250 mg, 0.617 mmol) in THF (50 mL) at 0oC was added 1.5M LiHMDS in THF (1.2 mL, 1.851 mmol). The reaction mixture was stirred at 0oC for 10 min and followed by addition of a solution of 4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2- fluorobenzoyl chloride (204 mg, 0.740 mmol) in THF (5 mL). The reaction mixture was stirred for 30 min before it was quenched with ice cold water and extracted with EtOAc (2x50 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by Combi-flash using 80% EtOAc first and further purified by Prep-HPLC [Conditions: Column: Luna OMEGA C-18 (250x21.2x5μm), Mobile phase A: 0.1% formic acid in water (100 %), Mobile phase B: MeCN (100%), Gradient: T / %B: 0 / 65, 10 / 95, Flow: 15 mL / min, Dilution: MeCN / H2O / THF]. Pure fractions were dried by lyophilization to afford tert-butyl (R)-3-(4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3- yl)-N-(6-bromoisoquinolin-1-yl)-2-fluorobenzamido)piperidine-1-carboxylate (120 mg) as a white solid. Step 3:

[0549] To a solution of tert-butyl (R)-3-(4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-(6- bromoisoquinolin-1-yl)-2-fluorobenzamido)piperidine-1-carboxylate (200 mg, 0.31 mmol) in 1,4-dioxane (4 mL) & H2O (1 mL) were added (1H-pyrazol-4-yl)boronic acid (69.3 mg, 0.620 mmol) and K2CO3(128.5mg,0.93 mmol). The reaction mixture was degassed with nitrogen for 5 minutes. Then, Pd(dppf)Cl2 DCM (25.3 mg, 0.031mmol) was added to reaction mixture, and the reaction was stirred at 90oC for 16 h in a sealed tube. The reaction mixture was diluted with EtOAc (100 mL), filtered through celite, and the filtrate was washed with water. The organic layer was washed with brine, dried over Na2SO4,and concentrated under reduced pressure. The residue was further purified by Prep-HPLC (Conditions: Luna OMEGA C-18 (250x21.2x5μm), Mobile phase A: 0.1% formic acid in water (100%), Mobile phase B: 100% MeCN, Gradient: T / %B: 0 / 50, 10 / 85, Flow: 15mL / min, Dilution: MeCN+H2O+THF). The pure fractions were concentrated under reduced pressure to afford tert-butyl (R)-3-(N-(6-(1H-pyrazol-4-yl)isoquinolin-1-yl)-4-(3H-[1,2,3]triazolo[4,5-Attorney Docket No.: 01317-0001-00PCT b]pyridin-3-yl)-2-fluorobenzamido)piperidine-1-carboxylate (60 mg, 0.09 mmol, 30%) as a white solid. LC-MS: [M+H+] = 634.25. Step 4:

[0550] To a solution of tert-butyl (R)-3-(N-(6-(1H-pyrazol-4-yl)isoquinolin-1-yl)-4-(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluorobenzamido)piperidine-1-carboxylate (25 mg, 0.045 mmol) in THF (2 mL) at 0oC was added sodium hydride (4 mg, 0.157 mmol, 60%). The reaction was stirred for 15 min and followed by addition of MeI (11.1 mg, 0.078 mmol). The reaction was stirred at room temperature for 1 h before it was diluted with water (15 mL) and extracted with EtOAc (2x30 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Conditions: Luna OMEGA C-18 (250x21.2x5μm) Mobile phase A: 0.1% formic acid in water (100%), Mobile phase B: 100% MeCN, Gradient: Time (min) / %B: 0 / 10, 2 / 10, 10 / 65 Flow: 15mL / min, Dilution: MeCN+H2O+THF). The pure fractions were combined and dried by lyophilization to afford tert-butyl (R)-3-(4-(3H-[1,2,3]triazolo[4,5- b]pyridin-3-yl)-2-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1- yl)benzamido)piperidine-1-carboxylate (15 mg) as a white solid. LC-MS: [M+H+] = 648.30. Step 5:

[0551] Deprotection method A: To a solution of tert-butyl (R)-3-(4-(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-1- yl)benzamido)piperidine-1-carboxylate (15 mg, 0.023 mmol) in DCM (2 mL) at 0oC was added 4M HCl in 1,4-dioxane (2 mL). The reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and dried by lyophilization to afford the title compound hydrochloride salt (9 mg) as a yellow solid. LC- MS: [M+H+] = 548.30.1H NMR (DMSO-d6, 400 MHz): δ ppm 8.78 (d, J=4.4 Hz, 1H), 8.65 (d, J=8.4 Hz, 1H), 8.43-8.35 (m, 2H), 8.18-8.15 (m, 1H), 8.10-8.03 (m, 2H), 7.98-7.95 (m, 2H), 7.82-7.80 (m, 1H), 7.73-7.71 (m, 1H), 7.73-7.71 (m, 1H), 7.59-7.56 (m, 1H), 7.42-7.34 (m, 1H), 5.19-5.15 (m, 1H), 3.93-3.89 (m, 1H), 3.88 (s, 3H), 3.87-3.80 (m, 1H), 3.21-3.18 (m, 2H), 1.97-1.91 (m, 1H), 1.79-1.76 (m, 2H), 1.24-1.23 (m, 1H).

[0552] Synthesis of ethyl (R,E)-3-(1-(4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro- N-(piperidin-3-yl)benzamido)isoquinolin-6-yl)acrylate (Example 98)Attorney Docket No.: 01317-0001-00PCT

[0553] Example 98 was prepared according to the procedure described for Example 97 by substituting (1H-pyrazol-4-yl)boronic acid with (E)-(3-ethoxy-3-oxoprop-1-en-1-yl)boronic acid, provided the title compound trifluoroacetic acid salt as an off-white solid. LC-MS: [M+H+] = 566.35.1H NMR (CD3OD, 400 MHz) δ 8.73 (d, J=4.8 Hz, 1H), 8.50-8.44 (m, 2H), 8.19 (d, J=9.2Hz, 1H), 8.04-7.99 (m, 3H), 7.92-7.89 (m, 1H), 7.80-7.72 (m, 2H), 7.52- 7.49 (m, 1H), 7.41-7.30 (m, 1H), 6.71 (d, J=16.0 Hz, 1H), 5.31-5.23 (m, 1H), 4.27-4.22 (m, 1H), 3.98-3.95 (m, 1H), 3.81-3.70 (m, 1H), 2.90-2.83 (m, 1H), 3.33-3.00 (m, 1H), 2.90-2.83 (m, 1H), 2.11-1.85 (m, 3H), 1.39-1.28 (m, 4H).

[0554] Synthesis of (R,E)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-(2-(3-((tert- butyldimethylsilyl)oxy)prop-1-en-1-yl)thieno[3,2-c]pyridin-4-yl)-2-fluoro-N-(piperidin-3-

[0555] Example 99 was prepared from the precursor of Example of 104 by removing the Boc group with ZnBr2to provide the title compound as a white solid. LC-MS: [M+H+] = 644.1H NMR (400 MHz, DMSO-d6) δ 8.89–8.77 (m, 1H), 8.74–8.59 (m, 1H), 8.36–8.21 (m, 1H), 8.03–7.94 (m, 1H), 7.93–7.78 (m, 2H), 7.70–7.56 (m, 1H), 7.55–7.49 (m, 1H), 7.48– 7.28 (m, 1H), 7.04–6.88 (m, 1H), 6.39–6.20 (m, 1H), 4.74–4.47 (m, 1H), 4.36 (br d, J = 1.5 Hz, 2H), 2.91–2.72 (m, 1H), 2.23–2.11 (m, 2H), 1.75–1.41 (m, 3H), 1.29–1.20 (m, 2H), 0.93 (s, 9H), 0.88–0.78 (m, 1H), 0.16–0.01 (m, 6H).

[0556] Synthesis of ethyl (R,E)-3-(1-(4-(1-methyl-1H-1,2,3-triazol-4-yl)-N-(piperidin-3- yl)benzamido)isoquinolin-8-yl)acrylate (Example 100)Attorney Docket No.: 01317-0001-00PCT

[0557] Example 100 was prepared according to the procedure described for Example 111 by substituting tert-butyl (R)-3-((8-methylisoquinolin-1-yl)amino)piperidine-1-carboxylate with tert-butyl (R,E)-3-((8-(3-ethoxy-3-oxoprop-1-en-1-yl)isoquinolin-1- yl)amino)piperidine-1-carboxylate, provided the title compound trifluoroacetic acid salt as an off-white solid. LC-MS: [M+H+] = 532.2.

[0558] Synthesis of (R)-N-(3-(1H-pyrazol-3-yl)pyridin-2-yl)-4-(1-methyl-1H-1,2,3- triazol-4- -N- 3- benzamideStep 1:

[0559] A mixture of 3-bromo-2-fluoropyridine (5 g, 28.41 mmol), tert-butyl (R)-3- aminopiperidine-1-carboxylate (4.74 g, 23.68 mmol), and DIEA (20.62 mL, 118.38 mmol,) in N-methyl-2-pyrrolidone (75 mL) at 25 °C was purged with N2for 3 times, and then the mixture was heated to 120 °C and stirred for 48 h under N2 atmosphere. The reaction mixture was quenched by addition of water (750 mL) at 25 °C, and the product was extracted with ethyl acetate (3x300 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=25 / 1 to 20 / 1) to give tert-butyl (3R)-3- [[2-fluoro-4-(1-methyltriazol-4-yl) benzoyl]-[2-(1H-indol-6-yl)thieno[3, 2-c]pyridin-4- yl]amino]piperidine-1-carboxylate (3.1 g, 36%) as a white solid. LC-MS: [M+H+] = 356.2. Step 2:

[0560] A mixture of tert-butyl (3R)-3-[[2-fluoro-4-(1-methyltriazol-4-yl) benzoyl]-[2- (1H-indol-6-yl) thieno[3, 2-c] pyridin-4-yl] amino]piperidine-1-carboxylate (500 mg, 1.40 mmol), 1-(tetrahydro-2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazole (796.76 mg, 2.80 mmol), Cs2CO3 (1.37 g, 4.22 mmol) and XPhos Pd G3 (118.8 mg, 170.34 μmol) in dioxane (10 mL) and H2O (2 mL) at 20 °C was purged with N2. The mixture was heated to 90 °C and stirred for 12 h under N2 atmosphere. The reaction mixture wasAttorney Docket No.: 01317-0001-00PCT concentrated under reduced pressure. The crude product was purified by reversed-phase Prep- HPLC (neutral condition) to give tert-butyl (3R)-3-((3-(1-(tetrahydro-2H-pyran-2-yl)-1H- pyrazol-3-yl) pyridin-2-yl) amino) piperidine-1-carboxylate (600 mg, 50%) as a white solid. LC-MS: [M+H+] = 428.4. Step 3:

[0561] A mixture of 4-(1-methyltriazol-4-yl) benzoic acid (201.99 mg, 994.06 μmol), POCl3(44.48 μL, 477.15 μmol,), and tert-butyl (3R)-3-[[3-(1-tetrahydropyran-2-ylpyrazol-3- yl)-2-pyridyl] amino] piperidine-1-carboxylate (170 mg, 398 μmol) in pyridine (3 mL) at 25 °C was purged with N2 for 3 times, and then the mixture was heated to 50 °C and stirred for 3 h under N2atmosphere. The reaction mixture was quenched by addition of water (30 mL) at 25 °C, and then extracted with ethyl acetate (3x10 mL). The combined organic layer was washed with brine (20 m)L, dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [H2O (10mM NH4HCO3)-MeCN]; gradient: 35%-65% B over 8.0 min) to give tert- butyl (3R)-3-[[4-(1-methyltriazol-4-yl)benzoyl]-[3-(1-tetrahydropyran-2-ylpyrazol-3-yl)-2- pyridyl] amino] piperidine-1-carboxylate (50 mg, 20%) as a white solid. Step 4:

[0562] A solution of tert-butyl (3R)-3-[[4-(1-methyltriazol-4-yl) benzoyl]-[3-(1- tetrahydropyran-2-ylpyrazol-3-yl)-2-pyridyl] amino] piperidine-1-carboxylate (45 mg, 73.44 μmol) in 4M HCl in dioxane (1 mL) was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um; mobile phase: [H2O (0.04% HCl)-MeCN]; gradient: 1%-25% B over 8.0 min) to give 4-(1-methyltriazol-4-yl)-N-[(3R)-3-piperidyl]-N- [3-(1H-pyrazol-3-yl)-2-pyridyl] benzamide hydrochloride salt (13.1 mg, 41%) as a white solid. LC-MS: [M+H+] = 429.3.1H NMR (400 MHz, CD3OD) : δ 8.74 (br s, 1H), 8.36 (d, J = 5.5 Hz, 2H), 7.89–7.77 (m, 2H), 7.63 (t, J = 7.7 Hz, 1H), 7.56–7.42 (m, 2H), 4.40–4.06 (m, 5H), 2.90 (br d, J = 12.0 Hz, 2H), 2.76 (s, 3H), 2.46 (br d, J = 12.5 Hz, 1H), 2.35 (br t, J = 11.5 Hz, 1H), 2.27–1.99 (m, 4H), 1.81 (br d, J = 13.8 Hz, 1H), 1.71–1.55 (m, 1H).

[0563] Synthesis of (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(piperidin- 3- -N- 1- benzamideStep 1:Attorney Docket No.: 01317-0001-00PCT

[0564] To a solution of tert-butyl (3R)-3-[(8-bromo-1-isoquinolyl)amino]piperidine-1- carboxylate (0.5 g, 1.23 mmol) in dioxane (5 mL) and H2O (1 mL) was added 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (313.09 μL, 1.85 mmol), Cs2CO3 (1.20 g, 3.69 mmol, 3 eq), and Pd(dppf)Cl2(1.80 g, 2.46 mmol) at 20oC under N2. The mixture was heated to 80°C and stirred for 2 h under N2. The reaction mixture was then filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=5 / 1 to 3 / 1) to give tert-butyl (3R)-3-[(8-vinyl-1-isoquinolyl) amino] piperidine-1-carboxylate (0.3 g, 65%) as a yellow oil. Step 2:

[0565] To a solution of tert-butyl (3R)-3-[(8-vinyl-1-isoquinolyl) amino] piperidine-1- carboxylate (0.1 g, 282.92 μmol) in THF (5 mL) was added LiHMDS (1 M, 848.76 μL) at 0 °C under N2 atmosphere The mixture was stirred at 0 °C for 0.5 h and followed by a solution of 2-fluoro-4-(triazolo[4,5-b]pyridin-3-yl)benzoyl chloride (101.75 mg, 367.80 μmol) in THF (1 mL) The reaction mixture was stirred at 20 °C for 0.5 h under N2atmosphere before it was poured into a saturated aq. NH4Cl solution (8 mL) very slowly over 10 min. The aqueous phase was extracted with ethyl acetate (3x5 mL), and the combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a residue, which was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [A: H2O (10mM NH4HCO3); B: MeCN]; B%: 40.00%-70.00%,8.00 min) to give tert-butyl (3R)-3-[[2-fluoro-4-(triazolo[4,5- b]pyridin-3-yl)benzoyl]-(8-vinyl-1-isoquinolyl)amino]piperidine-1-carboxylate (50 mg, 28%) as a white solid. Step 3:

[0566] To a solution of tert-butyl (3R)-3-[[2-fluoro-4-(triazolo[4,5-b]pyridin-3- yl)benzoyl]-(8-vinyl-1-isoquinolyl)amino]piperidine-1-carboxylate (50 mg, 84.22 μmol) in DCM (1 mL) at 0 °C under N2 atmosphere was added TMSOTf (91.32 μL, 505.35 μmol,) and 2,6-dimethylpyridine (54.15 mg, 505.35 μmol). The mixture was stirred at 20° C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (column: Waters Xbridge BEH C18100*30mm*10um;mobile phase: [A: H2O(10mM NH4HCO3); B: MeCN]; B%: 45.00%-75.00%,8.00 min) to give (R)-4-(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(piperidin-3-yl)-N-(8-vinylisoquinolin-1- yl)benzamide as a white solid. LC-MS: [M+H+] = 494.2.1H NMR (400 MHz, DMSO-d6) : δ 8.80 (br d, J=3.38 Hz, 1H), 8.66 (br d, J=8.26 Hz, 1H), 8.41–8.48 (m, 1H), 7.81–7.92 (m, 2H), 7.67–7.79 (m, 4H), 7.42–7.60 (m, 2H), 7.13–7.25 (m, 1H), 5.74–5.83 (m, 1H), 5.60 (brAttorney Docket No.: 01317-0001-00PCT d, J=10.88 Hz, 1H), 4.35–4.53 (m, 1H), 3.55 (br d, J=11.38 Hz, 1H), 3.03–3.10 (m, 1H), 2.83 (br d, J=11.76 Hz, 1H), 2.06–2.36 (m, 2H), 1.43–1.76 (m, 3H), 0.88–1.14 (m, 1H).

[0567] Synthesis of (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(7-(3- 1- 1- 1- -N- 3- benzamideStep 1:

[0568] To a solution of tert-butyl (R)-3-(4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-(7- bromoisoquinolin-1-yl)-2-fluorobenzamido)piperidine-1-carboxylate (250 mg, 0.386 mmol) in THF (5 mL) at room temperature were added prop-2-yn-1-ol (43 mg, 0.767 mmol) followed by CuI (36 mg, 0.189 mmol) and TEA (0.2 mL). The reaction mixture was purged with nitrogen for 5 min and followed by addition of PdCl2(PPh3)2 (30 mg, 0.038 mmol). The reaction mixture was heated to 90 °C and stirred for 16 h before it was allowed to cool to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2x20 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Conditions: LUNA, Mobile phase A: 0.1% formic acid in water, Mobile phase B: 100% MeCN, Gradient: T / %B: 0 / 60, 10 / 80, Flow: 15mL / min, Dilution: MeCN+H2O+THF). Pure fractions were concentrated under reduced pressure and dried by lyophilization to afford tert- butyl (R)-3-(4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(7-(3-hydroxyprop-1-yn-1- yl)isoquinolin-1-yl)benzamido)piperidine-1-carboxylate (30 mg, 0.04 mmol, 30%) as an off- white solid. LC-MS: [M+H+] = 622.25. Step 2:

[0569] To a solution of tert-butyl (R)-3-(4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2- fluoro-N-(7-(3-hydroxyprop-1-yn-1-yl)isoquinolin-1-yl)benzamido)piperidine-1-carboxylate (30 mg, 0.048 mmol ) in DCM (3 mL) at 0 °C was added 4M HCl in 1,4-dioxane (0.2 mL). The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure and dried by lyophilization to afford the title compound hydrochloride salt (30 mg, 30%) as an off-white solid. LC-MS: [M+H+] = 522.25.1H NMR (CD3OD, 400 MHz): δ 8.75 (d, J=4.4 Hz, 1H), 8.51-8.47 (m, 2H), 8.22 (s, 1H), 8.06 (d, J=10.8 Hz, 1H), 7.94-7.92 (m, 1H), 7.82-7.80 (m, 1H), 7.76-7.75 (m, 1H), 7.71-7.65 (m,Attorney Docket No.: 01317-0001-00PCT 1H), 7.54-7.51 (m, 1H), 7.30-7.26 (m, 1H), 5.34-5.22 (m, 1H), 4.50 (s, 2H), 3.97-3.94 (m, 1H), 3.73-3.67 (m, 1H), 3.92-3.83 (m, 1H), 2.01-1.91 (m, 3H), 1.68-1.52 (m, 1H), 1.33-1.28 (m, 1H).

[0570] Synthesis of 2-fluoro-N-[3-[(E)-4-hydroxybut-1-enyl]-2-pyridyl]-N-[(3R)-3- -4- 3- benzamideStep 1:

[0571] A mixture of tert-butyl-dimethyl-[(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)but-3-enoxy]silane (157.09 mg, 502.98 μmol), tert-butyl (3R)-3-[(3-bromo-2-pyridyl)- [2-fluoro-4-(triazolo[4...

Claims

Attorney Docket No.: 01317-0001-00PCT What is Claimed is:

1. A method of modulating c-MYC activity comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein * denotes a stereocenter; M is C1-9heteroaryl, C1-9heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; Rcis absent, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10 arylene, C3-9 heteroarylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, or C1-9 heterocyclylene, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH- heteroaryl, and cyano; Z is a bond, -O-, S, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, -N(Rb)(C1-3alkylene), where Rbis H, or C1-3 alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C2-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted orAttorney Docket No.: 01317-0001-00PCT unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH-heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond.

2. The method of claim 1, wherein the MYC activity is modulated in a cell.

3. The method of claim 1, wherein the MYC activity is modulated in a cellular assay.

4. The method of claim 1, wherein the MYC activity is modulated in an In Vitro Multiple Point Translation Screening Assay.

5. The method of claim 1, wherein the MYC activity is modulated in a subject in need thereof, wherein the subject is a model animal or a human.

6. The method of claim 1, wherein the MYC activity modulates transcriptional regulation of a gene that is a biomarker.

7. The method of claim 1, wherein the MYC activity modulates transcriptional regulation of a gene that is a biomarker that predicts anti-MYC activity.

8. The method of anyone of claims 1-7, wherein the compound of Formula I inhibits MYC activity.

9. The method of any one of claims 1 to 7, wherein the compound of Formula I activates MYC activity.

10. A method of treating a condition associated with MYC activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein * denotes a stereocenter; M is C1-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstitutedAttorney Docket No.: 01317-0001-00PCT haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; Rcis H, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10 arylene, C3-9 heteroarylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, or C1-9 heterocyclylene, each optionally substituted with 1, 2 or 3 substituents chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH-heteroaryl, and cyano; Z is a bond, -O-, -S-, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, -N(Rb)(C1-3alkylene), where Rbis H, or C1-3alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C2-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH-heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond.

11. The method of claim 10, wherein the condition associated with MYC activity is cancer.

12. The method of claim 11, wherein the cancer is chosen from solid and hematopoietic cancers such as breast, prostate, pancreatic, hepatocellular, renal, multiple myeloma, lymphoma, lung, skin, oral squamous, haemopoietic, and neuroblastoma.

13. The method of claim 11, wherein the cancer is derived from breast, colon, lung or hematopoietic lineages.

14. The method of any one of claims 11 to 13, wherein the method further comprises administering to the subject an effective amount of a second anti-cancer agent.Attorney Docket No.: 01317-0001-00PCT 15. The method of claim 14, wherein the second anti-cancer agent is chosen from PARP inhibitors, immune oncology (I / O) drugs, tyrosine kinase inhibitors, CHK1 inhibitor, GLS inhibitor, SAE1 / 2 modulators, BUD31 modulators, TRRAP modulators and BRD4 modulators.

16. The method of claim 14, wherein the second anti-cancer agent is chosen from Olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula), nivolumab (Opdivo), atezolizumab (Tecentriq), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi) and cemiplimab-rwlc (Libtayo), axitinib (Inlyta) dasatinib (Sprycel), erlotinib (Tarceva), imatinib (Glivec), nilotinib (Tasigna), pazopanib (Votrient), sunitinib (Sutent).

17. A method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein * denotes a stereocenter; M is C1-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; Rcis H, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; L is a bond, C6-10 arylene, C3-9 heteroarylene, C3-10 cycloalkylene, C3-10 cycloalkenylene, or C1-9 heterocyclylene, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, haloalkyl, carboxylic acid, ester, amide, alkoxy, alkoxyaryl, alkoxyheteroaryl, thioether, amino, NH-aryl, NH-Attorney Docket No.: 01317-0001-00PCT heteroaryl, and cyano; Z is a bond, -O-, -S-, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, -N(Rb)(C1-3alkylene), where Rbis H, or C1-3 alkyl; and T is absent, C6-10 aryl, C3-10 cycloalkyl, C2-9 heteroaryl, C1-9 heterocyclyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH-heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when L is a bond, T is not absent and when T is absent, then L is not a bond.

18. The method of claim 17, wherein the cancer is chosen from solid and hematopoietic cancers such as breast, prostate, pancreatic, hepatocellular, renal, multiple myeloma, lymphoma, lung, skin, oral squamous, haemopoietic, and neuroblastoma.

19. The method of claim 17, wherein the cancer is derived from breast, colon, lung or hematopoietic lineages.

20. The method of any one of claims 17 to 19, wherein the method further comprises administering to the subject an effective amount of a second anti-cancer agent.

21. The method of claim 20, wherein the second anti-cancer agent is chosen from PARP inhibitors, immune oncology (I / O) drugs, tyrosine kinase inhibitors, CHK1 inhibitor, GLS inhibitor, SAE1 / 2 modulators, BUD31 modulators, TRRAP modulators and BRD4 modulators.

22. The method of claim 20, wherein the second anti-cancer agent is chosen from Olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula), nivolumab (Opdivo), atezolizumab (Tecentriq), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi) and cemiplimab-rwlc (Libtayo), axitinib (Inlyta) dasatinib (Sprycel), erlotinib (Tarceva), imatinib (Glivec), nilotinib (Tasigna), pazopanib (Votrient), sunitinib (Sutent).

23. The method of any one of claims 1 to 22, wherein M is pyrrolo[2,3-c] pyridinyl, pyrrolo[3,2-c] pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, quinolinyl-2-one, 1,6-naphthyridinyl, 1,6-naphthyridinyl, pyridinyl, or 2-pyrazinyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted orAttorney Docket No.: 01317-0001-00PCT unsubstituted alkenyl, substituted or unsubstituted alkynyl, ester, carboxylic acid, substituted or unsubstituted amido, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents.

24. The method of any one of claims 1 to 22, wherein M is, , , , , or ; wherein each R1is independently absent halo, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted ester, substituted or unsubstituted acetyl, carboxylic acid, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate; substituted or unsubstituted alkoxy, substituted or unsubstituted thioether, substituted or unsubstituted amino, cyano, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl, wherein each substituted group has 1, 2 or 3 substituents; n* is 0, 1, 2 or 3; R2is absent, halo, alkyl, alkenyl, alkynyl, aryl heteroaryl or cyano; R1*is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2*is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, cyano, heteroaryl, cycloalkyl or heterocyclyl; and each W, X, and Y are independently -CH, -N, -NH, N-alkyl, O, or S; R2#is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amide, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl or C-heteroaryl; Y2is CH or N; R2^is absent, alkyl, alkenyl, alkynyl, cyano or halo; and R3is absent, alkyl, alkenyl, alkynyl, halo, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, alkoxy, thioether, or amino; and ---- is a bond that is a double bond or a single bond.Attorney Docket No.: 01317-0001-00PCT 25. The method of one of claims 1 to 22, wherein M is, or ; wherein each R1is independently absent, cyano; chloro; bromo; fluoro; acetyl; amido; carbamate; alkylcarbamate; pyrazinyl; tetrazolyl; hydroxycarbonyl; alkoxycarbonyl; pyridinyl-2-one; C1-6 alkoxy; C1-6haloalkyl; C1-6cycloalkyl; C1-6alkyl optionally substituted with OH, pyridinyl, amido, or phenyl; C2-6 alkenyl optionally substituted with amido, OH, pyrazolyl, pyridinyl, isoxazolyl, thiophenyl, alkyl substituted amido, hydroxyalkylamido, arylalkylamido, alkoxycarbonyl, or hydroxycarbonyl; C2-6alkynyl optionally substituted with OH; phenyl optionally substituted with OH, halo, hydroxyalkyl, sulfonyl, or alkylsulfonyl; pyrazolyl optionally substituted with C1-6 alkyl, C1-6 hydroxyalkyl, or acetamide; pyridinyl optionally substituted with amino; triazolyl optionally substituted with C1-6hydroxyalkyl; thiazolyl optionally substituted with C1-6alkyl; or 1,3,4-thiadiazolyl optionally substituted with C1-6alkyl; n* is 0, 1 or 2; R2is absent, halo, or C1-6 alkyl, or cyano.

26. The method of any one of claims 1 to 22, wherein M is; wherein Y2is CH or N; R1*is absent; chloro; cyano; amido; alkylamido; allyl; alkoxycarbonyl; pyrazolyl; methylpyrazolyl; hydroxyethylpyrazolyl; isoxazolyl; 2,5-dihydro-pyrrolyl; thiophenyl; thieno[3,2-c]pyridinyl; C1-6 alkyl; C2-6 alkenyl optionally substituted with OH; or C2-6 alkynyl optionally substituted with OH; R2*is absent; C1-6alkyl; halo; pyrazolyl; C2-6alkenyl optionally substituted with phenyl, methylpyrazolyl, or pyridinyl.

27. The method of one of claims 1 to 22, wherein M isor ; whereinAttorney Docket No.: 01317-0001-00PCT R1is absent, bromo, fluoro; chloro; amido; alkyl substituted amido; cyano; C1-6 cycloalkyl; C1-6 alkyl optionally substituted with phenyl or pyridinyl; C2-6alkenyl optionally substituted with OH, amido, alkyl substituted amido, or alkoxycarbonyl; C2-6 alkynyl optionally substituted with OH, alkyl substituted amido, or pyridinyl; phenyl optionally substituted with one, two or three groups chosen from halo, OH, hydroxyalkyl, halohydroxyalkyl, cyano, CH3O-, carboxyl, amino, amido, amidoalkyl, amidoalkoxy, alkyl substituted amido, phenyl substituted amido, hydroxyalkylamido, acetamido, aldehyde, acetyl, hydroxyalkylamido, sulfonylamino, alkylsulfonyl, isoxazolyl, pyrazolyl, and thiourea; pyridinyl optionally substituted with one or two groups chosen from C1-6alkyl, halo, amino, cyano, cyanoalkyl, haloalkyl, and alkoxy; 1,2,3- triazolyl optionally substituted with C1-6 alkyl; thiazolyl optionally substituted with C1-6 alkyl, hydroxyalkyl, alkoxycarbonyl, or hydroxycarbonyl; pyrazolyl optionally substituted with C1-6 alkyl, hydroxyalkyl, pyridinyl, methylpyridinyl, or acetamido; benzo[d]isoxazolyl optionally substituted with amino; thiophenyl optionally substituted with hydroxyalkyl, cyano, or amido; pyrimidinyl optionally substituted with amino or alkylamino; pyridylcarbonyl; [1,2,4]triazolo[1,5-a]pyridinyl; pyrazinyl; pyridazinyl; pyridinyl-2-one; isoindolinyl-1-one; indolinyl; indolinyl-2-one; 1,3-dihydro-2H-benzo[d]imidazolyl-2-one; or indazolyl, wherein each substituted group has 1, 2 or 3 substituents.

28. The method of any one of claims 1 to 22, wherein M is; wherein X2is CH, N, C-alkyl, C-alkenyl, C-alkynyl, C-aryl or C-heteroaryl; R2#is absent, halo, alkyl, alkenyl, alkynyl, aryl, ester, carboxylic acid, amido, alkoxy, thioether, amino, cyano, heteroaryl, cycloalkyl or heterocyclyl; R2^is absent, alkyl, alkenyl, alkynyl, cyano or halo; and R3 is H, alkyl, alkenyl, alkynyl, halo, cyano, ester, carboxylic acid, amide, aryl, heteroaryl, alkoxy, thioether, or amino.

29. The method of any one of claims 1 to 28, wherein L is a bond, phenylene, pyridinylene, piperidinylene, or piperazinylene, each optionally substituted with 1 or 2 substituents chosen from halo, C1-3alkyl, C1-3alkyloxy and combinations thereof, or -NRa-, where Rais H or C1-3alkyl.

30. The method of any one of claims 1 to 28, wherein L is a bond.Attorney Docket No.: 01317-0001-00PCT 31. The method of any one of claims 1 to 28, wherein L is phenylene, pyridinylene, piperidinylene, or piperazinylene, each optionally substituted with 1 or 2 substituents chosen from halo, C1-3 alkyl, C1-3 alkyloxy and combinations thereof.

32. The method of any one of claims 1 to 28, wherein L is chosen from phenylene, fluorophenylene, chlorophenylene, methoxyphenylene, methylphenylene, ethylphenylene, pyridinylene, piperidinylene, and piperazinylene.

33. The method of any one of claims 1 to 32, wherein Z is a bond.

34. The method of any one of claims 1 to 32, wherein Z is C1-3 alkylene.

35. The method of any one of claims 1 to 32, wherein Z is methylene.

36. The method of any one of claims 1 to 32, wherein Z is -NH.

37. The method of any one of claims 1 to 32, wherein Z is -N(CH3)-.

38. The method of any one of claims 1 to 37, wherein T is a substituted or unsubstituted group chosen from [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6- dihydropyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, pyrrolidinyl, isoxazolyl, isoindolyl, piperidinyl, oxetanyl, thiophenyl, morpholino, thiazolyl, pyridinyl-2-one, pyrazinyl-2-one, indazolyl, 4,5,6,7- tetrahydro-indazolyl, isoindolinyl-1,3-dione, 1,3,4-oxadiazolyl, 1,3,4-oxadiazolyl-2-one, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,3-dihydro-2H- imidazolyl-2-one, phthalazinyl, isoquinolinyl, 2λ5-quinolinyl-2-one, 6,7-dihydro-4H- [1,2,3]triazolo[5,1-c][1,4]oxazinyl, 2,3-dihydro-4λ2-pyrido[3,2-b][1,4]oxazinyl, thiazolo[5,4- c]pyridinyl, and quinazolinyl.

39. The method of claim 38, wherein T is [1,2,3]triazolo[4,5-b]pyridinyl optionally substituted with halo, haloalkyl, cyano, methyl, methoxy, ethyl, pyrazolyl, alkoxycarbonyl, hydroxycarbonyl, amido, or phenyl; 5,6-dihydropyrrolo[2,3-d]pyrimidinyl optionally substituted with methyl; isoxazolyl optionally substituted with methyl, haloalkyl, alkyoxycarbonyl, or amido; thiazolyl optionally substituted with methyl; pyrazolyl optionally substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, amino, phenyl, hydroxycarbonyl or any combination of two or three thereof; pyrimidinyl optionally substituted with amido, amino, or one or two methyl groups; 1,2,3-triazolyl optionally substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, halo, or any combination of two or three thereof; 1,2,4-triazolyl optionally substituted with methyl; phenyl optionally substituted with OH, pyrazolyl, pyridinyl, cyano, indazolyl, amidoindazolyl, methoxy, benzyloxy, C2-6 alkynyl, or any combination of two or three thereof, and wherein the C2-6 alkynyl is further substituted by OH, oxo, alkoxy, isoindolinyl-1,3- dione, morpholino, amino, hydroxyalkyl substituted amino, pyrrolidinyl substituted amino,Attorney Docket No.: 01317-0001-00PCT hydroxypyrrolidinyl substituted amino, pyridinyl substituted amino, pyridinylmethyl substituted amino, or any combination of two or three thereof; pyridinyl optionally substituted with halo, methyl, amino pyridinyl or any combination of two or three thereof; pyrazolo[3,4-d]pyrimidinyl optionally substituted with phenoxyphenyl; imidazolyl optionally substituted phenyl, methyl, amino, or any combination of two or three thereof; pyrazinyl optionally substituted with OH, halo, cyano, amino, substituted amino, C1-6alkoxycarbonyl, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, C1-8 cycloalkyl, substituted C1-8 cycloalkyl, C1-3 alkyl substituted with cycloalkyl, C1-3 alkyl substituted with substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, C1-3 alkyl substituted with heterocyclyl, C1-3alkyl substituted with substituted heterocyclyl, heteroaryl, substituted heteroaryl, C1-3 alkyl substituted with heteroaryl, C1-3 alkyl substituted with substituted heteroaryl, aryl, substituted aryl, C1-3 alkyl substituted with aryl, C1-3 alkyl substituted with substituted aryl, C2-6alkenyl, C2-6hydroxyalkenyl, C2-6alkoxyalkenyl, C2-6alkynyl, C2-6 hydroxyalkynyl, C2-6 alkoxyalkynyl or any combination of two or three thereof; tetrazolyl optionally substituted with methyl, ethyl, or haloalkyl; 1,3,4-oxadiazolyl optionally substituted with C1-6alkyl, C3-6cycloalkyl; 1,3,4-thiadiazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, C3-6cycloalkyl, CD3, OH; pyridinyl-2-one optionally substituted with methyl; 1,3-dihydro-2H-imidazolyl-2-one optionally substituted with methyl; 1,3,4-oxadiazolyl-2-one optionally substituted with methyl; pyrrolidinyl optionally substituted with methyl; benzo[d]isothiazolyl optionally substituted with methyl; 1,2,4-oxadiazolyl optionally substituted with C1-6 alkyl, cyclopropyl or phenyl; morpholino optionally substituted with 1 or 2 C1-6 alkyl groups; or pyridazinyl optionally substituted with halo, wherein each substituted group has 1, 2 or 3 substituents.

40. The method of any one of claims 1 to 39, wherein the * stereocenter is in the (R) configuration.

41. The method of any one of claims 1 to 39, wherein the compound is selected from Table 1, and / or a pharmaceutically acceptable.

42. The method of one of claims 1 to 33, wherein the is selected from, , , , ,Attorney Docket No.: 01317-0001-00PCT, , , pharmaceutically acceptable salts thereof.

43. The method of any one of claims 1 to 33, wherein the compound is selected from N-(6-chloro-8-methyl-1-isoquinolyl)-2-fluoro-4-(1-methyltriazol-4-yl)-N-[(3R)-3-piperidyl] benzamide; (R)-N-(6-chloro-8-methylisoquinolin-1-yl)-2-fluoro-4-(1-(methyl-d3)-1H-1,2,3-triazol-4-yl)-N- (piperidin-3-yl)benzamide; (R)-2-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(8-methylisoquinolin-1-yl)-N-(piperidin-3- yl)benzamide; (R)-2-fluoro-4-(5-(methyl-d3)-1,3,4-thiadiazol-2-yl)-N-(8-methylisoquinolin-1-yl)-N-(piperidin- 3-yl)benzamide; (R)-N-(6-chloro-8-methylisoquinolin-1-yl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-N-(piperidin-3- yl)benzamide; (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-(8-methylisoquinolin-1-yl)-N-(piperidin-3- yl)benzamide; (R)-2-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3-methylthieno[3,2-c]pyridin-4-yl)-N- (piperidin-3-yl)benzamide; (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(piperidin-3-yl)-N-(2-(pyridin-4- yl)thieno[3,2-c]pyridin-4-yl)benzamide; and pharmaceutically acceptable salts thereof.

44. The method of any one of claims 1 to 43, wherein the compound of Formula (I) is provided in a pharmaceutical composition comprising a compound and / or or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

45. A method of treating cancer by administering to a patient in need thereof a therapeutically effective amount of a compound that selectively inhibits the translation of c-MYC mRNA to c-MYC protein.

46. The method of claim 45, wherein translation stalls by targeting a cytosolic nascent chain / ribosome complex.

47. The method of claim 46, wherein a ternary complex between small molecule, ribosome and nascent c-MYC polypeptide is visible by Cryo-electron microscopy.Attorney Docket No.: 01317-0001-00PCT 48. The method of claim 45, wherein translation is stalled to deliver 50% partial inhibition of translation.

49. The method of claim 46, wherein translation is stalled resulting in 90% partial inhibition of translation.

50. The method of claim 45, wherein the compound has an IC50 below about 50 µM in an In Vitro Multiple Point Translation Screening Assay.

51. The method of claim 45, wherein the compound has an IC50 below about 5 µM in an In Vitro Multiple Point Translation Screening Assay.

52. The method of claim 45, wherein the selective inhibition of MYC is such that less than 1% of non-MYC proteins are inhibited in a Global Proteomic Assay.

53. The method of claim 45, wherein the selective inhibition of MYC is such that less than 0.1% of non-MYC proteins are inhibited in a Global Proteomic Assay.

54. The method of claim 44, wherein the compound is administered by oral administration.

55. The method of claim 44, wherein the compound has a MW of about 300 to about 600 Da.

56. A compound of Formula (Ia), (Ib), (Ic), or a pharmaceutically acceptable salt thereof:wherein * denotes a stereocenter; M is pyrrolo[2,3-c] pyridinyl, pyrrolo[3,2-c] pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[2,3- c]pyridinyl, thieno[3,2-c]pyridinyl, quinolinyl, isoquinolinyl, quinolinyl-2-one, 1,6- naphthyridinyl, 1,6-naphthyridinyl, pyridinyl, 2-pyrazinyl, thiazolo[5,4-c]pyridinyl, or thiazolyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from halo,Attorney Docket No.: 01317-0001-00PCT substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted ester, carboxylic acid, substituted or unsubstituted acetyl, substituted or unsubstituted amido, substituted or unsubstituted carbamate, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted thioether, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, and combinations thereof, wherein each substituted group has 1, 2 or 3 substituents; V is N, or CH; Rdis absent, halo, cyano, C1-3 alkyl, or C1-3 alkyloxy; Rcis H, C1-C6 alkyl, OH, NH2, fluoro or gem-difluoro; n is 0, 1 or 2; X3is CH2 (or CH if bonded to T through Z), NH (or N if bonded to T through Z); Reis H or C1-3 alkyl; Z2is a bond or C1-3alkylene; and Z is a bond, C1-3alkylene, -(CH2)2C(O)NH-, -N(Rb)-, where Rbis H, or C1-3alkyl; and T is [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6-dihydropyrrolo[2,3- d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, pyrrolidinyl, isoxazolyl, isoindolyl, piperidinyl, oxetanyl, thiophenyl, morpholino, thiazolyl, pyridinyl-2-one, pyrazinyl-2-one, indazolyl, 4,5,6,7-tetrahydro-indazolyl, isoindolinyl- 1,3-dione, 1,3,4-oxadiazolyl, 1,3,4-oxadiazolyl-2-one, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,3-dihydro-2H-imidazolyl-2-one, phthalazinyl, isoquinolinyl, 2λ5-quinolinyl-2-one, 6,7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazinyl, 2,3- dihydro-4λ2-pyrido[3,2-b][1,4]oxazinyl, thiazolo[5,4-c]pyridinyl, or quinazolinyl, each optionally substituted with 1, 2 or 3 substituents independently chosen from OH, halo, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, substituted or unsubstituted ester, substituted or unsubstituted amido, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxyaryl, substituted or unsubstituted alkoxyheteroaryl, substituted or unsubstituted thioether, substituted or unsubstituted amino, NH-aryl, and NH-heteroaryl, wherein each substituted group has 1, 2 or 3 substituents; provided that when the compound is of Formula (Ia) thenAttorney Docket No.: 01317-0001-00PCT i) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is 3-chloropyridin-2-yl or 3- methylpyridin-2-yl, then T is not unsubstituted pyrazolo[2,3-a]pyrimidinyl; methyl substituted pyrazolo[2,3-a]pyrimidinyl; unsubstituted [1,2,3]triazolo[4,5-b]pyridinyl; methyl substituted [1,2,3]triazolo[4,5-b]pyridinyl; or pyrazolyl substituted with a methyl group, a substituted carboxyl group, a substituted or unsubstituted tetrazolyl group, or a substituted or unsubstituted 1,3,4-oxadiazolyl-2-one group; or ii) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is unsubstituted isoquinolinyl or methyl substituted pyrrolo[2,3-c]pyridinyl, then T is not a pyrazolyl substituted with methyl, substituted carboxyl or both methyl and substituted carboxyl; or iii) when M is phenyl or pyridinyl, and Z is a bond, then T is not 5,5-dimethylisoxazolyl-4(5H)- one or 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl.

57. The compound of claim 56, of Formula (Ia), or a pharmaceutically acceptable saltwherein * denotes a stereocenter with (R) configuration; Rdis absent, Cl, F, cyano, methyl, ethyl, methoxy or ethoxy; Rcis absent, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 1 or 2; Z is a bond, C1-3 alkylene, -N(Rb)-, where Rbis H, or C1-3 alkyl; and further wherein i) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is 3-chloropyridin-2-yl or 3- methylpyridin-2-yl, then T is not unsubstituted pyrazolo[2,3-a]pyrimidinyl; methyl substituted pyrazolo[2,3-a]pyrimidinyl; unsubstituted [1,2,3]triazolo[4,5-b]pyridinyl; methyl substituted [1,2,3]triazolo[4,5-b]pyridinyl; or pyrazolyl substituted with a methyl group, a substituted carboxyl group, a substituted or unsubstituted tetrazolyl group, or a substituted or unsubstituted 1,3,4-oxadiazolyl-2-one group; or ii) when n is 1, Rcis absent, Rdis absent, Z is a bond, and M is unsubstituted isoquinolinyl or methyl substituted pyrrolo[2,3-c]pyridinyl, then T is not a pyrazolyl substituted with methyl, substituted carboxyl or both methyl and substituted carboxyl; orAttorney Docket No.: 01317-0001-00PCT iii) when M is phenyl or pyridinyl, and Z is a bond, then T is not 5,5-dimethylisoxazolyl-4(5H)- one or 4-alkoxy-5,5-dimethyl-4,5-dihydroisoxazolyl.

58. The compound of claim 57, wherein Rcis absent, methyl, ethyl, OH, NH2, or fluoro and Z is a bond, methylene, -NH- or -N(CH3)-.

59. The compound of claim 56, of Formula (Ib), or a pharmaceutically acceptable salt thereof:wherein * denotes a stereocenter with (R) configuration; X3is CH2 (or CH if bonded to T through Z), NH (or N if bonded to T through Z); Rcis absent, C1-C6alkyl, OH, NH2, fluoro or gem-difluoro; n is 1; and Z is a bond, C1-3 alkylene, -(CH2)2C(O)NH-, -N(Rb)-, where Rbis H, or C1-3 alkyl.

60. The compound of claim 59, wherein X3is CH2(or CH if bonded to T through Z).

61. The compound of claim 59, wherein X3is NH (or N if bonded to T through Z).

62. The compound of any one of claims 59 to 61, wherein Z is Z is a bond, methylene, - (CH2)2C(O)NH-, -NH- or -N(CH3)-.

63. The compound of claim 56, of Formula (Ic), or a pharmaceutically acceptable salt thereof:wherein * denotes a stereocenter with (R) configuration;Attorney Docket No.: 01317-0001-00PCT Reis H or C1-3 alkyl; and Z2is a bond or C1-3alkylene.

64. The compound of claim 63, wherein Reis H, methyl, or isopropyl.

65. The compound of claim 63 or 64, wherein Z2is a bond.

66. The compound of claim 63 or 64, wherein Z2is methylene.

67. The of one of claims 56 to 66, wherein M is, or ; wherein each R1is independently absent cyano; chloro; bromo; fluoro; acetyl; amido; carbamate; alkylcarbamate; pyrazinyl; tetrazolyl; hydroxycarbonyl; alkoxycarbonyl; pyridinyl-2-one; C1-6 alkoxy; C1-6 haloalkyl; C1-6 cycloalkyl; C1-6 alkyl optionally substituted with OH, pyridinyl, amido, or phenyl; C2-6alkenyl optionally substituted with amido, OH, pyrazolyl, pyridinyl, isoxazolyl, thiophenyl, alkyl substituted amido, hydroxyalkylamido, arylalkylamido, alkoxycarbonyl, or hydroxycarbonyl; C2-6 alkynyl optionally substituted with OH; phenyl optionally substituted with OH, halo, hydroxyalkyl, sulfonyl, or alkylsulfonyl; pyrazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, or acetamide; pyridinyl optionally substituted with amino; triazolyl optionally substituted with C1-6 hydroxyalkyl; thiazolyl optionally substituted with C1-6 alkyl; or 1,3,4-thiadiazolyl optionally substituted with C1-6 alkyl; n* is 0, 1 or 2; R2is absent, halo, or C1-6 alkyl, or cyano.

68. The compound of any one of claims 56 to 66, wherein M is; wherein Y2is CH or N; R1*is absent; chloro; cyano; amido; alkylamido; allyl; alkoxycarbonyl; pyrazolyl; methylpyrazolyl; hydroxyethylpyrazolyl; isoxazolyl; 2,5-dihydro-pyrrolyl; thiophenyl; thieno[3,2-c]pyridinyl; C1-6alkyl; C2-6alkenyl optionally substituted with OH; C2-6alkenyl optionally substituted with OH; R2*is absent; C1-6 alkyl; halo; pyrazolyl; C2-6 alkenyl optionally substituted with phenyl, methylpyrazolyl, or pyridinyl.Attorney Docket No.: 01317-0001-00PCT 69. The of one of claims 56 to 66, wherein M isor ; wherein R1is absent, bromo, fluoro; chloro; amido; alkyl substituted amido; cyano; C1-6 cycloalkyl, C1-6 alkyl optionally substituted with phenyl or pyridinyl; C2-6 alkenyl optionally substituted with OH, amido, alkyl substituted amido, or alkoxycarbonyl; C2-6alkynyl optionally substituted with OH, alkyl substituted amido, or pyridinyl; phenyl optionally substituted with one, two or three groups chosen from halo, OH, hydroxyalkyl, halohydroxyalkyl, cyano, CH3O-, carboxyl, amino, amido, amidoalkyl, amidoalkoxy, alkyl substituted amido, phenyl substituted amido, hydroxyalkylamido, acetamido, aldehyde, acetyl, hydroxyalkylamido, sulfonylamino, alkylsulfonyl, isoxazolyl, pyrazolyl, and thiourea; pyridinyl optionally substituted with one or two groups chosen from C1-6alkyl, halo, amino, cyano, cyanoalkyl, haloalkyl, and alkoxy; 1,2,3- triazolyl optionally substituted with C1-6alkyl; thiazolyl optionally substituted with C1-6alkyl, hydroxyalkyl, alkoxycarbonyl, or hydroxycarbonyl; pyrazolyl optionally substituted with C1-6 alkyl, hydroxyalkyl, pyridinyl, methylpyridinyl, or acetamido; benzo[d]isoxazolyl optionally substituted with amino; thiophenyl optionally substituted with hydroxyalkyl, cyano, or amido; pyrimidinyl optionally substituted with amino or alkylamino; pyridylcarbonyl; [1,2,4]triazolo[1,5-a]pyridinyl; pyrazinyl; pyridazinyl; pyridinyl-2-one; isoindolinyl-1-one; indolinyl; indolinyl-2-one; 1,3-dihydro-2H-benzo[d]imidazolyl-2-one; or indazolyl.

70. The compound of any one of claims 56 to 66, wherein T is a substituted or unsubstituted group chosen from [1,2,3]triazolo[4,5-b]pyridinyl, pyrazolo[2,3-a]pyrimidinyl, 5,6- dihydropyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, phenyl, purinyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazolyl, tetrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, imidazolyl, benzo[d]imidazolyl, pyrrolyl, pyrrolidinyl, isoxazolyl, isoindolyl, piperidinyl, oxetanyl, thiophenyl, morpholino, thiazolyl, pyridinyl-2-one, pyrazinyl-2-one, indazolyl, 4,5,6,7- tetrahydro-indazolyl, isoindolinyl-1,3-dione, 1,3,4-oxadiazolyl, 1,3,4-oxadiazolyl-2-one, benzo[d]isoxazolyl, benzo[d]isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,3-dihydro-2H- imidazolyl-2-one, phthalazinyl, isoquinolinyl, 2λ5-quinolinyl-2-one, 6,7-dihydro-4H- [1,2,3]triazolo[5,1-c][1,4]oxazinyl, 2,3-dihydro-4λ2-pyrido[3,2-b][1,4]oxazinyl, thiazolo[5,4- c]pyridinyl, and quinazolinyl.

71. The compound of claim 70, wherein T is [1,2,3]triazolo[4,5-b]pyridinyl optionally substituted with halo, haloalkyl, cyano, methyl, methoxy, ethyl, pyrazolyl, alkoxycarbonyl,Attorney Docket No.: 01317-0001-00PCT hydroxycarbonyl, amido, or phenyl; 5,6-dihydropyrrolo[2,3-d]pyrimidinyl optionally substituted with methyl; isoxazolyl optionally substituted with methyl, haloalkyl, alkyoxycarbonyl, or amido; thiazolyl optionally substituted with methyl; pyrazolyl optionally substituted with C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, amino, phenyl, hydroxycarbonyl or any combination of two or three thereof; pyrimidinyl optionally substituted with amido, amino, or one or two methyl groups; 1,2,3-triazolyl optionally substituted with C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, halo, or any combination of two or three thereof; 1,2,4-triazolyl optionally substituted with methyl; phenyl optionally substituted with OH, pyrazolyl, pyridinyl, cyano, indazolyl, amidoindazolyl, methoxy, benzyloxy, C2-6alkynyl, or any combination of two or three thereof, and wherein the C2-6 alkynyl is further substituted by OH, oxo, alkoxy, isoindolinyl-1,3- dione, morpholino, amino, hydroxyalkyl substituted amino, pyrrolidinyl substituted amino, hydroxypyrrolidinyl substituted amino, pyridinyl substituted amino, pyridinylmethyl substituted amino, or any combination of two or three thereof; pyridinyl optionally substituted with halo, methyl, amino pyridinyl or any combination of two or three thereof; pyrazolo[3,4-d]pyrimidinyl optionally substituted with phenoxyphenyl; imidazolyl optionally substituted phenyl, methyl, amino, or any combination of two or three thereof; pyrazinyl optionally substituted with OH, halo, cyano, amino, substituted amino, C1-6 alkoxycarbonyl, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-8 cycloalkyl, substituted C1-8 cycloalkyl, C1-3 alkyl substituted with cycloalkyl, C1-3alkyl substituted with substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, C1-3alkyl substituted with heterocyclyl, C1-3 alkyl substituted with substituted heterocyclyl, heteroaryl, substituted heteroaryl, C1-3 alkyl substituted with heteroaryl, C1-3 alkyl substituted with substituted heteroaryl, aryl, substituted aryl, C1-3alkyl substituted with aryl, C1-3alkyl substituted with substituted aryl, C2-6 alkenyl, C2-6 hydroxyalkenyl, C2-6 alkoxyalkenyl, C2-6 alkynyl, C2-6 hydroxyalkynyl, C2-6 alkoxyalkynyl or any combination of two or three thereof; tetrazolyl optionally substituted with methyl, ethyl, or haloalkyl; 1,3,4-oxadiazolyl optionally substituted with C1-6alkyl, C3-6cycloalkyl; 1,3,4-thiadiazolyl optionally substituted with C1-6alkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C3-6 cycloalkyl, CD3, OH; pyridinyl-2-one optionally substituted with methyl; 1,3-dihydro-2H-imidazolyl-2-one optionally substituted with methyl; 1,3,4-oxadiazolyl-2-one optionally substituted with methyl; pyrrolidinyl optionally substituted with methyl; benzo[d]isothiazolyl optionally substituted with methyl; 1,2,4-oxadiazolyl optionally substituted with C1-6 alkyl, cyclopropyl or phenyl; morpholino optionally substituted with 1 or 2 C1-6alkyl groups; or pyridazinyl optionally substituted with halo.Attorney Docket No.: 01317-0001-00PCT 72. The compound of Formula Ia, and pharmaceutically acceptable salts thereof,* denotes a stereocenter with (R) configuration; wherein M is isoquinolinyl or a 9 membered fused bicyclic heteroaryl ring having 2 heteroatoms selected independently from nitrogen and sulfur, the isoquinolinyl or 9 membered ring optionally substituted with 1 to 2 substituents independently selected from pyridinyl, C1-3 alkyl, C1-3 alkoxy, fluoro or chloro; V is CH; n is 1; Rcis absent; Rdis absent, C1-3alkyl, C1-3alkoxy, fluoro or chloro; Z is a bond; and T is a 5 membered heteroaryl or a 9 membered fused bicyclic ring each 5 or 9 membered ring having 3-4 heteroatoms selected independently from nitrogen and sulfur and each 5 or 9 membered ring optionally substituted with 1 to 2 substituents selected independently from C1-3alkyl, C(D)3, C1-3alkoxy, or fluoro.

73. The compound of claim 72, wherein M is thieno[3,2-c]pyridinyl or isoquinolinyl substituted with 1 to 2 substituents independently selected from pyridinyl, methyl, fluoro or chloro; T is a 9 membered fused bicyclic ring having 4 nitrogens and is optionally substituted with 1 to 2 substituents selected independently from fluoro, C1-3 alkyl, C(D)3.

74. The compound of claim 72, wherein M is thieno[3,2-c]pyridinyl or isoquinolinyl substituted with 1 to 2 substituents independently selected from pyridinyl, methyl fluoro, or chloro; and T is a 5 membered heteroaryl having 3 heteroatoms selected independently from nitrogen and sulfur optionally substituted with 1 substituent selected independently from fluoro, C1-3alkyl, C(D)3.

75. The compound of claim 72, wherein M is thieno[3,2-c]pyridin-4-yl or isoquinolin-1-yl substituted with 1 to 2 substituents independently selected from pyridinyl, methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, fluoro or chloro; Z is a bond; and T is [1,2,3]triazolo[4,5- b]pyridin-3-yl, thieno[3,2-c]pyridinyl, 1,2,3-triazol-4-yl or 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

76. The compound of claim 72, wherein M is thieno[3,2-c]pyridin-4-yl substituted with pyridinyl, methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, fluoro or chloro; Z is a bond; and T is [1,2,3]triazolo[4,5-b]pyridin-3-yl, thieno[3,2-c]pyridinyl, 1,2,3-triazol-4-yl orAttorney Docket No.: 01317-0001-00PCT 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

77. The compound of claim 72, wherein M is thieno[3,2-c]pyridin-4-yl substituted with pyridinyl or methyl; n is 1; Rcis absent; V is CH, Rdis fluoro or chloro; Z is a bond; and T is [1,2,3]triazolo[4,5-b]pyridin-3-yl, thieno[3,2-c]pyridinyl, or 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

78. A compound of Formula Iawherein * denotes a stereocenter with (R) configuration; M is isoquinolinyl substituted with 1 to 2 substituents independently selected from C1-3 alkyl, C1- 3 alkoxy, fluoro or chloro; n is 1; Rcis absent; V is CH, Rdis absent, C1-3 alkyl, C1-3 alkoxy, fluoro or chloro; Z is a bond; and T is a 5 membered heteroaryl having 3 heteroatoms selected independently from nitrogen and sulfur optionally substituted with 1 to 2 substituents selected independently from C1-3 alkyl, C(D)3, C1-3 alkoxy, or fluoro; and further wherein T is not a pyrazolyl substituted with methyl, substituted carboxyl or both methyl and substituted carboxyl.

79. The compound of claim 72, wherein M is isoquinolinyl substituted with 1 to 2 substituents independently selected from methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, methyl, fluoro or chloro; Z is a bond; and T is a 5 membered heteroaryl having 3 heteroatoms selected independently from nitrogen and sulfur optionally substituted with 1 substituent selected independently from methyl, C(D)3, or fluoro.

80. The compound of claim 72, wherein M is isoquinolin-1-yl substituted with 1 to 2 substituents independently selected from methyl or chloro; n is 1; Rcis absent; V is CH, Rdis absent, fluoro or chloro; Z is a bond; and T is 1,2,3-triazol-4-yl or 1,3,4-thiadiazol-2-yl optionally substituted with 1 substituent selected independently from methyl or C(D)3.

81. A compound selected from Table 1, and / or pharmaceutically acceptable salts thereof.Attorney Docket No.: 01317-0001-00PCT 82. A selected from, , , thereof.

83. A compound selected from N-(6-chloro-8-methyl-1-isoquinolyl)-2-fluoro-4-(1-methyltriazol-4-yl)-N-[(3R)-3-piperidyl] benzamide; (R)-N-(6-chloro-8-methylisoquinolin-1-yl)-2-fluoro-4-(1-(methyl-d3)-1H-1,2,3-triazol-4-yl)-N- (piperidin-3-yl)benzamide; (R)-2-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(8-methylisoquinolin-1-yl)-N-(piperidin-3- yl)benzamide; (R)-2-fluoro-4-(5-(methyl-d3)-1,3,4-thiadiazol-2-yl)-N-(8-methylisoquinolin-1-yl)-N-(piperidin- 3-yl)benzamide; (R)-N-(6-chloro-8-methylisoquinolin-1-yl)-4-(1-methyl-1H-1,2,3-triazol-4-yl)-N-(piperidin-3- yl)benzamide; (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-N-(8-methylisoquinolin-1-yl)-N-(piperidin-3- yl)benzamide; (R)-2-fluoro-4-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(3-methylthieno[3,2-c]pyridin-4-yl)-N- (piperidin-3-yl)benzamide; (R)-4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-2-fluoro-N-(piperidin-3-yl)-N-(2-(pyridin-4- yl)thieno[3,2-c]pyridin-4-yl)benzamide; and pharmaceutically acceptable salts thereof.

84. A compound of any one of claims 56 to 83, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.Attorney Docket No.: 01317-0001-00PCT 85. A pharmaceutical composition comprising a compound and / or a pharmaceutically acceptable salt of any one of claims 56 to 84 and a pharmaceutically acceptable excipient.

86. A compound of any one of claims 56 to 6784 for use as a medicament.

87. The compound of claim 86, wherein the compound is for use in treating a cancer associated with MYC activity.

88. Use of a compound of any one of claims 56 to 84 in the manufacture of a medicament for treating a disease in a subject in which MYC contributes to the pathology and / or symptoms of the disease.

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