WO2023141522A2

WO2023141522A2 - Multicyclic compounds

Info

Publication number: WO2023141522A2
Application number: PCT/US2023/060928
Authority: WO
Inventors: Sunil Paliwal; Ahmed Abdi Samatar; Lawrence Saunders CRIPE
Original assignee: Slap Pharmaceuticals Llc
Priority date: 2022-01-21
Filing date: 2023-01-19
Publication date: 2023-07-27
Also published as: WO2023141522A3

Abstract

Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Description

MULTICYCLIC COMPOUNDS

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63/301,866, filed January 21, 2022, which is incorporated by reference in its entireties.

BACKGROUND

Field

[0002] The present application relates to the fields of chemistry, biochemistry and medicine. Disclosed herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Description

[0003] According to the National Cancer Institute, an estimated 1,806,590 new cases of cancer will be diagnosed in the United States and 606,520 people will die from the disease in 2020. The most common cancers are breast cancer, lung and bronchus cancer, prostate cancer, colon and rectum cancer, melanoma of the skin, bladder cancer, non-Hodgkin lymphoma, kidney and renal pelvis cancer, endometrial cancer, leukemia, pancreatic cancer, thyroid cancer, and liver cancer.

SUMMARY

[0004] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments described herein relate to a method of treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.

[0007] Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0008] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0009] Some embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase in a cell that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of DNA- dependent protein kinase. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of DNA-dependent protein kinase.

[0010] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of DNA-dependent protein kinase using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase.

[0011] These are other embodiments are described in greater detail below.

DETAILED DESCRIPTION

[0012] DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase that plays an important role in the proliferation and survival of cells. In addition, DNA-PK is necessary for multiple cellular functions, including the regulation of transcription and in the maintenance of telomeres. It is a member of the phosphatidylinositol 3 -kinase-related kinase family and it mediates the cellular response to DNA damage. DNA-PK consists of a catalytic subunit and a Ku heterodimer that is made up of the Ku70 and Ku80 subunits. DNA-PK plays an important role in the maintenance of genomic integrity because of its involvement in cellular response to DNA damage and in the repair of DNA double-strand break (DNA-DSBs). DNA-PK is involved in repairing double-strand breaks (DSBs) through non-homologous end-joining (NHEJ). NHEJ pathway consist of several steps that include detection of DSBs by the Ku70/80 with subsequent recruitment and stabilization of the NHEJ complex at the damage location. The activation of DNA-PK then leads to ligation of broken DNA ends. Because of the role played by DNA-PK in cellular response to DNA damage and its deregulation in tumor cells, it has become an attractive therapeutic target in cancer. There is an effort to develop selective small molecules that will inhibit the activity of DNA-PK in several cancers as a single agent or in combination with other targeted therapeutics and/or ionizing radiation therapy.

Definitions

[0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) (such as 1, 2 or 3) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido(alkyl), isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amine and a di-substituted amine.

[0015] As used herein, “C_a to C_b” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.

[0016] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C₁-C₄ alkyl” or similar designations. By way of example only, “C₁-C₄ alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

[0017] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. The length of an alkenyl can vary. For example, the alkenyl can be a C_2-4 alkenyl, C_2-6 alkenyl or C_2-8 alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.

[0018] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The length of an alkynyl can vary. For example, the alkynyl can be a C_2-4 alkynyl, C_2-6 alkynyl or C_2-8 alkynyl. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted. [0019] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused- or spiro-fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s). 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0020] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused- or spiro-fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted.

[0021] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0022] As used herein, “heteroaryl” refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.

[0023] As used herein, “heterocyclyl” refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The number of atoms in the ring(s) of a heterocyclyl group can vary. For example, the heterocyclyl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quatemized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4- dioxane, 1,2-dioxolane, 1,3 -dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3- oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4- piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4- methy lenedioxypheny 1) .

[0024] As used herein, “cycloalkyl(alkyl)” refer to a cycloalkyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of a cycloalkyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to cyclopropyl-CH₂-, cyclobutyl-CH₂-, cyclopentyl-CH₂-, cyclohexyl-CH₂-, cyclopropyl-CH₂CH₂-, cyclobutyl- CH₂CH₂-, cyclopentyl-CH₂CH₂-, cyclohexyl-CH₂CH₂-, cyclopropyl-CH₂CH₂CH₂-, cyclobutyl-CH₂CH₂CH₂-, cyclopentyl-CH₂CH₂CH₂-, cyclohexyl-CH₂CH₂CH₂-, cyclopropyl- CH₂CH₂CH₂CH₂-, cyclobutyl-CH₂CH₂CH₂CH₂-, cyclopentyl-CH₂CH₂CH₂CH₂- and cyclohexyl-CH₂CH₂CH₂CH₂-.

[0025] As used herein, “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

[0026] As used herein, “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to 2- thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs.

[0027] A “heterocyclyl(alkyl)” refer to a heterocyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H- thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).

[0028] “Lower alkylene groups” are straight-chained -CH₂- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (-CH₂CH₂CH₂-) and butylene (-CH₂CH₂CH₂CH₂-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.” Further, when a lower alkylene group is substituted, the lower alkylene can be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g.,

)•

[0029] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec -butoxy, tert-butoxy, phenoxy and benzyloxy. In some instances, an alkoxy can be -OR, wherein R is an unsubstituted C_1-4 alkyl. An alkoxy may be substituted or unsubstituted.

[0030] As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.

[0031] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3 -hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0032] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0033] As used herein, “haloalkoxy” refers to a O-alkyl group and O-monocyclic cycloalkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chlorosubstituted cyclobutyl and fluoro-substituted cyclobutyl. In some instances, a haloalkoxy can be -OR, wherein R is a C_1-4 alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted.

[0034] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.

[0035] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0036] A “sulfonyl” group refers to an “SO₂R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted. [0037] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0038] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0039] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0040] A “trihalomethanesulfonyl” group refers to an “X₃CSO₂-” group wherein each X is a halogen.

[0041] A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(RA)-” group wherein each X is a halogen, and RA is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0042] The term “amino” as used herein refers to a -NH₂ group.

[0043] As used herein, the term “hydroxy” refers to a -OH group.

[0044] A “cyano” group refers to a “-CN” group.

[0045] The term “azido” as used herein refers to a -N3 group.

[0046] An “isocyanato” group refers to a “-NCO” group.

[0047] A “thiocyanato” group refers to a “-CNS” group.

[0048] An “isothiocyanato” group refers to an “-NCS” group.

[0049] A “mercapto” group refers to an “-SH” group.

[0050] A “carbonyl” group refers to a “C(=O)” group.

[0051] An “S-sulfonamido” group refers to a “-SO₂N(R_AR_B)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

[0052] An “N-sulfonamido” group refers to a “RSO₂N(R_A)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted. [0053] An “O-carbamyl” group refers to a “-OC(=O)N(R_AR_B)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0054] An “N-carbamyl” group refers to an “ROC(=O)N(R_A)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0055] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(R_AR_B)” group in which R_A and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0056] An “N-thiocarbamyl” group refers to an “ROC(=S)N(R_A)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0057] A “C-amido” group refers to a “-C(=O)N(R_AR_B)” group in which R_A and R_B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0058] An “N-amido” group refers to a “RC(=O)N(R_A)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

[0059] A “mono-substituted amine” refers to a “-NHR_A” in which RA can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be -NHRA, wherein RA can be an unsubstituted C_1-6 alkyl or an unsubstituted or a substituted benzyl.

[0060] A “di-substituted amine” refers to a “-NR_AR_B” in which RA and RB can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be -NR_AR_B, wherein RA and RB can be independently an unsubstituted C_1-6 alkyl or an unsubstituted or a substituted benzyl.

[0061] A “ketoamide” group refers to a -C(=O)-C(=O)N(R_AR_B) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A ketoamide may be substituted or unsubstituted.

[0062] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

[0063] Where the numbers of substituents is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C₁-C₃ alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0064] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).

[0065] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0066] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components but may also include additional features or components.

[0067] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality.

[0068] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of (R)-configuration or (S)-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. [0069] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).

[0070] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo halflife or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0071] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

Compounds

[0072] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein: R¹ can be selected from

wherein R¹ can be unsubstituted or substituted with 1 or 2 substituents selected from a halogen, an unsubstituted C_1-4 alkyl, a deuterium-substituted C_1-4 alkyl and an unsubstituted C_1-4 alkoxy; and R^1A can be hydrogen or an unsubstituted C_1-4 alkyl; R² can be selected from an unsubstituted or a substituted monocyclic cycloalkyl and an unsubstituted or a substituted monocyclic heterocyclyl; R³ can be selected from hydrogen, an unsubstituted C_1-4 alkyl, an unsubstituted C_1-4 alkoxy and an unsubstituted monocyclic C_3-6 cycloalkyl; and R⁴ can be selected from hydrogen, an unsubstituted C_1-4 alkyl, a deuterium-substituted C_1-4 alkyl, an unsubstituted monocyclic C_3-6 cycloalkyl, an unsubstituted bicyclic C_5-6 cycloalkyl and an unsubstituted C_1-4 haloalkyl.

[0073] In some embodiments, R¹ can be

In other embodiments,

R¹ can be . In still other embodiments, R¹ can be In yet

still other embodiments, R¹ can be Each bicyclic structure for R¹ can be

unsubstituted or substituted. Various groups can be present on a substituted version of R¹, such as those provided for “optionally substituted.” For example, R¹ can be substituted one or more times (1, 2 or 3 times) with a group independently selected from a halogen (such as F, Cl or Br), an unsubstituted C_1-4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl and tert-butyl) and a deuterium-substituted C_1-4 alkyl (for example, -CH₂D, -CHD₂, -CD₃, -CH₂CD₃ and -CD₂CD₃)

[0074] Exemplary R¹ bicyclic structures can be selected from:

[0075] Various monocyclic moieties can be present for R². In some embodiments, R² can be a monocyclic cycloalkyl, such as a monocyclic C4-6 cycloalkyl. In other embodiments, R² can be a monocyclic heterocyclyl. The monocyclic heterocyclyl for R² can include 1 or 2 ring heteroatoms. As an example, the monocyclic heterocyclyl for R² can include 1 or 2 ring heteroatoms selected from O (oxygen), S (sulfur) or N (nitrogen). Examples of monocyclic cycloalkyls for R² include cyclobutyl, cyclopentyl and cyclohexyl, including the following: wherein each shown ring can be unsubstituted or substituted. Various sizes

of monocyclic heterocyclyls can be present for R². For example, R² can be a 4-6 membered monocyclic heterocyclyl. Exemplary monocyclic heterocyclyls for R² include tetrahydrofuran, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1 -dioxide, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, piperidine, piperazine and 3,6-dihydro-2H-pyran. In some embodiments, R² can be selected from

unsubstituted or substituted.

[0076] In some embodiments, R² can be unsubstituted. In other embodiments, R² can be substituted. A variety of substituents can be present for R². Similarly, the number of substituents present on R² can vary. In some embodiments, R² can be substituted 1, 2 or 3 times with a substituent described herein, including those provided for “optionally substituted.” For example, R² can be substituted with one or more substituents selected from halogen, cyano, hydroxy, an unsubstituted C_1-4 alkyl, an unsubstituted C_1-4 alkoxy, an unsubstituted monocyclic C_3-6 cycloalkyl and an unsubstituted C_1-4 haloalkyl. In some embodiments, R² can be substituted with one or more substituents selected from fluoro, chloro, cyano, hydroxy, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF₃, -CHF₂, -C(CH₃)F₂, -CHCI2, -CH₂F, -CH(CH₃)F, -CH₂CF₃, -CH₂CI, -CH₂CH₂F, -CH₂CH₂Cl, -CH₂CH₂CH₂F and -CH₂CH₂CH₂Cl. When R² is substituted, one or both hydrogens on a ring carbon and/or the hydrogen on a ring nitrogen can be replaced with a substituent described herein. For example, the ring NH group of a piperazine can be substituted with an unsubstituted C_1-4 alkyl group, such as methyl.

[0077] In some embodiments, R³ can be hydrogen. In other embodiments, R³ can be an unsubstituted C_1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In still other embodiments, R³ can be an unsubstituted C_1-4 alkoxy (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy). In yet still other embodiments, R³ can be an unsubstituted monocyclic C_3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0078] In some embodiments, R⁴ can be hydrogen. In other embodiments, R⁴ can be an unsubstituted C_1-4 alkyl, such as those described herein. In still other embodiments, R⁴ can be a deuterium-substituted C_1-4 alkyl. For example, R⁴ can be -CH₂D, -CHD₂, -CD₃, -CH₂CD₃ and -CD₂CD₃. In yet still other embodiments, R⁴ can be an unsubstituted monocyclic C₃-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R⁴ can be an unsubstituted bicyclic C_5-6 cycloalkyl. Exemplary bicyclic C_5-6 cycloalkyls include bicyclo [1.1.1] pentyl and bicyclo [2.1.1] hexyl. In other embodiments, R⁴ can be an unsubstituted C_1-4 haloalkyl, such as those described herein and including -CF₃, -CHF₂, -C(CH₃)F₂, -CHCI2, -CH₂F, -CH(CH₃)F, -CH₂CF₃, -CH₂CI, -CH₂CH₂F, -CH₂CH₂CI, -CH₂CH₂CH₂F and -CH₂CH₂CH₂CI.

[0079] Examples of compounds of Formula (I), include the following:

[0080] Further examples of a compound of Formula (I), include the following:

, or a pharmaceutically acceptable salt of any of the foregoing. [0081] Additional examples of a compound of Formula (I) can be selected from:

, or a pharmaceutically

acceptable salt of any of the foregoing.

[0082] Some embodiments disclosed herein relate to a compound having the structure or a pharmaceutically acceptable salt thereof. Other embodiments disclosed

herein relate to a compound having the structure or a pharmaceutically

acceptable salt thereof, wherein PG¹ can be a protecting group. Suitable protecting groups are known to those skilled in the art. For example, PG¹ can be a triflate. Still other embodiments disclosed herein relate to a compound having the structure

or a pharmaceutically acceptable salt thereof.

[0083] Some embodiments disclosed herein relate to a method of preparing a compound having the structure

, or a pharmaceutically acceptable salt thereof, that can include coupling a boronic ester to a compound having the structure

A variety of boronic ester can be used in the coupling reaction. In some embodiments, the boronic ester can have the structure

wherein each R^B1 and R^B2 can be a C_1-6 alkyl (such as an unsubstituted C_1-6 alkyl), or R^B1 and R^B2 can be taken together along with the -O-B-O- to form a

5- to 7-membered heterocyclyl (for example, a 5- to 7-membered monocyclic heterocyclyl). In some embodiments, the boronic ester can be Other embodiments disclosed herein

relate to a method of preparing a compound having the structure

or a pharmaceutically acceptable salt thereof, that can include hydrogenating a compound having the structure or a pharmaceutically acceptable salt thereof. In some embodiments,

the hydrogenation of can include using a suitable hydrogenation compound, such

as palladium on carbon.

Synthesis

[0084] Compounds of Formula (I) along with those described herein may be prepared in various ways. General synthetic routes for preparing compounds of Formula (I) are shown and described herein along with some examples of starting materials used to synthesize compounds described herein. Additionally, for the purpose of the general synthetic routes, the structures depicted are appropriately protected, as known by one skilled in the art and the generic structures are meant to include these protecting groups. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

Scheme 1

Pharmaceutical Compositions

[0085] Some embodiments described herein relate to a pharmaceutical composition, which can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof. A pharmaceutical composition described herein is suitable for human and/or veterinary applications.

[0086] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0087] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood. [0088] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.

[0089] Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection, inhalation and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0090] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue- specific antibody. The liposomes may be targeted to and taken up selectively by the organ.

[0091] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. As described herein, compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.

Methods of Use

[0092] Some embodiments described herein relate to a method for treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.

[0093] Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0094] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.

[0095] Some embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of DNA- dependent protein kinase. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of DNA-dependent protein kinase. Some embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting the activity of DNA-dependent protein kinase.

[0096] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of DNA-dependent protein kinase using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of DNA-dependent protein kinase. Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of DNA-dependent protein kinase.

[0097] Some embodiments disclosed herein relate to a method for inhibiting the activity of DNA-dependent protein kinase that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein. Other embodiments disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of DNA-dependent protein kinase. Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of DNA-dependent protein kinase.

[0098] Examples of suitable cancers include, but are not limited to: a lung cancer, a pancreatic cancer, a colon cancer (e.g., colorectal cancer), a myeloid leukemia (e.g., AML, CML, and CMML), a thyroid cancer, a myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers (e.g., squamous cell cancer of the head and neck), an ovarian cancer, a brain cancer (e.g., gliomas, such as glioma blastoma multiforme), a cancer of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma or an anaplastic thyroid carcinoma.

[0099] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0100] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human, for example a human subject that is 18 years old or older.

[0101] The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, which elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

EXAMPLES

[0102] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

[0103] Compound 17 (100 g, 598.92 mmol, eq.), dichloropalladium;triphenylphosphane (8.41 g, 11.98 mmol, 0.02 eq.), tributyl(l- ethoxyvinyl)stannane (237.93 g, 658.81 mmol, 222.36 mL, 1.1 eq.) in dioxane (1000 mL) was de- gassed and then heated to 100°C for 1 h under N₂. The reaction was quenched by the addition of saturated solution of potassium fluoride (aq., 500 mL). The mixture was stirred at 20 °C for 2 h. The aqueous phase was extracted with EA (3 x 2000 mL). The combined organic phase was washed with brine (1000 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the crude product, which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE:EA = 100:1, 80:1) to afford 18 (110 g, 542.91 mmol, yield 90.65%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d ) δ ppm 1.44 (t, J=7.03 Hz, 3 H) 3.98 (q, J=7.03 Hz, 2 H) 4.73 (d, J=3.01 Hz, 1 H) 5.32 (d, J=3.01 Hz, 1 H) 8.47 (d, J=2.76 Hz, 1 H).

[0104] To a solution of 18 (110 g, 542.91 mmol, 1 eq.) in dioxane (1000 mL) was added a solution of NaIO₄ (232.25 g, 1.09 mol, 60.17 mL, 2 eq.) in H₂O (500 mL), then KMnO₄ (86.62 g, 548.11 mmol, 1.01 eq.) was added to the mixture in one portion at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was filtered, and the resulting filtrate was diluted with EtOAc (1050 mL), aqueous sodium bicarbonate (1000 mL) and aqueous NaCl (1000 mL). The mixture was stirred for 5 mins. The aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over sodium sulfate, filtrated and concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE:EA = 100:1, 10:1) to afford 19 (27.5 g, 134.42 mmol, yield 24.76%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d ) δ ppm 1.45 (t, J=7.13 Hz, 3 H) 4.52 (q, J=7.13 Hz, 2 H) 8.70 (d, J=1.63 Hz, 1 H).

[0105] To a mixture of 19 (27.5 g, 134.42 mmol, 1 eq.) in DCM (50 mL) was added methanamine●hydrochloride (907.56 mg, 13.44 mmol, 0.1 eq.) and TEA (40.80 g, 403.25 mmol, 56.13 mL, 3 eq.) in one portion at 20 °C under N₂. The mixture was stirred at 20 °C for 12 h. Compound 20 (28.99 g, crude) was obtained as yellow oil solution and used in the next step directly. LCMS (ESI+): m/z 216 [M+1], (RT: 0.623 min).

[0106] To a mixture of 20 (28.99 g, 134.44 mmol, 1 eq.) in DCM (300 mL) was added

TEA (27.22 g, 268.88 mmol, 37.44 mL, 2 eq.) and acetyl chloride (105.57 g, 1.34 mol, 95.97 mL, 10 eq.) dropwise at 20 °C under N₂. The mixture was stirred at 20 °C for 3 h. The mixture was concentrated in vacuum to give the crude product. The residue was poured into ice-water (150 mL) and stirred for 5 mins. The aqueous phase was extracted with EA (3 x 200 mL). The combined organic phase was washed with brine (150 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE:EA = 100:1, 9:1) to afford 21 (13 g, 50.45 mmol, yield 37.53%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d ) δ ppm 1.41 (td, J=7.07, 2.96 Hz, 3 H) 1.78 - 2.31 (m, 3 H) 3.16 - 3.49 (m, 3 H) 4.44 (dq, J=19.43, 7.12 Hz, 2 H) 8.55 - 8.74 (m, 1 H). [0107] To a mixture of 21 (1 g, 3.88 mmol, 1 eq.) and in MeOH (20 mL) was added DIEA (2.01 g, 15.52 mmol, 2.70 mL, 4 eq.) in one portion at 20°C under N₂. The mixture was stirred at 60°C for 12 h. Twelve additional vials were set up as described above. All thirteen mixtures were combined. The mixture was filtered and then concentrated in vacuum to give the crude product. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, PE:EA=50:1, 8:1) to afford 25 (9.8 g, 40.97 mmol, yield 81.20%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃-d) δ ppm 1.83 - 2.28 (m, 3 H) 3.16 - 3.40 (m, 3 H) 3.93 - 4.00 (m, 3 H) 4.05 - 4.12 (m, 3 H) 8.45 - 8.57 (m, 1 H).

[0108] To a mixture of 25 (500 mg, 2.09 mmol, 1 eq.) in THF (20 mL) was added NaHMDS (I M, 6.27 mL, 3 eq.) dropwise at -60 °C under N₂. The mixture was stirred at -60 °C for 1 h. Eighteen additional vials were set up as described above. All nineteen mixtures were combined, and the reaction was quenched by water (30 mL). The aqueous phase was extracted with EA (100 mL). The aqueous was added to HC1 (1 N, 10 mL). The aqueous phase was lyophilization to give the crude product. The crude product was triturated with DCM (100 mL) and TEA (3 g) to give 26 (6 g, crude) as a yellow solid. ¹H NMR (400 MHz, CDCl₃-d) δ ppm 3.69 (s, 3 H) 4.12 (s, 3 H) 6.50 (s, 1 H) 8.75 (s, 1 H).

[0109] To a mixture of 26 (6 g, 28.96 mmol, 1 eq.) in DCM (5 mL) was added TEA (8.79 g, 86.88 mmol, 12.09 mL, 3 eq.) and Tf₂O (12.26 g, 43.44 mmol, 7.17 mL, 1.5 eq.) dropwise at 0 °C under N₂. The mixture was stirred at 0 °C for 1 h. The mixture was cooled to 0 °C and then concentrated under reduced pressure at 30 °C. The residue was poured into ice-water (10 mL) and stirred for 5 mins. The aqueous phase was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine (1 x 10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give 27 (6 g, crude) as a yellow oil. LCMS (ESI+): m/z 340 [M+l], (RT: 0.762 min).

[0110] To a mixture of 27 (6 g, 17.69 mmol, 1 eq.) and in dioxane (50 mL) and H2O (50 mL) was added Na₂CO₃ (3.75 g, 35.37 mmol, 2 eq.), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (5.57 g, 26.53 mmol, 1.5 eq.) and Pd(dppf)Cl₂ (258.82 mg, 353.72 umol, 0.02 eq.) in one portion at 20 °C under N₂. The mixture was stirred at 80 °C for 2 h. The residue was poured into ice-water (30 mL) and stirred for 5 mins. The aqueous phase was extracted with EA (3 x 100 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give 28 (6 g, crude). LCMS (ESI+): m/z 274 [M+l], (RT: 0.647 min).

[0111] To a mixture of 28 (6.00 g, 22.11 mmol, 1 eq.) in MeOH (60 mL) was added palladium/C (235.34 mg, 2.21 mmol, 0.1 eq.) in one portion at 20 °C under N₂. The mixture was stirred under H₂ (15 psi) at 20 °C for 10 mins. The mixture was filtered, and the filter was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE:EA=100:l to 1:1 to give 29 (350 mg, 1.27 mmol, yield 5.75%) as a yellow solid. ¹H NMR (400 MHz, CDCI₃-d) δ ppm 1.70 - 1.83 (m, 2 H) 1.89 - 1.97 (m, 2 H) 3.50 (s, 3 H) 3.61 - 3.75 (m, 6 H) 4.04 - 4.16 (m, 5 H) 6.95 (s, 1 H) 8.75 (s, 1 H).

[0112] To a mixture of 9 (24.22 mg, 163.46 umol, 1.5 eq.) and 29 (30 mg, 108.97 umol, 1 eq.) in THE (1 mL) was added KHMDS (I M, 163.46 uL, 1.5 eq.) dropwise at 20 °C under N₂. The mixture was stirred at 50 °C for 1.5 h. Five additional vials were set up as described above. All six mixtures were combined, and the reaction were quenched by addition of MeOH (5 mL). The mixture was purified by prep-HPLC (HC1 as additive) and twice purification by prep-HPLC (NH4HCO3 as additive) to give A1 (2.5 mg, 6.39 umol, 9.77e-l% yield). Column: C18-1 150*30mm*5um;mobile phase: [water(HCl)-ACN];B%: l%-45%,8min. Column: C18-1 150*30mm*5um;mobile phase: [water( NH₄HCO₃)-ACN];B%: 15%-40%,20min. ¹H NMR (400 MHz, CDCI₃-d) δ ppm 1.79 (qd, J=12.34, 4.00 Hz, 2 H) 1.96 (br d, J=12.26 Hz, 2 H) 2.56 (s, 3 H) 3.66 - 3.77 (m, 4 H) 3.83 (br t, J=11.38 Hz, 2 H) 4.13 (br dd, J=11.26, 3.38 Hz, 2 H) 6.97 (s, 2 H) 7.62 (s, 1 H) 8.29 (s, 1 H) 8.73 (s, 1 H) 9.82 (s, 1 H). LCMS (ESI+): m/z 392 (M + 1), (RT: 2.137 min).

[0113] To a solution of C1 (25 g, 163.25 mmol, 1 eq.) in toluene (250 mL) was added

DMFDMA (58.36 g, 498.75 mmol, 3 eq.) at 20 °C. The mixture was stirred at 120 °C for 1 h. The mixture was filtered and dried in high vacuum to give C2 (32.8 g, 96.49% yield, 90% purity) as a yellow solid. ¹H NMR: (400 MHz, DMSO-d₆) δ ppm 8.68 (s, 1 H) 6.79 (s, 1 H) 3.16 (s, 3 H) 3.05 (s, 3 H) 2.51 (s, 3 H).

[0114] To a solution of C2 (32.8 g, 157.53 mmol, 1 eq.) in MeOH (330 mL) was added hydroxylamine hydrochloride (21.89 g, 315.06 mmol, 2 eq.) at 20°C. The vessel was evacuated and backfilled with nitrogen (3x) at 20 °C. The mixture was stirred at 80 °C for 1 h. The mixture was concentrated under reduced pressure, and then water (50 mL) was added. The mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give C3 (30.06 g, 97.28% yield, 90% purity) as a yellow solid. ¹H NMR: (400 MHz, DMSO-d₆ ) δ ppm 10.54 (s, 1 H) 10.12 (d, J=9.66 Hz, 1 H) 8.88 (s, 1 H) 7.88 (d, J=9.66 Hz, 1 H) 7.04 (s, 1 H) 2.51 (s, 3 H).

[0115] To a solution of C3 (10.4 g, 53.02 mmol, 1 eq.) in THE (100 mL) cooled at 0 °C was added TFAA (16.7 g, 79.53 mmol, 1.5 eq.) dropwise. The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel eluted with EA and PE (eluted with EA in PE from 0% to 12%). The product was recrystallized from PE. The product was filtered and the cake was dried in vacuo to give C4 (4.65 g, 49.23% yield, 90% purity) as a pale-yellow solid. ¹H NMR: (400 MHz, DMSO-d₆) δ ppm 9.98 (s, 1 H) 8.72 (s, 1 H) 7.95 (s, 1 H) 2.66 (d, J=0.88 Hz, 3 H). [0116] To a suspension of Pd/C (6.34 g, 5.22 mmol, 10% purity) in EtOH (40 mL) at 20 °C was added a solution of C4 (4.65 g, 26.1 mmol, 1 eq.) in EtOH (50 mL). Ammonium formate (8.23 g, 130.51 mmol, 5 eq.) was added in the mixture at 20 °C. The mixture was stirred at 80 °C for 2 h, and then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was dried in vacuo to give C5 (3.02 g, 78.09% yield, 90% purity) was obtained as a pale brown solid. ¹H NMR: (400 MHz, DMSO- d₆) δ ppm 8.11 (s, 1 H) 8.08 (s, 1 H) 7.46 (s, 1 H) 4.97 - 5.05 (m, 2 H) 2.25 (s, 3 H).

[0117] To a solution of 79 (350 mg, 1.45 mmol, 1 eq.) in DMSO (6 mL) was added DIEA (561.47 mg, 4.34 mmol, 756.70 uL, 3 eq.) and morpholine (252.32 mg, 2.90 mmol, 254.86 uL, 2 eq.) at 25 °C under N₂. The mixture was stirred at 90 °C for 12 h. The mixture was poured into ice water (15 mL) at 0 °C, stirred for 10 min and filtered. The filter cake was dried under high vacuum to give the product, which was used in the next step directly without further purification. Compound 79A (340 mg, 80.31% yield) was obtained as a brown solid.

[0118] To a solution of 79A (340 mg, 1.16 mmol, 1 eq.) in DCM (6 mL) was added MCPBA (247.91 mg, 1.22 mmol, 85% purity, 1.05 eq.) at 25 °C under N₂. The mixture was stirred at 25 °C for 2 h. The mixture was poured into water and extracted with DCM (3 x 5 mL). The combined organic phase was washed with NaSO₃ (20 mL), dried over Na₂SO₄ and concentrated to give the crude product. The residue was purified by column chromatography (SiO₂, PE:EA=50: 1 to 2:1). Compound 79B (200 mg, 55.77% yield) was obtained as a light brown solid.

[0119] To a solution of 79B (100 mg, 324.30 umol, 1 eq.) and 6-methyl-3aH- benzotriazol-5-amine (57.66 mg, 389.16 umol, 1.2 eq.) in DMF (3 mL) was added KOtBu (90.98 mg, 810.75 umol, 2.5 eq.) at 0 °C under N₂. The mixture was stirred at 20 °C for 2 h. The mixture was poured into water and extracted with DCM (3 x 5 mL). The combined organic phase was dried over Na₂SO₄ and concentrated to give the crude product. The crude product was purified by reversed-phase HPLC( 0.1% FA condition, prep-HPLC (column: Phenomenex Luna 80*30mm*3um; liquid phase: [A-FA/H2O=0.1% v/v; B-ACN]B%: 10%-35%,8min])). Compound A2 (41 mg, 104.48 umol, 32.22% yield) was obtained as a yellow solid. ¹H NMR: 400 MHz, CDOD₃) δ ppm 9.16 (s, 1H), 9.05 (s, 1H), 8.93 (s, 1H), 8.42 (s, 1H), 8.15 (br s, 1H), 7.76 (s, 1H), 6.05 (s, 1H), 3.55 (s, 3H), 3.44 (br d, J = 4.8 Hz, 4H), 3.27 (br d, J = 4.4 Hz, 4H), 2.38 (s, 3H). Example 3 Additional Compounds

[0120] Additional compounds of Formula (I) can be prepared using similar materials and methods described herein, such as those described herein.

Example A DNA-PK Kinase Assay

[0121] A kinase buffer (40 mM Tris, pH 7.5, 0.0055% Brij-35, 20 mM MgCl₂, 0.05 mM DTT) was prepared, and the compounds were diluted to 100X of the final desired highest inhibitor concentration in reaction by 100% DMSO. The compounds were in tubes to one well on a 96-well storage plate and serially by transferring 15 μL to 30 μL of 100% DMSO into the well. 50 nL of compound was transferred from source plate to 384-well plate. [0122] Solution (2X) of substrate and ATP in kinase reaction buffer was prepared, and 2.5 μL of substrate solution was added to each well of the assay plate to initiate the reaction. DNA- PK in 1x kinase buffer at 2-fold the final concentration of each reagent was prepared, and 2.5 μL of kinase solution was added to each well. 2.5 μL of substrate solution was added to each well of the assay plate to start reaction and incubated at room temperature for 3 h. 5 μL of ADP-Glo reagent was added to each well of the assay plate to terminate the reaction. The solution was mixed briefly, centrifuged and equilibrated for 120 min. 10 uL Kinase Detection Reagent was added to each well, and shaken and left to equilibrate for 30 min before reading on a plate reader for luminescence. Percent inhibition = (max-sample RLU)/(max-min) x 100 was calculated and fitted the data in XLFit excel add-in version 5.4.0.8 to obtain IC₅₀ values.

[0123] The results of the assays are provided in Table 1. In Table 1, ‘A’ indicates an

IC₅₀ of < 0.01 μM, ‘B’ indicates an IC₅₀ of ≥ 0.01 μM and < 0.10 μM, and ‘C’ indicates an IC₅₀ of ≥ 0.10 μM. As shown by the results in Table 1, compounds of Formula (I), including pharmaceutically acceptable salts thereof, are effective DNA-dependent protein kinase inhibitors.

Table 1

[0124] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein:

R¹ is selected from the group consisting of

wherein R¹ is unsubstituted or substituted with 1 or 2

substituents selected from the group consisting of a halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C_1-4 alkyl and an unsubstituted C_1-4 alkoxy; and R^1A is hydrogen or an unsubstituted C_1-4 alkyl;

R² is selected from the group consisting of an unsubstituted or a substituted monocyclic cycloalkyl and an unsubstituted or a substituted monocyclic heterocyclyl;

R³ is selected from the group consisting of hydrogen, an unsubstituted C_1-4 alkyl, an unsubstituted C_1-4 alkoxy and an unsubstituted monocyclic C_3-6 cycloalkyl; and

R⁴ is selected from the group consisting of hydrogen, an unsubstituted C_1-4 alkyl, a deuterium-substituted C_1-4 alkyl, an unsubstituted monocyclic C_3-6 cycloalkyl, an unsubstituted bicyclic C_5-6 cycloalkyl and an unsubstituted C_1-4 haloalkyl.

2. The compound of Claim 1, wherein R¹ is

3. The compound of Claim 1, wherein R¹ is

4. The compound of Claim 1, wherein R¹ is

5. The compound of Claim 1, wherein R¹ is

6. The compound of any one of Claims 1-4, wherein R¹ is unsubstituted.

7. The compound of any one of Claims 1-4, wherein R¹ is substituted.

8. The compound of Claim 7, wherein R¹ is substituted with a halogen.

9. The compound of Claim 7, wherein R¹ is substituted with an unsubstituted C_1-4 alkyl.

10. The compound of Claim 7, wherein R¹ is substituted with a deuterium-substituted

C_1-4 alkyl.

11. The compound of Claim 1, wherein R¹ is selected from the group consisting of

12. The compound of any one of Claims 1-11, wherein R² is a monocyclic cycloalkyl.

13. The compound of any one of Claims 1-11, wherein R² is a monocyclic C_4-6 cycloalkyl.

14. The compound of any one of Claims 1-11, wherein R² is a monocyclic heterocyclyl.

15. The compound of any one of Claims 1-11, wherein R² is a 4-6 membered monocyclic heterocyclyl.

16. The compound of any one of Claims 1-11, wherein R² is selected from the group consisting of cyclopentyl and cyclohexyl.

17. The compound of any one of Claims 1-11, wherein R² is selected from the group consisting of tetrahydrofuran, tetrahydro-2H-pyran, tetrahydro-2H-thiopyran 1,1 -dioxide, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, piperidine, piperazine and 3,6-dihydro- 2H-pyran.

18. The compound of any one of Claims 1-11, wherein R² is selected from the group consisting of:

19. The compound of any one of Claims 1-11, wherein R² is selected from the group consisting of:

20. The compound of any one of Claims 1-19, wherein R² is unsubstituted.

21. The compound of any one of Claims 1-19, wherein R² is substituted.

22. The compound of Claim 21, wherein R² is substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxy, an unsubstituted C_1-4 alkyl, an unsubstituted C_1-4 alkoxy, an unsubstituted monocyclic C_3-6 cycloalkyl and an unsubstituted C_1-4 haloalkyl.

23. The compound of any one of Claims 1-22, wherein R³ is hydrogen.

24. The compound of any one of Claims 1-22, wherein R³ is an unsubstituted C_1-4 alkyl.

25. The compound of any one of Claims 1-22, wherein R³ is an unsubstituted C_1-4 alkoxy.

26. The compound of any one of Claims 1-22, wherein R³ is an unsubstituted monocyclic C_3-6 cycloalkyl.

27. The compound of any one of Claims 1-26, wherein R⁴ is hydrogen.

28. The compound of any one of Claims 1-26, wherein R⁴ is an unsubstituted C_1-4 alkyl.

29. The compound of any one of Claims 1-26, wherein R⁴ is a deuterium-substituted C_1-4 alkyl.

30. The compound of any one of Claims 1-26, wherein R⁴ is an unsubstituted monocyclic C_3-6 cycloalkyl.

31. The compound of any one of Claims 1-26, wherein R⁴ is an unsubstituted bicyclic

C5-6 cycloalkyl.

32. The compound of any one of Claims 1-26, wherein R⁴ is an unsubstituted C_1-4 haloalkyl.

33. The compound of Claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt of any of the foregoing.

34. The compound of Claim 1 selected from the group consisting of:

, or a pharmaceutically acceptable salt of any of the foregoing.

35. The compound of Claim 1 selected from the group consisting of:

and

, or a pharmaceutically acceptable salt of any of the foregoing.

36. The compound of Claim 1 selected from the group consisting of:

, or a pharmaceutically acceptable salt of any of the foregoing.

37. A pharmaceutical composition comprising a compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

38. Use of an effective amount of a compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 37 in the manufacture of a medicament for treating a cancer.

39. The use of Claim 38, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer (e.g., colorectal cancer), a myeloid leukemia (e.g., AML, CML, and CMML), a thyroid cancer, a myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers (e.g., squamous cell cancer of the head and neck), an ovarian cancer, a brain cancer (e.g., gliomas, such as glioma blastoma multiforme), a cancer of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma or an anaplastic thyroid carcinoma.

40. Use of an effective amount of a compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 37 in the manufacture of a medicament for inhibiting DNA-dependent protein kinase.

41. A method for treating a cancer comprising administering an effective amount of a compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 37 to a subject in need thereof.

42. A method for treating a cancer comprising contacting a cancer cell with an effective amount of a compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 37 to a subject having the cancer.

43. The method of Claim 41 or 42, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer (e.g., colorectal cancer), a myeloid leukemia (e.g., AML, CML, and CMML), a thyroid cancer, a myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers (e.g., squamous cell cancer of the head and neck), an ovarian cancer, a brain cancer (e.g., gliomas, such as glioma blastoma multiforme), a cancer of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma or an anaplastic thyroid carcinoma.

44. A method for inhibiting DNA-dependent protein kinase comprising contacting a cell with an effective amount of a compound of any one of Claims 1-36, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 37, wherein the cell is a cancer cell.

45. A compound having the structure: , or a pharmaceutically

acceptable salt thereof.

46. A compound having the structure: , , or a pharmaceutically

acceptable salt thereof, wherein LG¹ is a protecting group.

47. A compound having the structure: or a pharmaceutically

acceptable salt thereof.

48. A method of preparing the compound of Claim 45 comprising coupling a boronic ester to the compound of Claim 46:

wherein PG¹ is a protecting group; and wherein the boronic ester has the structure:

49. The method of Claim 46 or 48, wherein the PG¹ is a triflate group.

50. A method of preparing the compound of Claim 47 comprising hydrogenating the compound of Claim 45:

51. The method of Claim 50, wherein the hydrogenation comprises the use of palladium on carbon.