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. 63/264,561, filed November 24, 2021, 63/265,918, filed December 22, 2021, 63/363,151, filed April 18, 2022 and 63/367,073, filed June 27, 2022, each of which is incorporated by reference in their 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 PARP1 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 PARP1. 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 P ARP 1.

[0010] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of PARP1 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 PARP1. 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 PARP1.

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

DETAILED DESCRIPTION

[0012] Accumulation of DNA damage without repair over a period can lead to the development of cancer. Poly (ADP-ribose) polymerases (P ARP 1/2) are enzymes that sense DNA damage and add branched PAR chains to facilitate DNA repair. PARP inhibitors are a class of small molecules that inhibit both PARP1 and PARP2 and have been approved as cancer drugs for tumors with BRCA1/2 mutations. [0013] Although PARP1 is considered the major target of PARP inhibitors, the currently approved PARP inhibitors also inhibit PARP2 and PARP3. Beyond its DNA repair role, PARP1 has additional biological roles which include the regulation of transcription of several genes implicated in several cancers. Inhibition of PARP 1 with a PARP1 selective small molecule could potentially overcome some of the major toxi cities observed with the current PARP 1/2 inhibitors and bring meaningful benefit to cancer patients.

[0014] Poly (ADP -ribose) polymerases (PARP) 1/2 Poly inhibitors selectively kill cancer cells that have a defect in the homologous recombination repair pathway and have been approved for use in ovarian cancer, metastatic breast cancer and prostate cancer. Although clinical studies have shown that the PARP1/2 inhibitors have antitumor activity in tumors with BRCA1/2 mutations, cancer patients with alterations in other DNA damage repair pathway may be able to benefit from PARP inhibitors. Mutations in DNA damage repair pathway is observed in a broad range of tumor types suggesting that the PARP1/2 inhibitors could potentially have antitumor activity in several cancer types.

[0015] Although PARP inhibitors have demonstrated antitumor activity, the adverse events seen in patients treated with the PARP 1/2 inhibitors have necessitated dose reductions and discontinuation of the PARP 1/2 inhibitors. The adverse events of the PARP 1/2 inhibitors are thought to arise from inhibition of PARP2, hence small molecules that are potent and selective for PARP1 could retain the antitumor activity and potentially minimize the adverse events observed with the current PARP 1/2 inhibitors.

Definitions

[0016] 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.

[0017] 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.

[0018] As used herein, “C _a to Cb” 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 “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH ₃ ) ₂ CH-, CH3CH2CH2CH2-, CH3CH ₂ CH(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.

[0019] 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.

[0020] 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 C2-4 alkenyl, C2-6 alkenyl or C2-8 alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.

[0021] 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 C2-4 alkynyl, C2-6 alkynyl or C2-8 alkynyl. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.

[0022] 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.

[0023] 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.

[0024] 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 Ce- C14 aryl group, a Ce-Cio aryl group, or a Ce aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0025] 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.

[0026] 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 thiosystems 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-di oxolane, 1,3-dioxolane, 1,4-di oxolane, 1,3- oxathiane, 1,4-oxathiin, 1,3 -oxathiolane, 1 ,3-dithiole, 1,3 -dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, mal eimide, 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 A-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-methylenedioxyphenyl).

[0027] 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-CEb- cyclobutyl-CEE-, cyclopentyl-CEE-, cyclohexyl-CEE-, cyclopropyl-CEECEE-, cyclobutyl- CH2CH2-, cyclopentyl-CEECEE-, cyclohexyl-CEECEE-, cyclopropyl-CEECEbCEh- cyclobutyl-CEECEECEh-, cyclopentyl-CEECEECEE-, cyclohexyl-CEECEECEE-, cyclopropyl- CH2CH2CH2CH2-, cyclobutyl-CH2CH2CH ₂ CH2-, cyclopentyl-CJECJLCJLCJL- and cyclohexyl-CH2CH2CH ₂ CH2-.

[0028] As used herein, “aryl(alkyl)” refers 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).

[0029] 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.

[0030] 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). [0031] “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 (

[0032] 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.

[0033] 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.

[0034] 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-hydroxy ethyl, 3 -hydroxypropyl, 2-hydroxypropyl and 2,2- dihydroxy ethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0035] 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 -chi oro-2-fluorom ethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0036] 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, l-chloro-2- fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro- substituted cyclopropyl, chloro-substituted 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.

[0043] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.

[0044] 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).

[0045] The term “amino” as used herein refers to a -NH2 group.

[0046] As used herein, the term “hydroxy” refers to a -OH group.

[0047] A “cyano” group refers to a “-CN” group.

[0048] The term “azido” as used herein refers to a -N3 group.

[0049] An “isocyanato” group refers to a “-NCO” group. [0050] A “thiocyanato” group refers to a “-SCN” group.

[0051] An “isothiocyanate” group refers to an “-NCS” group.

[0052] A “mercapto” group refers to an “-SH” group.

[0053] A “carbonyl” group refers to a -C(=O)- group.

[0054] An “S-sulfonamido” group refers to a “-SO2N(RARB)” 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.

[0055] An “N-sulfonamido” group refers to a “RSO2N(RA)-” 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.

[0056] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” 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.

[0057] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” 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.

[0058] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” 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-thiocarbamyl may be substituted or unsubstituted.

[0059] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” 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.

[0060] A “C-amido” group refers to a “-C(=O)N(RARB)” 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 C-amido may be substituted or unsubstituted.

[0061] An “N-amido” group refers to a “RC(=O)N(RA)-” 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.

[0062] A “mono-substituted amine” refers to a “-NHRA” 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 Ci-6 alkyl or an unsubstituted or a substituted benzyl.

[0063] A “di-substituted amine” refers to a “-NRARB” 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 -NRARB, wherein RA and RB can be independently an unsubstituted Ci-6 alkyl or an unsubstituted or a substituted benzyl.

[0064] A “ketoamide” group refers to a -C(=O)-C(=O)N(RARB) 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.

[0065] 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.

[0066] Where the numbers of substituents are 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.

[0067] 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)).

[0068] 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.

[0069] 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. [0070] 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.

[0071] 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 (Reconfiguration 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.

[0072] 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).

[0073] 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 half-life 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.

[0074] 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

[0075] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C _1-4 alkoxy, an unsubstituted C _1-4 haloalkoxy and an unsubstituted C _1-4 haloalkyl; Ring B can be selected from a 6-membered monocyclic nitrogen-containing heterocyclyl, a 7- membered bicyclic nitrogen-containing heterocyclyl and a 8-membered bicyclic nitrogencontaining heterocyclyl; n can be 0 or 1; wherein when n is 0, then Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted , wherein when the aryl, the heteroaryl and the y y can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C _1-4 haloalkyl; Ring DI can be a phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl; Ring

D2 can be selected from an unsubstituted or a substituted , an unsubstituted or a substituted an unsubstituted or a substituted an unsubstituted or a substituted an unsubstituted or a substituted and an unsubstituted or a substituted , wherein the asterisks indicate the points of attachment to Ring DI; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl; R ¹ can be selected from hydrogen, an unsubstituted C _1-4 alkyl, a substituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl, an unsubstituted C _1-4 hydroxyalkyl, an unsubstituted monocyclic C3- 6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl) and a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl), wherein the substituted Ci- 4 alkyl and the substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) can be substituted by 1 or more deuteriums; R ² and R ³ can be independently hydrogen, deuterium or an unsubstituted C _1-4 alkyl; or R ² and R ³ can be taken together along with the carbon to which R ² and R ³ are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; ml can be 0, 1 or 2; m2 can be 0, 1 or 2; R ^3a can be deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R ^3b can be deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R ⁴ can be - C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen, an unsubstituted C _1-4 alkyl, a substituted C _1-4 alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C _1-4 alkyl), wherein the substituted C _1-4 alkyl can be substituted by 1 or more deuteriums.

[0076] In some embodiments, Ring A can be a pyrrole. In other embodiments, Ring A can be a thiophene. In still other embodiments, Ring A can be a pyridine. In yet still other embodiments, Ring A can be a phenyl. Each of the pyrrole, the thiophene, the pyridine and the phenyl can substituted with 1 or more times with a moiety (such as 1, 2 or 3 moi eties) independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted C _1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), a deuterium-substituted C _1-4 alkyl (including -CD3, -CD2H, -CDH2, -CHDCEE, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and

-CD2CD3,), an unsubstituted C _1-4 alkoxy (such as methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy and tert-butoxy), an unsubstituted C _1-4 haloalkoxy (for example, -OCF3, -OCC13, -OCHF2, -OC(CH ₃ )F ₂ , -OCHCh, -OCH2F, -OCH(CH ₃ )F, -OCH2CF3, -0CH2CI, -OCH2CH2F, -OCH2CH2CI, -OCH2CH2CH2F and -OCH2CH2CH2CI) and an unsubstituted C _1-4 haloalkyl (including -CF3, -CCI3, -CHF2, -C(CH3)F2,

-CHCh, -CH2F, -CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and

-CH2CH2CH2CI). Examples of rings for Ring A include the following: , wherein the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I). For example, when Ring A , a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure: In some embodiments, Ring A can be substituted 1 time with halogen (F or Cl) or deuterium. As an example, Ring A can be that can be substituted 1 time for a halogen (F or Cl) or deuterium.

[0077] A variety or heterocyclic ring(s) can be present for Ring B. The heterocyclyl for Ring B can be a monocyclic or a bicyclic ring. When Ring B is a bicyclic ring, the rings can be connected in a fused-fashion. In other instances, when Ring B is a bicyclic ring, the rings can be connected in a spiro-fashion. As provided herein, Ring B can include a ring nitrogen. Additional ring heteroatoms, such as an additional nitrogen, oxygen and/or sulfur, can be present in Ring B. In some embodiments, Ring B can be an unsubstituted 6-membered monocyclic nitrogen-containing heterocyclyl. In other embodiments, Ring B can be a substituted 6- membered monocyclic nitrogen-containing heterocyclyl. In still other embodiments, Ring B can be an unsubstituted 7-membered bicyclic nitrogen-containing heterocyclyl. In yet still other embodiments, Ring B can be a substituted 7-membered bicyclic nitrogen-containing heterocyclyl. In some embodiments, Ring B can be an unsubstituted 8-membered bicyclic nitrogen-containing heterocyclyl. In other embodiments, Ring B can be a substituted 8- membered bicyclic nitrogen-containing heterocyclyl.

[0078] In some embodiments, Ring B can be unsubstituted when ml is 0. In other embodiments, Ring B can be substituted with R ^3a when ml is 1 or 2. When Ring B is substituted, a variety of substituents can be present. In some embodiments, Ring B can be substituted with a substituent selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl. Suitable halogens, unsubstituted C _1-4 alkyls, unsubstituted C _1-4 haloalkyls and an unsubstituted monocyclic C3-6 cycloalkyls are described herein, and include chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CF3, -CHF2, -C(CH3)F2, -CHCh, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0079] Exemplary Ring B groups include, but are not limited to, the following:

[0080] In some embodiments, n can be 0; and Ring C can such that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure: can be substituted 1 or more times (such as 1, 2, 3 or 4 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl (such as a monocyclic C3-6 cycloalkyl) and an unsubstituted C _1-4 haloalkyl. Suitable halogens, C _1-4 alkyls, C3-6 cycloalkyls and C _1-4 haloalkyls are described herein. For example, can be substituted 1 or more times (for example, 1, 2, 3 or 4 times) with a moiety independently selected from F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, - CHF2, -C(CH ₃ )F ₂ , -CHCh, -CH2F,

-CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI.

[0081] As provided herein, Ring DI can be a phenyl, a 5-membered heteroaryl or a 6- membered heteroaryl. In some embodiments, Ring DI can be a phenyl. In other embodiments, Ring DI can be a 5-membered heteroaryl. In still other embodiments, Ring DI can be a 6- membered heteroaryl. The heteroaryl for Ring DI can include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). A non-limiting list of heteroaryls for Ring DI include pyridine, thiophene, furan and pyrrole. In some embodiments, embodiments, Ring D2 can be . In other embodiments, Ring D2 can

> ^NH still other embodiments, Ring D2 can be In yet still other embodiments, Ring D2 can In some embodiments, Ring D2 can be In other embodiments, Ring D2 can be In still other embodiments, Ring D2 can be For each of the Ring D2 moi eties shown, the asterisks indicate the points of attachment to Ring DI. Examples of

can be optionally substituted 1 or more times (for example, 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted C _1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl) and an unsubstituted C _1-4 haloalkyl (including -CF3, -CHF2, -C(CH3)F2, -CHCh, -CH2F, - CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI).

[0083] In some embodiments, n can be 0; and Ring C can be an unsubstituted aryl. In other embodiments, n can be 0; and Ring C can be a substituted aryl substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C _1-4 haloalkyl. For example, Ring C can be an unsubstituted or a substituted phenyl. When Ring C is a substituted phenyl, the phenyl can be substituted 1, 2 or 3 times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C _1-4 haloalkyl. In still other embodiments, n can be 0; and Ring C can be an unsubstituted monocyclic heteroaryl. In yet still other embodiments, n can be 0; and Ring C can be a substituted monocyclic heteroaryl substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl (such as a monocyclic C3-6 cycloalkyl) and an unsubstituted C _1-4 haloalkyl. An example of a suitable aryl can be an unsubstituted or a substituted phenyl. Exemplary monocyclic heteroaryls for Ring C can be a 5- or 6-membered monocyclic heteroaryl that includes 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). A non-limiting list of monocyclic heteroaryls for Ring C include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine and pyrazine. When the aryl and/or the heteroaryl is substituted, suitable moieties include deuterium, F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CDs, -CD2H, -CDH2, -CHDCEE, -CH2CHD2, -CH2CH2D, CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3, -CD2CD3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -CHF2, -C(CH ₃ )F ₂ , -CHC12, -CH2F, -CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI.

[0084] In some embodiments, n can be 1, and R ⁴ can be a C-amido. In some embodiments, ring C can be pyrrole. In other embodiments, Ring C can be thiophene. In still other embodiments, Ring C can be thiazole. In yet still other embodiments, Ring C can be pyridine. In some embodiments, Ring C can be pyridazine. In other embodiments, Ring C can be pyrimidine. In still other embodiments, Ring C can be pyrazine. Exemplary rings for Ring C

[0085] Additionally moieties can be present on Ring C. Suitable moieties that can be present on Ring C include, but are not limited to, deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3- 6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl. In some embodiments, Ring C can be substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuteriumsubstituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl. In some embodiments, Ring C can be substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, tert-butyl, -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3, -CD2CD3, ethenyl, propenyl, butenyl, cyclopropyl-CH2-, cyclobiityl-CFh-, cyclopentyl-CFh-, cyclohexyl-Cth- cyclopropyl-CH2CH2-, cyclobiityl-CFhCFh-, cyclopentyl-CFhCFh-, cyclohexyl-CthCth- cyclopropyl-CH2CH2CH2-, cyclobutyl-CFhCFhCFh-, cyclopentyl-CFhCFhCFh-, cyclohexyl- CH2CH2CH2-, cyclopropyl-CH2CH2CH2CH2-, cyclobutyl-CH2CH2CH2CH2-, cyclopentyl- CH2CH2CH2CH2-, cyclohexyl-CEECEECEECEb-, -CF3, -CHF2, -C(CH ₃ )F ₂ , -CHCh, -CH2F, -CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI. In some embodiments, Ring C can be substituted 1 time with a moiety provided herein, such as those moieties provided in this paragraph. For example, Ring C can be substituted 1 time with F, Cl or -CD ₃ .

[0086] As provided herein, Ring C can be substituted with -C(=O)NR ⁵ R ⁶ when n is 1. In some embodiments, R ⁵ can be hydrogen, such that Ring C can be substituted with - C(=O)NHR ⁶ . In other embodiments, R ⁵ can be an unsubstituted C _1-4 alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In some embodiments, Ring C can be substituted with -C(=O)N(CH3)R ⁶ . In some embodiments, R ⁶ can be hydrogen. In other embodiments, R ⁶ can be an unsubstituted C _1-4 alkyl. When R ⁶ is a deuterium substituted C _1-4 alkyl, one or more hydrogens (such as 1, 2, 3, 4, 5 or 6 hydrogens) can be replaced with deuteriums. Examples of deuterium substituted C _1-4 alkyls for R ⁶ include -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3, -CD2CD3. In still other embodiments, R ⁶ can be a deuteriumsubstituted C _1-4 alkyl. In yet still other embodiments, R ⁶ can be an unsubstituted monocyclic C3-6 cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ⁶ can be an unsubstituted bicyclic C5-8 cycloalkyl, such as bicyclo[l.l. l]pentyl, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane and bicyclo[2.2.2]octane. In some embodiments, R ⁵ and R ⁶ cannot be each hydrogen, such that -C(=O)NR ⁵ R ⁶ is -C(=O)NH2.

[0087] In some embodiments, when n is 1 and m2 is 0, Ring C can be unsubstituted except for -C(=O)NR ⁵ R ⁶ . In other embodiments, when n is 1 and m2 is 1, Ring C can be substituted with one R ^3b group. In still other embodiments, when m2 is 2, Ring C can be substituted with two R ^3b groups. As provided herein, each R ^3b can be independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl. Exemplary moieties for each R ^3b can be deuterium, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CD ₃ , -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3, -CD2CD3, -CF3, CHF2, -C(CH ₃ )F ₂ , -CHCh, -CH2F, -CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0088] As provided herein, the nitrogen of the pyrimidine-2,4(lH,3H)-dione can be unsubstituted or substituted. In some embodiments, R ¹ can be hydrogen. In other embodiments, R ¹ can be an unsubstituted C _1-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl. In some embodiments, R ¹ can be a deuterium-substituted C _1-4 alkyl. Examples of deuterium-substituted C _1-4 alkyls includes -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and -CD2CD3. In still other embodiments, R ¹ can be an unsubstituted C _1-4 haloalkyl. For example, when R ¹ is an unsubstituted C _1-4 haloalkyl, R ¹ can be -CF3, -CHF2, -C(CH ₃ )F ₂ , -CHCh, -CH2F, -CH(CH ₃ )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI. In yet still other embodiments, R ¹ can be an unsubstituted C _1-4 hydroxyalkyl, such as -CH2-OH, -CH2CH2-OH, -CH2CH2CH2-OH and -CH2CH2CH2CH2-OH. In some embodiments, R ¹ can be an unsubstituted monocyclic C3-6 cycloalkyl. In other embodiments, R ¹ can be an unsubstituted bicyclic C5-8 cycloalkyl. In still other embodiments, R ¹ can be an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl). In yet still other embodiments, R ¹ can be a deuterium-substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl). When R ¹ is a deuterium-substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), one or more hydrogens (for example, 1, 2, 3, 4, 5 or 6 hydrogen) can be placed with deuteriums. Possible cycloalkyls that can be present for a monocyclic C3-6 cycloalkyl and a monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary bicyclic C5-8 cycloalkyls that can be present for a bicyclic C5-8 cycloalkyl include, but are not limited to, bicyclo[l.l. l]pentyl, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane and bicyclo[2.2.2]octane.

[0089] In some embodiments, R ² and R ³ can be each hydrogen. In other embodiments, R ² and R ³ can be each deuterium. In other embodiments, R ² and R ³ can be each an unsubstituted C _1-4 alkyl. For example, R ² and R ³ can be independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In still other embodiments, one of R ² and R ³ can be deuterium; and the other of R ² and R ³ can be hydrogen or an unsubstituted C _1-4 alkyl. In some embodiments, R ² and R ³ can be taken together along with the carbon to which R ² and R ³ are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. For example, R ² and R ³ can be taken together along with the carbon to which R ² and R ³ are attached to form an unsubstituted or a substituted cyclopropyl, an unsubstituted or a substituted cyclobutyl, an unsubstituted or a substituted cyclopentyl or an unsubstituted or a substituted cyclohexyl.

[0090] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be a phenyl; Ring B can be an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl; n can be 1; Ring C can be selected from a pyridine, a pyrimidine and a phenyl, wherein the pyridine, the pyrimidine and the phenyl can be each optionally substituted with 1 or 2 moieties independently selected from the group consisting of deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl; R ¹ can be selected hydrogen, an unsubstituted C _1-4 alkyl and an unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; ml can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ^3b can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ⁴ is - C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen, an unsubstituted C _1-4 alkyl. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be a pyridine; Ring B can be an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl; n can be 1; Ring C can be selected from a pyridine, a pyrimidine and a phenyl, wherein the pyridine, the pyrimidine and the phenyl can be each optionally substituted with 1 or 2 moieties independently selected from the group consisting of deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl; R ¹ can be selected hydrogen, an unsubstituted C _1-4 alkyl and an unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; ml can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ^3b can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ⁴ is - C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen, an unsubstituted C _1-4 alkyl. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be a phenyl; Ring B can be an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl; n can be 1; Ring C can be selected from a pyridine, a pyrimidine and a phenyl, wherein the pyridine, the pyrimidine and the phenyl can be each optionally substituted with 1 or 2 moieties independently selected from the group consisting of deuterium, halogen and an unsubstituted C _1-4 alkyl; R ¹ can be selected hydrogen, an unsubstituted C _1-4 alkyl and an unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; ml can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ^3b can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ⁴ is -C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen, an unsubstituted C _1-4 alkyl. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be a phenyl; Ring B can be an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl; n can be 1; Ring C can be selected from a pyridine optionally substituted with 1 or 2 moieties independently selected from the group consisting of deuterium, halogen and an unsubstituted Ci- 4 alkyl; R ¹ can be selected hydrogen, an unsubstituted C _1-4 alkyl and an unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; ml can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ^3b can be deuterium, halogen or an unsubstituted C _1-4 alkyl; R ⁴ is -C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen, an unsubstituted C _1-4 alkyl.

[0091] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl and an unsubstituted C _1-4 haloalkyl; Ring B can be selected from an unsubstituted or a substituted 6- membered monocyclic nitrogen-containing heterocyclyl, an unsubstituted or a substituted 7- membered bicyclic nitrogen-containing heterocyclyl and an unsubstituted or a substituted 8- membered bicyclic nitrogen-containing heterocyclyl; n can be 0 or 1; wherein when n is 0, then Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted , wherein when the aryl, the heteroaryl and the , y , y can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C _1-4 haloalkyl; Ring DI can be a phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl; Ring D2 can be selected from an unsubstituted or a substituted an unsubstituted or a substituted

, an unsubstituted or a substituted ° an unsubstituted or a substituted an unsubstituted or a substituted , an unsubstituted or a substituted and an unsubstituted or a substituted , wherein the asterisks indicate the points of attachment to Ring DI; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl; R ¹ can be selected from hydrogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl, an unsubstituted C _1-4 hydroxyalkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl) and a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl), wherein the substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) can be substituted by 1 or more deuteriums; R ² and R ³ can be independently hydrogen, deuterium or an unsubstituted C _1-4 alkyl; or R ² and R ³ can be taken together along with the carbon to which R ² and R ³ can be taken together along with the carbon to which R ² and R ³ are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen, an unsubstituted C _1-4 alkyl, a substituted C _1-4 alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C _1-4 alkyl), wherein the substituted C _1-4 alkyl can be substituted by 1 or more deuteriums.

[0092] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl and an unsubstituted C _1-4 haloalkyl; Ring B can be selected from an unsubstituted or a substituted 6- membered monocyclic nitrogen-containing heterocyclyl, an unsubstituted or a substituted 7- membered bicyclic nitrogen-containing heterocyclyl and an unsubstituted or a substituted 8- membered bicyclic nitrogen-containing heterocyclyl; n can be 0 or 1; wherein when n is 0, then

Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted , wherein when the aryl, the heteroaryl and the , , can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C _1-4 haloalkyl; Ring DI can be a phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl; Ring D2 can be selected from an unsubstituted or a substituted an unsubstituted or a substituted

, an unsubstituted or a substituted ⁰ an unsubstituted or a substituted an unsubstituted or a substituted an unsubstituted or a substituted and an unsubstituted or a substituted , wherein the asterisks indicate the points of attachment to Ring DI; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl; R ¹ can be selected from hydrogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl, an unsubstituted C _1-4 hydroxyalkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl) and a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl), wherein the substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) can be substituted by 1 or more deuteriums; R ² and R ³ can be independently hydrogen, deuterium or an unsubstituted C _1-4 alkyl; or R ² and R ³ can be taken together along with the carbon to which R ² and R ³ can be taken together along with the carbon to which R ² and R ³ are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; ml can be 0 or 1; m2 can be 0, 1 or 2; R ^3a can be deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R ^3b can be deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen, an unsubstituted C _1-4 alkyl, a substituted C _1-4 alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C _1-4 alkyl), wherein the substituted C _1-4 alkyl can be substituted by 1 or more deuteriums.

[0093] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuteriumsubstituted C _1-4 alkyl and an unsubstituted C _1-4 haloalkyl; Ring B can be selected from an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl, an unsubstituted or a substituted 7-membered bicyclic nitrogen-containing heterocyclyl and an unsubstituted or a substituted 8-membered bicyclic nitrogen-containing heterocyclyl; n can be 0 or 1; wherein when n is 0, then Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C _1-4 haloalkyl; Ring DI can be a phenyl, a 5-membered heteroaryl or a 6- membered heteroaryl; Ring D2 can be selected from an unsubstituted or a substituted an unsubstituted or a substituted an unsubstituted or a substituted ⁰ , an unsubstituted or a substituted an unsubstituted or a substituted an unsubstituted or a substituted and an unsubstituted or a substituted wherein the asterisks indicate the points of attachment to Ring DI; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) and an unsubstituted C _1-4 haloalkyl; R ¹ can be selected from hydrogen, an unsubstituted C _1-4 alkyl, a substituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl, an unsubstituted C _1-4 hydroxyalkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl), an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl) and a substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkenyl), wherein the substituted C _1-4 alkyl and the substituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) can be substituted by 1 or more deuteriums; R ² and R ³ can be independently hydrogen, deuterium or an unsubstituted C _1-4 alkyl; or R ² and R ³ can be taken together along with the carbon to which R ² and R ³ can be taken together along with the carbon to which R ² and R ³ are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; ml can be 0 or 1; m2 can be 0, 1 or 2; R ^3a can be deuterium, halogen, an unsubstituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R ^3b can be deuterium, halogen, an unsubstituted C _1-4 alkyl, a deuterium-substituted C _1-4 alkyl, an unsubstituted C _1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or an unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen, an unsubstituted C _1-4 alkyl, a substituted C _1-4 alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C _1-4 alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C _1-4 alkyl), wherein the substituted C _1-4 alkyl can be substituted by 1 or more deuteriums.

[0094] Examples of compounds of Formula (I), include the following:

[0095] Additional examples of compounds of Formula (I), include the following: or a pharmaceutically acceptable salt of any of the foregoing.

[0096] Further examples of compounds of Formula (I), include the following: pharmaceutically acceptable salt of any of the foregoing.

Synthesis

[0097] 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.

[0098] Scheme 1 provides an exemplary method for preparing a compound of

Formula (I), including pharmaceutically acceptable salts thereof. Pharmaceutical Compositions

[0099] Some embodiments described herein relate to a pharmaceutical composition, that 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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

[0106] 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.

[0107] 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.

[0108] 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. [0109] Some embodiments described herein relate to a method for inhibiting the activity of PARP1 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 PARP1. 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 PARP1. Some embodiments described herein relate to a method for inhibiting the activity of PARP1 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 PARP1 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 PARP1.

[0110] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of PARP1 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 PARP1. 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 PARP1. 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 PARP1.

[OHl] Some embodiments disclosed herein relate to a method for inhibiting the activity of PARP1 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 PARP1. 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 PARP1.

[0112] 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 tetracarcinoma, a nuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma or an anaplastic thyroid carcinoma.

[0113] 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.

[0114] 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.

[0115] The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, that 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

[0116] 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.

Example 1 Compound Al

[0117] To a solution of isocyanatoethane (5.44 g, 76.48 mmol) in toluene (80 mL) was added triethylamine (7.74 g, 76.48 mmol) and 1 (8 g, 38.24 mmol). The mixture was stirred at 80 °C for 24 h. The mixture was filtered, and the filter cake was washed with PE (3 x 50 mL). The filter cake was concentrated under reduced pressure to give a residue. The residue was dissolved with methanol (120 mL). HC1 (12 M, 25.49 mL) was added dropwise to the mixture. The mixture was stirred at 60 °C for 32 h. The mixture was filtered, and the filter cake was concentrated to give a residue. The crude product was stirred in a mixture of PE and EA (30 mL, 1 : 1) for 1 h to form a slurry. The solid was collected by filtration and concentrated to give 2 (8.4 g, 88.49% yield) as a white solid. ’H NMR: (400 MHz, DMSO-tL) 6 11.60 (s, 1H), 8.05 (d, J=8.25 Hz, 1H), 7.61-7.79 (m, 2H), 3.86-3.98 (m, 5H), 1.15 (t, J=7.00 Hz, 3H). [0118] To a solution of 2 (1 g, 4.03 mmol) in tetrahydrofuran (20 mL) was added LiAlH4 (305.79 mg, 8.06 mmol). The mixture was stirred at 0 °C for 0.5 h. To the mixture was added water (0.3 mL) dropwise. 15% sodium hydroxide (aq., 0.3 mL) and water (0.9 mL) were then added dropwise at 0 °C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The crude product was stirred in a mixture of PE and EA (15 mL, 5: 1) for 1 h to form a slurry. The solid was collected by filtration and concentrated to give 3 (1.1 g, 99.19% yield, 80% purity) as a white solid. ’H NMR: (400 MHz, DMSO-tL) 6 7.62 (d, J=7.89 Hz, 1H), 6.84 (s, 1H), 6.63 (dd, J=8.11, 1.10 Hz, 1H), 4.43 (s, 2H), 3.91 (q, J=6.94 Hz, 2H), 3.42-3.46 (m, 1H), 1.03-1.10 (m, 3H).

[0119] To a solution of 3 (1 g, 3.63 mmol) in dichloromethane (20 mL) and dimethyl formamide (0.2 mL) was added thionyl chloride (864.36 mg, 7.27 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The crude product was stirred in a mixture of PE and EA (10 mL, 5: 1) for 1 h to form a slurry. The solid was collected by filtration and concentrated to give 4 (0.8 g, 92.27% yield) as a light-yellow solid. ^X H NMR: (400 MHz, DMSO-tL) 6 11.57 (s, 1H), 7.92 (d, J=8.13 Hz, 1H), 7.11-7.40 (m, 2H), 4.83 (s, 2H), 3.92 (br d, J=7.00 Hz, 2H), 1.14 (t, J=7.00 Hz, 3H).

[0120] To a solution of N,6-dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (0.1 g, 369.33 umol, HC1) in dimethyl formamide (1 mL) was added 4 (105.78 mg, 443.20 umol), sodium iodide (166.08 mg, 1.11 mmol) and N,N-diisopropylethylamine (286.40 mg, 2.22 mmol). The mixture was stirred at 70 °C for 2 h and then filtered. The filtrate was purified by prep- HPLC and lyophilized to give Al (0.0687 g, 42.61% yield, 100% purity) as a white solid. ’H NMR: (400 MHz, DMSO-tL) 6 11.37 (br d, J=0.72 Hz, 1H), 8.42 (q, J=4.77 Hz, 1H), 7.90 (d, J=8.46 Hz, 1H), 7.79 (d, J=8.23 Hz, 1H), 7.48 (d, J=8.34 Hz, 1H), 7.18 (dd, J=4.05, 2.86 Hz, 2H), 3.92 (q, J=7.03 Hz, 2H), 3.62 (s, 2H) 2.95 (br s, 4H), 2.80 (d, J=4.89 Hz, 3H), 2.52-2.59 (m, 4H), 2.49 (br s, 3H), 1.14 (t, J=7.03 Hz, 3H). Example 2 Compound A2

[0121] To a solution of 5 (120 mg, 605.41 umol) and 7-(chloromethyl)-3-ethyl-lH- quinazoline-2, 4-dione (169.32 mg, 709.42 umol) in acetonitrile (2 mL) were added NaBr (145.99 mg, 1.42 mmol) and N,N-diisopropylethylamine (366.75 mg, 2.84 mmol) at 20°C. The mixture was stirred at 80 °C for 12 hrs. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Phenomenex Luna C18 75*30 mm*3 um; Mobile Phase: [water (FA)-ACN]; B%: 15%-45%, 8 min.) to provide A2 (58.7 mg 28.02% yield) was obtained as a white solid. 1H NMR: (400 MHz, DMSO-tL) 6 1.14 (t, J=7.00 Hz, 3H), 2.55 (br s, 4H), 2.98 (br s, 4H), 3.59 (s, 2H), 3.92 (q, J=7.00 Hz, 2H), 6.93- 7.12 (m, 2H), 7.13-7.23 (m, 3H), 7.89 (d, J=8.51 Hz, 1H), 11.36 (s, 1H). LCMS [ESI+]: 401.1 [M+H] ⁺ , RT: 1.942 min.

[0122] LC/MS Method: The gradient was 5%B in 0.40min and 5-95% B at 0.40-3.00 min, hold on 95% B for 1. OOmin, and then 95-5%B in O.Olmin, the flow rate was 1.0 ml/min. Mobile Phase A was 0.04% trifluoroacetic acid in water, Mobile Phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna Cl 8 50*2.0mm column (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000.

Example 3 Compound A3

[0123] A mixture of 5 (0.1 g, 504.51 umol) and 7-(chloromethyl)-3-ethyl-lH- pyrido[3,2-d]pyrimidine-2, 4-dione (181.36 mg, 756.77 umol), sodium bromide (155.73 mg, 1.51 mmol) and N, N-diisopropylethylamine (391.22 mg, 3.03 mmol) in acetonitrile (2 mL) was stirred at 80 °C for 16 hrs. The mixture was filtered. The filter cake was purified by prep-HPLC (Phenomenex Luna C18 75*30 mm*3 um; Mobile Phase: [water (FA)-ACN]; B%: l%-30%, 8 min.) and lyophilized to give A3 (40.2 mg, 18.86% yield) as a white solid. ^X H NMR: (400 MHz, DMSO-tL) 8 11.46 (br s, 1H), 8.43 (s, 1H), 7.55 (s, 1H), 7.12-7.24 (m, 1H), 6.91-7.10 (m, 2H), 3.93 (q, J=6.88 Hz, 2H), 3.66 (s, 2H), 2.98 (br s, 4H), 2.56 (br s, 4H), 1.15 (br t, J=6.88 Hz, 3H).

Example 4 Compound A4

[0124] To a solution of 6 (2 g, 9.08 mmol, 1.75 mL) in DCM (30 mL) was added methylimino(thioxo)methane (677.17 mg, 9.26 mmol, 632.87 uL) at 25 °C. The mixture was stirred at 25 °C for 3 hrs and then concentrated to give the product. Compound 7 (2.7 g, 91.22% yield, 90% purity) was obtained as a white solid, and was used in the next step directly without further purification. ^X H NMR: (400 MHz, CDCb4) 8 7.74 (br d, J = 3.4 Hz, 1H), 7.44-7.27 (m, 5H), 5.10 (s, 2H), 3.82-3.76 (m, 4H), 3.44 (br s, 4H), 2.91 (br d, J = 3.9 Hz, 3H).

[0125] To a solution of 7 (2.7 g, 9.20 mmol) in MeOH (40 mL) was added CH3I (1.57 g, 11.04 mmol, 687.50 uL) at 25 °C. The mixture was stirred at 60 °C for 2 hrs. The mixture was concentrated to give the product. Compound 8 (2.8 g, 98.97% yield) was obtained as a white solid, and was used in the next step directly without further purification.

[0126] A solution of 8 (2.8 g, 9.11 mmol) and prop-2-yn-l -amine (1.76 g, 31.89 mmol, 2.04 mL) in pyridine (50 mL) was stirred at 110 °C for 2 hrs. The mixture was concentrated to give the product. The residue was purified by column chromatography (SiCh, PE:EA = 50: 1 to 1 : 1). Compound 9 (1.6 g, 55.87% yield) was obtained as light-yellow oil.

[0127] A solution of 9 (200 mg, 636.17 umol) in HC1 (1 mL) and H2O (1 mL) was stirred at 50 °C for 12 hrs. The mixture was concentrated to give the product. Compound 10 (110 mg, 79.79% yield, HC1) was obtained as a white solid, and was used in the next step directly without further purification. The product was used in the next step directly without further purification.

[0128] To a solution 7-(chloromethyl)-3-ethyl-lH-pyrido[3,2-d]pyrimidine-2, 4-dione (100 mg, 418.99 umol) in MeCN (2 mL) was added 10 (108.96 mg, 502.79 umol, HC1), NaBr (129.33 mg, 1.26 mmol, 40.42 uL) and DIEA (270.75 mg, 2.09 mmol, 364.89 uL) at 25 °C. The mixture was stirred at 80 °C for 2 hrs. The reaction was filtered, and the filtrate was concentrated to give crude product. The crude product was purified by reverse-phase HPLC (0.1% FA condition). Prep-HPLC (column: Phenomenex C18 75*30 mm*3 um; liquid phase: [A-FATLO = 0.1% v/v; B-ACN]; B%: 15%-40%, 8 min.). Compound A4 (50.6 mg, 27.28% yield, 96.8% purity, FA) was obtained as a white solid. ^T H NMR: (400 MHz, CDsOD-t/v) 6 11.37 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.21 - 7.15 (m, 2H), 6.35 (d, J = 1.1 Hz, 1H), 3.93 (q, J = 7.0 Hz, 2H), 3.60 (s, 2H), 3.30 (s, 3H), 2.94 (br t, J = 4.6 Hz, 4H), 2.56 - 2.51 (m, 4H), 2.08 (d, J = 0.9 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H).

Example 5 Compounds A5 and A6

[0129] A mixture of 11 (2.5 g, 10.82 mmol), isocyanatoethane (1.54 g, 21.64 mmol) and triethylamine (2.19 g, 21.64 mmol) in toluene (20 mL) was stirred at 100 °C for 48 hrs. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a residue. The residue was stirred in EA (20 mL) for 2 hrs to form slurry. The solid was collected by filtration and concentrated to give 12 (1.7 g, 58.17% yield) as a white solid. ^T H NMR: (400 MHz, DMSO-tL) 6 11.38-11.78 (m, 1H), 8.56 (d, J=1.75 Hz, 1H), 7.75 (d, J=1.97 Hz, 1H), 3.91 (q, J=7.09 Hz, 2H), 1.15 (t, J=7.02 Hz, 3H).

[0130] A mixture of 12 (1.7 g, 6.29 mmol), triethylamine (1.27 g, 12.59 mmol) and cyclopentyl(diphenyl)phosphane;dichloromethane;dichloropalla dium;iron (514.02 mg, 629.44 umol) in dimethyl formamide (200 mL) and methanol (100 mL) was stirred at 80°C for 24 hrs under CO at 50 psi. The mixture was concentrated under reduced pressure to give a residue. The residue was stirred in methanol (20 mL) for 16 hrs to form slurry. The solid was collected by filtration and the solid was stirred in dichloromethane (20 mL) for 2 hrs to form slurry. The solid was collected by filtration and concentrated to give 13 (1.4 g, 89.25% yield) as a gray solid. ’H NMR: (400 MHz, DMSO-tL) 6 11.67 (s, 1H), 8.89 (s, 1H), 8.05 (s, 1H), 3.85-4.01 (m, 5H), 1.16 (t, J=7.02 Hz, 3H).

[0131] To a solution of 13 (0.5 g, 2.01 mmol) in tetrahydrofuran (10 mL) was added lithium borohydride (87.41 mg, 4.01 mmol) at 0 °C. The mixture was stirred at 20 °C for 3 hrs. The reaction was quenched by addition 1 N hydrochloric (6 mL) at 0 °C, and then filtered. The filter cake was concentrated under reduced pressure to give a residue. The residue was stirred in tetrahydrofuran (5 mL) for 2 hrs to form slurry. The solid was collected by filtration and concentrated to give 14 (0.35 g, 78.86% yield) as a light-yellow solid.

[0132] To a solution of 14 (0.35 g, 1.58 mmol) in dichloromethane (7 mL) and N,N- dimethyl formamide (0.01 mL) was added sulfoxide chloride (752.93 mg, 6.33 mmol). The mixture was stirred at 20 °C for 2 hrs. The mixture was filtered, and the filter cake was concentrated to give a residue. The residue was stirred in EA (3 mL) for 1 hr at 20 °C to form slurry. The filter cake was concentrated to give 15 (0.3 g, 79.12% yield) as a yellow solid.

[0133] A mixture of N, 6-dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (0.15 g, 554.00 umol), 15 (265.54 mg, 1.11 mmol) N, N-diisopropylethylamine (429.59 mg, 3.32 mmol) and sodium bromide (171.00 mg, 1.66 mmol) in acetonitrile (0.5 mL) was stirred at 80 °C for 12 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex C18 80*40 mm*3 um; Mobile Phase: [water (NH4HCO ₃ )-ACN]; B%: 15%-35%, 8 min.) and lyophilized to give A5 (21.6 mg, 7.98% yield) as a white solid. ’H NMR: (400 MHz, CD ₃ Cl-t/ ₃ ) 8 9.97 (s, 1H), 8.55 (d, J=1.25 Hz, 1H), 8.02-8.14 (m, 2H), 7.79 (s, 1H), 7.35 (d, J=8.25 Hz, 1H), 4.20 (q, J=6.96 Hz, 2H), 3.74 (s, 2H), 3.11 (d, J=5.00 Hz, 3H), 3.02 (br s, 4H), 2.71 (br s, 4H), 2.53 (s, 3H), 1.33 (t, J=7.00 Hz, 3H).

[0134] A mixture of N-methyl-5-piperazin-l-yl-pyridine-2-carboxamide (0.08 g, 311.61 umol) and 15 (112.02 mg, 467.41 umol), N, N-diisopropylethylamine (241.63 mg, 1.87 mmol) and sodium bromide (96.18 mg, 934.83 umol) in acetonitrile (0.5 mL) was stirred at 8 0°C for 12 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex C18 80*40 mm*3 um; Mobile Phase: [water (NH4HCCh)-ACN]; B%: 10%-30%, 8 min.) and lyophilized to give A6 (4.0 mg, 3%) as a white solid. ’H NMR: (400 MHz, DMSO-afc) 5 11.47 (br s, 1H), 8.35- 8.47 (m, 2H), 8.27 (d, ./=2.74 Hz, 1H), 7.83 (d, J=8.82 Hz, 1H), 7.56 (d, J=1.55 Hz, 1H), 7.40 (dd, J=8.82, 2.86 Hz, 1H), 3.94 (q, J=6.99 Hz, 2H), 3.67 (s, 2H), 3.33-3.38 (m, 4H), 2.78 (d, J=4.77 Hz, 3H), 2.53-2.61 (m, 4H), 1.15 (t, J=7.03 Hz, 3H).

Example 6 Compounds A7

[0135] A mixture of 16 (5 g, 23.14 mmol), tert-butyl piperazine- 1 -carboxylate (4.74 g, 25.46 mmol), CS2CO3 (15.08 g, 46.29 mmol), Xantphos (1.34 g, 2.31 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.06 g, 1.16 mmol) in dioxane (50 mL) was degassed and purged with Argon (3x). The mixture was stirred at 100 °C for 16 hrs under an Argon atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1:2) to give 17 (4.6 g, 61.84% yield) as a yellow solid. ^X H NMR: (400 MHz, DMSO-tL) 6 8.37 (d, J=2.75 Hz, 1H), 7.88 (d, J=8.75 Hz, 1H), 7.34 (dd, J=8.88, 3.00 Hz, 1H), 3.80 (s, 3H), 3.43-3.51 (m, 4H), 3.34-3.42 (m, 4H), 1.42 (s, 9H).

[0136] A mixture of 17 (2.2 g, 6.85 mmol) and methanamine (11.00 g, 106.26 mmol, 30% in water) in methanol (5 mL) was stirred at 20 °C for 4 hrs. The mixture was concentrated. The residue was diluted with NH4Q (30 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 18 (2.1 g, 95.75% yield) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-tL) 6 8.41 (br d, J=4.77 Hz, 1H), 8.27 (d, J=2.76 Hz, 1H), 7.84 (d, J=8.78 Hz, 1H), 7.40 (dd, J=8.85, 2.95 Hz, 1H), 3.42-3.51 (m, 4H), 3.26-3.34 (m, 4H), 2.78 (d, J=4.77 Hz, 3H), 1.42 (s, 9H).

[0137] A mixture of 18 (2.1 g, 6.55 mmol) in dioxane (20 mL) and 4 N HC1 in dioxane (20 mL) was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give 19 (1.6 g, 95.08% yield) as a light-yellow solid. ’H NMR: (400 MHz, DMSO- d6) 5 8.76-8.90 (m, 1H), 8.33 (d, J=2.85 Hz, 1H), 8.09 (d, J=8.77 Hz, 1H), 7.68 (dd, J=8.88, 2.52 Hz, 1H), 3.61-3.69 (m, 4H), 3.56 (s, 1H), 3.20 (br s, 4H), 2.80 (d, ./=3.51 Hz, 3H).

[0138] A mixture of 19 (0.15 g, 584.27 umol) and 7-(chloromethyl)-3-ethyl-lH- quinazoline-2, 4-dione (167.34 mg, 701.12 umol), N, N-diisopropylethylamine (453.07 mg, 3.51 mmol) and sodium bromide (180.35 mg, 1.75 mmol) in acetonitrile (1.5 mL) was stirred at 80 °C for 16 hrs. The mixture was filtered, and the filter cake was concentrated to give a residue. The residue was purified by prep-HPLC (Phenomenex Luna Cl 8 200*40 mm* 10 um; Mobile Phase: [water (FA)-ACN]; B%: l%-40%, 8 min.) and lyophilized to give A7 (55.9 mg, 22.65% yield) as a white solid. ’H NMR: (400 MHz, DMSO-afc) 8 11.37 (s, 1H), 8.33-8.43 (m, 1H), 8.26 (d, J=2.75 Hz, 1H), 8.14 (s, 1H), 7.78-7.94 (m, 2H), 7.39 (dd, J=8.76, 2.75 Hz, 1H), 7.14-7.22 (m, 2H), 3.93 (q, J=6.96 Hz, 2H), 3.60 (s, 2H), 3.34 (br s, 4H), 2.78 (d, J=4.88 Hz, 3H), 2.51-2.57 (m, 4H), 1.14 (t, J=7.00 Hz, 3H). Example 7 Compounds A8

[0139] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H- pyridine- 1 -carboxylate (572.52 mg, 1.85 mmol) and 20 (400 mg, 1.85 mmol) in tetrahydrofuran (8 mL) was added K3PO4 (786.05 mg, 3.70 mmol) in H2O (2 mL) at 20 °C. The mixture was degassed and purged with N2 (3x). Pd(dppf)C12 (135.48 mg, 185.16 umol) was added to the mixture under N2 atmosphere, and the mixture was stirred at 80 °C for 6 hrs. The reaction was quenched by the addition H2O (50 mL) at 25 °C. The mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 25% to 50%) to obtain 21 (460 mg, 74.13% yield) was obtained as a white solid. ^T H NMR: (400 MHz, DMSO-de) 6 1.43 (s, 9H), 2.52 (br d, J=1.50 Hz, 2H), 3.56 (br t, J=5.57 Hz, 2H), 3.88 (s, 3H), 4.05 (br s, 2H), 6.46 (br s, 1H), 7.96- 8.08 (m, 2H), 8.81 (s, 1H).

[0140] A mixture of 21 (0.46 g, 1.44 mmol), methanamine (1.50 g, 14.45 mmol) in MeOH (1.25 mL) stirred at 20 °C for 4 hrs. The mixture was concentrated. The residue was diluted with NH4Q (5 mL) and extracted with di chloromethane (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was used for the next step without further purification. Compound 22 (0.45 g, 98.13% yield) was obtained as a light-yellow solid. LCMS [ESI+]: 318.1 [M+H] ⁺ , RT: 0.591 min 5-95AB 2 min: LC/MS (column: Agilent Poroshell SB- C18 3.0*30 mm, 2.7 um. Detection methods are diode array (DAD). MS mode was positive electrospray ionization. MS range was 100-1000. Mobile Phase A was 0.04% trifluoroacetic acid in water, and Mobile Phase B was 0.02% trifluoroacetic acid in HPLC grade acetonitrile.

[0141] To a solution of 22 (450 mg, 1.45 mmol) in dioxane (2 mL) was added HCl/dioxane (2 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hrs and then concentrated under reduced pressure to give the crude product, which was used in the next step without further purification. Compound 23 (330 mg, 89.74% yield) was obtained as a white solid. ^T H NMR: (400 MHz, DMSO-tA) 6 1.14 (t, J=7.00 Hz, 3H), 2.55 (br s, 4H), 2.98 (br s, 4H), 3.59 (s, 2H), 3.92 (q, J=7.00 Hz, 2H), 6.93-7.12 (m, 2H), 7.13-7.23 (m, 3H), 7.89 (d, J=8.51 Hz, 1H), 11.36 (s, 1H).

[0142] To a solution of 7-(chloromethyl)-3-ethyl-lH-quinazoline-2, 4-dione (141.10 mg, 591.19 umol) and 23 (100 mg, 394.12 umol) in acetonitrile (2 mL) were added NaBr (121.65 mg, 1.18 mmol) and N,N-diisopropylethylamine (305.63 mg, 2.36 mmol) at 20 °C. The mixture was stirred at 80 °C for 12 hrs. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex luna C18 100*40 mm*3 um; Mobile Phase: [water (FA)-ACN]; B%: 10%-50%, 8 min.) to obtain A8 (39.4 mg, 21.72% yield) as a white solid. ’H NMR: (400 MHz, DMSO-t/e) 6 1.14 (t, J=7.00 Hz, 3H), 2.54 (br d, J=1.88 Hz, 2H), 2.68 (br t, J=5.38 Hz, 2H), 2.82 (d, J=4.88 Hz, 3H), 3.14 (br s, 2H), 3.66 (s, 2H), 3.92 (q, J=6.88 Hz, 2H), 6.40 (br s, 1H), 7.12-7.23 (m, 2H), 7.88 (d, J=8.13 Hz, 1H), 7.97 (d, J=l.13 Hz, 2H), 8.63-8.76 (m, 2H), 11.35 (s, 1H). LCMS [ESI+]: 420.1 [M+H] ⁺ , RT: 1.672 min. LC/MS: The gradient was 5%B in 0.40 min and 5-95% B at 0.40-3.00 min, hold on 95% B for 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 mL/min. Mobile Phase A was 0.04% trifluoroacetic acid in water, Mobile Phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna Cl 8 50*2.0mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode was positive electrospray ionization. MS range was 100-1000. Example 8 Compounds A9

[0143] To a solution of 1A (10 g, 42.51 mmol) in dimethyl formamide (200 mL) was added N,N-diisopropylethylamine (21.98 g, 170.04 mmol). The mixture was cooled to 0 °C. 1- hydroxybenzotriazole hydrate (8.62 g, 63.77 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (12.22 g, 63.77 mmol) were added in portions, and then methyl 2-aminoacetate;hydrochloride (6.40 g, 51.01 mmol) was added. The mixture was stirred at 20 °C for 12 hrs. The mixture was diluted with water (200 mL) and extracted with EA (10 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 :4) to give 2A (9 g, 69.12% yield) as a colorless oil. ^X H NMR: (400 MHz, DMSO-tL) 6 8.18 (br t, J=5.13 Hz, 1H), 7.92 (s, 1H), 7.24-7.42 (m, 5H), 5.02 (s, 2H), 3.82 (br d, J=5.75 Hz, 2H), 3.62 (s, 3H), 1.21-1.30 (m, 2H), 0.88-1.00 (m, 2H).

[0144] To a solution of 2A (9 g, 29.38 mmol) in methanol (180 mL) was added Pd/C (2 g, 29.38 mmol). The suspension was degassed and purged with H2 (3x). The mixture was stirred under H2 (15 psi) at 20 °C for 16 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3A (5 g, 98.83% yield) as a colorless oil. ’H NMR: (400 MHz, DMSO-tL) 6 8.44 (br t, J=5.19 Hz, 1H), 3.87 (d, J=6.00 Hz, 2H), 3.63 (s, 3H), 2.32 (s, 2H), 1.04 (q, J=3.46 Hz, 2H), 0.78 (q, J=3.54 Hz, 2H).

[0145] Compound 3A (5 g, 29.04 mmol) was stirred at 150 °C for 10 minutes. The mixture was stirred in a mixture of PE and EA (30 mL, 1 : 1) for 2 hrs to form slurry. The solid was collected by filtration and dried in high vacuo to give 4A (3.8 g, 93.38% yield) as a lightyellow solid. ’H NMR: (400 MHz, DMSO-afc) 8 8.19-8.34 (m, 1H), 8.03 (br s, 1H), 3.87 (d, J=1.88 Hz, 2H), 1.12-1.23 (m, 2H), 0.86-1.03 (m, 2H).

[0146] To a solution of 4A (3.3 g, 23.55 mmol) in dimethyl formamide (300 mL) were added 4-dimethylaminopyridine (863.04 mg, 7.06 mmol) and triethylamine (7.15 g, 70.64 mmol) at 20 °C, and then di-tert-butyl dicarbonate (15.42 g, 70.64 mmol) was added dropwise at 0 °C. The mixture was stirred at 20 °C for 16 hrs. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 4: 1) to give 5A (5.5 g, 68.62% yield) as a white solid. ’H NMR: (400 MHz, DMSO-tL) 6 4.51 (s, 2H), 1.52-1.57 (m, 2H), 1.45 (d, J=9.26 Hz, 18H), 1.36-1.42 (m, 2H).

[0147] To a solution of 5A (5.3 g, 15.57 mmol) in tetrahydrofuran (150 mL) was added diisobutylaluminum hydride (1 M, 77.86 mL) dropwise at -78 °C under N2. The mixture was stirred at -78°C for 1 hour. The reaction was quenched by addition methanol (50 mL) at - 78° C, and then warmed to 20 °C. The mixture was extracted with EA and washed with Rochelle's salt solution (100 mL) and brine (1 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6A (5.3 g, 98.83% yield) as a white solid. ’H NMR: (400 MHz, DMSO-tL) 6 6.39-6.97 (m, 1H), 4.76-5.63 (m, 1H), 3.73 (br d, J=5.88 Hz, 1H), 2.93 (br t, J=5.82 Hz, 1H), 1.32-1.44 (m, 18H), 1.09-1.20 (m, 2H), 0.76-0.90 (m, 2H).

[0148] To a solution of 6A (5.3 g, 15.39 mmol) in di chloromethane (180 mL) were added EtsSiH (8.95 g, 76.94 mmol) and BF3.Et2O (10.92 g, 76.94 mmol) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 2 hrs. The reaction was quenched by saturated NaHCCh solution (100 mL) at 0 °C, and then warmed to 20 °C. The mixture was washed with EA (20 mL), and Na2CCh (9.79 g, 92.33 mmol) and BOC2O (20.15 g, 92.33 mmol) were added at 0 °C. Tetrahydrofuran (180 mL) was added to the mixture. The mixture was stirred at 20 °C for 16 hrs. The mixture was diluted with water (100 mL), extracted with EA (3 x 100 mL), washed with brine (50 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 4: 1) to give 7A (1.3 g, 27.04% yield) as a white solid. ’H NMR: (400 MHz, DMSO-tL) 6 4.19 (br s, 2H), 3.96 (t, J=5.69 Hz, 1H), 3.42-3.53 (m, 2H), 3.14 (q, J=5.71 Hz, 1H), 1.97-2.02 (m, 4H), 1.39 (s, 18H).

[0149] To a solution of 7A (1.3 g, 4.16 mmol) in dichloromethane (13 mL) was added triethylamine (20.02 g, 175.58 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give a residue. The residue was stirred in a mixture of PE and EA (5 mL, 3: 1) for 30 minutes to form slurry. The solid was collected by filtration and dried in high vacuum to give 8A (0.9 g, 63.57% yield, 2TFA) as a white solid. ’H NMR: (400 MHz, DMSO-afc) 8 3.96-4.05 (m, 2H), 3.33-3.41 (m, 3H), 3.14-3.24 (m, 2H), 2.09- 2.35 (m, 4H).

[0150] To a solution of methanamine (5.63 g, 83.32 mmol, HC1) in DMF (180 mL) was added DIEA (21.54 g, 166.64 mmol, 29.03 mL) at 20 °C. The mixture was stirred for 30 min and then 24 (9 g, 41.66 mmol) and HATU (31.68 g, 83.32 mmol) were added at 0 °C. The mixture stirred 20 °C for 12 hrs. The mixture was poured into ice-water and extracted with EtOAc (4 x lOOmL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give residue. The residue was purified by column chromatography (SiCh, PE_EA = 50: 1 to 2: 1) to obtain 25 (9 g, 94.31% yield) as a white solid. ^X H NMR: (400 MHz, DMSO-tL) 6 8.66 (br d, J = 4.0 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 2.81 (d, J = 4.9 Hz, 3H), 2.64 (s, 3H).

[0151] A mixture of 25 (200 mg, 873.08 umol), 2,5-diazabicyclo[4.2.0]octane (297.04 mg, 873.08 umol), sodium tert-butoxide (335.61 mg, 3.49 mmol), RuPhos Pd G3 (73.02 mg, 87.31 umol) in toluene (6 mL) was degassed and purged with Argon (3x). The mixture was stirred at 100 °C for 16 hrs under an Argon atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiCh, dichloromethane: methanol = 10: 1) to give 26 (60 mg, 26.40% yield) as a brown oil. ’H NMR: (400 MHz, DMSO-tL) 6 8.38 (br d, J=4.75 Hz, 1H), 7.75 (d, J=8.25 Hz, 1H), 7.32 (d, J=8.38 Hz, 1H), 5.75 (s, 3H), 3.79 (br d, J=4.75 Hz, 1H), 3.58 (q, J=6.30 Hz, 1H), 3.17 (ddd, J=12.26, 5.75, 2.50 Hz, 1H), 3.08 (ddd, J=12.38, 8.00, 2.38 Hz, 1H), 2.73-2.84 (m, 4H), 2.57 (ddd, J=12.16, 8.04, 1.94 Hz, 1H), 2.50 (s, 3H), 1.98-2.11 (m, 1H), 1.72-1.84 (m, 1H), 1.58-1.70 (m, 2H).

[0152] A mixture of 4 (50 mg, 192.06 umol), 26 (68.76 mg, 288.09 umol), sodium bromide (59.28 mg, 576.18 umol), N,N-diisopropylethylamine (148.93 mg, 1.15 mmol) in acetonitrile (2 mL) were stirred at 80 °C for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, Waters Xbridge Prep OBD C18 150 x 40 mm x 10 um; Mobile Phase: [water

(NH4HCO3)-CH3CN]; B%: 35%-65%, 8 min) and lyophilized to give A9 (44.6 mg, 49.65% yield, 98.9% purity) as a white solid. ^X H NMR: (400 MHz, DMSO-tL) 6 11.34 (br s, 1H), 8.40 (q, J=4.79 Hz, 1H), 7.90 (d, J=8.00 Hz, 1H), 7.76 (d, J=8.25 Hz, 1H), 7.38 (d, J=8.38 Hz, 1H), 7.15-7.26 (m, 2H), 3.88-3.99 (m, 3H), 3.72 (d, J=14.13 Hz, 1H), 3.48 (d, J=14.01 Hz, 1H), 3.29

(s, 2H), 2.76-2.84 (m, 4H), 2.69-2.76 (m, 1H), 2.51-2.53 (m, 3H), 2.42-2.48 (m, 1H), 1.85-2.02

(m, 2H), 1.61-1.77 (m, 2H), 1.14 (t, J=7.07 Hz, 3H).

Example 9 Compounds A10

[0153] To a solution of 27 (10 g, 46.29 mmol) in dichloromethane (200 mL) was added m-CPBA (18.80 g, 92.58 mmol) in portions at 0 °C. The mixture was stirred at 45 °C for

12 hrs. The reaction was quenched by the addition Na2SO3 (100 mL) at 0 °C. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 :1) to give 28 (8.2 g, 76.35% yield) as a light-yellow solid. ^X H NMR: (400 MHz, DMSO-tL) 6 8.72 (d, J=0.88 Hz, 1H), 7.69 (s, 2H), 3.86 (s, 3H).

[0154] A solution of 28 (8.2 g, 35.34 mmol) in POCh (135.30 g, 882.40 mmol) was stirred at 95 °C for 2 hrs. The mixture was distilled in vacuum (120 °C, oil pump). The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 8: 1) to give 29 (5 g, 56.49% yield) as a light-yellow solid. ^X H NMR: (400 MHz, DMSO-afc) 8 8.45 (d, J=8.13 Hz, 1H), 7.94 (d, J=8.13 Hz, 1H), 3.89 (s, 3H).

[0155] To a solution of 29 (5 g, 19.96 mmol) in methanol (48 mL) was added a solution of MeNH2 (33.38 g, 322.44 mmol) in ethanol (48 mL). The mixture was stirred at 20 °C for 2 hrs. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 30 (4.9 g, 98.39% yield) as a lightyellow solid. ’H NMR: (400 MHz, DMSO-tL) 6 8.69 (br d, J=4.00 Hz, 1H), 8.36-8.46 (m, 1H), 7.88 (d, J=8.13 Hz, 1H), 2.80 (d, J=4.88 Hz, 3H).

[0156] A mixture of 30 (3 g, 12.02 mmol), tert-butyl piperazine- 1 -carboxylate (4.48 g, 24.05 mmol), CS2CO3 (9.79 g, 30.06 mmol), Xantphos (695.76 mg, 1.20 mmol) and Pd2(dba)3 (550.55 mg, 601.22 umol) in dioxane (60 mL) was degassed and purged with Argon (3x). The mixture was stirred at 80 °C for 16 hrs under Argon atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 :2) to give 31 (2.7 g, 63.28% yield) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-tL) 6 8.46 (br d, J=4.82 Hz, 1H), 7.94 (d, J=8.11 Hz, 1H), 7.68 (d, J=8.11 Hz, 1H), 3.49 (br d, J=4.38 Hz, 4H), 2.98-3.09 (m, 4H), 2.79 (d, J=4.60 Hz, 3H), 1.42 (s, 9H).

[0157] A mixture of 32 (0.2 g, 563.65 umol) in dioxane (2 mL) and HCl/di oxane (2 mL) was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give 32 (160 mg, 97.49% yield, HC1) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-tL) 5 9.15- 9.29 (m, 2H), 8.48 (br d, J=4.75 Hz, 1H), 7.97 (d, J=8.13 Hz, 1H), 7.76 (d, J=8.13 Hz, 1H), 3.22- 3.34 (m, 8H), 2.79 (d, J=4.75 Hz, 3H).

[0158] A mixture of 32 (150 mg, 515.15 umol, HC1), 4 (184.43 mg, 772.73 umol), sodium bromide (106.01 mg, 1.03 mmol), N,N-diisopropylethylamine (399.47 mg, 3.09 mmol) in acetonitrile (3 mL) was stirred at 80 °C for 2 hrs under N2 atmosphere. The mixture was diluted with water (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (1 x 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 0: 1) and lyophilized to give A10 (119.8 mg, 49.62% yield, 97.5% purity) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-afc) 8 11.38 (s, 1H), 8.43 (br d, J=4.75 Hz, 1H), 7.92 (br dd, J=14.13, 8.25 Hz, 2H), 7.67 (br d, J=8.13 Hz, 1H), 7.06-7.26 (m, 2H), 3.86-3.98 (m, 2H), 3.62 (s, 2H), 3.12 (br s, 4H), 2.79 (br d, J=4.38 Hz, 3H), 2.58 (br s, 4H), 1.14 (br t, J=6.82 Hz, 3H).

Example 10 Compounds Al l

[0159] To a solution 4 (80 mg, 335.19 umol) in MeCN (2 mL) was added 33 (87.85 mg, 319.78 umol, HC1), NaBr (103.47 mg, 1.01 mmol, 32.33 uL) and DIEA (216.61 mg, 1.68 mmol, 291.92 uL) at 25 °C. The mixture was stirred at 80 °C for 2 hrs. The mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by reversed-phase HPLC (0.1% FA condition, Phenomenex Luna C18 75 x 30 mm x 3 um; Mobile Phase: [water (NELElCOs^CEhCN]; B%: 15%-45%, 8 min.) to obtain All (24.1 mg, 16.32% yield) as a white solid. 'H NMR: (400 MHz, CDsOD-tL) 6 11.37 (s, 1H), 8.39 (q, J = 4.5 Hz, 1H), 8.14 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.57 (dd, J = 8.2, 10.6 Hz, 1H), 7.20-7.15 (m, 2H), 3.92 (q, J = 7.0 Hz, 2H), 3.60 (s, 2H), 3.18 (br s, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.56 (br d, J = 4.3 Hz, 4H), 1.14 (t, J = 7.0 Hz, 3H). Example 11 Compounds Al 2

[0160] A mixture of 34 (0.2 g, 563.65 umol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2 dioxaborolane (104.17 mg, 676.38 umol), K3PO4 (239.29 mg, 1.13 mmol), ditertbutyl(cyclopsentyl)-phosphane;dichloropalladium;iron (36.74 mg, 56.36 umol) in tetrahydrofuran (6 mL) and water (1.5 mL) was degassed and purged with Argon (3x). The mixture was stirred at 80 °C for 16 hrs under Argon atmosphere. The mixture was diluted with water (10 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (1 x 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 : 1) to give 34A (0.1 g, 51.21% yield) as a brown oil. ^X H NMR: (400 MHz, DMSO-tL) 6 8.59 (br d, J=5.00 Hz, 1H), 7.86 (d, J=8.38 Hz, 1H), 7.57 (d, J=8.38 Hz, 1H), 7.06 (dd, J=17.20, 10.69 Hz, 1H), 6.68 (dd, J=17.20, 2.44 Hz, 1H), 5.49-5.61 (m, 1H), 3.51 (br d, J=4.00 Hz, 5H), 3.02-3.08 (m, 1H), 2.86-2.91 (m, 4H), 2.83 (d, J=4.88 Hz, 3H), 1.42 (s, 9H).

[0161] To a mixture of Pd/C (0.02 g, 288.66 umol) in EA (3 mL) was added 34A (0.1 g, 288.66 umol). The suspension was degassed and purged with H2 (3x). The mixture was stirred under H2 (15 psi) at 20 °C for 16 hrs. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 35 (90 mg, 89.48% yield) as a yellow oil.

[0162] To a solution of 35 (0.09 g, 258.30 umol) in dioxane (1 mL) was added HCl/dioxane (1 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hrs and then concentrated under reduced pressure to give 36 (70 mg, 95.16% yield, HC1) as a brown solid. [0163] A mixture of 36 (0.07 g, 245.80 umol), 4 (88.00 mg, 368.70 umol), N,N- diisopropylethylamine (190.60 mg, 1.47 mmol), sodium bromide (75.87 mg, 737.40 umol,) in acetonitrile (2 mL) was stirred at 80 °C for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, Phenomenex Cl 8 75 x 30 mm x 3 um; Mobile Phase: [water (NH4HCO3)- CH3CN]; B%: 25%-55%, 8 min.) and lyophilized to give All (25.7 mg, 23.07% yield, 99.4% purity) as a white solid. ^X H NMR: (400 MHz, DMSO-tfc) 5 11.35 (br s, 1H), 8.55 (q, J=4.61 Hz, 1H), 7.90 (d, J=7.95 Hz, 1H), 7.80 (d, J=7.82 Hz, 1H), 7.65 (d, J=7.83 Hz, 1H), 7.14-7.26 (m, 2H) 5.71 (br s, 1H), 3.93 (q, J=6.97 Hz, 2H), 3.68 (s, 2H), 3.11 (br d, J=2.81 Hz, 2H), 2.82 (d, J=4.89 Hz, 3H), 2.67 (t, J=5.50 Hz, 2H), 2.53 (s, 3H), 2.36 (br s, 2H), 1.14 (t, J=7.03 Hz, 3H).

Example 12 Compounds Al 3 and Al 4

[0164] To a solution of 37 (2 g, 9.30 mmol) in tetrahydrofuran (60 mL) was added N,N-diisopropylethylamine (6.01 g, 46.50 mmol) at 20 °C, and isobutyl chloroformate (1.40 g, 10.23 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hrs. and then MeNH2 (1.88 g, 27.90 mmol, HC1) was added at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 : 1) to give 38 (1.78 g, 83.91% yield) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-tL) 6 8.32-8.51 (m, 1H), 7.80 (d, J=1.88 Hz, 1H), 7.67 (d, J=8.25 Hz, 1H), 7.56 (dd, J=8.32, 1.81 Hz, 1H), 2.75-2.78 (m, 3H), 2.39 (s, 3H).

[0165] A mixture of 38 (0.2 g, 876.86 umol), tert-butyl piperazine- 1 -carboxylate (326.63 mg, 1.75 mmol), CS2CO3 (714.25 mg, 2.19 mmol), Xantphos (50.74 mg, 87.69 umol) and Pd2(dba)3 (40.15 mg, 43.84 umol) in dioxane (4 mL) was degassed and purged with Argon (3x). The mixture was stirred at 8 0°C for 16 hours under Argon atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 :2) to give 39 (0.25 g, 85.51% yield) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-afc) 8 8.24 (br d, J=4.50 Hz, 1H), 7.59-7.69 (m, 2H), 7.03 (d, J=8.38 Hz, 1H), 3.47 (br s, 4H), 2.78-2.87 (m, 4H), 2.75 (d, J=4.50 Hz, 3H), 2.28 (s, 3H), 1.42 (s, 9H). [0166] A mixture of 39 (0.25 g, 749.80 umol) in dioxane (3 mL) and HCl/di oxane (3 mL) was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give 40 (0.2 g, 98.88% yield, HC1) as a light-yellow solid.

[0167] A mixture of 40 (0.08 g, 296.55 umol, HC1), 4 (84.93 mg, 355.86 umol,), N,N-diisopropylethylamine (229.96 mg, 1.78 mmol) and sodium bromide (91.54 mg, 889.65 umol) in acetonitrile (2 mL) was stirred at 80 °C for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (neutral condition, Phenomenex C18 75*30 mm*3 um; Mobile Phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min.) and lyophilized to give A13 (29.2 mg, 22.61% yield, 100% purity) as a white solid. ’H NMR: (400 MHz, DMSO-afc) 8 11.35 (br s, 1H), 8.55 (q, J=4.61 Hz, 1H), 7.90 (d, J=7.95 Hz, 1H), 7.80 (d, J=7.82 Hz, 1H), 7.65 (d, J=7.83 Hz, 1H), 7.14- 7.26 (m, 2H), 5.71 (br s, 1H), 3.93 (q, J=6.97 Hz, 2H), 3.68 (s, 2H), 3.11 (br d, J=2.81 Hz, 2H), 2.82 (d, J=4.89 Hz, 3H), 2.67 (t, J=5.50 Hz, 2H), 2.53 (s, 3H), 2.36 (br s, 2H), 1.14 (t, J=7.03 Hz, 3H).

[0168] A mixture of 25 (0.15 g, 654.81 umol), tert-butyl 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-l-carboxylate (242.97 mg, 785.77 umol), K ₃ PO ₄ (277.99 mg, 1.31 mmol) and Pd(dppf)cl2 (47.91 mg, 65.48 umol) in tetrahydrofuran (6 mL) and water (1.5 mL) was degassed and purged with Argon (3x). The mixture was stirred at 80 °C for 2 hrs under Argon atmosphere. The mixture was diluted with water (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (1 x 5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 3: 1) to give 41 (0.19 g, 87.55% yield) as a light-yellow solid. ’H NMR: (400 MHz, DMSO-tL) 6 8.51-8.60 (m, 1H), 7.81 (d, J=7.91 Hz, 1H), 7.66 (d, J=7.91 Hz, 1H), 5.68-5.79 (m, 1H), 3.94-4.00 (m, 2H), 3.55 (t, J=5.52 Hz, 2H), 2.82 (d, J=4.89 Hz, 3H), 2.51 (s, 3H), 2.33 (br d, J=1.63 Hz, 2H), 1.44 (s, 9H).

[0169] To a solution of 41 (0.19 g, 573.31 umol) in dioxane (2 mL) was added HCl/dioxane (2 mL). The mixture was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give 42 (0.15 g, 97.72% yield, HC1) as a light-yellow solid.

[0170] A mixture of 42 (100 mg, 373.48 umol, HC1), 7-(chloromethyl)-3-ethyl-lH- quinazoline-2, 4-dione (106.97 mg, 448.17 umol), N,N-diisopropylethylamine (193.08 mg, 1.49 mmol) and sodium bromide (76.86 mg, 746.95 umol) in acetonitrile (2 mL) was stirred at 80 °C for 2 hrs under N2 atmosphere. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, Waters Xbridge BEH Cl 8 100*30 mm* 10 um; Mobile Phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 8 min) and lyophilized to give A14 (53.4 mg, 32.95% yield, 99.9% purity) as a white solid. ’H NMR: (400 MHz, DMSO-PL) 8 11.35 (br s, 1H), 8.55 (q, J=4.61 Hz, 1H), 7.90 (d, J=7.95 Hz, 1H), 7.80 (d, J=7.82 Hz, 1H), 7.65 (d, J=7.83 Hz, 1H), 7.14-7.26 (m, 2H), 5.71 (br s, 1H), 3.93 (q, J=6.97 Hz, 2H), 3.68 (s, 2H), 3.11 (br d, J=2.81 Hz, 2H), 2.82 (d, J=4.89 Hz, 3H), 2.67 (t, J=5.50 Hz, 2H), 2.53 (s, 3H), 2.36 (br s, 2H), 1.14 (t, J=7.03 Hz, 3H).

Example 12

Compound Al 5

[0171] To a solution of 43 (2 g, 7.97 mmol) and (2,4-dimethoxyphenyl)methanamine (1.40 g, 8.37 mmol, 1.26 mL) in DMF (50 mL) was added K ₂ CO ₃ (2.20 g, 15.93 mmol) at 20 °C. The mixture was stirred at 80 °C for 4 hrs. The mixture was poured into ice-water (150 mL) and filtered. The cake was dried under high vacuum to give the crude product, which was used in the next step directly without further purification. Compound 43A (2 g, 63.04% yield) was obtained as a white solid. 'H NMR: (400 MHz, CDCb4) 8 7.98 (br s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.60 (s, 1H), 6.45-6.31 (m, 3H), 4.22 (d, J = 5.6 Hz, 2H), 3.79 (d, J = 3.9 Hz, 6H), 3.73 (s, 3H). [0172] A solution of 43A (2 g, 5.02 mmol) in DCM (20 mL) and HC1 (10 mL) was stirred at 20 °C for 2 hrs. The mixture was concentrated to give the crude product. The crude product was adjusted pH=7 with NaHCOs. The mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 50: 1 to 2: 1) to obtain 43B (1 g, 80.27% yield) as a white solid.

[0173] To a solution of 43B (1 g, 4.03 mmol) in H2O (10 mL) and dioxane (10 mL) was added LiOH’EbO (422.94 mg, 10.08 mmol) at 20 °C. The mixture was stirred at 20 °C for 6 hrs. The mixture was adjusted the pH=3 with HC1 (1 N) at 0 °C. The mixture was filtered, and the filtered cake was dried under high vacuum to give the crude product, which was used in the next step directly without further purification. Compound 43C (500 mg, 53.00% yield) was obtained as a white solid.

[0174] To a solution of 43C (400 mg, 1.71 mmol) and DIEA (883.61 mg, 6.84 mmol, 1.19 mL) in THF (1 mL) was added isobutyl carb onochlori date (466.88 mg, 3.42 mmol, 448.93 uL) at 0 °C. The mixture was stirred at 0 °C for 1 hr and then ethanamine (231.17 mg, 5.13 mmol, 335.52 uL) was added at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The mixture was poured into water and extracted with ethyl acetate (3 x lOmL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 50: 1 to 3:1) to give 43D (110 mg, 24.65% yield) as a white solid. ^X H NMR: (400 MHz, DMSO-afc) 8 8.23 (br s, 1H), 6.73 (s, 1H), 6.58 (dd, J = 1.8, 10.0 Hz, 1H), 6.10 (s, 2H), 3.28 - 3.19 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H).

[0175] To a solution of bis(trichloromethyl) carbonate (137.53 mg, 463.44 umol) and TEA (85.26 mg, 842.62 umol, 117.28 uL) in THF (3 mL) was added 43D (110 mg, 421.31 umol) at 20 °C. The mixture was stirred at 20 °C for 12 hrs. The mixture was poured into 5% NaHCOs (10 mL) at 0 °C then extracted with EA (3 x 15 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was used in the next step directly without further purification. Compound 44 (100 mg, 82.68% yield) was obtained as a white solid.

[0176] To a solution of 44 (100 mg, 348.33 umol) and XPhos-Pd-G2 (27.41 mg, 34.83 umol) in dioxane (2 mL) was added tributyl stannylmethanol (167.77 mg, 522.49 umol) at 25 °C. The mixture was stirred at 80 °C for 12 hrs. The mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was triturated with EA (5 mL) for 30 min to provide 45 (70 mg, 84.36% yield) as a white solid.

[0177] To a solution of 45 (70 mg, 293.85 umol) in DCM (2 mL) was added SOCh (69.92 mg, 587.71 umol, 42.63 uL) at 2 5°C. The mixture was stirred at 25 °C for 2 hrs and then concentrated to give the crude product, which was used in the next step directly without further purification. Compound 46 (70 mg, 272.73 umol, 92.81% yield) was obtained as an off-white solid.

[0178] To a solution of 46 (70 mg, 272.73 umol), NaBr (56.12 mg, 545.47 umol, 17.54 uL) and DIEA (140.99 mg, 1.09 mmol, 190.02 uL) in MeCN (1.5 mL) was added N,6- dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (96.00 mg, 354.55 umol, HC1) at 25 °C. The mixture was stirred at 80 °C for 2 hrs. The mixture was filtered, and the cake was collected. The filtered cake was purified by prep-HPLC (0.1% FA, column: Phenomenex C18 75*30 mm*3 um; liquid phase: [A-FA/H2O=0.1% v/v; B-ACN]; B%: 15%-40%, 8 min.) to obtain A15(53.6 mg, 39.26% yield) as a white solid. 'H NMR: (400 MHz, CDsOD-t/v) 6 11.50 (s, 1H), 8.41 (q, J = 4.5 Hz, 1H), 8.13 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.94 (d, J = 11.9 Hz, 1H), 3.88 (q, J = 7.0 Hz, 2H), 3.60 (s, 2H), 2.96 (br s, 4H), 2.80 (d, J = 4.9 Hz, 3H), 2.58 (br s, 4H), 2.49 (br s, 3H), 1.13 (t, J = 7.0 Hz, 3H).

Example 13 Compound Al 6

A16

[0179] To a solution of 47 (1 g, 4.27 mmol) and TEA (864.78 mg, 8.55 mmol, 1.19 mL) in THF (10 mL) was added isobutyl carb onochlori date (875.41 mg, 6.41 mmol, 841.74 uL) at 0 °C. The mixture was stirred at 0 °C for 1 hr and then ethanamine (385.29 mg, 8.55 mmol, 559.20 uL) was added at 0 °C. The mixture was stirred at 20 °C for 12 hrs. The mixture was poured into ice water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 50: 1 to 3 : 1) to give 48 (0.69 g, 61.85% yield) as a white solid.

[0180] To a solution of bis(trichloromethyl) carbonate (727.41 mg, 2.45 mmol) and TEA (496.08 mg, 4.90 mmol, 682.37 uL) in THF (12 mL) was added 48 (640 mg, 2.45 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. The mixture was poured into 5% NaHCOs (20 mL) at 0 °C and then extracted with EA (3 x 15 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product, which was used in the next step directly without further purification. Compound 49 (0.4 g, 56.84% yield) was obtained as a white solid.

[0181] To a solution of 49 (400 mg, 1.39 mmol) and XPhos-Pd-G2 (109.37 mg, 139.00 umol) in dioxane (8 mL) was added tributyl stannylmethanol (669.46 mg, 2.09 mmol) at 25 °C. The mixture was stirred at 80 °C for 12 hrs. The mixture was filtered, and the filtrate was concentrated to give the crude product. The crude product was triturated with EA (5 mL) for 30 min to give 50 (240 mg, 72.48% yield) was obtained as a white solid.

[0182] To a solution of 50 (240 mg, 1.01 mmol) in DCM (10 mL) was added SOCh (239.72 mg, 2.01 mmol, 146.17 uL) at 25 °C. The mixture was stirred at 25 °C for 2 hrs and then concentrated to give the product, which was used in the next step directly without further purification. Compound 51 (240 mg, 92.81% yield) was obtained as an off-white solid. [0183] To a solution of 51 (60 mg, 233.77 umol, 1 eq), NaBr (48.11 mg, 467.54 umol, 15.03 uL, 2 eq) and DIEA (120.85 mg, 935.09 umol, 162.88 uL, 4 eq) in MeCN (2 mL) was added N,6-dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (65.73 mg, 242.75 umol, 1.04 eq, HC1) at 25°C. Then the mixture was stirred at 80°C for 2 hrs. LCMS showed the reaction was completed. The reaction was filtered, and the cake was collected. The filtered cake was purified by prep-HPLC (0.1% FA, Phenomenex C18 75*30 mm*3 um; liquid phase: [A- FA/H ₂ O=0.1% V/V; B-ACN]; B%: 15%-40%,8 min.). A16 (36.7 mg, 31.37% yield) was obtained as a white solid. ’H NMR: (400 MHz, CDsOD-t/v) 6 11.55 (br s, 1H), 8.41 (q, J = 4.8 Hz, 1H), 8.15 (br s, 1H), 7.77 (dd, J = 8.2, 11.8 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 6.2, 8.1 Hz, 1H), 3.94 (q, J = 7.0 Hz, 2H), 3.70 (s, 2H), 2.94 (br s, 4H), 2.79 (d, J = 4.9 Hz, 3H), 2.60 (br s, 4H), 2.48 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H).

Example 14 Compound Al 7

[0184] To a solution of 30 (2 g, 8.02 mmol) in DMF (40 mL) was added CsF (3.65 g, 24.05 mmol, 886.66 uL), tetramethylammonium;chloride (87.86 mg, 801.63 umol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (211.89 mg, 801.63 umol) at 25 °C. The mixture was stirred at 80 °C for 12 hrs. The mixture was poured into water (100 mL) and extracted with EA (3 x 30mL). The combined organic phase was washed with brine (100 mL), dried oved Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 50: 1 to 3:1) to provide 30A (1 g, 53.53% yield) as a white solid.

[0185] A mixture of 30A (0.8 g, 3.43 mmol), tert-butyl piperazine- 1 -carboxylate (1.28 g, 6.87 mmol), Cs ₌ CO ₃ (2.24 g, 6.87 mmol), Pd2(dba)3 (157.18 mg, 171.65 umol) and Xantphos (198.64 mg, 343.29 umol) in dioxane (15 mL) was degassed and purged with N2 (3x). The mixture was stirred at 80 °C for 12 hrs under N2 atmosphere. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 20: 1 to 1 : 1) to give 52 (0.9 g, 77.48% yield) as a white solid.

[0186] A solution of 52 (0.9 g, 2.66 mmol, 1 eq) in HCl/dioxane (20 mL) was stirred at 25 °C for 2 hrs. The mixture was concentrated under reduced pressure at 30 °C to give the crude product, which was used in the next step directly without further purification. Compound 53 (0.7 g, 95.80% yield, HC1) was obtained as a pink solid.

[0187] To a solution of 53 (60 mg, 233.77 umol), NaBr (48.11 mg, 467.54 umol, 15.03 uL) and DIEA (120.85 mg, 935.09 umol, 162.87 uL) in MeCN (2 mL) was added 6-fluoro- N-methyl-5-piperazin-l-yl-pyridine-2-carboxamide (67.43 mg, 245.46 umol, HC1) at 25 °C. The mixture was stirred at 80 °C for 2 hrs. The mixture was filtered, and the cake was collected. The filtered cake was purified by prep-HPLC (0.1% FA, Phenomenex C18 75*30 mm*3 um; liquid phase: [A-FA/H ₂ O=0.1% v/v; B-ACN]; B%: 15%-40%, 8 min.) to obtain A17 (41.2 mg, 38.44% yield) as a white solid. ’H NMR: (400 MHz, CD3OD-A) 5 11.54 (br s, 1H), 8.47 - 8.33 (m, 1H), 8.21 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 8.3, 10.3 Hz, 1H), 7.30 - 7.19 (m, 1H), 3.93 (q, J = 6.8 Hz, 2H), 3.68 (s, 2H), 3.16 (br s, 4H), 2.76 (d, J = 4.6 Hz, 3H), 2.58 (br s, 4H), 1.15 (t, J = 7.0 Hz, 3H).

Example 15 Compound Al 8

[0188] To a solution 54A (1 g, 4.44 mmol) and N-ethyl-N-isopropyl-propan-2-amine (4.02 g, 31.09 mmol) in tetrahydrofuran (30 mL) was added isobutyl carb onochlori date (667.25 mg, 4.89 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hrs, and then methanamine-hydrochloride (899.62 mg, 13.32 mmol) was added. The mixture was slowly warm to 20 °C and then stirred at 20 °C for 14 hrs. The reaction was quenched by the addition ice-water (50 mL) at 0 °C. The mixture was diluted with EA (20 mL) and extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 100: 1 to 9: 11) to provide 54B (560 mg, 52.93% yield) as a white solid.

[0189] To a solution of 54B (480 mg, 2.02 mmol) in EA (25 mL) was added Pd/C (237.79 mg, 201.51 umol, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 (3x). The mixture was stirred under H2 (15 Psi) at 20 °C for 4 hrs. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give 54C (400 mg, 95.33% yield) as a white solid. ’H NMR: (400 MHz, DMSO4) 6 8.35 (br d, J = 4.4 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 7.07-7.01 (m, 1H), 6.63-6.53 (m, 2H), 3.86-3.75 (m, 3H), 2.77-2.69 (m, 3H).

[0190] To a solution of 54C 400 mg, 1.92 mmol) and N,N-diethylethanamine (388.79 mg, 3.84 mmol) in tetrahydrofuran (6 mL) was added a solution of triphosgene (570.08 mg, 1.92 mmol) in tetrahydrofuran (2 mL) at 20 °C. The mixture was stirred at 20 °C for 16 hrs. The reaction was quenched by the addition ice-water (30 mL). The mixture was filtered and concentrated under reduced pressure to give 54 (400 mg, 88.90% yield) as a yellow solid.

[0191] To a solution of 54 (200 mg, 853.94 umol) in tetrahydrofuran (4 mL) was added lithium aluminium hydride (64.82 mg, 1.71 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hour. The reaction was quenched by the addition water (0.1 mL), 15% NaOH (0.1 mL) and water (0.3 mL). The mixture was stirred at 0 °C for 30 mins. The mixture was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was triturated with EA (10 mL) at 20 °C for 30 minutes, filtered and concentrated under reduced pressure to give 55 (170 mg, 96.55% yield) as a light-yellow solid.

[0192] To a solution of 55 (170 mg, 824.45 umol) in dichloromethane (4 mL) were added N,N-dimethylformamide (cat.) and thionyl dichloride (196.17 mg, 1.65 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give the crude product, which was used in the next step directly. Compound 56 (180 mg, 97.19% yield) was obtained as a yellow solid.

[0193] To a solution of 56 (180 mg, 801.27 umol) and N,6-dimethyl-5-piperazin-l- yl- pyridine-2-carboxamide (225.28 mg, 961.52 umol) in acetonitrile (4 mL) were added N- ethyl-N-propan-2-ylpropan-2-amine (724.89 mg, 5.61 mmol) and NaBr (247.33 mg, 2.40 mmol). The mixture was stirred at 80 °C for 2 hrs. The mixture was added into ice-water (20 mL) at 0 °C and then filtered. The filter cake was washed with water and acetonitrile, concentrated under reduced pressure and lyophilized to give A18 (129.7 mg, 37.32% yield, 97.4% purity) as a lightyellow solid. ’H NMR: (400 MHz, DMSO-t/6) 8 11.46-11.34 (m, 1H), 8.41 (br d, J = 4.8 Hz, 1H), 7.96-7.87 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.53-7.43 (m, 1H), 7.24-7.13 (m, 2H), 3.62 (s, 2H), 3.29-3.20 (m, 3H), 2.96 (br s, 4H), 2.80 (d, J = 4.9 Hz, 3H), 2.63 - 2.51 (m, 7H). LCMS [ESI+]: 423.1 [M+H] ⁺ , RT: 1.597 min.

[0194] LC/MS: The gradient was 5%B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1. OOmin, and then 95-5%B in 0.01 min, the flow rate was 1.0 mL/min. Mobile Phase A was 0.04% Trifluoroacetic Acid in water, Mobile Phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Luna Cl 8 50*2.0 mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000. Example 16 Compounds Al 9 and A20

[0195] To a solution of 57 (1 g, 4.27 mmol) and N-ethyl-N-propan-2-ylpropan-2- amine (3.87 g, 29.91 mmol) in tetrahydrofuran (30 mL) was added dropwise isobutyl carb onochlori date (641.97 mg, 4.70 mmol) at 0 °C. After addition, the mixture was stirred at this temperature for 2 hrs, and then methanamine-hydrochloride (865.53 mg, 12.82 mmol) was added. The mixture was slowly warm to 20 °C and stirred at 20 °C for 14 hrs. The mixture was added to ice-water (40 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 100: 1 to 3: 1) to provide 58 (630 mg, 59.67% yield) as a white solid.

[0196] To a solution of 58 (630 mg, 2.55 mmol) and N,N-diethylethanamine (516.05 mg, 5.10 mmol) in tetrahydrofuran (9 mL) was added a solution of triphosgene (756.69 mg, 2.55 mmol) in tetrahydrofuran (3 mL) at 20 °C. The mixture was stirred at 20 °C for 16 hrs. The reaction was quenched by the addition ice-water (50 mL), filtered and concentrated under reduced pressure to give 59 (600 mg, 86.17% yield) as a light-yellow solid. ^T H NMR: (400 MHz, DMSO-tA) 6 11.78 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 5.9, 8.6 Hz, 1H), 3.25 (s, 3H).

[0197] A mixture of 59 (600 mg, 2.20 mmol), tributyl stannylmethanol (1.06 g, 3.30 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-( 2,4,6- triisopropylphenyl)phenyl]phosphane (259.33 mg, 329.60 umol) in dioxane (15 mL) was degassed and purged with N2 (3x). The mixture was stirred at 80 °C for 16 hrs under N2 atmosphere. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was triturated with EA (20 mL) at 20 °C for 20 minutes, filtered and concentrated under reduced pressure to give 60 (400 mg, 81.20% yield) as an off-white solid.

[0198] To a solution of 60 (120 mg, 535.26 umol) in dichloromethane (2.5 mL) were added N,N-dimethylformamide (cat.) and thionyl dichloride (127.36 mg, 1.07 mmol) at 0 °C under N2. The mixture was stirred at 20 °C for 2 hrs. The mixture was concentrated under reduced pressure to give the crude product, which was used for the next step directly. Compound 61 (120 mg, 92.40% yield) was obtained as a yellow solid.

[0199] To a solution of 61 (120 mg, 494.57 umol) and N,6-dimethyl-5-piperazin-l- yl- pyridine-2-carboxamide (139.05 mg, 593.49 umol) in acetonitrile (2.5 mL) were added N- ethyl-N-propan-2-ylpropan-2-amine (447.44 mg, 3.46 mmol) and NaBr (152.67 mg, 1.48 mmol). The mixture was stirred at 80 °C for 2 hrs. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (FA condition, Phenomenex Luna 80*30 mm*3 um; Mobile Phase: [water (FA)-ACN]; B%: 10%- 35%, 8 min.) to give A19 (71.2 mg, 29.50% yield, 99.7% purity, FA) as a white solid. ¹ H NMR: (400 MHz, DMSO-t/6) 8 = 11.70 - 11.43 (m, 1H), 8.41 (q, J = 4.7 Hz, 1H), 7.77 (dd, J = 8.2, 11.9 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 6.1, 8.1 Hz, 1H), 3.70 (s, 2H), 3.26 (s, 3H), 2.94 (br s, 4H), 2.84 - 2.75 (m, 3H), 2.61 (br s, 4H), 2.48 (s, 3H). LCMS [ESI+]: 441.1 [M+H] ⁺ , RT: 1.575 min.

[0200] To a solution of 61 (80 mg, 329.71 umol) and 6-fluoro-N-methyl-5-piperazin- 1-yl- pyridine-2-carboxamide (108.70 mg, 395.66 umol, HC1) in acetonitrile (2 mL) were added N-ethyl-N-propan-2-ylpropan-2-amine (426.12 mg, 3.30 mmol) and NaBr (101.77 mg, 989.14 umol). The mixture was stirred at 80 °C for 2 hrs. The mixture was added into ice-water (10 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition, Phenomenex Luna 80*30 mm*3 um; Mobile Phase: [water (FA)-ACN]; B%: 5%-25%, 8 min.) to give A20 (67.3 mg, 40.78% yield, 98.0% purity, FA) was obtained as a white solid. ^T H NMR: (400 MHz, DMSO-t/6) 6 11.58 (br s, 1H), 8.39 (q, J = 4.6 Hz, 1H), 8.18 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 8.2, 10.6 Hz, 1H), 7.25 (dd, J = 6.3, 8.0 Hz, 1H), 3.68 (s, 2H), 3.26 (s, 3H), 3.20 - 3.13 (m, 4H), 2.76 (d, J = 4.8 Hz, 3H), 2.59 (br d, J = 4.0 Hz, 4H). LCMS [ESI+]: 445.1 [M+H] ⁺ , RT: 1.578 min.

[0201] LC/MS: (The gradient was 5%B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5%B in 0.01 min, the flow rate was 1.0 mL/min. Mobile Phase A was 0.04% Trifluoroacetic Acid in water, Mobile Phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Luna Cl 8 50*2.0 mm column (5 um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization. MS range was 100-1000.

Example 17 Compound A21

[0202] To a solution of 62 (1.18 g, 6.84 mmol) and TEA (2.08 g, 20.51 mmol, 2.86 mL) in THF (12 mL) was added ethanamine (2 M, 8.55 mL) at 0°C. HATU (5.20 g, 13.68 mmol) was then added to the mixture at 0 °C. The mixture was stirred at 25 °C for 12 hrs. The mixture was poured into water (35mL) and extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 1 :0 to 1 : 1) to give 63 (1.1 g, 80.58% yield) as a white solid. ^X H NMR: (400 MHz, DMSO-t/6) 8 11.98 (br s, 1H), 8.67 (s, 1H), 7.39-6.92 (m, 1H), 4.08-3.81 (m, 2H), 1.30-1.11 (m,

3H).

[0203] To a solution of 63 (1.3 g, 6.51 mmol) in THF (26 mL) were added TEA (988.39 mg, 9.77 mmol, 1.36 mL) and triphosgene (2.13 g, 7.16 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hrs and then filtered. The cake was collected dried under high vacuum to give a residue, which was used in the next step directly without further purification. Compound 64 (600 mg, 40.84% yield) was obtained as yellow solid.

[0204] To a solution of 64 (380 mg, 1.68 mmol) in MeOH (2 mL) were added TEA (340.84 mg, 3.37 mmol, 468.83 pL) and Pd(dppf)Ch (123.23 mg, 168.42 pmol) at 25 °C. The mixture was stirred at 80 °C under CO (50 psi) for 12 hrs. The mixture filtered and the filter cake was collected. The product was used in the next step directly without further purification. Compound 65 (0.3 g, 71,47% yield) was obtained as a yellow solid. ’H NMR: (400 MHz, DMSO-t/6) 8 12.11-11.85 (m, 1H), 9.04 (s, 1H), 7.73 (s, 1H), 3.96-3.86 (m, 5H), 1.15 (t, J = 7.0 Hz, 3H). [0205] To a solution of 65 (50 mg, 200.62 pmol) in THF (2 mL) was added LiAlHi (2.5 M, 64.20 pL) dropwise at -10 °C under N2. The mixture was stirred at -10 °C for 0.5 hr and then cooled to 0 °C. Water (0.04 mL) was added, NaOH (0.04 mL, 15%) and additional water (0.12 mL) was added to the mixture. The mixture stirred at 0 °C for 30 min and then Na2SO4 was added to the mixture. The mixture was filtered, and the filtrate was concentrated to give a residue, which was used in the next step directly without further purification. Compound 66 (40 mg, 90.13% yield) was obtained as a yellow solid.

[0206] To a solution of 66 (80 mg, 361.64 pmol) in DCM (3 mL) was added SOCI2 (86.05 mg, 723.29 pmol, 52.53 pL) dropwise at 0 °C under N2. The mixture was stirred at 20 °C for 2 hrs. The mixture was concentrated to give a residue, which was used in the next step directly without further purification. Compound 67 (50 mg, 57.69% yield) was obtained as brown solid.

[0207] To a solution of 67 (100 mg, 443.20 pmol) and N,6-dimethyl-5- piperazin-1- yl-pyridine-2-carboxamide (103.84 mg, 443.20 pmol) in MeCN (0.5 mL) were added DIEA (343.68 mg, 2.66 mmol, 463.19 pL) and NaBr (136.81 mg, 1.33 mmol, 42.71 pL) at 25 °C. The mixture was stirred at 80 °C for 2 hrs. The reaction was used to condition screening and discarded without further purification. The crude product was purified by reversed-phase HPLC (0.1% FA condition, Phenomenex luna C18 100*40 mm*5 um Mobile phase: [H2O (0.2% FA)- ACN]; gradient: l%-30% B over 8.0 min.) to obtain A21 (9.8 g, 5221.63% yield) as a white solid. ^X H NMR: (400 MHz, DMSO-t/6) 8 11.70 (br d, J = 3.8 Hz, 1H), 8.93 (s, 1H), 8.51-8.37 (m, 1H), 8.15 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.25 (s, 1H), 3.92 (q, J = 7.0 Hz, 2H), 3.73 (s, 2H), 2.98 (br s, 4H), 2.81 (d, J = 4.9 Hz, 3H), 2.66 (br s, 4H), 1.15 (t, J = 7.0 Hz, 3H).

Example 18 Compound A22

80°C, 2 hrs

[0208] To a solution of 68 (2.5 g, 12.05 mmol) in DMSO (40 mL) and H ₂ O (40 mL) were added DABCO (540.71 mg, 4.82 mmol, 530.11 uL) and NaCN (602.39 mg, 12.29 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. The mixture was diluted with water (100 mL) and extracted with EA (3 x 80 mL). The combined organic phase was washed with brine (150 mL), dried over Na ₂ SO ₄ and concentrated to give a residue that was purified by column chromatography (SiCh, PE:EA = 50: 1 to 10: 1) to provide 69 (1.7 g, 71.24% yield) as a lightyellow solid.

[0209] A solution of 69 (1.7 g, 8.58 mmol) in HC1 (10 mL) and MeOH (10 mL) was stirred at 80 °C for 2 hrs. The mixture was diluted with water (100 mL) and extracted with EA (3 x 80 mL). The combined organic phase was washed with brine (150 mL), dried over Na2SO4 and concentrated to give a residue which was purified by column chromatography (SiCh, PE:EA = 50: 1 to 5:1) to give 70 (1 g, 50.42% yield) as a yellow solid.

[0210] A mixture of 70 (400 mg, 1.73 mmol), tert-butyl piperazine- 1 -carboxylate (483.67 mg, 2.60 mmol), Cs ₂ CO ₃ (1.13 g, 3.46 mmol), Pd(OAc)2 (58.30 mg, 259.69 umol) and [l-(2-diphenylphosphanyl-l-naphthyl)-2-naphthyl]-diphenyl-ph osphane (161.70 mg, 259.69 umol) in dioxane (8 mL) was degassed and purged with N2 (3x). The mixture was stirred at 100 °C for 12 hrs under N ₂ atmosphere. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 20: 1 to 1 :1) to obtain 71 (220 mg, 37.78% yield) as a yellow solid.

[0211] A mixture of 71 (200 mg, 594.56 pmol), methanamine (1.32 g, 42.50 mmol, 2 mL, 71.49) in MeOH (2 mL) was stirred at 25 °C for 3 hrs under N2 atmosphere. The mixture was concentrated to give the product which was used in the next step directly without further purification. Compound 72 (150 mg, 75.22% yield) was obtained as a pink solid.

[0212] A mixture of 72 (150 mg, 447.23 pmol) in HCl/EtOAc (4 mL) was stirred at 25 °C for 2 hrs. The mixture was concentrated to give the product which was used in the next step directly without further purification. Compound 73 (80 mg, 76.03% yield) was obtained as a pink solid. ’H NMR: (400 MHz, DMSO-t/6) 8 9.48 (br s, 2H), 8.68 (br d, J = 4.6 Hz, 1H), 8.48 (s, 1H), 3.27 (br s, 8H), 2.79 (d, J = 4.9 Hz, 3H), 2.51 (br s, 3H).

[0213] To a solution of 73 (80 mg, 294.39 pmol, HC1) and 7-(chloromethyl)-3-ethyl - lH-quinazoline-2, 4-dione (70.26 mg, 294.39 pmol) in MeCN (0.5 mL) were added DIEA (190.24 mg, 1.47 mmol, 256.39 pL) and NaBr (90.87 mg, 883.18 pmol, 28.37 pL) at 25 °C. The mixture was stirred at 80 °C for 2 hrs and then concentrated to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition, Phenomenex Luna C18 75 x 30 mm x 3 um; Mobile Phase: [water (FA)-CH3CN]; B%: l%-40%,8 min.) to obtain A22 (46.6 mg, 32.74% yield, FA salt) was obtained as a yellow solid. ’H NMR: (400 MHz, DMSO-t/6) 6 11.39 (s, 1H), 8.62 (br d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.26-7.11 (m, 2H), 3.92 (q, J = 7.0 Hz, 2H), 3.62 (s, 2H), 3.06 (br s, 4H), 2.78 (d, J = 4.9 Hz, 3H), 2.58 (br s, 4H), 2.48 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H)

Example 19 Additional Compounds

[0214] Additional compounds of Formula (I) can be prepared using similar materials and methods described herein, such as those described herein.

(including stereoisomer and/or pharmaceutically acceptable salts of any of the foregoing). Example A PARP Assay

FP binding assay (PARPL PARP2)

[0215] The PARP1 and PARP 2 protein and the PARPi-FL were purchased from BPS Bioscience. The assay buffer was 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCh, 150 mM NaCl. The compounds were diluted into top point concentration in 384PP-plate and transferred serially into an Optiplate-384F plate. Compound (20 nL) or DMSO was added to assay plate and then 10 uL of 40 nM PARP1 or PARP2 (diluted using assay buffer) was added. The assay plate was centrifuged at 1000 rpm for 1 min and then incubated for 30 min at rt. 6 nM PARPi-FL (diluted using assay buffer) (10 uL) was added to the plate (final concentration of PARP1 and PARP2 was 20nM, and PARPi-FL was 3 nM). After centrifuging at 1000 rpm for 1 min, the assay plate was incubated at rt 4 h. The plates were read using Envision with Excitation filter. The data analysis was done by calculating the inhibition rate using mP value using the following equation. Inhibition (%) = (l-mpC-mpL)/mpH-mpL XI 00%. Compound Al had an PARP1 ICso of < 0.01 μM.

Proliferation Assay (PARP inhibitors) in DLD-1 wt and DLD-1 BRCA2

[0216] DLD-1 -wt and DLD-1 mutant cells are cultured in RPMI 1640+10%FBS+l%PS. The cells are harvested into culture media for 2-3 days. The cells are diluted into culture media (density 2~3 x 10 ⁶ ) and 40 uL of cell suspension (50 cells/well for DLD-1 wt and 50 cells/well for DLD-1 BRCA (-/-). The plates are covered and spun at rt at 1000 rpm, for 1 minute and then transferred. The plates are placed into 37 °C 5% CO2 incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution and then 40 uL of stock solution is transferred to a 384 PP-plate. A 10-point dilution is carried out by transferring 10 uL compound into 30 pL DMSO by using TECAN (EV0200) liquid handler. The plates are spun at rt at 1000 rpm for 1 minute and then shaken on a plate shaker for 2 minutes. Forty nL of diluted compound is transferred into the cell plate by using a liquid handler. After 7 days of incubation, a CTG detection assay is performed. The CTG detection assay is carried out by removing the plates from the incubators and then equilibrated at rt for 15 minutes. The CellTiter Gio reagents are thawed and equilibrated at rt. CellTiter-Glo reagent (30 pL) is added into each well, and the plates are placed at rt for 30 minutes followed by reading on EnVision. The inhibition activity is calculated using the formula: % Inhibition = 100 x (LumHC - LumSample) / (LumHC -LumLC). The results of the assay are provided in Table 2. In Table 2, ‘A’ indicates an ICso of < 0. 1 μM, ‘B’ indicates an IC50 of > 0. 1 μM and < 1.0 μM, and ‘C’ indicates an IC50 of> 1.0 μM.

[0217] As shown by the results of both assays, compounds of Formula (I), including pharmaceutically acceptable salts thereof, are effective PARP1 inhibitors.

Table 2

[0218] 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.