TW202340166A - Multicyclic compounds - Google Patents

Abstract

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

Description

Polycyclic compounds

This application is in the fields of chemistry, biochemistry and medicine. Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing compounds described herein (including pharmaceutically acceptable salts of compounds described herein) and methods for their synthesis. Also disclosed herein are methods of treating diseases and/or conditions using compounds of Formula (I) or pharmaceutically acceptable salts thereof.

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 bronchial cancer, prostate cancer, colon and rectal cancer, skin melanoma, bladder cancer, non-Hodgkin lymphoma, kidney and renal pelvis cancer, endometrial cancer, Leukemia, pancreatic cancer, thyroid cancer and liver cancer.

Some embodiments disclosed herein relate to compounds of formula (I) or pharmaceutically acceptable salts thereof.

Some embodiments disclosed herein relate to pharmaceutical compositions that may contain an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments described herein are directed to methods of treating a cancer described herein, which may comprise administering to a subject having a cancer described herein an effective amount of a compound described herein (e.g., a compound of Formula (I) or its a pharmaceutically acceptable salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to using an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The use of pharmaceutical compositions of the above acceptable salts) for the manufacture of medicaments for the treatment of cancer as described herein. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). pharmaceutical compositions of the above acceptable salts) for use in the treatment of cancers described herein.

Some embodiments described herein are directed to methods of inhibiting the growth of malignant growths or tumors, which may comprise contacting the growths or tumors with an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable compound thereof). salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is caused by a cancer described herein. Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Acceptable salts) of a pharmaceutical composition for the manufacture of a medicament for inhibiting the growth of malignant growths or tumors, wherein the malignant growths or tumors are caused by cancer as described herein. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The above acceptable salts) pharmaceutical compositions for inhibiting the growth of malignant growths or tumors, wherein the malignant growths or tumors are caused by cancer as described herein.

Some embodiments described herein are directed to methods of treating cancers described herein, which may include exposing a malignant growth or tumor in a subject having a cancer described herein with an effective amount of a compound described herein (e.g., formula ( I) compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The use of a pharmaceutical composition of an acceptable salt) for the manufacture of a medicament for the treatment of a cancer as described herein (which may include exposure to a malignant growth or tumor as described herein), wherein the malignant growth or tumor is a Caused by cancer. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). a pharmaceutical composition of an acceptable salt thereof) for use in the treatment of a cancer as described herein (which may include exposure to a malignant growth or tumor), wherein the malignant growth or tumor is caused by a cancer as described herein.

Some embodiments described herein are directed to methods of inhibiting PARP1 activity in a cell, which may comprise providing to cancer cells from a cancer described herein an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable compound thereof). an acceptable salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). acceptable salt) for the manufacture of pharmaceutical agents for inhibiting PARP1 activity. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). above acceptable salts), which is used to inhibit PARP1 activity.

Some embodiments described herein are directed to methods of treating cancers described herein, which may comprise using an effective amount of a compound described herein (eg, a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprising Pharmaceutical compositions of compounds (eg, compounds of formula (I) or pharmaceutically acceptable salts thereof) inhibit PARP1 activity. Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Acceptable salt) of a pharmaceutical composition for the manufacture of a medicament for treating cancer as described herein by inhibiting PARP1 activity. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). (above acceptable salts) for use in treating cancers described herein by inhibiting PARP1 activity.

These and other embodiments are described in greater detail below.

The accumulation of DNA damage that is not repaired over a period of time can lead to the development of cancer. Poly(ADP-ribose) polymerase (PARP1/2) is an enzyme that senses DNA damage and adds branched PAR chains to promote DNA repair. PARP inhibitors are a class of small molecules that inhibit PARP1 and PARP2 and have been approved as cancer drugs for tumors with BRCA1/2 mutations.

Although PARP1 can be considered the primary target of PARP inhibitors, currently approved PARP inhibitors also inhibit PARP2 and PARP3. In addition to its DNA repair role, PARP1 also has other biological roles, including regulating the transcription of several genes related to some cancers. Inhibiting PARP1 using PARP1-selective small molecules could potentially overcome some of the major toxicities observed with current PARP1/2 inhibitors and provide significant benefits to cancer patients.

Poly(ADP-ribose) polymerase (PARP) 1/2 Poly inhibitors selectively kill cancer cells with homologous recombination repair pathway defects and have been approved for ovarian cancer, metastatic breast cancer, and prostate cancer. Although clinical studies have demonstrated antitumor activity of PARP1/2 inhibitors in tumors with BRCA1/2 mutations, patients with other cancers with altered DNA damage repair pathways may also benefit from PARP inhibitors. Mutations in DNA damage repair pathways have been observed in numerous tumor types, suggesting that PARP1/2 inhibitors may potentially have anti-tumor activity in several cancer types.

Although PARP inhibitors have shown antitumor activity, adverse events seen in patients treated with PARP1/2 inhibitors require dose reduction and discontinuation of PARP1/2 inhibitors. It is believed that the adverse events of PARP1/2 inhibitors result from PARP2 inhibition, so potent and selective small molecules of PARP1 may retain anti-tumor activity and potentially minimize the adverse events observed with current PARP1/2 inhibitors. definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, the entire contents of all patents, applications, published applications and other publications mentioned herein are incorporated by reference. Unless otherwise stated, in the event there are multiple definitions for a term herein, the definitions in this section shall prevail.

Whenever a group is stated as "optionally substituted," the group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted," if substituted, the substituent may be selected from one or more of the indicated substituents. If no substituent is indicated, it is intended that the indicated "optionally substituted" or "substituted" group may be individually and independently selected from the following groups by one or more (e.g., 1, 2 or 3) Substitution: deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-thioamineformyl, N-thio Aminoformamide group, C-amide group, N-amide group, S-sulfonamide group, N-sulfonamide group, C-carboxyl group, O-carboxyl group, C-amide group (alkyl), iso Cyanate group, thiocyanate group, nitro group, azido group, silicone group, sulfide group, sulfinyl group, sulfonyl group, haloalkyl group, haloalkoxy group, trihalomethanesulfonyl group, trihalomethane Sulfonamide, amine, monosubstituted amine and disubstituted amine.

As used herein, "C _a to C _b " (where "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or cycloalkyl, cycloalkenyl, The number of carbon atoms in the ring of an aryl, heteroaryl or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring or heterocyclyl ring may contain "a" to "b" ( Contains "a" and "b") carbon atoms. Thus, for example, "C ₁ to C ₄ alkyl" refers to all alkyl groups having 1 to 4 carbons, that is, CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH (CH ₃ )-, and (CH ₃ ) ₃ C-. If "a" and "b" are not specified with respect to alkyl, alkenyl, alkynyl, cycloalkylcycloalkenyl, aryl, heteroaryl or heterocyclyl, the broadest range set forth in those definitions is assumed .

As used herein, "alkyl" refers to straight or branched hydrocarbon chains including fully saturated (no double or triple bonds) hydrocarbon radicals. An alkyl group may have 1 to 20 carbon atoms (wherever it appears herein, a numerical range (e.g., "1 to 20") refers to each integer in the stated range; for example, "1 to 20 carbon atoms" means Refers to an alkyl group that can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also covers the term "alkyl" in which an unspecified numerical range appears. Alkyl groups can also It is a medium-sized alkyl group with 1 to 10 carbon atoms. The alkyl group can also be a lower alkyl group with 1 to 6 carbon atoms. The alkyl group of the compound can be designated as "C ₁ -C ₄ alkyl" or Similar designations. By way of example only, "C ₁ -C ₄ alkyl" indicates the presence of 1 to 4 carbon atoms in the alkyl chain, i.e. the alkyl chain system is selected from methyl, ethyl, propyl, isopropyl , n-butyl, isobutyl, second butyl and third butyl. Typical alkyl groups include (but are by no means limited to) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Tributyl, pentyl and hexyl. Alkyl groups may be substituted or unsubstituted.

As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The length of the alkenyl group can vary. For example, the alkenyl group may be C _2-4 alkenyl, C _2-6 alkenyl, or C _2-8 alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and vinyl. Alkenyl groups may be unsubstituted or substituted.

As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. The length of the alkynyl group can vary. For example, the alkynyl group may be C _2-4 alkynyl, C _2-6 alkynyl, or C _2-8 alkynyl. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted.

As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bonds) mono- or poly-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or spiro manner. Cycloalkyl groups may contain 3 to 10 atoms in the ring, 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring. Cycloalkyl groups may be unsubstituted or substituted. Typical cycloalkyl groups include, but are by no means limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, "cycloalkenyl" refers to a mono- or poly-cyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one is present, the double bonds may not extend through all of them. The ring forms a fully electron-shifted pi electron system (otherwise the group may be an "aryl" group as defined herein). When composed of two or more rings, the rings may be linked together in a fused or spiro manner. Cycloalkenyl groups may contain 3 to 10 atoms in the ring or 3 to 8 atoms in the ring. Cycloalkenyl groups may be unsubstituted or substituted.

As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two Carbon rings share chemical bonds). The number of carbon atoms in the aryl group can vary. For example, the aryl group may be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups may be substituted or unsubstituted.

As used herein, "heteroaryl" means one or more heteroatoms (e.g., 1 to 5 heteroatoms) containing one or more heteroatoms (i.e., elements other than carbon, including (but not limited to) nitrogen, oxygen, and Sulfur) monocyclic, bicyclic and tricyclic aromatic ring systems (ring systems with a complete electron shift π electron system). The number of ring atoms in a heteroaryl group may vary. For example, a heteroaryl group can contain 4 to 14 ring atoms, 5 to 10 ring atoms, or 5 to 6 ring atoms. Additionally, the term "heteroaryl" encompasses fused ring systems in which two rings (eg, 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, furoxan, 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, benzopyridine Azole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pterin, quinoline, isoquin quinazoline, quinoxaline, azoline and triazine. Heteroaryl groups may be substituted or unsubstituted.

As used herein, "heterocyclyl" refers to monocyclic, bicyclic and tricyclic ring systems in which carbon atoms and 1 to 5 heteroatoms make up the ring system. Heterocycles may optionally contain one or more unsaturated bonds positioned in a manner such that the completely delocalized π-electron system does not occur in all rings. The number of atoms in the ring of a heterocyclyl group can vary. For example, a heterocyclyl group may contain 4 to 14 ring atoms, 5 to 10 ring atoms, or 5 to 6 ring atoms. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. Heterocycles may further contain one or more carbonyl or thiocarbonyl functional groups, such that this definition includes pendant oxy systems as well as thio systems, such as lactams, lactones, cyclic imines, cyclic thioesters Imines and cyclic carbamates. When composed of two or more rings, the rings may be fused together. In addition, any nitrogen in the heterocyclyl group can be quaternary ammonized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such "heterocyclyl groups" include (but are not limited to) 1,3-dioxane, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane , 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiazine, 1,3-oxothiazine, 1,3- Dithiolane, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, horse Lesimide, succinimide, barbituric acid, thiobarbituric acid, dioxyhexahydropyrazine, hydantoin, dihydrouracil, trioxane, hexahydropyrazine, 3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, ethylene oxide, Hexahydropyridine N -oxide, hexahydropyridine, hexahydropyrazine, pyrrolidine, pyrrolidone, pyrrolidinone, 4-hexahydropyridinone, pyrazoline, pyrazolidine, 2-pentanoxypyrrolidine, Tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, thiomorpholinoxide, thiomorpholinoid and their benzo-fused analogues (e.g., benzimidazolidinone, tetrahydroquinol pholine and 3,4-methylenedioxyphenyl).

As used herein, "cycloalkyl (alkyl)" refers to a cycloalkyl group linked as a substituent via a lower carbon alkylene group. The lower alkylene and aryl groups of the cycloalkyl (alkyl) group may be substituted or unsubstituted. Examples include, but are not limited to, cyclopropyl-CH ₂ -, cyclobutyl- _{CH 2} -, cyclopentyl-CH ₂ -, cyclohexyl-CH ₂ -, cyclopropyl-CH ₂ CH ₂ -, cyclobutyl Base -CH ₂ CH ₂ -, cyclopentyl -CH ₂ CH ₂ -, cyclohexyl -CH ₂ CH ₂ -, cyclopropyl -CH ₂ CH ₂ CH ₂ -, cyclobutyl -CH ₂ CH ₂ CH ₂ - , cyclopentyl-CH ₂ CH ₂ CH ₂ -, cyclohexyl-CH ₂ CH ₂ CH ₂ -, cyclopropyl-CH ₂ CH ₂ CH ₂ CH ₂ -, cyclobutyl-CH ₂ CH ₂ CH ₂ CH ₂ -, cyclopentyl-CH ₂ CH ₂ CH ₂ CH ₂ - and cyclohexyl-CH ₂ CH ₂ CH ₂ CH ₂ -.

As used herein, "aryl (alkyl)" refers to an aryl group linked as a substituent via a lower alkylene group. The lower alkylene group and aryl group of the aryl group (alkyl group) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl).

As used herein, "heteroaryl(alkyl)" refers to a heteroaryl group attached as a substituent via a lower carbon alkylene group. The lower alkylene group and heteroaryl group of the heteroaryl (alkyl) group 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) base), isoxazolyl (alkyl), imidazolyl (alkyl) and their benzo-fused analogues.

"Heterocyclyl (alkyl)" refers to a heterocyclic group linked via a low-carbon alkylene group as a substituent. The lower carbon alkylene group and heterocyclyl group of the heterocyclyl group (alkyl group) may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), hexahydropyridin-4-yl (ethyl), hexahydropyridin-4-yl (propyl), tetrahydropyridin-4-yl (propyl), tetrahydropyran-4-yl (methyl), 2H-Thiopyran-4-yl (methyl) and 1,3-thiazin-4-yl (methyl).

A "lower alkylene group" is a straight-chain _-CH2 -tethering group, thereby forming a bond connecting the molecular fragments via their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), and butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -). A lower alkylene group may be substituted by using one or more hydrogens of the lower alkylene group as a substituent listed under the definition of "substituted." Additionally, when a lower alkylene group is substituted, the lower alkylene group can be substituted by using a cycloalkyl group in place of two hydrogens on the same carbon (e.g. ).

As used herein, "alkoxy" refers to the formula -OR, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, as defined herein base, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, 2-butoxy group, tert-butoxy group, phenoxy group and benzyloxy group. In some cases, alkoxy can be -OR, where R is unsubstituted C _1-4 alkyl. Alkoxy groups may be unsubstituted or substituted.

As used herein, "carboxyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aromatic group attached as a substituent via a carbonyl group. base (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). Examples include formyl, acetyl, propyl, butyl and acryl. The acyl group may be substituted or unsubstituted.

As used herein, "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl groups. Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. Hydroxyalkyl groups may be substituted or unsubstituted.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen (eg, mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. Haloalkyl groups may be substituted or unsubstituted.

As used herein, "haloalkoxy" refers to O-alkyl and O-monocyclic cycloalkyl groups in which one or more hydrogen atoms are replaced by halogen (e.g., mono-haloalkoxy, di-haloalkoxy and Tri-haloalkoxy). These groups include (but are not limited to) chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy , chlorine-substituted cyclopropyl, fluorine-substituted cyclopropyl, chlorine-substituted cyclobutyl and fluorine-substituted cyclobutyl. In some cases, haloalkoxy can be -OR, where R is C _1-4 alkyl substituted with 1, 2, or 3 halogens. Haloalkoxy groups may be substituted or unsubstituted.

"Sulfylene" refers to the "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aromatic base (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). The thiooxyl group may be substituted or unsubstituted.

"Sulfinyl" refers to a "-S(=O)-R" group, where R can be the same as defined for a thiooxyl group. The sulfinyl group may be substituted or unsubstituted.

"Sulfonyl" refers to a "SO ₂ R" group, where R may be as defined with respect to a thiooxyl group. The sulfonyl group may be substituted or unsubstituted.

"O-carboxy" refers to the group "RC(=O)O-", where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, as defined herein, Heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The O-carboxy group may be substituted or unsubstituted.

The terms "ester" and "C-carboxy" refer to the "-C(=O)OR" group, where R can be the same as defined for O-carboxy. The ester and C-carboxy groups may be substituted or unsubstituted.

"Thiocarbonyl" refers to a "-C(=S)R" group, where R may be as defined for O-carboxy. The thiocarbonyl group may be substituted or unsubstituted.

"Trihalomethanesulfonyl" refers to the "X ₃ CSO ₂ -" group, where each X is a halogen.

"Trihalomethanesulfonamide" refers to the group "X ₃ CS(O) ₂ N( _RA )-", where each X is halogen, and R _A is hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

The term "amine" as used herein refers to the -NH ₂ group.

The term "hydroxyl" as used herein refers to the -OH group.

"Cyano" refers to the "-CN" group.

As used herein, the term "azido" refers to an -N ₃ group.

"Isocyanato" refers to the "-NCO" group.

"Thiocyanato" refers to the "-CNS" group.

"Isothiocyanato" refers to the "-NCS" group.

"Sulfhydryl" refers to the "-SH" group.

"Carbonyl" refers to the -C(=O)- group.

"S-Sulfonamide group" refers to the "-SO ₂ N (R _A R _B )" group, where R _A and R _B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The S-sulfonamide group may be substituted or unsubstituted.

"N-Sulfonamide" refers to the group "RSO ₂ N( _RA )-", where R and _RA can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-sulfonamide group may be substituted or unsubstituted.

"O-Aminomethyl" refers to the "-OC(=O)N(R _A R _B )" group, where R _A and R _B can independently be hydrogen, alkyl, alkenyl, alkynyl, cyclo Alkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The O-aminoformyl group may be substituted or unsubstituted.

"N-Aminoformyl" refers to the "ROC(=O)N(RA ₎ -" group, where R and R _A can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, Cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). N-Aminoformyl may be substituted or unsubstituted.

"O-Thioaminemethyl" refers to the "-OC(=S)-N(R _A R _B )" group, where R _A and R _B can independently be hydrogen, alkyl, alkenyl, or alkyne base, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The O-thiocarbamoyl group may be substituted or unsubstituted.

"N-Thioaminoformyl" refers to the "ROC(=S)N( _RA )-" group, where R and R _A can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl radical, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). N-Thiocarbamide group may be substituted or unsubstituted.

"C-amide group" refers to the "-C(=O)N(R _A R _B )" group, where R _A and R _B can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl base, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The C-amide group may be substituted or unsubstituted.

"N-amide group" refers to the "RC(=O)N( _RA )-" group, where R and _RA can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, Alkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). The N-amide group may be substituted or unsubstituted.

"Monosubstituted amine" means " _-NHRA ", where R _A can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), heteroaryl (alkyl) or heterocyclyl (alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, the monosubstituted amine can be _-NHRA , where _RA can be unsubstituted C _1-6 alkyl or unsubstituted or substituted benzyl.

"Disubstituted amine" refers to "-NR _A R _B ", where R _A and _RB can independently be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, hetero Cyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). Monosubstituted amines may be substituted or unsubstituted. In some cases, the monosubstituted amine can be -NR _ARB , where _RA and _RB can independently be unsubstituted C _1-6 alkyl _or unsubstituted or substituted benzyl.

"Ketoamide" refers to the "-C(=O)N(R _A R _B )" group, where R _A and R _B can independently be hydrogen, alkyl, alkenyl, alkynyl, or cycloalkyl , cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). Ketamides may be substituted or unsubstituted.

The term "halogen atom" or "halogen" as used herein means any of the radiostable atoms in row 7 of the periodic table of elements, such as fluorine, chlorine, bromine and iodine.

If the number of substituents (eg haloalkyl) is not specified, one or more substituents may be present. For example, "haloalkyl" may contain one or more halogens that may be the same or different. As another example, "C ₁ -C ₃ alkoxyphenyl" may include one or more the same or different alkoxy groups containing 1, 2 or 3 atoms.

As used herein, unless otherwise indicated, abbreviations for any protecting groups, amino acids, and other compounds are based on common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 11:942-944 (1972)).

The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate 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 compounds with inorganic acids such as hydrohalic acids (eg, hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be prepared by combining the compound with an organic acid such as an aliphatic or aromatic carboxylic acid or a sulfonic acid such as formic acid, acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, etc. acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid or naphthalenesulfonic acid). Pharmaceutical salts can also be obtained by reacting a compound with a base to form salts such as ammonium salts; alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; organic bases. Salts such as dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine, C ₁ -C ₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine; and with e.g. Salts of amino acids such as arginine and lysine.

Unless otherwise expressly stated, the terms and phrases used in this application, especially in the appended patent scope, and their variations should be understood as open-ended rather than restrictive. As an example of the foregoing description, the term "includes" should be read to mean "includes (without limitation)," "includes (but is not limited to)," or the like; as used herein, the term "includes" is the same as "includes," "contains." or "characterized by" is synonymous with, is inclusive or open-ended and does not exclude other elements or method steps not listed; the term "having" should be interpreted as "at least having"; the term "includes" should be interpreted as "including (but not "Limited to)"; the term "Examples" is used to provide illustrative examples of the items discussed and is not an exhaustive or limiting list thereof. In addition, the term "including" shall be interpreted to have the same meaning as the phrase "at least having" or "at least including". When used in the context of a compound or composition, the term "comprising" means that the compound or composition contains at least the recited features or components, but may also contain other features or components.

With respect to the use of substantially any plural and/or singular term herein, one skilled in the art may convert the plural into the singular and/or the singular into the plural as appropriate to the context and/or application. For the sake of clarity, various singular/plural permutations may be explicitly stated. The indefinite article "a (a or an)" does not exclude the plural.

It will be understood that in any compound described herein having one or more chiral centers, each center may independently be in the (R)-configuration or the (S)-configuration, unless the absolute stereochemistry is explicitly indicated. or mixtures thereof. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomers mixture. Additionally, it should be understood that in any compound described herein that has one or more double bonds that can be defined as E or Z to form geometric isomers, each double bond can independently be E or Z or a mixture thereof. Likewise, it is to be understood that in any compound illustrated, all tautomeric forms are also intended to be included.

It will be understood that if a compound disclosed herein has unfilled valencies, hydrogen or its isotopes (eg, hydrogen-1 (protium) and hydrogen-2 (deuterium)) are used to fill those valencies.

It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Each chemical element as represented in a compound structure may contain any isotope of that element. For example, in a compound structure, hydrogen atoms may be explicitly revealed or understood to be present in the compound. Wherever a hydrogen atom may be present in a compound, the hydrogen atom may be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, references herein to a compound encompass all potential isotopic forms unless the context clearly indicates otherwise.

When a range of values is provided, it is understood that the upper and lower limits, as well as every intervening value between the upper and lower limits of the range, are encompassed within the embodiments. compound

Some embodiments disclosed herein relate to compounds of formula (I) or pharmaceutically acceptable salts thereof: Among them: Ring A can be selected from pyrrole, thiophene, pyridine and phenyl, wherein pyrrole, thiophene, pyridine and phenyl can be substituted as appropriate, and when substituted, each can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkoxy and unsubstituted C _1-4 The haloalkyl group is partially substituted 1 or more times; ring B can be selected from the group consisting of 6-membered monocyclic nitrogen-containing heterocyclyl, 7-membered bicyclic nitrogen-containing heterocyclyl and 8-membered bicyclic nitrogen-containing heterocyclyl; n can be 0 or 1; When n is 0, ring C can be an unsubstituted or substituted aryl group, an unsubstituted or substituted monocyclic heteroaryl group, or an unsubstituted or substituted aryl group. , among which in aryl, heteroaryl and When substituted, aryl, heteroaryl and Can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _3-6 cycloalkyl and unsubstituted C _{1- 4} haloalkyl partially substituted 1 or more times; ring D1 can be phenyl, 5-membered heteroaryl or 6-membered heteroaryl; ring D2 can be selected from unsubstituted or substituted , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded and unsubstituted or superseded , where the asterisk indicates the point of connection with ring D1; where n is 1, ring C can be selected from pyrrole, thiophene, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and phenyl, where pyrrole, thiophene, thiazole, Pyridine, pyridazine, pyrimidine, pyrazine and phenyl are optionally substituted, and when substituted, each may be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _{1- 4} haloalkyl partially substituted 1 or more times; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, Unsubstituted C _1-4 hydroxyalkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 ring Alkyl (unsubstituted C _1-4 alkyl), substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), unsubstituted monocyclic C _3-6 Cycloalkyl (unsubstituted C _1-4 alkenyl) and substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl), wherein substituted C _1-4 alkyl The base and the substituted monocyclic C _3-6 cycloalkyl group (unsubstituted C _1-4 alkyl group) can be substituted by 1 or more deuterium; R ² and R ³ can be independently hydrogen, deuterium or unsubstituted C _1-4 alkyl; or R ² and R ³ can form an unsubstituted or substituted monocyclic C _3-6 cycloalkyl group together with the carbon to which R ² and R ³ are connected; m1 can be 0, 1 Or 2; m2 can be 0, 1 or 2; R ^3a can be deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _{3 -6} cycloalkyl; R ^3b can be deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted Monocyclic C _3-6 cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen, unsubstituted Substituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted Monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) or unsubstituted bicyclic C _5-8 cycloalkyl (unsubstituted C _1-4 alkyl), wherein Substituted C _1-4 alkyl groups may be substituted by 1 or more deuteriums.

In some embodiments, Ring A can be pyrrole. In other embodiments, Ring A can be thiophene. In yet other embodiments, Ring A can be pyridine. In yet other embodiments, Ring A can be phenyl. Each of pyrrole, thiophene, pyridine and phenyl may be substituted one or more times with moieties (e.g. 1, 2 or 3 moieties) independently selected from: deuterium, halogen (e.g. F, Cl or Br), Unsubstituted C _1-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl), deuterium-substituted C _{1 -4} alkyl (including -CD ₃ , -CD ₂ H, -CDH ₂ , -CHDCH ₃ , -CH ₂ CHD ₂ , -CH ₂ CH ₂ D, -CHDCHD ₂ , -CHDCH ₂ D, -CD ₂ CHD ₂ , -CD ₂ CH ₂ D, -CH ₂ CD ₃ , -CD ₂ CH ₃ and -CD ₂ CD ₃ ,), unsubstituted C _1-4 alkoxy (such as methoxy, ethoxy, n- Propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy and third butoxy), unsubstituted C _1-4 haloalkoxy (such as -OCF ₃ , - OCCl ₃ , -OCHF ₂ , -OC(CH ₃ )F ₂ , -OCHCl ₂ , -OCH ₂ F , -OCH(CH ₃ )F, -OCH ₂ CF ₃ , -OCH ₂ Cl, -OCH ₂ CH ₂ F , -OCH ₂ CH ₂ Cl, -OCH ₂ CH ₂ CH ₂ F and -OCH ₂ CH ₂ CH ₂ Cl) and unsubstituted C _1-4 haloalkyl (including -CF ₃ , -CCl ₃ , -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F , -CH(CH ₃ )F , -CH ₂ CF ₃ , -CH ₂ Cl , -CH ₂ CH ₂ F , -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F and -CH ₂ CH ₂ CH ₂ Cl). Examples of Ring A include the following: and , where the asterisk indicates the point of attachment to the pyrimidine-2,4(1H,3H)-dione ring of formula (I). For example, in the ring A system When , the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the structure . In some embodiments, Ring A can be substituted once with halogen (F or Cl) or deuterium. As an example, Ring A may be substituted once by halogen (F or Cl) or deuterium. .

A variety of heterocycles can be present in Ring B. The heterocyclic group of Ring B may be monocyclic or bicyclic. When ring B is a bicyclic ring, the rings can be connected by fusion. In other cases, when Ring B is a bicyclic ring, the rings may be joined in a spiral manner. As provided herein, Ring B may contain a ring nitrogen. Other ring heteroatoms (eg other nitrogen, oxygen and/or sulfur) may 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 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.

In some embodiments, when m1 is 0, Ring B may be unsubstituted. In other embodiments, when m1 is 1 or 2, Ring B can be substituted with R ^3a . When Ring B is substituted, various substituents may be present. In some embodiments, Ring B may be substituted with a substituent selected from deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, or unsubstituted monocyclic ring C _3-6 cycloalkyl. Suitable halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl and unsubstituted monocyclic C _3-6 cycloalkyl are described herein, and include chlorine, fluorine, methyl base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, -CF ₃ , -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl _2. -CH ₂ F, -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F, - CH ₂ CH ₂ CH ₂ Cl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Exemplary Ring B groups include, but are not limited to, the following: and . In some embodiments, Ring B can be .

In some embodiments, n can be 0; and ring C can be , whereby the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the structure . In some embodiments, May not be replaced. In other embodiments, can be replaced, among which Can be substituted 1 or more times (e.g. 1, 2, 3 or 4 times) with moieties independently selected from: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl , unsubstituted C _3-6 cycloalkyl (such as monocyclic C _3-6 cycloalkyl) and unsubstituted C _1-4 haloalkyl. Suitable halogens, C _1-4 alkyl, C _3-6 cycloalkyl and C _1-4 haloalkyl are described herein. For example, Can be substituted 1 or more times (e.g. 1, 2, 3 or 4 times) with moieties independently selected from the following: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, second butyl, third butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF ₃ , -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F, -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F, and -CH ₂ CH ₂ CH ₂ Cl.

As provided herein, Ring D1 can be phenyl, 5-membered heteroaryl, or 6-membered heteroaryl. In some embodiments, Ring D1 can be phenyl. In other embodiments, Ring D1 can be a 5-membered heteroaryl. In yet other embodiments, Ring D1 can be a 6-membered heteroaryl. The heteroaryl group of ring D1 may contain 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). A non-limiting list of heteroaryl groups in ring D1 includes pyridine, thiophene, furan and pyrrole. In some embodiments, Can be selected from and .

A variety of monocyclic heterocyclyl groups can be present in ring D2. In some embodiments, ring D2 can be . In other embodiments, ring D2 may be . In yet other embodiments, ring D2 may be . In yet other embodiments, ring D2 may be . In some embodiments, ring D2 can be . In other embodiments, ring D2 may be . In yet other embodiments, ring D2 may be . For each ring D2 portion shown, an asterisk indicates the connection point to ring D1. Examples include the following: and , each of which may be independently selected from the group consisting of partially substituted 1 or more times (e.g. 1, 2 or 3 times) deuterium, halogen (e.g. F, Cl or Br), unsubstituted C _1-4 alkane groups (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl) and unsubstituted C _1-4 haloalkyl (including -CF _3. -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F , -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl , -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F and -CH ₂ CH ₂ CH ₂ Cl).

In some embodiments, n can be 0; and Ring C can be unsubstituted aryl. In other embodiments, n can be 0; and Ring C can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted Partially substituted substituted aryl groups of C _3-6 cycloalkyl and unsubstituted C _1-4 haloalkyl substituted one or more times (eg 1, 2 or 3 times). For example, Ring C can be unsubstituted or substituted phenyl. When ring C is a substituted phenyl group, the phenyl group can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _{3- 6} cycloalkyl and unsubstituted C _1-4 haloalkyl are partially substituted 1, 2 or 3 times. In still other embodiments, n can be 0; and Ring C can be unsubstituted monocyclic heteroaryl. In yet other embodiments, n can be 0; and Ring C can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted Partially substituted C _3-6 cycloalkyl (such as monocyclic C _3-6 cycloalkyl) and unsubstituted C _1-4 haloalkyl substituted 1 or more times (such as 1, 2 or 3 times) Monocyclic heteroaryl. An example of a suitable aryl group may be unsubstituted or substituted phenyl. Exemplary monocyclic heteroaryls of Ring C may be 5- or 6-membered monocyclic heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N (nitrogen), O (oxygen), and S (sulfur) base. A non-limiting list of monocyclic heteroaryls of ring C includes pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, pyrimidine and pyrazine. When aryl and/or heteroaryl are substituted, suitable moieties include deuterium, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl , tertiary butyl, -CD ₃ , -CD ₂ H, -CDH ₂ , -CHDCH ₃ , -CH ₂ CHD ₂ , -CH ₂ CH ₂ D, CHDCHD ₂ , -CHDCH ₂ D, -CD ₂ CHD ₂ , -CD ₂ CH ₂ D, -CH ₂ CD ₃ , -CD ₂ CH ₃ , -CD ₂ CD ₃ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF ₃ , -CHF ₂ , -C (CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F, -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, - CH ₂ CH ₂ CH ₂ F and -CH ₂ CH ₂ CH ₂ Cl.

In some embodiments, n can be 1, and ^R4 can be C-amide. In some embodiments, Ring C can be pyrrole. In other embodiments, Ring C can be thiophene. In yet other embodiments, Ring C can be thiazole. In yet other embodiments, Ring C can be pyridine. In some embodiments, Ring C can be pyridazine. In other embodiments, Ring C can be pyrimidine. In yet other embodiments, Ring C can be pyrazine. Example rings of ring C are as follows: and .

Other moieties may be present on ring C. Suitable moieties that may be present on ring C include (but are not limited to) deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl , unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl. In some embodiments, Ring C may be substituted 1 or more times (eg, 1, 2, or 3 times) with moieties independently selected from: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _{1 -4} haloalkyl. In some embodiments, Ring C can be substituted 1 or more times (eg, 1, 2, or 3 times) with moieties independently selected from: F, Cl, Br, methyl, ethyl, n-propyl, isopropyl base, n-butyl, isobutyl, second butyl, third butyl, -CD ₃ , -CD ₂ H , -CDH ₂ , -CHDCH ₃ , -CH ₂ CHD ₂ , -CH ₂ CH ₂ D, -CHDCHD ₂ , -CHDCH ₂ D , -CD ₂ CHD ₂ , -CD ₂ CH ₂ D , -CH ₂ CD ₃ , -CD ₂ CH ₃ , -CD ₂ CD ₃ , vinyl, propenyl, butenyl, Cyclopropyl-CH ₂ -, cyclobutyl-CH ₂ -, cyclopentyl-CH 2 -, cyclohexyl-CH _{2 -} , cyclopropyl-CH ₂ CH ₂ -, cyclobutyl-CH ₂ CH ₂ - , cyclopentyl-CH ₂ CH ₂ -, cyclohexyl-CH ₂ CH ₂ -, cyclopropyl-CH ₂ CH ₂ CH ₂ -, cyclobutyl-CH ₂ CH ₂ CH ₂ -, cyclopentyl-CH ₂ CH ₂ CH ₂ -, cyclohexyl-CH ₂ CH ₂ CH ₂ -, cyclopropyl-CH ₂ CH ₂ CH ₂ CH ₂ -, cyclobutyl-CH ₂ CH ₂ CH ₂ CH ₂ -, cyclopentyl-CH ₂ CH ₂ CH ₂ CH ₂ -, cyclohexyl-CH ₂ CH ₂ CH ₂ CH ₂ -, -CF ₃ , -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F, -CH (CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl, -CH ₂ CH ₂ F, -CH ₂ CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F, and -CH ₂ CH ₂ CH ₂ Cl. In some embodiments, Ring C can be substituted once with a moiety provided herein, such as those provided in this paragraph. For example, Ring C can be substituted once with F, Cl or _-CD3 .

As provided herein, when n ^is 1, Ring C can be substituted with -C(=O) ^NR5R6 . In some embodiments, R ^can be hydrogen, such that Ring C can be substituted with -C(=O) ^NHR . In other embodiments, R ⁵ may be an unsubstituted C _1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, and third Tributyl. In some embodiments, Ring C can be substituted with -C(=O)N( _CH3 ) ^R6 . In some embodiments, ^R6 can be hydrogen. In other embodiments, R ⁶ may be unsubstituted C _1-4 alkyl. When R ⁶ is a deuterium-substituted C _1-4 alkyl group, one or more hydrogens (eg, 1, 2, 3, 4, 5 or 6 hydrogens) may be replaced by deuterium. Examples of deuterium-substituted C _1-4 alkyl groups for R ⁶ include -CD ₃ , -CD ₂ H, -CDH ₂ , -CHDCH ₃ , -CH ₂ CHD ₂ , -CH ₂ CH ₂ D, -CHDCHD ₂ , - CHDCH ₂ D, -CD ₂ CHD ₂ , -CD ₂ CH ₂ D, -CH ₂ CD ₃ , -CD ₂ CH ₃ , -CD ₂ CD ₃ . In yet other embodiments, R ⁶ may be deuterium-substituted C _1-4 alkyl. In still other embodiments, R ⁶ can be an unsubstituted monocyclic C _3-6 cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R ⁶ can be unsubstituted bicyclo C _5-8 cycloalkyl, such as bicyclo[1.1.1]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 each be hydrogen such that -C(=O)NR ⁵ R ⁶ is -C(=O)NH ₂ .

In some embodiments, when n is 1 and m2 is 0, Ring C may be unsubstituted (except -C(=O)NR ⁵ R ⁶ ). In other embodiments, when n is 1 and m2 is 1, Ring C can be substituted with an R ^3b group. In yet 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, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, or Unsubstituted monocyclic C _3-6 cycloalkyl. Exemplary moieties for each R ^3b may be deuterium, chlorine, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CD ₃ , -CD ₂ H, -CDH ₂ , -CHDCH ₃ , -CH ₂ CHD ₂ , -CH ₂ CH ₂ D, CHDCHD ₂ , -CHDCH ₂ D, -CD ₂ CHD ₂ , -CD ₂ CH ₂ D, - CH ₂ CD ₃ , -CD ₂ CH ₃ , -CD ₂ CD ₃ , -CF ₃ , CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F, -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl , -CH ₂ CH ₂ F , -CH ₂ CH ₂ Cl , -CH ₂ CH ₂ CH ₂ F , -CH ₂ CH ₂ CH ₂ Cl , cyclopropyl, cyclobutyl , cyclopentyl and cyclohexyl.

As provided herein, the nitrogen of pyrimidine-2,4(1H,3H)-dione may be unsubstituted or substituted. In some embodiments, ^R1 can be hydrogen. In other embodiments, R ¹ can be an unsubstituted C _1-4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third Tributyl. In some embodiments, R ¹ can be deuterium-substituted C _1-4 alkyl. Examples of deuterium-substituted C _1-4 alkyl groups include -CD ₃ , -CD ₂ H, -CDH ₂ , -CHDCH ₃ , -CH ₂ CHD ₂ , -CH ₂ CH ₂ D, -CHDCHD ₂ , -CHDCH ₂ D , -CD ₂ CHD ₂ , -CD ₂ CH ₂ D, -CH ₂ CD ₃ , -CD ₂ CH ₃ and -CD ₂ CD ₃ . In still other embodiments, R ¹ can be unsubstituted C _1-4 haloalkyl. For example, when R ¹ is an unsubstituted C _1-4 haloalkyl group, R ¹ can be -CF ₃ , -CHF ₂ , -C(CH ₃ )F ₂ , -CHCl ₂ , -CH ₂ F, -CH(CH ₃ )F, -CH ₂ CF ₃ , -CH ₂ Cl _, -CH ₂ CH ₂ F, -CH 2 CH ₂ Cl, -CH ₂ CH ₂ CH ₂ F, and -CH ₂ CH ₂ CH ₂ Cl . In still other embodiments, R ¹ can be unsubstituted C _1-4 hydroxyalkyl, such as -CH ₂ -OH, -CH ₂ CH ₂ -OH, -CH ₂ CH ₂ CH ₂ -OH and -CH ₂ CH ₂ CH ₂ CH ₂ -OH. In some embodiments, R ¹ can be unsubstituted monocyclic C _3-6 cycloalkyl. In other embodiments, R ¹ can be unsubstituted bicyclic C _5-8 cycloalkyl. In yet other embodiments, R ¹ can be unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl). In yet other embodiments, R ¹ can be deuterium-substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl). When R ¹ is deuterium-substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), one or more hydrogens (e.g., 1, 2, 3, 4, 5 or 6 hydrogens) Can be replaced by deuterium. Possible cycloalkyl groups that can exist in monocyclic C _3-6 cycloalkyl and monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) include cyclopropyl, cyclobutyl, cycloalkyl Pentyl and cyclohexyl. Exemplary bicyclo C _5-8 cycloalkyl groups that may be present in bicyclo C _5-8 cycloalkyl groups include, but are not limited to, bicyclo[1.1.1]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 ² and R ³ can each be hydrogen. In other embodiments, R ² and R ³ can each be deuterium. In other embodiments, R ² and R ³ may each be unsubstituted C _1-4 alkyl. For example, R ² and R ³ may be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl. In yet 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 unsubstituted C _1-4 alkyl. In some embodiments, R ² and R ³ may be taken together with the carbon to which R ² and R ³ are attached to form an unsubstituted or substituted monocyclic C _3-6 cycloalkyl group. For example, R ² and R ³ can be taken together with the carbon to which R ² and R ³ are attached to form unsubstituted or substituted cyclopropyl, unsubstituted or substituted cyclobutyl, unsubstituted or substituted cyclopentyl or unsubstituted or substituted cyclohexyl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following characteristics: Ring A may be phenyl; Ring B may be an unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocycle base; n can be 1; ring C can be selected from pyridine, pyrimidine and phenyl, wherein pyridine, pyrimidine and phenyl can each be optionally substituted by 1 or 2 moieties independently selected from the group consisting of: deuterium, halogen , unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; m1 can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or unsubstituted C _1-4 alkyl; R ^3b can be is deuterium, halogen or unsubstituted C _1-4 alkyl; R ⁴ is -C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ is Hydrogen, unsubstituted C _1-4 alkyl. In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following characteristics: Ring A may be pyridine; Ring B may be an unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocyclyl group ; n can be 1; Ring C can be selected from pyridine, pyrimidine and phenyl, wherein pyridine, pyrimidine and phenyl can each be replaced by 1 or 2 parts independently selected from the group consisting of: deuterium, halogen, Unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; m1 can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or unsubstituted C _1-4 alkyl; R ^3b can be Deuterium, halogen or unsubstituted C _1-4 alkyl; R ⁴ is -C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen , unsubstituted C _1-4 alkyl group. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following characteristics: Ring A may be phenyl; Ring B may be an unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocycle base; n can be 1; ring C can be selected from pyridine, pyrimidine and phenyl, wherein pyridine, pyrimidine and phenyl can each be optionally substituted by 1 or 2 moieties independently selected from the group consisting of: deuterium, halogen and unsubstituted C _1-4 alkyl; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently Hydrogen or deuterium; m1 can be 0, 1 or 2; m2 can be 0 or 1; R ^3a can be deuterium, halogen or unsubstituted C _1-4 alkyl; R ^3b can be deuterium, halogen or unsubstituted C _1-4 alkyl; R ⁴ is -C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen or unsubstituted C _{1 -4} alkyl. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following characteristics: Ring A may be phenyl; Ring B may be an unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocycle Base; n can be 1; Ring C can be selected from pyridine optionally partially substituted by 1 or 2 independently selected from the group consisting of: deuterium, halogen and unsubstituted C _1-4 alkyl; R ¹ Can be selected from hydrogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 hydroxyalkyl; R ² and R ³ are independently hydrogen or deuterium; m1 can be 0, 1 or 2; m2 Can be 0 or 1; R ^3a can be deuterium, halogen or unsubstituted C _1-4 alkyl; R ^3b can be deuterium, halogen or unsubstituted C _1-4 alkyl; R ⁴ is -C( =O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen or unsubstituted C _1-4 alkyl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof can have the following characteristics: Ring A can be selected from pyrrole, thiophene, pyridine and phenyl, wherein pyrrole, thiophene, pyridine and phenyl can optionally be Substituted, and when substituted, each may be substituted 1 or more times by a moiety independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 haloalkyl; Ring B Can be selected from unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocyclyl, unsubstituted or substituted 7-membered bicyclic nitrogen-containing heterocyclyl and unsubstituted or substituted 8-membered bicyclic nitrogen-containing heterocyclyl group; n can be 0 or 1; where n is 0, ring C can be unsubstituted or substituted aryl, unsubstituted or substituted monocyclic heteroaryl, or unsubstituted or substituted Of , among which in aryl, heteroaryl and When substituted, aryl, heteroaryl and Can be partially substituted one or more times independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _3-6 cycloalkyl and unsubstituted C _1-4 haloalkyl ; Ring D1 can be phenyl, 5-membered heteroaryl or 6-membered heteroaryl; Ring D2 can be selected from unsubstituted or substituted , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded and unsubstituted or superseded , where the asterisk indicates the point of connection with ring D1; where n is 1, ring C can be selected from pyrrole, thiophene, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and phenyl, where pyrrole, thiophene, thiazole, Pyridine, pyridazine, pyrimidine, pyrazine and phenyl are optionally substituted, and when substituted each can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl are partially substituted one or more times; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl, unsubstituted monocyclic C _{3- 6} cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl) and substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl), wherein the substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) can be composed of 1 or more Deuterium substitution; R ² and R ³ may be independently hydrogen, deuterium or unsubstituted C _1-4 alkyl; or R ² and R ³ may be combined with the carbon to which R ² and R ³ are connected to form an unsubstituted or unsubstituted C 1-4 alkyl group. Substituted monocyclic C _3-6 cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen , unsubstituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted Substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) or unsubstituted bicyclic C _5-8 cycloalkyl (unsubstituted C _1-4 alkyl), The substituted C _1-4 alkyl group may be substituted by 1 or more deuteriums.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following characteristics: Ring A may be selected from the group consisting of pyrrole, thiophene, pyridine and phenyl, wherein pyrrole, thiophene, pyridine and phenyl may optionally be Substituted, and when substituted, each may be substituted 1 or more times with a moiety independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 haloalkyl; Ring B Can be selected from unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocyclyl, unsubstituted or substituted 7-membered bicyclic nitrogen-containing heterocyclyl and unsubstituted or substituted 8-membered bicyclic nitrogen-containing heterocyclyl group; n can be 0 or 1; where n is 0, ring C can be an unsubstituted or substituted aryl group, an unsubstituted or substituted monocyclic heteroaryl group, or an unsubstituted or substituted group. Of , among which in aryl, heteroaryl and When substituted, aryl, heteroaryl and Can be substituted one or more times with a moiety independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _3-6 cycloalkyl and unsubstituted C _1-4 haloalkyl ; Ring D1 can be phenyl, 5-membered heteroaryl or 6-membered heteroaryl; Ring D2 can be selected from unsubstituted or substituted , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded and unsubstituted or superseded , where the asterisk indicates the point of connection with ring D1; where n is 1, ring C can be selected from pyrrole, thiophene, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and phenyl, where pyrrole, thiophene, thiazole, Pyridine, pyridazine, pyrimidine, pyrazine and phenyl are optionally substituted, and when substituted, each can be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl are partially substituted one or more times; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl, unsubstituted monocyclic C _{3- 6} cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl) and substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl), wherein the substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) can be composed of 1 or more Deuterium substitution; R ² and R ³ may be independently hydrogen, deuterium or unsubstituted C _1-4 alkyl; or R ² and R ³ may be combined with the carbon to which R ² and R ³ are connected to form an unsubstituted or unsubstituted C 1-4 alkyl group. Substituted monocyclic C _3-6 cycloalkyl; m1 can be 0 or 1; m2 can be 0, 1 or 2; R ^3a can be deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl; R ^3b can be deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl group or unsubstituted monocyclic C _3-6 cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen, unsubstituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted bicyclic C _5-8 ring Alkyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) or unsubstituted bicyclic C _5-8 cycloalkyl (unsubstituted C _1-4 Alkyl), wherein the substituted C _1-4 alkyl may be substituted by 1 or more deuterium.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may have the following characteristics: Ring A may be selected from the group consisting of pyrrole, thiophene, pyridine and phenyl, wherein pyrrole, thiophene, pyridine and phenyl may optionally be Substituted, and when substituted, each may be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl and unsubstituted C _1-4 haloalkyl Partially substituted 1 or more times; ring B can be selected from unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocyclyl, unsubstituted or substituted 7-membered bicyclic nitrogen-containing heterocyclyl and unsubstituted or Substituted 8-membered bicyclic nitrogen-containing heterocyclyl; n can be 0 or 1; when n is 0, ring C can be an unsubstituted or substituted aryl group, an unsubstituted or substituted monocyclic ring Heteroaryl may be unsubstituted or substituted , among which in aryl, heteroaryl and When substituted, aryl, heteroaryl and Can be substituted one or more times with a moiety independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _3-6 cycloalkyl and unsubstituted C _1-4 haloalkyl ; Ring D1 can be phenyl, 5-membered heteroaryl or 6-membered heteroaryl; Ring D2 can be selected from unsubstituted or substituted , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded and unsubstituted or superseded , where the asterisk indicates the point of connection with ring D1; where n is 1, ring C can be selected from pyrrole, thiophene, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and phenyl, where pyrrole, thiophene, thiazole, Pyridine, pyridazine, pyrimidine, pyrazine and phenyl are optionally substituted, and when substituted each may be independently selected from deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium substituted C _{1 -4} alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 The haloalkyl group is partially substituted 1 or more times; R ¹ can be selected from hydrogen, unsubstituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted Substituted C _1-4 hydroxyalkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 cycloalkyl Base (unsubstituted C _1-4 alkyl), substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), unsubstituted monocyclic C _3-6 ring Alkyl (unsubstituted C _1-4 alkenyl) and substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl), wherein substituted C _1-4 alkyl And the substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) can be substituted by 1 or more deuterium; R ² and R ³ can be independently hydrogen, deuterium or unsubstituted C _1-4 alkyl; or R ² and R ³ can together with the carbon to which R ² and R ³ are connected form an unsubstituted or substituted monocyclic C _3-6 cycloalkyl; m1 can be 0 or 1; m2 Can be 0, 1 or 2; R ^3a can be deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl group; R ^3b can be deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _{3 -6} cycloalkyl; R ⁴ can be -C(=O)NR ⁵ R ⁶ ; R ⁵ can be hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ can be hydrogen or unsubstituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) or unsubstituted bicyclo C _5-8 cycloalkyl (unsubstituted C _1-4 alkyl), wherein substituted C _{1 -4Alkyl} may be substituted by 1 or more deuterium.

Examples of compounds of formula (I) include the following: and or a pharmaceutically acceptable salt of any of the above.

Other examples of compounds of formula (I) include the following: and or a pharmaceutically acceptable salt of any of the above.

Other examples of compounds of formula (I) include the following: and or a pharmaceutically acceptable salt of any of the above. synthesis

Compounds of formula (I) and those described herein can be prepared in various ways. General synthetic routes for the preparation of compounds of formula (I) as well as some examples of starting materials for the synthesis of the compounds described herein are shown and described herein. Additionally, for purposes of general synthetic pathways, the depicted structures are appropriately protected (as known to those skilled in the art) and the general structures are intended to contain such protecting groups. The approaches shown and described herein are illustrative only and are not intended to, and in any event should not be construed as, in any way limiting the scope of the claims. Those skilled in the art will be able to recognize modifications to the disclosed synthesis and devise alternative approaches based on the disclosure herein; all such modifications and alternative approaches are within the scope of the patent claims. Reaction diagram 1

Scheme 1 provides an exemplary method for preparing compounds of Formula (I), including pharmaceutically acceptable salts thereof. Pharmaceutical composition

Some embodiments described herein relate to pharmaceutical compositions, which may include an effective amount of a compound described herein (eg, a compound as described herein or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, Excipients or combinations thereof. The pharmaceutical compositions described herein are suitable for human and/or veterinary use.

As used herein, "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, but not limited to, dimethylsulfoxide (DMSO) is a common carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

As used herein, "diluent" refers to an ingredient of a pharmaceutical composition that is not pharmacologically active but may be pharmaceutically necessary or desirable. For example, diluents can be used to increase the volume of a drug that is too small to manufacture and/or administer a powerful drug. It may also be a liquid used to dissolve a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the industry is a buffered aqueous solution such as, but not limited to, phosphate buffered saline that simulates the composition of human blood.

As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. to the composition. "Diluents" are a class of excipients.

Suitable formulations depend on the route of administration chosen. Techniques for formulating and administering the compounds described herein are known to those skilled in the art. A variety of techniques for administering compounds exist in the industry, including (but not limited to) oral, rectal, topical, aerosol, injection, inhalation, and parenteral delivery (including intramuscular, subcutaneous, intravenous, intramedullary injection, intrathecal, Direct indoor, intraperitoneal, intranasal and intraocular injection). Pharmaceutical compositions are often tailored for a specific intended route of administration.

Compounds may also be administered locally rather than systemically, for example, by injection of the compound directly into the infected area (usually in a depot or sustained release formulation). Additionally, compounds can be administered in targeted drug delivery systems, such as liposomes coated with tissue-specific antibodies. Liposomes can be targeted to and selectively absorbed by organs.

The pharmaceutical compositions disclosed herein may be manufactured in a manner known in the art, for example, by means of conventional mixing, dissolving, granulating, tableting, comminution, emulsifying, encapsulating, entrapping or tableting processes. As set forth herein, compounds used in pharmaceutical compositions may be provided in the form of salts with pharmaceutically compatible counterions. Instructions

Some embodiments described herein are directed to methods of treating a cancer described herein, which may comprise administering to a subject having a cancer described herein an effective amount of a compound described herein (e.g., a compound of Formula (I) or its a pharmaceutically acceptable salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to using an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprising a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The use of pharmaceutical compositions of the above acceptable salts) for the manufacture of medicaments for the treatment of cancer as described herein. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). pharmaceutical compositions of the above acceptable salts) for use in the treatment of cancers described herein.

Some embodiments described herein are directed to methods of inhibiting the growth of malignant growths or tumors, which may comprise contacting the growths or tumors with an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable compound thereof). salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is caused by a cancer described herein. Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Acceptable salts) of a pharmaceutical composition for the manufacture of a medicament for inhibiting the growth of malignant growths or tumors, wherein the malignant growths or tumors are caused by cancer as described herein. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The above acceptable salts) pharmaceutical compositions for inhibiting the growth of malignant growths or tumors, wherein the malignant growths or tumors are caused by cancer as described herein.

Some embodiments described herein are directed to methods of treating cancers described herein, which may include exposing a malignant growth or tumor in a subject having a cancer described herein with an effective amount of a compound described herein (e.g., formula ( I) compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). The use of a pharmaceutical composition of an acceptable salt) for the manufacture of a medicament for the treatment of cancer (which may include exposure to a malignant growth or tumor), wherein the malignant growth or tumor is caused by a cancer as described herein. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). (the above acceptable salts) for use in the treatment of cancer (which may include exposure to a malignant growth or tumor), wherein the malignant growth or tumor is caused by a cancer as described herein.

Some embodiments described herein are directed to methods of inhibiting PARP1 activity, which may comprise providing to cancer cells from cancers described herein an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable version thereof). salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). acceptable salt) for the manufacture of pharmaceutical agents for inhibiting PARP1 activity. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). above acceptable salts), which is used to inhibit PARP1 activity. Some embodiments described herein are directed to methods of inhibiting PARP1 activity, which may comprise providing to cancer cells from cancers described herein an effective amount of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable version thereof). salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein are directed to methods of inhibiting PARP1 activity, which may include combining cancer cells from cancers described herein with an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable version thereof). salt) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), and thereby inhibits PARP1 activity.

Some embodiments described herein are directed to methods of treating cancers described herein, which may comprise using an effective amount of a compound described herein (eg, a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprising Pharmaceutical compositions of compounds (eg, compounds of formula (I) or pharmaceutically acceptable salts thereof) inhibit PARP1 activity. Other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). Acceptable salt) of a pharmaceutical composition for the manufacture of a medicament for treating cancer as described herein by inhibiting PARP1 activity. Yet other embodiments described herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). (above acceptable salts) for use in treating cancers described herein by inhibiting PARP1 activity. Some embodiments described herein are directed to methods of treating cancers described herein, which may comprise contacting cancer cells with an effective amount of a compound described herein (eg, a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprising Contact with a pharmaceutical composition of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the compound inhibits PARP1 activity.

Some embodiments disclosed herein are directed to methods of inhibiting PARP1 activity, which may comprise providing an effective amount of a compound described herein (e.g., formula (I) compound or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments disclosed herein are directed to effective amounts of a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) or comprise a compound described herein (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof). acceptable salt) for the manufacture of pharmaceutical agents for inhibiting PARP1 activity. Yet other embodiments disclosed herein are directed to or comprise compounds described herein (e.g., compounds of Formula (I) or pharmaceutically acceptable salts thereof) salt) pharmaceutical composition, which is used to inhibit PARP1 activity.

Examples of suitable cancers include, but are not limited to: lung cancer, pancreatic cancer, colon cancer (e.g., colorectal cancer), myeloid leukemia (e.g., AML, CML, and CMML), thyroid cancer, myelodysplastic syndrome (MDS), bladder Carcinoma, epidermal cancer, melanoma, breast cancer, prostate cancer, head and neck cancer (such as head and neck squamous cell carcinoma), ovarian cancer, brain cancer (such as glioma, such as glioblastoma multiforme), of stromal origin Cancer (such as fibrosarcoma and rhabdomyosarcoma), sarcoma, teratoma, neuroblastoma, renal cancer, hepatoma, non-Hodgkin's lymphoma, multiple myeloma or anaplastic thyroid cancer.

The terms "treat, treating, treatment", "therapeutic" and "therapy" as used herein do not necessarily imply complete cure or disappearance of a disease or condition. Any alleviation of any undesirable signs or symptoms to any extent of a disease or condition may be considered treatment and/or therapy. Additionally, treatment may include actions that worsen the subject's overall perception of physical condition or appearance.

As used herein, "subject" means an animal that is the subject of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates, such as fish, shellfish, reptiles and especially mammals. "Mammals" include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cattle, horses, camels, non-human primates such as monkeys, chimpanzees and orangutans and especially humans . In some embodiments, the subject may be a human, such as a human subject 18 years of age or older.

The term "effective amount" is used to refer to that amount of an active compound or pharmaceutical agent that induces the indicated biological or medical response. For example, an effective amount of a compound may be that amount required to alleviate or ameliorate disease symptoms or prolong survival of the subject treated. This response may occur in tissues, systems, animals, or humans and may involve alleviation of signs or symptoms of the disease being treated. A person skilled in the art is fully capable of determining the effective amount based on the disclosure provided herein. The effective amount of a compound disclosed herein required as a dose will depend on the route of administration, the type of mammal (including humans) being treated, and the physical characteristics of the particular animal considered. Dosage may be adjusted to achieve the desired effect but will depend on factors such as weight, diet, concomitant medications, and other factors that will be recognized by those skilled in the medical art. Example

Other embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claimed patent in any way. Abbreviation h hours EA Ethyl acetate PE Petroleum ether Example 1 Compound A1

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 × 50 mL). The filter cake was concentrated under reduced pressure to obtain a residue. The residue was dissolved in methanol (120 mL). HCl (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 afford 2 as a white solid (8.4 g, 88.49% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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. Water (0.3 mL) was added dropwise to the mixture. Then 15% sodium hydroxide (aq., 0.3 mL) and water (0.9 mL) were added dropwise at 0°C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 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 afford 3 as a white solid (1.1 g, 99.19% yield, 80% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To a solution of 3 (1 g, 3.63 mmol) in dichloromethane (20 mL) and dimethylformamide (0.2 mL) at 0 °C was added thionite chloride (864.36 mg, 7.27 mmol). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to obtain 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 afford 4 as a pale yellow solid (0.8 g, 92.27% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To a solution of N,6-dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-formamide (0.1 g, 369.33 umol, HCl) in dimethylformamide (1 mL) 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) were added. The mixture was stirred at 70 °C for 2 h and then filtered. The filtrate was purified by preparative HPLC and lyophilized to give A1 as a white solid (0.0687 g, 42.61% yield, 100% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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

To 5 (120 mg, 605.41 umol) and 7-(chloromethyl)-3-ethyl-1H-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). The mixture was stirred at 80°C for 12 hr. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative 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- d ₆ ) δ 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.

LC/MS method: Gradient is as follows: 5% B in 0.40 min and 5-95% B in 0.40-3.00 min, hold at 95% B for 1.00 min, and then 95-5% B in 0.01 min, flow rate is 1.0ml/min. Mobile phase A is 0.04% trifluoroacetic acid in water, and mobile phase B is 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography is Luna C18 50*2.0mm column (5 um particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode is positive electrospray ionization. MS range is 100-1000. Example 3 Compound A3

5 (0.1 g, 504.51 umol) and 7-(chloromethyl)-3-ethyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione (181.36 mg, 756.77 umol), A mixture of 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 hr. Strain the mixture. The filter cake was purified by preparative HPLC (Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 1%-30%, 8 min.) and lyophilized to obtain A3 as a white solid (40.2 mg, 18.86% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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

To a solution of 6 (2 g, 9.08 mmol, 1.75 mL) in DCM (30 mL) was added methylimino(pendantthio)methane (677.17 mg, 9.26 mmol, 632.87 uL) at 25 °C. The mixture was stirred at 25°C for 3 hr and then concentrated to give the product. Compound 7 was obtained as a white solid (2.7 g, 91.22% yield, 90% purity) and used directly in the next step without further purification. ¹ H NMR: (400 MHz, CDCl ₃ - d ₃ ) δ 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).

To a solution of 7 (2.7 g, 9.20 mmol) in MeOH (40 mL) was added CH ₃ I (1.57 g, 11.04 mmol, 687.50 uL) at 25 °C. The mixture was stirred at 60°C for 2 hr. The mixture was concentrated to give the product. Compound 8 was obtained as a white solid (2.8 g, 98.97% yield) and used directly in the next step without further purification.

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

A solution of 9 (200 mg, 636.17 umol) in HCl (1 mL) and H ₂ O (1 mL) was stirred at 50 °C for 12 hr. The mixture was concentrated to give the product. Compound 10 was obtained as a white solid (110 mg, 79.79% yield, HCl) and used directly in the next step without further purification. The product was used directly in the next step without further purification.

To 7-(chloromethyl)-3-ethyl-1H-pyrido[3,2-d]pyrimidine-2,4-dione (100 mg, 418.99 umol) in MeCN (2 mL) at 25 °C ), add 10 (108.96 mg, 502.79 umol, HCl), NaBr (129.33 mg, 1.26 mmol, 40.42 uL) and DIEA (270.75 mg, 2.09 mmol, 364.89 uL). The mixture was stirred at 80°C for 2 hr. The reaction solution was filtered, and the filtrate was concentrated to obtain crude product. The crude product was purified by reverse phase HPLC (0.1% FA conditions). Preparative HPLC (column: 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.). Compound A4 was obtained as a white solid (50.6 mg, 27.28% yield, 96.8% purity, FA). ¹ H NMR: (400 MHz, CD ₃ OD- d ₄ ) δ 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

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 hr. . 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 hr to form a slurry. The solid was collected by filtration and concentrated to afford 12 as a white solid (1.7 g, 58.17% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

Dissolve 12 (1.7 g, 6.29 mmol), triethylamine (1.27 g, 12.59 mmol) and cyclopentyl(diphenyl)phosphane/dichloromethane/dichloropalladium/iron (514.02 mg, 629.44 umol) in di A mixture of methylformamide (200 mL) and methanol (100 mL) was stirred at 80°C, CO, and 50 psi for 24 hr. The mixture was concentrated under reduced pressure to obtain a residue. The residue was stirred in methanol (20 mL) for 16 hr to form a slurry. The solid was collected by filtration and stirred in dichloromethane (20 mL) for 2 hr to form a slurry. The solid was collected by filtration and concentrated to afford 13 as a gray solid (1.4 g, 89.25% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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

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

Combine N, 6-dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-carboxamide (0.15 g, 554.00 umol), 15 (265.54 mg, 1.11 mmol), N, N-diiso A mixture of propylethylamine (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 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (Phenomenex C18 80*40 mm*3 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 15%-35%, 8 min.) and lyophilized. To obtain A5 as a white solid (21.6 mg, 7.98% yield). ¹ H NMR: (400 MHz, CD ₃ Cl- d ₃ ) δ 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).

Combine N-methyl-5-hexahydropyrazin-1-yl-pyridin-2-methamide (0.08 g, 311.61 umol) and 15 (112.02 mg, 467.41 umol), N, N-diisopropylethyl A mixture of amine (241.63 mg, 1.87 mmol) and sodium bromide (96.18 mg, 934.83 umol) in acetonitrile (0.5 mL) was stirred at 80°C for 12 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (Phenomenex C18 80*40 mm*3 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 10%-30%, 8 min.) and lyophilized. To obtain A6 as a white solid (4.0 mg, 3%). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 11.47 (br s, 1H), 8.35-8.47 (m, 2H), 8.27 (d, J =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 Compound A7

16 (5 g, 23.14 mmol), tert-butyl hexahydropyrazine-1-carboxylate (4.74 g, 25.46 mmol), Cs ₂ CO ₃ (15.08 g, 46.29 mmol), Xantphos (1.34 g, 2.31 mmol) ) and ginseng(dibenzylideneacetone)dipalladium(0) (1.06 g, 1.16 mmol) in dioxane (50 mL) was degassed and purged with argon (3×). The mixture was stirred at 100°C under an argon atmosphere for 16 hr. 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 (SiO ₂ , PE:EA = 1:0 to 1 : 2) to obtain 17 as a yellow solid (4.6 g, 61.84% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

A mixture of 17 (2.2 g, 6.85 mmol) and methylamine (11.00 g, 106.26 mmol, 30% in water) in methanol (5 mL) was stirred at 20 °C for 4 hr. Concentrate the mixture. The residue was diluted with NH ₄ Cl (30 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over _Na2SO4 , _filtered and concentrated under reduced pressure to afford 18 as a pale yellow solid (2.1 g, 95.75% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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 ).

A mixture of 18 (2.1 g, 6.55 mmol) in dioxane (20 mL) and 4 N HCl/dioxane (20 mL) was stirred at 20 °C for 2 hr. The mixture was concentrated under reduced pressure to afford 19 as a pale yellow solid (1.6 g, 95.08% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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, J =3.51 Hz, 3H).

19 (0.15 g, 584.27 umol) and 7-(chloromethyl)-3-ethyl-1H-quinazoline-2,4-dione (167.34 mg, 701.12 umol), N, N-diisopropyl A mixture of ethylamine (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 hr. The mixture was filtered, and the filter cake was concentrated to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water (FA)-ACN]; B%: 1%-40%, 8 min.) and lyophilized to obtain A7 as a white solid (55.9 mg, 22.65% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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 Compound A8

At 20°C, to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)-3,6-dihydro-2H-pyridine-1- To a solution of tert-butyl formate (572.52 mg, 1.85 mmol) and 20 (400 mg, 1.85 mmol) in tetrahydrofuran (8 mL) was added K ₃ PO ₄ (786.05 mg in H ₂ O (2 mL) , 3.70 mmol). The mixture was degassed and purged with _N2 (3x). Pd(dppf) _Cl2 (135.48 mg, 185.16 umol) was added to the mixture under _N2 atmosphere, and the mixture was stirred at 80 °C for 6 hr. The reaction was stopped by adding _H2O (50 mL) at 25°C. The mixture was extracted using EA (3 × 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 (SiO ₂ , PE:EA = 25% to 50%) to obtain 21 as a white solid (460 mg, 74.13% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

A mixture of 21 (0.46 g, 1.44 mmol), methylamine (1.50 g, 14.45 mmol) in MeOH (1.25 mL) was stirred at 20 °C for 4 hr. Concentrate the mixture. The residue was diluted with NH ₄ Cl (5 mL) and extracted with dichloromethane (3 × 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 in the _next step without further purification. Compound 22 was obtained as a pale yellow solid (0.45 g, 98.13% yield). 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 method is diode array ( DAD). MS mode is positive electrospray ionization. MS range is 100-1000. Mobile phase A is 0.04% trifluoroacetic acid in water, and mobile phase B is 0.02% trifluoroacetic acid in HPLC grade acetonitrile.

To a solution of 22 (450 mg, 1.45 mmol) in dioxane (2 mL) at 20 °C was added HCl/dioxane (2 mL). The mixture was stirred at 20°C for 2 hr and then concentrated under reduced pressure to give crude product, which was used in the next step without further purification. Compound 23 was obtained as a white solid (330 mg, 89.74% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To 7-(chloromethyl)-3-ethyl-1H-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). The mixture was stirred at 80°C for 12 hr. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex luna C18 100*40 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 10%-50%, 8 min.) to obtain a white solid form of A8 (39.4 mg, 21.72% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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=1.13 Hz, 2H), 8.63-8.76 (m, 2H), 11.35 (s, 1H). LCMS [ESI+]: 420.1 [M+H] ⁺ , RT: 1.672 min. LC/MS: Gradient was as follows: 5% B in 0.40 min and 5-95% B in 0.40-3.00 min, hold at 95% B for 1.00 min, and then 95-5% B in 0.01 min, flow rate 1.0 mL/min. Mobile phase A is 0.04% trifluoroacetic acid in water, and mobile phase B is 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography is Luna C18 50*2.0mm column (5um particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection. MS mode is positive electrospray ionization. MS range is 100-1000. Example 8 Compound A9

To a solution of 1A (10 g, 42.51 mmol) in dimethylformamide (200 mL) was added N,N-diisopropylethylamine (21.98 g, 170.04 mmol). The mixture was cooled to 0°C. Add hydrated 1-hydroxybenzotriazole (8.62 g, 63.77 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.22 g, 63.77 mmol) 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 hr. The mixture was diluted with water (200 mL) and extracted with EA (10 × 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 (SiO ₂ , PE:EA = 1:0 to 1:4) to obtain 2A as a colorless oil (9 g, 69.12% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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) and 20°C for 16 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 3A as a colorless oil (5 g, 98.83% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

Compound 3A (5 g, 29.04 mmol) was stirred at 150 °C for 10 min. The mixture was stirred in a mixture of PE and EA (30 mL, 1:1) for 2 hr to form a slurry. The solid was collected by filtration and dried under high vacuum to afford 4A as a pale yellow solid (3.8 g, 93.38% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To a solution of 4A (3.3 g, 23.55 mmol) in dimethylformamide (300 mL) at 20 °C was added 4-dimethylaminopyridine (863.04 mg, 7.06 mmol) and triethylamine ( 7.15 g, 70.64 mmol), 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 hr. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (50 mL × 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 4 : 1) to obtain 5A as a white solid (5.5 g, 68.62% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 4.51 (s, 2H), 1.52-1.57 (m, 2H), 1.45 (d, J=9.26 Hz, 18H), 1.36-1.42 (m, 2H) .

To a solution of 5A (5.3 g, 15.57 mmol) in tetrahydrofuran (150 mL) was added dropwise diisobutylaluminum hydride (1 M, 77.86 mL) at -78 °C under _N2 . The mixture was stirred at -78°C for 1 hour. The reaction was stopped by adding methanol (50 mL) at -78°C and then warming to 20°C. The mixture was extracted using EA and washed with Rochelle's salt solution (100 mL) and brine (1 × 100 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give _a white solid Form 6A (5.3 g, 98.83% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To a solution of 6A (5.3 g, 15.39 mmol) in dichloromethane ( ₁₈₀ mL) was added dropwise Et ₃ SiH (8.95 g, 76.94 mmol) and BF ₃ .Et ₂ O at -78 °C and N 2 (10.92 g, 76.94 mmol). The mixture was stirred at -78°C for 2 hr. The reaction was stopped by saturated _NaHCO solution (100 mL) at 0°C and then warmed to 20°C. The mixture was washed with EA (20 mL) and Na ₂ CO ₃ (9.79 g, 92.33 mmol) and Boc ₂ O (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 hr. The mixture was diluted with water (100 mL), extracted with EA ( ₃ × 100 mL), washed with brine (50 mL × 1), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 4 : 1) to obtain 7A as a white solid (1.3 g, 27.04% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To a solution of 7A (1.3 g, 4.16 mmol) in dichloromethane (13 mL) at 20 °C was added triethylamine (20.02 g, 175.58 mmol). The mixture was stirred at 20°C for 2 hr. The mixture was concentrated under reduced pressure to obtain a residue. The residue was stirred in a mixture of PE and EA (5 mL, 3:1) for 30 min to form a slurry. The solid was collected by filtration and dried under high vacuum to afford 8A as a white solid (0.9 g, 63.57% yield, 2TFA). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 3.96-4.05 (m, 2H), 3.33-3.41 (m, 3H), 3.14-3.24 (m, 2H), 2.09-2.35 (m, 4H).

To a solution of methylamine (5.63 g, 83.32 mmol, HCl) in DMF (180 mL) at 20 °C was added DIEA (21.54 g, 166.64 mmol, 29.03 mL). 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 was stirred at 20°C for 12 hr. The mixture was poured into ice water and extracted with EtOAc (4 × 100 mL). The combined _organic phases were washed with brine, dried over _Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE_EA = 50:1 to 2:1) to obtain 25 as a white solid (9 g, 94.31% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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 ( A mixture of 73.02 mg, 87.31 umol) in toluene (6 mL) was degassed and purged with argon (3×). The mixture was stirred at 100°C under an argon atmosphere for 16 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (SiO ₂ , dichloromethane:methanol = 10:1) to afford 26 as a brown oil (60 mg, 26.40% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

Dissolve 4 (50 mg, 192.06 umol), 26 (68.76 mg, 288.09 umol), sodium bromide (59.28 mg, 576.18 umol), and N,N-diisopropylethylamine (148.93 mg, 1.15 mmol) in acetonitrile. (2 mL) was stirred at 80 °C under _N2 atmosphere for 2 hr. The mixture was concentrated under reduced pressure to obtain a residue. By preparative HPLC (neutral conditions, Waters Xbridge Prep OBD C18 150 × 40 mm × 10 um; mobile phase: [water (NH ₄ HCO ₃ )-CH ₃ CN]; B%: 35%-65%, 8 min) and lyophilized to obtain A9 as a white solid (44.6 mg, 49.65% yield, 98.9% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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 Compound A10

To a solution of 27 (10 g, 46.29 mmol) in dichloromethane (200 mL) at 0 °C was added m-CPBA (18.80 g, 92.58 mmol) portionwise. The mixture was stirred at 45°C for 12 hr. The reaction was stopped by adding _Na2SO3 (100 mL) at 0° _C . The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 1 : 1) to obtain 28 as a pale yellow solid (8.2 g, 76.35% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 8.72 (d, J=0.88 Hz, 1H), 7.69 (s, 2H), 3.86 (s, 3H).

A solution of 28 (8.2 g, 35.34 mmol) in POCl ₃ (135.30 g, 882.40 mmol) was stirred at 95°C for 2 hr. The mixture was distilled in vacuo (120°C, oil pump). The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 8 : 1) to obtain 29 as a pale yellow solid (5 g, 56.49% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 8.45 (d, J=8.13 Hz, 1H), 7.94 (d, J=8.13 Hz, 1H), 3.89 (s, 3H).

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 hr. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried over _Na2SO4 , filtered and concentrated _under reduced pressure to afford 30 as a pale yellow solid (4.9 g, 98.39% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

30 (3 g, 12.02 mmol), tert-butyl hexahydropyrazine-1-carboxylate (4.48 g, 24.05 mmol), Cs ₂ CO ₃ (9.79 g, 30.06 mmol), Xantphos (695.76 mg, 1.20 mmol) ) and Pd ₂ (dba) ₃ (550.55 mg, 601.22 umol) in dioxane (60 mL) was degassed and purged with argon (3×). The mixture was stirred at 80°C under an argon atmosphere for 16 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 1 : 2) to obtain 31 as a pale yellow solid (2.7 g, 63.28% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

A mixture of 32 (0.2 g, 563.65 umol) in dioxane (2 mL) and HCl/dioxane (2 mL) was stirred at 20 °C for 2 hr. The mixture was concentrated under reduced pressure to afford 32 as a pale yellow solid (160 mg, 97.49% yield, HCl). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

Combine 32 (150 mg, 515.15 umol, HCl), 4 (184.43 mg, 772.73 umol), sodium bromide (106.01 mg, 1.03 mmol), N,N-diisopropylethylamine (399.47 mg, 3.09 mmol) The mixture in acetonitrile (3 mL) was stirred at 80 °C under _N2 atmosphere for 2 hr. The mixture was diluted with water (5 mL) and extracted with EA (3 × 5 mL). The combined organic layers were _washed with brine (1 × 5 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 0:1) and lyophilized to obtain A10 as a pale yellow solid (119.8 mg, 49.62% yield, 97.5% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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 Compound A11

To a solution of 4 (80 mg, 335.19 umol) in MeCN (2 mL) was added 33 (87.85 mg, 319.78 umol, HCl), NaBr (103.47 mg, 1.01 mmol, 32.33 uL) and DIEA ( 216.61 mg, 1.68 mmol, 291.92 uL). The mixture was stirred at 80°C for 2 hr. The mixture was filtered, and the filtrate was concentrated to give crude product. By reversed-phase HPLC (0.1% FA conditions, Phenomenex Luna C18 75 × 30 mm × 3 um; mobile phase: [water (NH ₄ HCO ₃ )-CH ₃ CN]; B%: 15%-45%, 8 min .) The crude product was purified to obtain A11 as a white solid (24.1 mg, 16.32% yield). ¹ H NMR: (400 MHz, CD ₃ OD- d ₄ ) δ 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 Compound A12

Combine 34 (0.2 g, 563.65 umol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2dioxaboron (104.17 mg, 676.38 umol), K ₃ PO ₄ (239.29 mg, 1.13 mmol), a mixture of di-tert-butyl(cyclopentyl)-phosphane/palladium dichloride/iron (36.74 mg, 56.36 umol) in tetrahydrofuran (6 mL) and water (1.5 mL) was degassed and Use argon (3×) purge. The mixture was stirred at 80°C under an argon atmosphere for 16 hr. The mixture was diluted with water (10 mL) and extracted with EA (3 × 5 mL). The combined organic layers were _washed with brine (1 × 5 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 1:1) to obtain 34A as a brown oil (0.1 g, 51.21% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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) and 20°C for 16 hr. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford 35 (90 mg, 89.48% yield) as a yellow oil.

To a solution of 35 (0.09 g, 258.30 umol) in dioxane (1 mL) at 20 °C was added HCl/dioxane (1 mL). The mixture was stirred at 20 °C for 2 hr and then concentrated under reduced pressure to afford 36 as a brown solid (70 mg, 95.16% yield, HCl).

Dissolve 36 (0.07 g, 245.80 umol), 4 (88.00 mg, 368.70 umol), N,N-diisopropylethylamine (190.60 mg, 1.47 mmol) and sodium bromide (75.87 mg, 737.40 umol) in acetonitrile (2 mL) was stirred at 80 °C under _N2 atmosphere for 2 hr. The mixture was concentrated under reduced pressure to obtain a residue. By preparative HPLC (neutral conditions, Phenomenex C18 75 × 30 mm × 3 um; mobile phase: [water (NH ₄ HCO ₃ )-CH ₃ CN]; B%: 25%-55%, 8 min.) The residue was purified and lyophilized to give A12 as a white solid (25.7 mg, 23.07% yield, 99.4% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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 A13 and A14

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 dropwise at 0°C. Isobutyl chloroformate (1.40 g, 10.23 mmol) was added. The mixture was stirred at 0°C for 2 hr, and then _MeNH2 (1.88 g, 27.90 mmol, HCl) was added at 0°C. The mixture was stirred at 20°C for 12 hr. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (1 × 20 mL), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 1 : 1) to obtain 38 as a pale yellow solid (1.78 g, 83.91% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

38 (0.2 g, 876.86 umol), tert-butyl hexahydropyrazine-1-carboxylate (326.63 mg, 1.75 mmol), Cs ₂ CO ₃ (714.25 mg, 2.19 mmol), Xantphos (50.74 mg, 87.69 umol) ) and Pd ₂ (dba) ₃ (40.15 mg, 43.84 umol) in dioxane (4 mL) was degassed and purged with argon (3×). The mixture was stirred at 80°C under an argon atmosphere for 16 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 1 : 2) to obtain 39 as a pale yellow solid (0.25 g, 85.51% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

A mixture of 39 (0.25 g, 749.80 umol) in dioxane (3 mL) and HCl/dioxane (3 mL) was stirred at 20 °C for 2 hr. The mixture was concentrated under reduced pressure to afford 40 as a pale yellow solid (0.2 g, 98.88% yield, HCl).

Combine 40 (0.08 g, 296.55 umol, HCl), 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) The mixture in acetonitrile (2 mL) was stirred at 80 °C under _N2 atmosphere for 2 hr. The mixture was concentrated under reduced pressure to obtain a residue. The remaining residue was purified by preparative HPLC (neutral conditions, Phenomenex C18 75*30 mm*3 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 8 min.) and lyophilized to obtain A13 as a white solid (29.2 mg, 22.61% yield, 100% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

25 (0.15 g, 654.81 umol), 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaboron-2-yl)-3,6-dihydro-2H- tert-butylpyridine-1-carboxylate (242.97 mg, 785.77 umol), K ₃ PO ₄ (277.99 mg, 1.31 mmol) and Pd(dppf)cl ₂ (47.91 mg, 65.48 umol) in tetrahydrofuran (6 mL) and The mixture in water (1.5 mL) was degassed and purged with argon (3×). The mixture was stirred at 80°C under an argon atmosphere for 2 hr. The mixture was diluted with water (5 mL) and extracted with EA (3 × 5 mL). The combined organic layers were _washed with brine (1 × 5 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 3 : 1) to obtain 41 as a pale yellow solid (0.19 g, 87.55% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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 hr. The mixture was concentrated under reduced pressure to afford 42 as a pale yellow solid (0.15 g, 97.72% yield, HCl).

Combine 42 (100 mg, 373.48 umol, HCl), 7-(chloromethyl)-3-ethyl-1H-quinazoline-2,4-dione (106.97 mg, 448.17 umol), N,N-dione A mixture of isopropylethylamine (193.08 mg, 1.49 mmol) and sodium bromide (76.86 mg, 746.95 umol) in acetonitrile (2 mL) was stirred at 80°C under _N2 atmosphere for 2 hr. The mixture was concentrated under reduced pressure to obtain a residue. Purified by preparative HPLC (neutral conditions, Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 25%-55%, 8 min) The residue was lyophilized to give A14 as a white solid (53.4 mg, 32.95% yield, 99.9% purity). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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 A15

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) at 20 °C was added K ₂ CO ₃ (2.20 g, 15.93 mmol). The mixture was stirred at 80°C for 4 hr. Pour the mixture into ice water (150 mL) and filter. The filter cake was dried under high vacuum to obtain crude product, which was used directly in the next step without further purification. Compound 43A was obtained as a white solid (2 g, 63.04% yield). ¹ H NMR: (400 MHz, CDCl ₃ - d ₃ ) δ 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).

A solution of 43A (2 g, 5.02 mmol) in DCM (20 mL) and HCl (10 mL) was stirred at 20 °C for 2 hr. The mixture was concentrated to give crude product. The crude product was adjusted to pH=7 using _NaHCO3 . The mixture was extracted using EA (3 × 20 mL). The combined _organic phases were washed with brine, dried over _Na2SO4 and concentrated to give crude product. The residue was purified by column chromatography (SiO ₂ , PE:EA = 50:1 to 2 : 1) to obtain 43B as a white solid (1 g, 80.27% yield).

To a solution of 43B (1 g, 4.03 mmol) in H ₂ O (10 mL) and dioxane (10 mL) was added LiOH·H ₂ O (422.94 mg, 10.08 mmol) at 20 °C. The mixture was stirred at 20°C for 6 hr. The mixture was adjusted to pH=3 using HCl (1 N) at 0 °C. The mixture was filtered, and the filter cake was dried under high vacuum to give the crude product, which was used directly in the next step without further purification. Compound 43C was obtained as a white solid (500 mg, 53.00% yield).

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 chloroformate (466.88 mg, 3.42 mmol, 448.93 uL). The mixture was stirred at 0°C for 1 hr and then ethylamine (231.17 mg, 5.13 mmol, 335.52 uL) was added at 0°C. The mixture was stirred at 20°C for 12 hr. The mixture was poured into water and extracted with ethyl acetate (3 × 10 mL). The combined _organic phases were washed with brine, dried over _Na2SO4 and concentrated to give crude product. The residue was purified by column chromatography (SiO ₂ , PE:EA = 50:1 to 3 : 1) to obtain 43D as a white solid (110 mg, 24.65% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

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). The mixture was stirred at 20°C for 12 hr. The mixture was poured into 5% NaHCO ₃ (10 mL) at 0 °C and extracted with EA (3 × 15 mL). The combined organic phases were washed with brine, dried over _Na2SO4 and concentrated to give the _crude product which was used directly in the next step without further purification. Compound 44 was obtained as a white solid (100 mg, 82.68% yield).

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 tributylstannylmethanol (167.77 mg, 522.49 umol). The mixture was stirred at 80°C for 12 hr. The mixture was filtered, and the filtrate was concentrated to give crude product. The crude product was triturated using EA (5 mL) for 30 min to afford 45 as a white solid (70 mg, 84.36% yield).

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

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) at 25°C was added N ,6-Dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-methamide (96.00 mg, 354.55 umol, HCl). The mixture was stirred at 80°C for 2 hr. The mixture was filtered and the filter cake was collected. By preparative 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.) and purified the filter cake to obtain A15 as a white solid (53.6 mg, 39.26% yield). ¹ H NMR: (400 MHz, CD ₃ OD- d ₄ ) δ 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 A16

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 chloroformate (875.41 mg, 6.41 mmol, 841.74 uL). The mixture was stirred at 0°C for 1 hr and then ethylamine (385.29 mg, 8.55 mmol, 559.20 uL) was added at 0°C. The mixture was stirred at 20°C for 12 hr. The mixture was poured into ice water (15 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with brine ₍ 30 mL), dried over _Na2SO4 and concentrated to give crude product. The residue was purified by column chromatography (SiO ₂ , PE:EA = 50:1 to 3 : 1) to afford 48 as a white solid (0.69 g, 61.85% yield).

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). The mixture was stirred at 25°C for 12 hr. The mixture was poured into 5% NaHCO ₃ (20 mL) at 0 °C and then extracted with EA (3 × 15 mL). The combined organic phases were washed with brine, dried over _Na2SO4 and concentrated to give the _crude product which was used directly in the next step without further purification. Compound 49 was obtained as a white solid (0.4 g, 56.84% yield).

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 tributylstannylmethanol (669.46 mg, 2.09 mmol). The mixture was stirred at 80°C for 12 hr. The mixture was filtered, and the filtrate was concentrated to give crude product. The crude product was triturated using EA (5 mL) for 30 min to obtain 50 (240 mg, 72.48% yield) as a white solid.

To a solution of 50 (240 mg, 1.01 mmol) in DCM (10 mL) was added SOCl ₂ (239.72 mg, 2.01 mmol, 146.17 uL) at 25 °C. The mixture was stirred at 25°C for 2 hr and then concentrated to give the product, which was used directly in the next step without further purification. Compound 51 was obtained as an off-white solid (240 mg, 92.81% yield).

) to 51 (60 mg, 233.77 umol, 1 equiv), NaBr (48.11 mg, 467.54 umol, 15.03 uL, 2 equiv) and DIEA (120.85 mg, 935.09 umol, 162.88 uL, 4 equiv) in MeCN at 25°C. (2 mL) was added N,6-dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-carboxamide (65.73 mg, 242.75 umol, 1.04 equiv, HCl). The mixture was then stirred at 80°C for 2 hr. LCMS showed the reaction was complete. The reaction solution was filtered, and the filter cake was collected. By preparative 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 purify the filter cake. A16 was obtained as a white solid (36.7 mg, 31.37% yield). ¹ H NMR: (400 MHz, CD ₃ OD- d ₄ ) δ 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 A17

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) at 25°C. and 1,4,7,10,13,16-hexaoxacyclooctadecane (211.89 mg, 801.63 umol). The mixture was stirred at 80°C for 12 hr. The mixture was poured into water (100 mL) and extracted with EA (3 × 30 mL). The combined organic phases were washed with brine ₍ 100 mL), dried over _Na2SO4 and concentrated to give crude product. The residue was purified by column chromatography (SiO ₂ , PE:EA = 50:1 to 3 : 1) to provide 30A as a white solid (1 g, 53.53% yield).

30A (0.8 g, 3.43 mmol), tert-butyl hexahydropyrazine-1-carboxylate (1.28 g, 6.87 mmol), Cs ₂ CO ₃ (2.24 g, 6.87 mmol), Pd ₂ (dba) ₃ ( A mixture of Xantphos (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 under _N2 atmosphere for 12 hr. The 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 52 as a white solid (0.9 g, 77.48% yield).

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

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) at 25 °C was added 6 -Fluoro-N-methyl-5-hexahydropyrazin-1-yl-pyridin-2-methamide (67.43 mg, 245.46 umol, HCl). The mixture was stirred at 80°C for 2 hr. The mixture was filtered and the filter cake was collected. By preparative 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.) The filter cake was purified to obtain A17 in the form of a white solid (41.2 mg, 38.44% yield). ¹ H NMR: (400 MHz, CD ₃ OD- d ₄ ) δ 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 A18

To a solution of 54A (1 g, 4.44 mmol) and N-ethyl-N-isopropyl-propane-2-amine (4.02 g, 31.09 mmol) in tetrahydrofuran (30 mL) was added dropwise at 0 °C. Isobutyl chloroformate (667.25 mg, 4.89 mmol) was added. The mixture was stirred at 0°C for 2 hr, and then methylamine hydrochloride (899.62 mg, 13.32 mmol) was added. The mixture was slowly warmed to 20°C and then stirred at 20°C for 14 hr. The reaction was stopped by adding ice water (50 mL) at 0°C. The mixture was diluted with EA (20 mL) and extracted with EA (3 × 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 (SiO ₂ , PE:EA = 100:1 to 9:11) to provide 54B as a white solid (560 mg, 52.93% yield).

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 in _H2 (15 Psi) and 20°C for 4 hr. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford 54C as a white solid (400 mg, 95.33% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

To a solution of 54C 400 mg, 1.92 mmol) and N,N-diethylethylamine (388.79 mg, 3.84 mmol) in tetrahydrofuran (6 mL) was added triphosgene (570.08 mg, 1.92 mmol) at 20°C. Solution in tetrahydrofuran (2 mL). The mixture was stirred at 20°C for 16 hr. The reaction was stopped by adding ice water (30 mL). The mixture was filtered and concentrated under reduced pressure to afford 54 as a yellow solid (400 mg, 88.90% yield).

To a solution of 54 (200 mg, 853.94 umol) in tetrahydrofuran (4 mL) was added lithium aluminum hydride (64.82 mg, 1.71 mmol) at 0 °C and _N2 . The mixture was stirred at 0°C for 0.5 hours. The reaction was stopped by adding water (0.1 mL), 15% NaOH (0.1 mL), and water (0.3 mL). The mixture was stirred at 0 °C for 30 min. The mixture was dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give crude product. The crude product was triturated using EA (10 mL) at 20 °C for 30 min, filtered and concentrated under reduced pressure to afford 55 as a pale yellow solid (170 mg, 96.55% yield).

To a solution of 55 (170 mg, 824.45 umol) in dichloromethane (4 mL) was added N,N-dimethylformamide (cat.) and thionyl dichloride at 0 °C and _N2 (196.17 mg, 1.65 mmol). The mixture was stirred at 20°C for 2 hr. The mixture was concentrated under reduced pressure to obtain crude product, which was used directly in the next step. Compound 56 was obtained as a yellow solid (180 mg, 97.19% yield).

To 56 (180 mg, 801.27 umol) and N,6-dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-carboxamide (225.28 mg, 961.52 umol) in acetonitrile (4 mL) N-ethyl-N-propan-2-ylpropan-2-amine (724.89 mg, 5.61 mmol) and NaBr (247.33 mg, 2.40 mmol) were added to the solution. The mixture was stirred at 80°C for 2 hr. The mixture was added to 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 obtain A18 as a light yellow solid (129.7 mg, 37.32% yield, 97.4% purity). ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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.

LC/MS: Gradient as follows: 5% B in 0.40 min and 5-95% B in 2.60 min, hold at 95% B in 1.00 min, and then 95-5% B in 0.01 min, flow rate 1.0 mL/min. Mobile phase A is 0.04% trifluoroacetic acid in water, and mobile phase B is 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography is Luna C18 50*2.0 mm column (5um particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range is 100-1000. Example 16 Compounds A19 and A20

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 stepwise at 0 °C. Isobutyl chloroformate (641.97 mg, 4.70 mmol) was added dropwise. After the addition, the mixture was stirred at this temperature for 2 hr, and then methylamine hydrochloride (865.53 mg, 12.82 mmol) was added. The mixture was slowly warmed to 20°C and stirred at 20°C for 14 hr. The mixture was added to ice water (40 mL) and extracted with EA (3 × 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 (SiO ₂ , PE:EA = 100:1 to 3 : 1) to provide 58 as a white solid (630 mg, 59.67% yield).

To a solution of 58 (630 mg, 2.55 mmol) and N,N-diethylethylamine (516.05 mg, 5.10 mmol) in tetrahydrofuran (9 mL) was added triphosgene (756.69 mg, 2.55 mmol) at 20°C. ) in tetrahydrofuran (3 mL). The mixture was stirred at 20°C for 16 hr. The reaction was quenched by adding ice water (50 mL), filtered and concentrated under reduced pressure to afford 59 as a pale yellow solid (600 mg, 86.17% yield). ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 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).

59 (600 mg, 2.20 mmol), tributylstannylmethanol (1.06 g, 3.30 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium/dicyclohexyl-[3-( A mixture of 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 under _N2 atmosphere for 16 hr. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was triturated using EA (20 mL) at 20 °C for 20 min, filtered and concentrated under reduced pressure to afford 60 as an off-white solid (400 mg, 81.20% yield).

To a solution of 60 (120 mg, 535.26 umol) in dichloromethane (2.5 mL) was added N,N-dimethylformamide (cat.) and thionyl dichloride at 0 °C and _N2 (127.36 mg, 1.07 mmol). The mixture was stirred at 20°C for 2 hr. The mixture was concentrated under reduced pressure to obtain crude product, which was used directly in the next step. Compound 61 was obtained as a yellow solid (120 mg, 92.40% yield).

To 61 (120 mg, 494.57 umol) and N,6-dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-carboxamide (139.05 mg, 593.49 umol) in acetonitrile (2.5 mL) N-ethyl-N-propan-2-ylpropan-2-amine (447.44 mg, 3.46 mmol) and NaBr (152.67 mg, 1.48 mmol) were added to the solution. The mixture was stirred at 80°C for 2 hr. The mixture was concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative HPLC (FA conditions, Phenomenex Luna 80*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 10%-35%, 8 min.) to obtain white color A19 in solid form (71.2 mg, 29.50% yield, 99.7% purity, FA). ¹ H NMR: (400 MHz, DMSO- d6 ) δ = 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.

To 61 (80 mg, 329.71 umol) and 6-fluoro-N-methyl-5-hexahydropyrazin-1-yl-pyridin-2-carboxamide (108.70 mg, 395.66 umol, HCl) 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 hr. The mixture was added to ice water (10 mL) and extracted with dichloromethane (3 × 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 preparative HPLC (FA conditions, Phenomenex Luna 80*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 5%-25%, 8 min.) to obtain A20 (67.3 mg, 40.78% yield, 98.0% purity, FA) and was obtained as a white solid. ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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.

LC/MS: Gradient as follows: 5% B in 0.40 min and 5-95% B in 2.60 min, hold at 95% B in 1.00 min, and then 95-5% B in 0.01 min, flow rate 1.0 mL/min. Mobile phase A is 0.04% trifluoroacetic acid in water, and mobile phase B is 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography is Luna C18 50*2.0 mm column (5 um particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range is 100-1000. Example 17 Compound A21

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 ethylamine (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 hr. The mixture was poured into water (35 mL) and extracted with EA (3 × 20 mL). The combined organic phases were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure to give crude _product . The residue was purified by column chromatography (SiO ₂ , PE:EA = 1:0 to 1 : 1) to obtain 63 as a white solid (1.1 g, 80.58% yield). ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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).

To a solution of 63 (1.3 g, 6.51 mmol) in THF (26 mL) was 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 hr and then filtered. The filter cake was collected and dried under high vacuum to give a residue which was used directly in the next step without further purification. Compound 64 was obtained as a yellow solid (600 mg, 40.84% yield).

To a solution of 64 (380 mg, 1.68 mmol) in MeOH (2 mL) was added TEA (340.84 mg, 3.37 mmol, 468.83 μL) and Pd(dppf)Cl ₂ (123.23 mg, 168.42 μmol) at 25°C. . The mixture was stirred at 80°C and CO (50 psi) for 12 hr. The mixture was filtered and the filter cake collected. The product was used directly in the next step without further purification. Compound 65 was obtained as a yellow solid (0.3 g, 71.47% yield). ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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).

To a solution of 65 (50 mg, 200.62 μmol) in THF (2 mL) was added _LiAlH (2.5 M, 64.20 μL) dropwise at _-10 °C and N. 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) were added to the mixture. The mixture was 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 directly in the next step without further purification. Compound 66 was obtained as a yellow solid (40 mg, 90.13% yield).

To a solution of 66 (80 mg, 361.64 μmol) in DCM (3 mL) was added dropwise _SOCl (86.05 mg, 723.29 μmol, 52.53 μL) at 0 °C and _N2 . The mixture was stirred at 20°C for 2 hr. The mixture was concentrated to give a residue which was used directly in the next step without further purification. Compound 67 was obtained as a brown solid (50 mg, 57.69% yield).

To 67 (100 mg, 443.20 μmol) and N,6-dimethyl-5-hexahydropyrazin-1-yl-pyridin-2-methamide (103.84 mg, 443.20 μmol) in MeCN at 25°C (0.5 mL), DIEA (343.68 mg, 2.66 mmol, 463.19 μL) and NaBr (136.81 mg, 1.33 mmol, 42.71 μL) were added. The mixture was stirred at 80°C for 2 hr. This reaction was used for conditional screening and discarded without further purification. By reversed-phase HPLC (0.1% FA conditions, Phenomenex luna C18 100*40 mm*5 um, mobile phase: [H ₂ O (0.2% FA)-ACN]; gradient: 1%-30% in 8.0 min. B) Purify the crude product to obtain A21 as a white solid (9.8 g, 5221.63% yield). ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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

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

A solution of 69 (1.7 g, 8.58 mmol) in HCl (10 mL) and MeOH (10 mL) was stirred at 80 °C for 2 hr. The mixture was diluted with water (100 mL) and extracted with EA (3 × 80 mL). The combined organic phases were washed with brine (150 mL), dried over Na ₂ SO ₄ and concentrated to give a residue, which was purified by column chromatography (SiO ₂ , PE:EA = 50:1 to 5:1) to 70 was obtained as a yellow solid (1 g, 50.42% yield).

70 (400 mg, 1.73 mmol), tert-butyl hexahydropyrazine-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 [1-(2-diphenylphosphatyl-1-naphthyl)-2-naphthyl]-diphenyl-phosphane (161.70 mg, 259.69 umol) in dioxane (8 The mixture in mL) was degassed and purged with _N2 (3x). The mixture was stirred at 100°C under _N2 atmosphere for 12 hr. 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 as a yellow solid (220 mg, 37.78% yield).

A mixture of 71 (200 mg, 594.56 μmol), methylamine (1.32 g, 42.50 mmol, 2 mL, 71.49) in MeOH (2 mL) was stirred at 25 °C under _N2 atmosphere for 3 hr. The mixture was concentrated to give the product which was used directly in the next step without further purification. Compound 72 was obtained as a pink solid (150 mg, 75.22% yield).

A mixture of 72 (150 mg, 447.23 μmol) in HCl/EtOAc (4 mL) was stirred at 25 °C for 2 hr. The mixture was concentrated to give the product which was used directly in the next step without further purification. Compound 73 was obtained as a pink solid (80 mg, 76.03% yield). ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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).

To 73 (80 mg, 294.39 μmol, HCl) and 7-(chloromethyl)-3-ethyl-1H-quinazoline-2,4-dione (70.26 mg, 294.39 μmol) at 25°C DIEA (190.24 mg, 1.47 mmol, 256.39 μL) and NaBr (90.87 mg, 883.18 μmol, 28.37 μL) were added to the solution in MeCN (0.5 mL). The mixture was stirred at 80°C for 2 hr and then concentrated to give a residue. Purified by reversed-phase HPLC (0.1% FA conditions, Phenomenex Luna C18 75 × 30 mm × 3 um; mobile phase: [water (FA)-CH ₃ CN]; B%: 1%-40%, 8 min.) The crude product was obtained as A22 (46.6 mg, 32.74% yield, FA salt) and obtained as a yellow solid. ¹ H NMR: (400 MHz, DMSO- d6 ) δ 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 Other compounds

Other compounds of formula (I) can be prepared using similar materials and methods described herein, such as those described herein. and (Including stereoisomers and/or pharmaceutically acceptable salts of any of the above). Example A PARP analysis FP binding analysis (PARP1 , PARP2)

PARP1 and PARP 2 proteins and PARPi-FL were purchased from BPS Bioscience. The analysis buffer system is 50 mM Tris (pH 8.0), 0.001% Triton X-100, 10 mM MgCl ₂ , and 150 mM NaCl. Compounds were diluted to peak concentration in 384PP plates and serially transferred to Optiplate-384F plates. Add compound (20 nL) or DMSO to the assay plate and then add 10 uL of 40 nM PARP1 or PARP2 (diluted with assay buffer). The assay plate was centrifuged at 1000 rpm for 1 min and then incubated at room temperature for 30 min. Add 6 nM PARPi-FL (diluted in assay buffer) (10 uL) to the plate (final concentration of PARP1 and PARP2 is 20 nM, and PARPi-FL is 3 nM). After centrifugation at 1000 rpm for 1 min, the assay plate was incubated at room temperature for 4 h. Use the Envision reading plate with excitation filter. Data analysis was performed by using mP values and calculating inhibition rates using the following equation. Inhibition (%) = (1-mpC-mpL)/mpH-mpL ×100%. Compound A1 has a PARP1 _IC50 of <0.01 µM. Proliferation analysis in DLD-1 wt and DLD-1 BRCA2 (PARP inhibitor )

DLD-1-wt and DLD-1 mutant cells were cultured in RPMI 1640+10%FBS+1%PS. Cells were harvested into culture medium and maintained for 2-3 days. Dilute cells into medium (density 2~3 × 10 ⁶ ) and 40 uL cell suspension (50 cells/well for DLD-1 wt and 50 cells/well for DLD-1 BRCA (-/-)) . Cover the plate and spin at 1000 rpm for 1 minute at room temperature and then transfer. Place the plate in a 37°C 5% _CO2 incubator overnight. Test compounds were dissolved in 10 mM DMSO stock solution and 40 uL of stock solution was then transferred to 384 PP plates. A 10-point dilution was performed by transferring 10 uL of compound into 30 μL DMSO using a TECAN (EVO200) liquid handler. The plate was spun at 1000 rpm for 1 minute at room temperature and then shaken on a plate shaker for 2 minutes. Transfer 40 nL of diluted compound to the cell plate by using a liquid handler. After 7 days of incubation, CTG detection analysis was performed. CTG detection analysis was performed by removing the plate from the incubator and then equilibrating at room temperature for 15 minutes. Thaw CellTiter Glo reagent and equilibrate at room temperature. CellTiter-Glo reagent (30 μL) was added to each well and the plate was left at room temperature for 30 minutes before reading on EnVision. Inhibitory activity was calculated using the following formula: % inhibition = 100 × (LumHC - Lum sample) / (LumHC - LumLC). The results of the analysis are provided in Table 2. In Table 2, "A" indicates IC ₅₀ < 0.1 µM, "B" indicates IC ₅₀ ≥ 0.1 µM and < 1.0 µM, and "C" indicates IC ₅₀ ≥ 1.0 µM.

As demonstrated by the results of two assays, compounds of formula (I), including pharmaceutically acceptable salts thereof, are potent PARP1 inhibitors. Table 2 compound PARP1 IC ₅₀ A1 A A2 C A3 C A4 A A5 A A6 C A7 B A8 A A9 C A10 A A11 A A12 B A13 C A14 C A15 A A16 A A17 A A18 A A19 B A20 A

Although the foregoing has been set forth in considerable detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will appreciate that many different modifications may be made without departing from the spirit of the invention. Therefore, it is expressly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the invention, but are intended to cover all modifications and variations within the true scope and spirit of the invention.

Claims (46)

A compound of formula (I) or a pharmaceutically acceptable salt thereof, which has the following structure: wherein: Ring A is selected from the group consisting of: pyrrole, thiophene, pyridine and phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl are optionally substituted, and when substituted, each is independently One or more partial substitutions selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy , unsubstituted C _1-4 haloalkoxy group and unsubstituted C _1-4 haloalkyl group; Ring B is selected from the group consisting of: unsubstituted or substituted 6-membered monocyclic nitrogen-containing heterocyclic group , unsubstituted or substituted 7-membered bicyclic nitrogen-containing heterocyclic group and unsubstituted or substituted 8-membered bicyclic nitrogen-containing heterocyclic group; n is 0 or 1; where n is 0, then ring C is Unsubstituted or substituted aryl, unsubstituted or substituted monocyclic heteroaryl or unsubstituted or substituted , wherein in the aryl group, the heteroaryl group and the When substituted, the aryl, the heteroaryl and the Substituted one or more times with a moiety independently selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _3-6 Cycloalkyl and unsubstituted C _1-4 haloalkyl; Ring D1 is phenyl, 5-membered heteroaryl or 6-membered heteroaryl; Ring D2 is selected from the group consisting of: unsubstituted or substituted , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded , unsubstituted or superseded and unsubstituted or superseded , where the asterisk indicates the point of attachment to ring D1; where when n is 1, ring C is selected from the group consisting of: pyrrole, thiophene, thiazole, pyridine, pyridazine, pyrimidine, pyrazine and phenyl, where The pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl are optionally substituted, and when substituted, each is substituted with a moiety independently selected from the group consisting of 1 or more times: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _{3- 6} cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl; R ¹ is selected from the group consisting of: hydrogen, unsubstituted C _1-4 alkyl , substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl, unsubstituted C _1-4 hydroxyalkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted Substituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl), substituted monocyclic C _3-6 cycloalkyl ( Unsubstituted C _1-4 alkyl), unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkenyl) and substituted monocyclic C _3-6 cycloalkyl (Unsubstituted C _1-4 alkenyl), wherein the substituted C _1-4 alkyl and the substituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) Substituted by 1 or more deuterium; R ² and R ³ are independently hydrogen, deuterium or unsubstituted C _1-4 alkyl; or R ² and R ³ and the carbon to which R ² and R ³ are connected together form an unsubstituted Substituted or substituted monocyclic C _3-6 cycloalkyl; m1 is 0, 1 or 2; m2 is 0, 1 or 2; R ^3a is deuterium, halogen, unsubstituted C _1-4 alkyl, Unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl; R ^3b is deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 Alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl; R ⁴ is -C(=O)NR ⁵ R ⁶ ; R ⁵ is hydrogen or unsubstituted C _1-4 alkyl; and R ⁶ is hydrogen, unsubstituted C _1-4 alkyl, substituted C _1-4 alkyl, unsubstituted monocyclic C _3-6 cycloalkyl, unsubstituted Substituted bicyclic C _5-8 cycloalkyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) or unsubstituted bicyclic C _5-8 cycloalkyl (Unsubstituted C _1-4 alkyl), wherein the substituted C _1-4 alkyl is substituted by 1 or more deuterium. The compound of claim 1, wherein ring A is unsubstituted pyrrole. The compound of claim 1, wherein ring A is a substituted pyrrole that is partially substituted one or more times independently selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkoxy and unsubstituted C _1-4 haloalkyl. The compound of claim 1, wherein ring A is unsubstituted thiophene. The compound of claim 1, wherein ring A is a substituted thiophene that is partially substituted one or more times independently selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkoxy and unsubstituted C _1-4 haloalkyl. The compound of claim 1, wherein ring A is unsubstituted pyridine. The compound of claim 1, wherein ring A is a substituted pyridine that is partially substituted one or more times independently selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkoxy and unsubstituted C _1-4 haloalkyl. The compound of claim 1, wherein ring A is an unsubstituted phenyl group. Such as the compound of claim 1, wherein ring A is a substituted phenyl group that is partially substituted one or more times independently selected from the following group: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium substitution C _1-4 alkyl, unsubstituted C _1-4 alkoxy, unsubstituted C _1-4 haloalkoxy and unsubstituted C _1-4 haloalkyl. Such as the compound of claim 1, wherein ring A is selected from the group consisting of: and . The compound of any one of claims 1 to 10, wherein ring B is an unsubstituted 6-membered monocyclic nitrogen-containing heterocyclic group. The compound of any one of claims 1 to 10, wherein ring B is a substituted 6-membered monocyclic nitrogen-containing heterocyclic group. The compound of any one of claims 1 to 10, wherein ring B is an unsubstituted 7- or 8-membered bicyclic nitrogen-containing heterocyclyl group. The compound of any one of claims 1 to 10, wherein ring B is a substituted 7- or 8-membered bicyclic nitrogen-containing heterocyclyl. The compound of any one of claims 1 to 10, wherein ring B is selected from the group consisting of: and . The compound of any one of claims 1 to 15, wherein n is 0; and ring C is an unsubstituted aryl group. The compound of any one of claims 1 to 15, wherein n is 0; and ring C is a substituted aryl group that is independently selected from the group consisting of one or more partially substituted aryl groups: deuterium, halogen, unsubstituted aryl Substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _3-6 cycloalkyl and unsubstituted C _1-4 haloalkyl. The compound of any one of claims 1 to 15, wherein n is 0; and Ring C is an unsubstituted heteroaryl group. The compound of any one of claims 1 to 15, wherein n is 0; and ring C is a substituted heteroaryl group that is independently selected from the group consisting of one or more partially substituted heteroaryl groups: deuterium, halogen, unsubstituted heteroaryl Substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _3-6 cycloalkyl and unsubstituted C _1-4 haloalkyl. Such as the compound of any one of claims 1 to 15, wherein n is 0; and ring C is unsubstituted . The compound of any one of claims 1 to 15, wherein n is 0; and Substituted one or more times with a moiety independently selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _3-6 Cycloalkyl and unsubstituted C _1-4 haloalkyl. Such as the compound of any one of claims 1 to 15, wherein n is 1; Ring C is selected from the group consisting of: unsubstituted pyrrole, unsubstituted thiophene, unsubstituted thiazole, unsubstituted Pyridine, unsubstituted pyridazine, unsubstituted pyrimidine, unsubstituted pyrazine and unsubstituted phenyl; and R ⁴ is -C(=O)NR ⁵ R ⁶ . The compound of any one of claims 1 to 15, wherein n is 1; Ring C is substituted pyrrole, substituted thiophene, substituted thiazole, substituted pyridine, substituted pyridazine, substituted pyrimidine, substituted pyrazine and substituted phenyl, each of which is substituted one or more times with a moiety independently selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl base, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl; And R ⁴ is -C(=O)NR ⁵ R ⁶ . The compound of any one of claims 1 to 15, wherein n is 1; ring C is unsubstituted pyridine; and R ⁴ is -C(=O)NR ⁵ R ⁶ . The compound of any one of claims 1 to 15, wherein n is 1; ring C is a substituted pyridine that is independently selected from the group consisting of one or more partially substituted pyridines: deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _2-4 alkenyl, unsubstituted monocyclic C _3-6 cycloalkyl (unsubstituted C _1-4 alkyl) and unsubstituted C _1-4 haloalkyl; and R ⁴ is -C(=O)NR ⁵ R ⁶ . The compound of any one of claims 1 to 15, wherein ring C is selected from the group consisting of: and . The compound of any one of claims 1 to 15, wherein ring C is selected from the group consisting of: and , each of which is optionally independently substituted one or more times with a moiety selected from the group consisting of: deuterium, halogen, unsubstituted C _1-4 alkyl and unsubstituted C _1-4 haloalkyl. The compound of any one of claims 1 to 27, wherein R ¹ is an unsubstituted C _1-4 alkyl group. The compound of any one of claims 1 to 27, wherein R ¹ is a substituted C _1-4 alkyl group. The compound of any one of claims 1 to 29, wherein R ² and R ³ are each hydrogen. The compound of any one of claims 1 to 30, wherein m1 is 0. The compound of any one of claims 1 to 30, wherein m1 is 1 or 2, wherein each R ^3a is independently deuterium, halogen, unsubstituted C _1-4 alkyl, unsubstituted C _{1- 4} haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl. The compound of any one of claims 1 to 32, wherein m2 is 0. The compound of any one of claims 1 to 32, wherein m2 is 1, wherein R ^3b is deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl. The compound of any one of claims 1 to 32, wherein m2 is 2, wherein each R ^3b is independently deuterium, halogen, unsubstituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl , unsubstituted C _1-4 haloalkyl or unsubstituted monocyclic C _3-6 cycloalkyl. Such as the compound of claim 1, which is selected from the group consisting of: and or a pharmaceutically acceptable salt of any of the above. Such as the compound of claim 1, which is selected from the group consisting of: and or a pharmaceutically acceptable salt of any of the above. Such as the compound of claim 1, which is selected from the group consisting of: and or a pharmaceutically acceptable salt of any of the above. A pharmaceutical composition, which includes a compound as claimed in any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof. The use of an effective amount of a compound as claimed in any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 39, for the manufacture of a medicament for the treatment of cancer. The use of claim 40, wherein the cancer is selected from the group consisting of: lung cancer, pancreatic cancer, colon cancer (such as colorectal cancer), myeloid leukemia (such as AML, CML and CMML), thyroid cancer, bone marrow cancer Adverse syndrome (MDS), bladder cancer, epidermal cancer, melanoma, breast cancer, prostate cancer, head and neck cancer (e.g. head and neck squamous cell carcinoma), ovarian cancer, brain cancer (e.g. glioma, e.g. glioblastoma multiforme) tumors), cancers of mesenchymal origin (such as fibrosarcoma and rhabdomyosarcoma), sarcomas, teratoma, neuroblastoma, renal cancer, hepatoma, non-Hodgkin's lymphoma, multiple myeloma or anaplastic thyroid cancer. The use of an effective amount of a compound as claimed in any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 39, for the manufacture of a medicament for inhibiting PARP1. A method of treating cancer, comprising administering an effective amount of a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 39 to a subject in need thereof. A method of treating cancer, which includes allowing cancer cells of a subject suffering from the cancer to be mixed with an effective amount of a compound as claimed in any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof or as claimed in claim 39 Contact with pharmaceutical compositions. The method of claim 43 or 44, wherein the cancer is selected from the group consisting of: lung cancer, pancreatic cancer, colon cancer (such as colorectal cancer), myeloid leukemia (such as AML, CML and CMML), thyroid cancer, Myelodysplastic syndrome (MDS), bladder cancer, epidermal cancer, melanoma, breast cancer, prostate cancer, head and neck cancer (such as head and neck squamous cell carcinoma), ovarian cancer, brain cancer (such as glioma, such as glial multiforme blastoma), cancers of mesenchymal origin (such as fibrosarcoma and rhabdomyosarcoma), sarcoma, teratoma, neuroblastoma, renal cancer, hepatoma, non-Hodgkin's lymphoma, multiple myeloma, or Anaplastic thyroid cancer. A method of inhibiting PARP1, comprising contacting a cell with an effective amount of a compound as claimed in any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 39, wherein the cell is a cancer cells.