PARP1 inhibitors and their uses

Abstract

To provide PARP1 inhibitors and uses thereof.SOLUTION: Described herein are PARP1 inhibitors and pharmaceutical compositions comprising the inhibitors. Subject compounds and compositions are useful for the treatment of cancer. Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient. A method of treating a cancer that is present in the brain in a subject in need thereof comprises administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 301,907, filed January 21, 2022, and U.S. Provisional Application No. 63 / 376,338, filed September 20, 2022, which are incorporated by reference herein in their entireties. [Background technology]

[0002] Poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) synthase (PARS) plays an important role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These actions make PARP inhibitors targets for a wide range of diseases. PARP inhibitors have demonstrated efficacy in numerous models of disease, particularly in models of ischemia-reperfusion injury, inflammatory diseases, degenerative diseases, protection from the deleterious effects of cytotoxic compounds, and enhancement of cytotoxic cancer therapy. PARP has also been implicated in retroviral infections, and thus inhibitors may be used in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurotrauma, organ transplantation, and reperfusion of the eye, kidney, gut, and skeletal muscle. Inhibitors are effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown utility in several models of degenerative diseases, including diabetes (and complications) and Parkinson's disease. PARP inhibitors can ameliorate liver toxicity after acetaminophen overdose, cardiac and renal toxicity from doxorubicin and platinum-based antineoplastic drugs, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, reducing metastasis, and prolonging the survival of tumor-bearing animals.

[0003] PARP1 and PARP2 are the most widely studied PARPs for their role in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyze the addition of poly (ADP-ribose) (PAR) chains to target proteins. This post-translational modification, known as PARylation, mediates the recruitment of additional DNA repair factors to the DNA lesion.

[0004] Following completion of this recruitment role, autoPARylation of PARP releases the bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Thus, the binding of PARP to the damage site, its catalytic activity, and its eventual release from DNA are all important steps by which cancer cells respond to DNA damage caused by chemotherapy drugs and radiation therapy.

[0005] Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Numerous preclinical and clinical studies have demonstrated that tumor cells harboring deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors are characterized by defects in the homologous recombination repair (HRR) pathway. These tumors are dependent on the function of the PARP enzyme for survival. PARP inhibitor therapy primarily targets SRCA-mutated cancers, but PARP inhibitors have not been shown to be effective against non-SRCA-mutated tumors, i.e., tumors that exhibit homologous recombination deficiency (HRD). Clinical trials are being conducted on elephants.

[0006] PARP inhibitors with improved selectivity for PARP1 are believed to have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. Selective and strong inhibition of PARP1 is also believed to trap PARP1 in DNA, leading to DNA double-strand breaks (DSBs) caused by the collapse of replication forks in S phase. PARP1-DNA trapping is also believed to be an effective mechanism for selectively killing tumor cells with HRD. Thus, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors with selectivity for PARP1. Summary of the Invention [Means for solving the problem]

[0007] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 is a deuteroalkyl; X is N or CR 3 and Y is N or CR 4 and Z is N or CR 5 and R 3 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 4 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 5 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R 6 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R or Or, two R's 6 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally selected from deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl or C 1 ~C 6 is substituted with heteroalkyl; Each R 7 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl or C 2 ~C 6 alkynyl, or Or, two R on the same carbon 7 together to form oxo, or Or, two R on the same or different carbons 7taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4; T is N or CR 8 and U is N or CR 9 and R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 12 is cyano or halogen; Each R a is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently deuterium, halogen, -CN, -OH, -OC 1 ~C 6 Alkyl, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 Alkyl) 2 , -NHC(=O)OC 1 ~C 6 Alkyl, -C(=O)C 1 ~C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 ~C 6 Alkyl, -C(=O)NH 2 , -C(=O)N(C 1 ~C 6 Alkyl) 2 , -C(=O)NHC 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl or C 1 ~C 6 Heteroalkyl, or or two R on the same atom taken together form an oxo; However, X is CR 3 and Y is CR 4 and Z is CR 5 If R3 , R 4 , and R 5 One of the atoms is not hydrogen but R. 4 is not -OMe, However, when X is CH, Y is CH, and Z is CH, then R 2 is not hydrogen.

[0008] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0009] Also disclosed herein is a method of treating a cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method of treating a cancer comprising a mutation in a gene that confers a homologous repair deficiency in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene that confers a homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof. In some embodiments, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0010] A method of treating cancer present in the brain in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. A method of treating brain cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0011] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The present invention provides, for example, the following items. (Item 1) A compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 is a deuteroalkyl; X is N or CR 3 and Y is N or CR 4 and Z is N or CR 5 and R 3 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 4 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 5 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R 6 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Or, two R's 6 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally selected from deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl or C 1 ~C 6 is substituted with heteroalkyl; Each R 7 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl or C 2 ~C 6 alkynyl, or Or, two R on the same carbon 7together to form oxo, or Or, two R on the same or different carbons 7 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4; T is N or CR 8 and U is N or CR 9 and R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R; R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R; R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more R; R 12 is cyano or halogen; Each R a is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently deuterium, halogen, -CN, -OH, -OC 1 ~C 6 Alkyl, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 Alkyl) 2 , -NHC(=O)OC 1 ~C 6 Alkyl, -C(=O)C 1 ~C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 ~C 6 Alkyl, -C(=O)NH 2 , -C(=O)N(C 1 ~C 6 Alkyl) 2 , -C(=O)NHC 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl or C 1 ~C 6 Heteroalkyl, or or two R on the same atom taken together form an oxo; However, X is CR 3 and Y is CR 4 and Z is CR 5 If R3 , R 4 , and R 5 One of the atoms is not hydrogen but R. 4 is not -OMe, However, when X is CH, Y is CH, and Z is CH, then R 2 is not hydrogen, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 2) 2. The compound according to item 1, wherein X is N, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 3) X is CR 3 2. The compound according to item 1, wherein: (Item 4) 4. The compound according to any one of items 1 to 3, wherein Y is N, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 5) Y is CR 4 4. The compound according to any one of items 1 to 3, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, (Item 6) 6. The compound according to any one of items 1 to 5, wherein Z is N, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 7) Z is CR 5 6. The compound according to any one of items 1 to 5, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, (Item 8) 2. The compound according to item 1, wherein the compound is of formula (Ia), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. [ka] (Item 9) 2. The compound according to item 1, wherein the compound is of formula (Ib), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. [ka] (Item 10) 2. The compound according to item 1, wherein the compound is of formula (Ic), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [ka] (Item 11) The compound is of formula (Id) [ka] In the formula, R 3 , R 4 , and R 5 One of the atoms is not hydrogen but R. 4 is not -OMe, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 12) The compound is of formula (Ie) [ka] In the formula, R 2 Deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 2. The compound according to claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is deuteroalkyl. (Item 13) R 1 But halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 613. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is alkynyl, or cycloalkyl. (Item 14) R 1 But, C 1 ~C 6 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl or cycloalkyl. (Item 15) R 1 But, C 1 ~C 6 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 16) R 1 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: is cycloalkyl. (Item 17) R 1 13. The compound according to any one of items 1 to 12, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen. (Item 18) R 2 18. The compound according to any one of items 1 to 17, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen or halogen. (Item 19) R 2 19. The compound according to any one of items 1 to 18, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen. (Item 20) R 3 is hydrogen, halogen, or C 1 ~C 6 20. The compound according to any one of items 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 21) R 321. The compound according to any one of items 1 to 20, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen or halogen. (Item 22) R 3 22. The compound according to any one of items 1 to 21, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen. (Item 23) R 4 is hydrogen, halogen, or C 1 ~C 6 23. The compound according to any one of items 1 to 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 24) R 4 24. The compound according to any one of items 1 to 23, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen or halogen. (Item 25) R 4 25. The compound according to any one of items 1 to 24, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen. (Item 26) R 5 is hydrogen, halogen, or C 1 ~C 6 26. The compound according to any one of items 1 to 25, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 27) R 5 27. The compound according to any one of items 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen or halogen. (Item 28) R 5 28. The compound according to any one of items 1 to 27, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen. (Item 29) Each R 6 are independently hydrogen, deuterium, or C 1 ~C 629. The compound according to any one of items 1 to 28, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 30) On the other hand, R 6 is hydrogen, and the other R 6 But, C 1 ~C 6 30. The compound according to any one of items 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 31) Each R 6 30. The compound according to any one of items 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is deuterium. (Item 32) Each R 6 But independently, C 1 ~C 6 30. The compound according to any one of items 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 33) Each R 6 30. The compound according to any one of items 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen. (Item 34) Each R 7 But independently, C 1 ~C 6 34. The compound according to any one of items 1 to 33, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 35) Two R on the same or different carbons 7 or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein taken together, form a cycloalkyl. (Item 36) 36. The compound according to any one of items 1 to 35, wherein n is 0 or 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 37) 36. The compound according to any one of items 1 to 35, wherein n is 1 or 2, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 38) [ka] 38. The compound according to any one of items 1 to 37, wherein: (Item 39) [ka] 38. The compound according to any one of items 1 to 37, wherein: (Item 40) R 8 Hydrogen, halogen, -CN, -OR a , C 1 ~C 6 Alkyl or C 1 ~C 6 40. The compound according to any one of items 1 to 39, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl. (Item 41) R 9 But hydrogen, halogen, -C 1 ~C 6 Alkyl, C 1 ~C 6 41. The compound according to any one of items 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl, or cycloalkyl. (Item 42) R 10 However, hydrogen, halogens, C 1 ~C 6 Alkyl or C 1 ~C 6 42. The compound according to any one of items 1 to 41, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl. (Item 43) R 11 However, hydrogen, halogens, C 1 ~C6 Alkyl or C 1 ~C 6 43. The compound according to any one of items 1 to 42, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl. (Item 44) R 12 44. The compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is cyano. (Item 45) R 12 44. The compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen. (Item 46) R 12 44. The compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is fluoro or chloro. (Item 47) A compound according to item 1, selected from the compounds in Table 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 48) A pharmaceutical composition comprising a compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient. (Item 49) 48. A method of treating cancer in a subject in need thereof, comprising administering a compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 50) 50. The method of claim 49, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer, or lung cancer. (Item 51) 48. A method of treating cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, comprising administering a compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 52) 48. A method of treating a cancer comprising a mutation in a gene that confers a homologous repair deficiency in a subject in need thereof, comprising administering a compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 53) 53. The method of claim 52, wherein the mutation in a gene that confers homology repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof. (Item 54) 54. The method according to any one of items 49 to 53, wherein the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer. (Item 55) 55. The method according to any one of items 49 to 54, wherein the cancer is a metastatic cancer. (Item 56) 56. The method of any one of items 49 to 55, wherein the cancer has metastasized to the brain. (Item 57) 48. A method of treating cancer present in the brain in a subject in need thereof, comprising administering a compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. (Item 58) 48. A method for treating brain cancer in a subject in need thereof, comprising administering a compound according to any one of items 1 to 47, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one of ordinary skill in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, the word "comprise" and variations thereof, such as "comprises" and "comprising" are used throughout the following specification and claims. ) should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Moreover, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0013] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0014] As used herein, the following terms have the following meanings unless otherwise indicated.

[0015] "Oxo" refers to =O.

[0016] "Carboxyl" refers to --COOH.

[0017] "Cyano" refers to -CN.

[0018] "Alkyl" refers to straight or branched chain saturated hydrocarbon monoradicals having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Whenever appearing herein, "C 1 ~C 6 Alkyl" or "C 1 ~ 6 Numeric ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of the groups listed below. 1 ~ 10 In some embodiments, alkyl is C 1 ~ 6 In some embodiments, alkyl is C 1 ~ 5 In some embodiments, alkyl is C 1 ~ 4 In some embodiments, alkyl is C 1 ~ 3Unless otherwise specifically stated in the specification, alkyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0019] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include ethenyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH 3 =CH 2 ], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, "C 2 ~C 6 alkenyl" or "C 2 ~ 6Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, alkenyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkenyl is oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0020] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Whenever it appears herein, "C 2 ~C 6 alkynyl" or "C 2 ~ 6Numerical ranges such as "alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0021] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is an oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0022] "Alkoxy" means a group of the formula -OR a R refers to the radical of ais an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0024] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C 3 ~C 15 Cycloalkyl or C 3 ~C 15 cycloalkenyl), 3 to 10 carbon atoms (C 3 ~C 10 Cycloalkyl or C 3 ~C 10 cycloalkenyl), 3 to 8 carbon atoms (C 3 ~C 8 Cycloalkyl or C 3 ~C 8 cycloalkenyl), 3 to 6 carbon atoms (C 3 ~C 6 Cycloalkyl or C 3 ~C 6 cycloalkenyl), 3 to 5 carbon atoms (C 3 ~C 5 Cycloalkyl or C 3 ~C 5 cycloalkenyl), or 3 to 4 carbon atoms (C 3 ~C 4 Cycloalkyl or C 3 ~C 4Examples of monocyclic cycloalkyls include, but are not limited to, cycloalkyls having a cyclic ring structure (cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with, for example, oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0025] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0026] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0027] "Hydroxyalkyl" refers to an alkyl radical, as defined above, substituted with one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyls include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyls include, for example, CD 3 , C.H. 2 D, C.H.D. 2 , C.H. 2 CD 3 , CD 2 CD 3 , C.H.D.C. 3 , C.H. 2 CH 2 D or CH 2 C.H.D. 2 In some embodiments, the deuteroalkyl is CD 3 It is.

[0030] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C 1 ~C 6 Heteroalkyl, which is composed of 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and which is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3 )OCH 3, -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N(CH 3 ) 2 Unless stated otherwise specifically in the specification, heteroalkyl is optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0031] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless stated otherwise specifically in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C 2 ~C 15 Heterocycloalkyl or C 2 ~C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C 2 ~C 10 Heterocycloalkyl or C 2 ~C 10 heterocycloalkenyl), 2 to 8 carbon atoms (C 2 ~C 8 Heterocycloalkyl or C 2 ~C 8 heterocycloalkenyl), 2 to 7 carbon atoms (C 2 ~C 7 Heterocycloalkyl or C 2 ~C 7heterocycloalkenyl), 2 to 6 carbon atoms (C 2 ~C 6 Heterocycloalkyl or C 2 ~C 6 heterocycloalkenyl), 2 to 5 carbon atoms (C 2 ~C 5 Heterocycloalkyl or C 2 ~C 5 heterocycloalkenyl), or 2 to 4 carbon atoms (C 2 ~C 4 Heterocycloalkyl or C 2 ~C 4Examples of such heterocycloalkyl radicals include, but are not limited to, heterocycloalkyl having a heterocycloalkenyl group. Examples of such heterocycloalkyl radicals include aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidin ... Examples of heterocycloalkyl include, but are not limited to, pyrazolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl.In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, the heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF. 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0032] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, may contain fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized, and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, Examples include, but are not limited to, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyranidyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0033] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances where the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Additionally, an optionally substituted group can be an unsubstituted (e.g., -CH 2 CH 3 ), full substitutions (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F), or substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 One of ordinary skill in the art will understand that with respect to any group that contains one or more substituents, such groups are not intended to introduce any substitutions or substitution patterns that are sterically impractical and / or synthetically unfeasible (e.g., substituted alkyl may continue indefinitely as defined to include an optionally substituted cycloalkyl group, which in turn includes an optionally substituted alkyl group). Thus, any substituents described should generally be understood to have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

[0034] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the subject group is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the subject group is optionally substituted with 1 or 2 substituents. In some embodiments, the subject group is optionally substituted with 1 substituent. In some embodiments, the subject group is optionally substituted with 2 substituents.

[0035] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, that is effective to produce the desired therapeutic effect.

[0036] The terms "treat", "treated", "treatment", or "treating" as used herein refer to therapeutic treatment, the purpose of which is to delay (alleviate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical outcome. For purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the extent of the condition, disorder, or disease; stabilization (i.e., not worsening) of the appearance of the condition, disorder, or disease; delay in onset or slowing of progression of the condition, disorder, or disease; improvement of the condition, disorder, or disease state; and remission (whether partial or total), or enhancement or amelioration, whether detectable or undetectable, of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival in the absence of treatment. The terms "treat", "treated", "treatment", or "treating", as well as words derived therefrom, as used herein, do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that one of skill in the art will recognize as having potential benefit or therapeutic effect. In this regard, the disclosed methods can provide any amount of any level of treatment of a disorder in a mammal. For example, a disorder, including its symptoms or conditions, can be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. "Synergy" or "synergizing" refers to an effect of the combination that is greater than the additive effect of each component alone at the same dose.

[0037] As used herein, "PARP-associated disease or disorder" or "PARP-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.

[0038] As used herein, "PARP1-associated disease or disorder" or "PARP1-mediated disease or disorder" means any disease or other deleterious condition in which PARP1 or a mutant thereof is known or suspected to play a role.

[0039] compound Described herein are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, that are useful for the treatment of cancer.

[0040] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6Haloalkyl, or C 1 ~C 6 is a deuteroalkyl; X is N or CR 3 and Y is N or CR 4 and Z is N or CR 5 and R 3 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 4 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 5 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R 6 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R or Or, two R's 6taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally selected from deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl or C 1 ~C 6 is substituted with heteroalkyl; Each R 7 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl or C 2 ~C 6 alkynyl, or Or, two R on the same carbon 7 together to form oxo, or Or, two R on the same or different carbons 7 taken together to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4; T is N or CR 8 and U is N or CR 9and R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 10is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 12 is cyano or halogen; Each R a is independently1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene(heteroaryl), where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently deuterium, halogen, -CN, -OH, -OC 1 ~C 6 Alkyl, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 Alkyl) 2 , -NHC(=O)OC 1 ~C 6 Alkyl, -C(=O)C 1 ~C 6 Alkyl, -C(=O)OH, -C(=O)OC 1 ~C 6 Alkyl, -C(=O)NH 2 , -C(=O)N(C 1 ~C 6 Alkyl) 2 , -C(=O)NHC 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl or C 1 ~C 6 Heteroalkyl, or or two R on the same atom taken together form an oxo; However, X is CR 3 and Y is CR 4 and Z is CR 5 If R 3 , R 4 , and R 5 One of the atoms is not hydrogen but R. 4 is not -OMe, However, when X is CH, Y is CH, and Z is CH, then R 2 is not hydrogen.

[0041] In some embodiments of the compound of Formula (I), the compound is not 7-(1-(4-(2,4-difluorophenyl)piperazin-1-yl)ethyl)-3-methylquinolin-2(1H)-one.

[0042] In some embodiments of the compound of Formula (I), the compound is not 7-((4-(3,4-dichlorophenyl)piperazin-1-yl)methyl)-3-ethylquinolin-2(1H)-one.

[0043] In some embodiments of the compound of Formula (I), the compound is not 7-((5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)-3-ethylquinolin-2(1H)-one.

[0044] In some embodiments of the compound of Formula (I), the compound is not 6-(4-(cyclohexyl(3-methyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)nicotinonitrile.

[0045] In some embodiments of the compound of Formula (I), the compound is not 6-(4-((3-ethyl-5-methoxy-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)nicotinonitrile.

[0046] In some embodiments of the compound of Formula (I), the compound is not 6-(4-(2-methyl-1-(3-methyl-2-oxo-1,2-dihydroquinolin-7-yl)propyl)piperazin-1-yl)nicotinonitrile.

[0047] In some embodiments of the compound of Formula (I), the compound is not 6-(4-((3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)methyl)piperazin-1-yl)nicotinonitrile.

[0048] In some embodiments of the compound of Formula (I), the compound is not 6-(4-(1-(3-ethyl-2-oxo-1,2-dihydroquinolin-7-yl)-2-methylpropyl)piperazin-1-yl)nicotinonitrile.

[0049] In some embodiments of the compounds of Formula (I), X is N. In some embodiments of the compounds of Formula (I), X is CR 3 It is.

[0050] In some embodiments of the compounds of Formula (I), Y is N. In some embodiments of the compounds of Formula (I), Y is CR 4 It is.

[0051] In some embodiments of the compounds of Formula (I), Z is N. In some embodiments of the compounds of Formula (I), Z is CR 5 It is.

[0052] In some embodiments of the compounds of Formula (I), X is N and Y is N or CR 4 and Z is N or CR 5 In some embodiments of the compound of Formula (I), X is N or CR 3 and Y is N and Z is N or CR 5 In some embodiments of the compound of Formula (I), X is N or CR 3 and Y is N or CR 4 and Z is N. In some embodiments of the compound of Formula (I), one of X, Y, or Z is N. In some embodiments of the compound of Formula (I), two of X, Y, or Z are N. In some embodiments of the compound of Formula (I), X is CR 3 and Y is CR 4 and Z is CR 5 In some embodiments of the compound of formula (I), X is CH, Y is CH, and Z is CH. In some embodiments of the compound of formula (I), X is CR 3 and Y is N and Z is CR 5In some embodiments of the compound of formula (I), X is CH, Y is N, and Z is CH. In some embodiments of the compound of formula (I), X is N, and Y is CR 4 and Z is CR 5 In some embodiments of the compound of Formula (I), X is N, Y is CH and Z is CH.

[0053] In some embodiments of the compound of Formula (I), the compound is of Formula (Ia): [ka]

[0054] In some embodiments of the compound of Formula (I), the compound is of Formula (Ib). [ka]

[0055] In some embodiments of the compound of Formula (I), the compound is of Formula (Ic). [ka]

[0056] In some embodiments of the compound of Formula (I), the compound is of Formula (Id): [ka] In the formula, R 3 , R 4 , and R 5 One of the atoms is not hydrogen but R. 4 is not -OMe.

[0057] In some embodiments of the compound of Formula (I), the compound is of Formula (Ie): [ka] In the formula, R 2Deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl or C 1 ~C 6 It is a deuteroalkyl.

[0058] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R.

[0059] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 are hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, where the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1are hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, where the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is a halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 2 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1is methyl or ethyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is a halogen, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is halogen or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is fluoro or chloro. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 1 is chloro.

[0060] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is hydrogen, deuterium, halogen, -OR a , C 1 ~C 6 Alkyl or C 1 ~C 6In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is hydrogen, halogen, -OR a , or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 -OR a In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 -OCF 3 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 ~C 2 Alkyl, C 1 ~C 2 Haloalkyl, or C 1 ~C 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is hydrogen, halogen, -OR a , or C 1 ~C 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is halogen, -OR a , or C 1 ~C 2 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 2 is halogen or C 1~C 2 It is an alkyl.

[0061] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is hydrogen, deuterium, halogen, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is hydrogen, halogen, -OR a , or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is hydrogen, halogen, or C 1 ~C 6 It is an alkyl.

[0062] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is hydrogen or halogen.

[0063] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 3 is not hydrogen.

[0064] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is hydrogen, deuterium, halogen, -CN, -NR c R d , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 alkynyl, cycloalkyl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is hydrogen, deuterium, halogen, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is hydrogen, halogen, -OR a , or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is hydrogen, halogen, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 4 is not hydrogen.

[0065] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5is hydrogen, deuterium, halogen, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5 is hydrogen, halogen, -OR a , or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5 is hydrogen, halogen, or C 1 ~C 6 It is an alkyl.

[0066] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5 is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 5 is not hydrogen.

[0067] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 6 are independently hydrogen, deuterium, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 6 are independently hydrogen, deuterium, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), one R 6 is hydrogen, and the other R6 is C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 6 is independently 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 6 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), two R 6 together form a cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), two R 6 together to form a cyclopropyl group.

[0068] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 7 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), each R 7 is independently 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), two R on the same or different carbons are alkyl. 7 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), two R on the same or different carbons are 7 together to form a cyclopropyl group.

[0069] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 0 or 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 0-2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 1 or 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), n is 4.

[0070] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), T is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), T is CR 8 It is.

[0071] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), U is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), U is CR 9 It is.

[0072] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), [ka] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), [ka] It is.

[0073] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 8 is hydrogen, halogen, -CN, -OR a , C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 8 is hydrogen, halogen, -CN, -OR a , or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 8 is hydrogen, halogen, or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 8 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 8 is hydrogen.

[0074] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 9 is hydrogen, deuterium, halogen, -CN, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R9 is hydrogen, halogen, -C 1 ~C 6 Alkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 9 is hydrogen, halogen, or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 9 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 9 is hydrogen.

[0075] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 10 are hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 10 is hydrogen, halogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 10 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 10 is hydrogen.

[0076] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 11 are hydrogen, deuterium, halogens, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 11 is hydrogen, halogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 11 is hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 11 is hydrogen.

[0077] In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 12 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 12 is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 12 is fluoro or chloro. In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 12 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 12 In some embodiments of the compounds of Formula (I) or (Ia)-(Ie), R 12is fluoro or bromo.

[0078] In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene (heteroaryl), where each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 Alkyl, C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 In some embodiments of the compounds disclosed herein, each R a is independently 1 ~C 6 It is haloalkyl.

[0079] In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 alkylene (heteroaryl), where each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b are independently hydrogen or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b is independently 1 ~C 6 In some embodiments of the compounds disclosed herein, each R b is independently 1 ~C 6 It is haloalkyl.

[0080] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6alkylene (heteroaryl), where each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, cycloalkyl, or heterocycloalkyl, each of which is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Aminoalkyl, C 1 ~C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 ~C 6 Alkylene (cycloalkyl), C 1 ~C 6 Alkylene (heterocycloalkyl), C 1 ~C 6 Alkylene (aryl), or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen or C 1 ~C 6 In some embodiments of the compounds disclosed herein, each R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d is independently 1 ~C 6 In some embodiments of the compounds disclosed herein, each R c and R d is independently 1 ~C 6 It is haloalkyl.

[0081] In some embodiments of the compounds disclosed herein, each R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0082] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC 1 ~C 6 Alkyl, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Deuteroalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C6 Aminoalkyl or C 1 ~C 6 or heteroalkyl, or two R on the same atom taken together form oxo. In some embodiments of the compounds disclosed herein, each R is independently selected from deuterium, halogen, -CN, -OH, -OC 1 ~C 6 Alkyl, -NH 2 , -NHC 1 ~C 6 Alkyl, -N(C 1 ~C 6 Alkyl) 2 , C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl or C 1 ~C 6 or two R on the same atom taken together form oxo. In some embodiments of the compounds disclosed herein, each R is independently selected from deuterium, halogen, -CN, -OH, -OC 1 ~C 6 Alkyl, -NH 2 , C 1 ~C 6 Alkyl or C 1 ~C 6 haloalkyl, or two R on the same atom taken together form oxo.

[0083] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, such groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0084] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is selected from the compounds in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0085] The absolute label (abs) is added to the chiral center to indicate that it is a pure sample of the specifically depicted stereoisomer.

[0086] The OR label (or) indicates a pure substance, but the absolute configuration of the stereochemical centers is unknown. After chiral separation with isolated pure structures, multiple OR labels with the same numerical value (OR indicates purity) indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical centers is unknown).

[0087] The AND sign (and) indicates that both isomers are present at the indicated stereochemical center. Assigning different numerical values ​​to the AND signs indicates that they are independent of each other. Use of AND signs with the same value indicates that the two stereocenters are related to each other and can only change in concert.

[0088] In some embodiments, a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is [ka] is selected from.

[0089] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, with each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers obtained from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0090] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those listed herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, as well as pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Those in which a radioactive isotope, such as C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavy isotopes, such as deuterium, i.e. 2 Substitution with, for example, H, may provide certain therapeutic advantages through greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0091] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0092] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0093] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0094] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, or the like. Salt, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, iodide. Examples of suitable salts include phosphate, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0095] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, These include, but are not limited to, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, are not themselves pharmaceutically acceptable but are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0096] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations, with ammonia, or with pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, as well as aluminum salts. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 Alkyl) 4 etc.

[0097] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0098] solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention further provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0099] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed during the process of crystallization using pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0100] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the scope of the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0101] Treatment method Disclosed herein is a method for treating a disease in which inhibition of PARP is beneficial, the method comprising administering a compound disclosed herein. Also disclosed herein is a method for treating a disease in which inhibition of PARP1 is beneficial, the method comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer. In some embodiments, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

[0102] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0103] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0104] In some embodiments, the cancer containing a BRCA1 and / or BRCA2 mutation is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

[0105] In some embodiments, the cancer is a cancer with a deficiency in Flomologous Recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via a homologous mechanism and reforms a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), and MRE1 1. A (NM_005590), and NBS1 (NM_002485). FIR-dependent DNA Other proteins involved in the DSB repair pathway include regulators such as EMSY. In some embodiments, a cancer that is deficient in FIR-dependent DNA DSB repair comprises one or more cancer cells that have reduced or eliminated ability to repair DNA DSBs via that pathway compared to normal cells, i.e., activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in one or more cancer cells.

[0106] In some embodiments, activity of one or more components of the FIR-dependent DNA DSB repair pathway is impaired in one or more cancer cells of an individual having a cancer that is deficient in FIR-dependent DNA DSB repair.

[0107] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Cancer cells with this phenotype may be deficient in BRCA1 and / or BRCA2, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, by mutation or polymorphism in the coding nucleic acid, or by amplification, mutation or polymorphism in a gene encoding a regulator, for example, the EMSY gene encoding the BRCA2 regulator. BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene encoding a BRCA2 binding factor is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at increased risk of certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal, and lung cancers.

[0108] Also disclosed herein are methods of treating cancer comprising a mutation in a gene that confers a homologous repair deficiency in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene that confers a homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof.

[0109] Also disclosed herein is a method for treating cancer located in the brain, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0110] In some embodiments, the cancer present in the brain arises from a primary peripheral tumor that has metastasized to the brain, hi some embodiments, the cancer present in the brain arises from primary brain tissue.

[0111] Also provided herein is a method for treating brain cancer, the method comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0112] In some embodiments, the brain cancer is a primary brain tumor, which tends to start in the brain and stay there.

[0113] In some embodiments, the brain cancer is a secondary brain tumor. These cancers begin elsewhere in the body and travel to the brain. Lung, breast, kidney, colon, and skin cancers are among the most common cancers that spread to the brain.

[0114] In some embodiments, the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are capable of crossing the blood brain barrier (BBB). In some embodiments, the ratio of the compound that penetrates the BBB is >0.1, with 1 being complete BBB penetration and 0 being no penetration. In some embodiments, the ratio of the compound that penetrates the BBB is >0.2. In some embodiments, the ratio of the compound that penetrates the BBB is >0.3. In some embodiments, the ratio of the compound that penetrates the BBB is measured using a rat kp,uu assay. In some embodiments, the compound has a ratio of >0.3 (i.e., 0.3 to 1) as determined by the rat kp,uu assay.

[0115] Administration In certain embodiments, a composition containing a compound described herein is administered for prophylactic and / or therapeutic treatment. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, the patient's medical history, health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0116] In prophylactic uses, a composition containing a compound described herein is administered to a patient who is susceptible to or otherwise at risk of developing a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the patient's health status, weight, etc. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder, or condition, the patient's medical history, health status and response to the drug, as well as the judgment of the treating physician. In one aspect, prophylactic treatment involves administering to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, to prevent recurrence of the symptoms of the disease or condition.

[0117] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, the administration of the compound is continued long term, i.e., over a long period including the entire lifespan of the patient, to improve or otherwise control or limit the symptoms of the patient's disease or condition.

[0118] In certain embodiments where the patient's condition improves, the dose of the drug being administered is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday is, by way of example only, between 10% and 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0119] Once the patient's condition has improved, a maintenance dose is administered as needed. In specific embodiments, the dosage or frequency of administration, or both, are then reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. However, in certain embodiments, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0120] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0121] In general, however, the dose used for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In one aspect, the dose used for adult treatment is about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more divided doses per day.

[0122] In one embodiment, a suitable daily dosage for the compounds described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of active agent in the dosage form is lower or higher than the ranges set forth herein, based on a number of variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on a number of variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the physician's judgment.

[0123] The toxicity and therapeutic efficacy of such treatment regimens include, but are not limited to, LD 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is sufficient to achieve an ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0124] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is (a) administered systemically to the mammal, and / or (b) administered orally to the mammal, and / or (c) administered intravenously to the mammal, and / or (d) administered by injection to the mammal, and / or (e) administered locally to the mammal, and / or (f) administered non-systemically or locally to the mammal.

[0125] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times over a daily period to the mammal.

[0126] In any of the above aspects, further embodiments include multiple administration of an effective amount of the compound, including further embodiments where (i) the compound is administered continuously or intermittently as a single dose, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, or (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from two days to one year.

[0127] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Additionally, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, and intrathecal injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0128] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a fast-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0129] Pharmaceutical Compositions / Formulations The compounds described herein are administered to subjects in need of the compounds described herein, either alone or in combination with a pharma- ceutically acceptable carrier, excipient or diluent in a pharmaceutical composition, according to standard pharmaceutical practice.In one embodiment, the compounds of the present invention can be administered to animals.The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0130] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharma- ceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharma- ceutical acceptable excipients that facilitate processing of the active compound into a pharma- ceutical usable preparation. The appropriate formulation depends on the route of administration selected. A summary of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995), Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975, Liberman, HAand Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0131] In some embodiments, the pharma- ceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegration agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0132] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0133] Pharmaceutical compositions containing a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured in a conventional manner, including, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0134] Pharmaceutical compositions for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and optionally processing the mixture of granules after adding suitable auxiliary agents to obtain tablets or dragee cores.Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.Optionally, disintegrants are added, such as cross-linked-croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0135] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in a mixture of filler such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optional stabilizers. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0136] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the compounds described herein or their pharma- ceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent the growth of microorganisms.

[0137] combination Disclosed herein are methods of treating cancer using the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0138] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0139] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. EXAMPLES

[0140] The compounds described herein are synthesized as generally depicted in General Scheme 1 and General Scheme 2. General Scheme 1 [ka] General Scheme 2 [ka]

[0141] Example 1 [ka] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine: To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv.) in MeOH (50 mL), NaOMe (15.76 g, 87.49 mmol, 1.10 equiv., 30 wt%) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (Pet. Ether: EtOAc = 1:1, R f=0.4). Upon completion, the reaction was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL) and diluted with anhydrous Na 2 SO 4 It was dried over water, filtered and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d 6 )δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0142] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine: A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was monitored by TLC (Pet. Ether: EtOAc = 1:1, R f = 0.5). The mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give crude (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine. The crude product was used directly in the next step without further purification.

[0143] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: THF (100 mL) and H 2 To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in 2O (100 mL) was added NaIO 4 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by TLC (Pet. Ether: EtOAc = 5:1, R f=0.2). The reaction was quenched by adding saturated sodium hyposulfite (aq) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 )δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0144] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL) was added SnCl 2 (26.25 g, 134.09 mmol, 5.00 equiv) was added portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, in three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0

[0145] Step 5: Preparation of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv) in ACN (400 mL) was added TMSI (13.8 mL, 96.42 mmol, 6.00 equiv) dropwise at room temperature. The final reaction mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (3.8 g, 80%). LC-MS: (ES+H, m / z): [M+H] + =296.95.

[0146] Step 6: Preparation of ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3-carboxylate: Ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.50 g, 5.05 mmol, 1.00 equiv.), tert-butyl(ethynyl)dimethylsilane (850 mg, 6.05 mmol, 1.20 equiv.), CuI (0.19 g, 1.01 mmol, 0.20 equiv.), Et 3 N (1.53 g, 15.15 mmol, 3 equiv.), and Pd(PPh 3 ) 2 Cl 2 A mixture of (0.35 g, 0.51 mmol, 0.10 equiv) was stirred at 50° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (450 mL). The resulting mixture was extracted with EtOAc (3×450 mL). The combined organic layers were washed with brine (3×450 mL) and extracted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.5 g, 83%). LC-MS: (ES+H, m / z): [M+H] + =357.2.

[0147] Step 7: Preparation of 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.20 g, 3.37 mmol, 1.00 equiv.) in THF (30 mL) was added LiEt3BH (13.46 mL, 13.46 mmol, 4.00 equiv., 1M in THF) dropwise under nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding citric acid (5.05 mL, 5.05 mmol, 1.50 equiv., 1M) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (840 mg, 79%). LC-MS: (ES+H, m / z): [M+H] + =315.0.

[0148] Step 8: Preparation of 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (92 mg, 0.29 mmol, 1.00 equiv.) and DMF (1 mg, 0.01 mmol, 0.05 equiv.) in DCM (5 mL) was added SOCl. 2(0.06mL, 0.88mmol, 3.00eq, 1.64g / mL) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (97mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H,m / z):[M+H+MeCN] + =374.2.

[0149] Step 9: Preparation of 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridin-3-yl}methyl)piperazin-1-yl]pyridine-2-carbonitrile: To a stirred mixture of 5-(piperazin-1-yl)pyridine-2-carbonitrile hydrochloride (119 mg, 0.53 mmol, 1.48 equiv), DIEA (232 mg, 1.80 mmol, 5.00 equiv), and 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (120 mg, 0.36 mmol, 1.00 equiv) in MeCN (5 mL) was added KI (11 mg, 0.07 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridin-3-yl}methyl)piperazin-1-yl]pyridine-2-carbonitrile (120 mg, 69%).

[0150] Step 10: Preparation of 5-{4-[(7-ethynyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile: To a stirred mixture of 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridin-3-yl}methyl)piperazin-1-yl]pyridine-2-carbonitrile (120 mg, 0.24 mmol, 1.00 equiv.) in THF (2.5 mL) was added TBAF (0.27 mL, 0.27 mmol, 1.10 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine (1×50 mL) and purified with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by prepHPLC to give 5-{4-[(7-ethynyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile (31.3 mg, 34%). LC-MS: (ES+H,m / z):[M+H] + =369.1; 1 H NMR (300MHz, DMSO-d 6 )δ12.17(s,1H),8.48(d,1H),8.42(d,1H),8.15(s,1H),7.75(d,1H),7.64(d,1H) ),7.36(dd,1H),4.51(s,1H),3.67(s,2H),3.47-3.38(m,4H),2.60-2.52(m,4H).

[0151] Example 2 [ka] Step 1: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: Methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.52 g, 92.34 mmol, 2.00 equiv.), K 2 CO 3 (12.76 g, 92.34 mmol, 2.00 equiv.), and Pd(dppf)Cl 2 A mixture of (3.38 g, 4.62 mmol, 0.10 equiv) was stirred at 100° C. under nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The mixture was allowed to warm to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with saturated NaCl(aq) (3×100 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 48.74%) as a pale yellow oil. LC-MS: (ES+H,m / z):[M+H] + = 222.95; 1 H NMR (300MHz, DMSO-d 6 )δ9.25(d,1H),8.74(d,1H),5.41-5.47(m,1H),5.13-5.21(m,1H),3.94(s,3H),2.16(dd,3H).

[0152] Step 2: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) was added NH 4Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv.) were added. The reaction was stirred at 80° C. under nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 The organic layer was diluted with 1:1 ethanol / 2-propanol (200 mL) and washed with water (250 mL) and brine (250 mL). 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure to give methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90.17%), which was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + = 193.15; 1 H NMR (300MHz, DMSO-d 6 )δ8.29(d,1H),7.60(d,1H),5.51-5.47(m,1H),5.41(s,2H),5.39-5.36(m,1H),3.84(s,3H),2.08(t,3H).

[0153] Step 3: Preparation of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was diluted with methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et 3 To a solution of N (6.16 g, 60.87 mmol, 3.00 equiv) was added at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 60° C. overnight under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with MeOH (30 mL) at 0° C. The resulting mixture was diluted with water (200 mL) and diluted with CH 2 Cl 2 The combined organic layers were washed with water (3×100 mL) and extracted with anhydrous Na 2 SO 4The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.80 g, 40.66%). LC-MS: (ES+H, m / z): [M+H] + =219.1.; 1 H NMR (400MHz, DMSO-d 6 )δ11.92(s,1H),8.92(d,1H),8.15(d,1H),6.79(s,1H),3.93(s,3H),2.48(s,3H).

[0154] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: CH 3 To a solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv.) and NCS (587 mg, 4.40 mmol, 1.60 equiv.) in COOH (7 mL), 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 93.5%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1 H NMR (300MHz, DMSO-d 6 )δ8.90(d,1H),8.13(d,1H),3.93(s,3H),2.60(s,3H).

[0155] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL) was added LiAlH 4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (1 mL, 12 M) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43.1%). LC-MS: (ES+H, m / z): [M+H] + = 225.1; 1 H NMR (300MHz, DMSO-d 6 )δ12.24(br,1H),8.48(d,1H),7.77(d,1H),5.69(s,1H),4.63(s,2H),2.63(s,3H).

[0156] Step 6: Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv) and DMF (7 mg, 0.09 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl 2 (318 mg, 2.67 mmol, 3.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (98 mg, 45.2%). LC-MS: (ES+H, m / z): [M+H] + =243.0.

[0157] Step 7: Preparation of 4-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}benzonitrile: A solution of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (25 mg, 0.10 mmol, 1.00 equiv), DIEA (66 mg, 0.51 mmol, 5.00 equiv), KI (4 mg, 0.02 mmol, 0.20 equiv), and 4-(piperazin-1-yl)benzonitrile (19 mg, 0.10 mmol, 1.00 equiv) in MeCN (2 mL) was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. The pure fractions were concentrated and then lyophilized to give 4-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}benzonitrile (12 mg, 29.6%). LC-MS: (ES-H, m / z): [MH] - = 392.15; 1 H NMR (400MHz, DMSO-d 6 )δ12.30(s,1H),8.51(d,J=1.8Hz,1H),7.69(d,J=1.9Hz,1H),7.58(d,J=8.7Hz,2H),7 .02(d,J=8.7Hz,2H),3.67(s,2H),3.38-3.34(m,4H),2.64(s,3H),2.57-2.54(m,4H).

[0158] Example 3 [ka] Step 1: Preparation of methyl 6-methyl-5-nitropyridine-3-carboxylate: Toluene (60 mL) and H 2To a stirred mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (5 g, 273.08 mmol, 1.00 equiv.) and methylboronic acid (2.75 g, 46.17 mmol, 2.00 equiv.) in 20O (3 mL) was added Pd(dppf)Cl 2 (0.83 g, 1.15 mmol, 0.05 equiv.) and CsF (7 g, 46.17 mmol, 2.00 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The resulting mixture was added to 500 mL of water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give methyl 6-methyl-5-nitropyridine-3-carboxylate (2.9 g, 64%). LC-MS: (ES+H, m / z): [M+H] + = 197.0; 1H NMR (400 MHz, chloroform-d) δ 9.29 (d, 1H), 8.84 (d, 1H), 4.01 (s, 3H), 2.94 (s, 3H).

[0159] Step 2: Preparation of methyl 6-formyl-5-nitropyridine-3-carboxylate: Methyl 6-methyl-5-nitropyridine-3-carboxylate (35 g, 178.42 mmol, 1.00 equiv.) and SeO in dioxane (200 mL). 2 A mixture of (30 g, 267.64 mmol, 1.50 equiv) was stirred overnight at 110° C. under nitrogen atmosphere. The resulting mixture was then filtered and the filter cake was washed with EtOAc (5×200 mL). The filtrate was concentrated under reduced pressure and the crude product was then dissolved in THF (200 mL). The resulting mixture was filtered and the filter cake was washed with THF (3×100 mL). The filtrate was concentrated under reduced pressure to give nitropyridine-3-carboxylate (40 g, crude). LC-MS: (ES+H, m / z): [M+H] + =211.1.

[0160] Step 3: Preparation of methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate: To a stirred solution of NaH (11.42 g, 285.52 mmol, 1.50 equiv, 60 wt%) in THF (500 mL) was added dropwise ethyl 2-(diethoxyphosphoryl)butanoate (72 g, 285.52 mmol, 1.50 equiv) in THF (50 mL) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 10 min, then warmed to 40° C. and stirred under nitrogen atmosphere for 10 min. The resulting mixture was cooled to −78° C., then methyl 6-formyl-5-nitropyridine-3-carboxylate (40 g, 190.35 mmol, 1.00 equiv) in THF (50 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 30 min under nitrogen atmosphere. The reaction was monitored by LCMS. Saturated NH 4 The reaction was quenched by adding Cl(aq) (100 mL) at 0° C. The resulting mixture was added with 400 mL of water and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1×500 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The residue was purified by silica gel column chromatography to obtain methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (20 g, 36%, 2 steps) and methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (8.8 g). Data for methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate: LC-MS: (ES+H, m / z): [M+H] + = 309.1; 1H NMR (300MHz, chloroform-d) δ 9.27 (d, 1H), 8.88 (d, 1H), 7.10 (t, 1H), 4.22-4.16 (m, 2H), 4.03 (s, 3H), 2.59 (qd, 2H), 1.25 (t, 3H), 1.19 (t, 3H). Data for methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate: LC-MS: (ES+H, m / z): [M+H]+ =309.1; 1 H NMR (300 MHz, chloroform-d) δ 9.45 (d, 1H), 8.88 (d, 1H), 7.87 (s, 1H), 4.34 (q, 2H), 4.05 (s, 3H), 2.67 (q, 2H), 1.39 (t, 3H), 1.15 (t, 3H).

[0161] Step 4: Preparation of ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a stirred mixture of methyl 6-[(1Z)-3-ethoxy-2-ethyl-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (9.00 g, 29.19 mmol, 1.00 equiv.) and Fe (16.30 g, 291.93 mmol, 10.00 equiv.) in EtOH (200 mL) was added CaCl 2 (19.44 g, 175.16 mmol, 6.00 equiv) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc (5×100 mL), and the combined filtrate was concentrated. The resulting mixture was added to 250 mL of water and extracted with EtOAc (3×250 mL). The combined organic layers were washed with brine (1×250 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (5.2 g, 72%). LC-MS: (ES+H, m / z): [M+H] + = 247.1; 1H NMR (400MHz, DMSO-d 6 )δ12.06(s,1H),8.90(s,1H),8.16(s,1H),7.83(s,1H),4.38(q,2H),2.58(q,2H),1.36(t,3H),1.20(t,3H).

[0162] Step 5: Preparation of 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (4.00 g, 16.24 mmol, 1.00 equiv) in THF (50 mL) was added LiAlH 4 (13 mL, 32.49 mmol, 2.00 equiv, 2.5 M in THF) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (16 mL) at 0° C. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography to give 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (2.00 g, 60%). LC-MS: (ES+H, m / z): [M+H] + = 204.8; 1H NMR (400MHz, DMSO-d 6 )δ11.91(s,1H),8.38(d,1H),7.74(s,1H),7.62(d,1H),5.49(t,1H),4.62(d,2H),2.55(dd,2H),1.18(t,3H).

[0163] Step 6: Preparation of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (300 mg, 1.47 mmol, 1.00 equiv) and DMF (11 mg, 0.15 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl 2 (1.05 g, 8.81 mmol, 6.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was purified by silica gel column chromatography to give 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (300 mg, 92%). LC-MS: (ES+H, m / z): [M+H] + = 222.8; 1H NMR (400MHz, DMSO-d 6)δ11.99(s,1H),8.50(d,1H),7.76(s,1H),7.70(d,1H),4.93(s,2H),2.56(td,2H),1.19(t,3H).

[0164] Step 7: Preparation of 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile: To a stirred mixture of 5-(piperazin-1-yl)pyridine-2-carbonitrile, HCl salt (600 mg) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (500 mg, 2.25 mmol, 1.00 equiv) in ACN (4 mL) was added DIEA (1.45 g, 11.25 mmol, 5.00 equiv) and KI (75 mg, 0.45 mmol, 0.20 equiv) in portions at room temperature. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was poured into water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile (650 mg, 77%). LC-MS: (ES+H, m / z): [M+H] + = 375.2; 1 H NMR (300MHz, DMSO-d 6 )δ11.86(s,1H),8.41-8.35(m,2H),7.75(t,2H),7.61(s,1H),7.36(dd,1H),3.64(s,2H),3.52-3.42(m,4H),2.61-2.54(m,6H),1.18(t,3H).

[0165] Example 5 [ka] Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butanoate: To a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.02 mmol, 1.00 equiv.) and methyl 2-aminobutanoate hydrochloride (6.43 g, 42.02 mmol, 1.00 equiv.) in NMP (200 mL) was added DIEA (27.15 g, 210.10 mmol, 5.00 equiv.) dropwise at room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (8×300 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under vacuum to give methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butanoate (13.00 g, 92%). LC-MS: (ES+H,m / z):[M+H] + =334.9; 1 H NMR (400MHz, DMSO-d 6 )δ8.09(t,1H),7.88(dd,1H),7.79(dd,1H),4.56(dtd,1H),3.69(s,3H),1.97-1.79(m,2H),0.91(t,3H).

[0166] Step 2: Preparation of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one: To a stirred mixture of Fe (5.00 g, 89.52 mmol, 5.00 equiv) in AcOH (100 mL) was added methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butanoate (6.00 g, 17.90 mmol, 1.00 equiv) in AcOH (20 mL) dropwise at 80° C. under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by TLC (CH 2 Cl 2 / MeOH=10 / 1). The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with water (3×100 mL). The precipitated solid was collected by filtration and washed with water (3×20 mL). This gave 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.5 g, 92%). 1 H NMR (400MHz, DMSO-d 6 )δ10.52(s,1H),6.99(d,1H),6.72(s,1H),6.17(s,1H),3.78(d,1H),1.72-1.62(m,2H),0.88(t,3H).

[0167] Step 3: Preparation of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one: To a stirred solution of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.40 g, 16.11 mmol, 1.00 equiv) in DCM (100 mL) was added DDQ (4.39 g, 19.33 mmol, 1.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. Saturated NaHCO 3 The reaction was quenched by the addition of (aq) (100 mL) at 0 °C. The residue was diluted with saturated NaHCO 3 Purified by trituration with (aq) (5×100 mL). The precipitated solid was collected by filtration and washed with water (3×100 mL) to give 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one (3.50 g, 80%). LC-MS: (ES-H, m / z): [MH] - =269.0; 1 H NMR (400MHz, DMSO-d 6 )δ12.51(s,1H),7.44(d,1H),7.24(s,1H),2.79(q,2H),1.21(t,3H).

[0168] Step 4: Preparation of 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde: To a solution of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one (2.90 g, 10.70 mmol, 1.00 equiv) in toluene (100 mL) was added in a pressure tank a mixture of TMEDA (1.49 g, 12.84 mmol, 1.20 equiv), bis(adamantan-1-yl)(butyl)phosphane (0.77 g, 2.14 mmol, 0.20 equiv), Pd(OAc) 2 (0.24 g, 1.07 mmol, 0.10 equiv.) was added. The mixture was purged with nitrogen for 5 min and then (CO:H 2 =1:1) to 30 atm. The mixture was stirred at 100° C. overnight. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under vacuum to give 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde (1.40 g, 59%). LC-MS: (ES-H, m / z): [MH] - =219.0; 1 H NMR (300MHz, DMSO-d 6 )δ12.74(s,1H),10.01(d,1H),7.65-7.47(m,2H),2.86(q,2H),1.24(t,3H).

[0169] Step 5: Preparation of 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile: To a stirred solution of 6-(piperazin-1-yl)pyridine-3-carbonitrile (200 mg, 1.06 mmol, 1.00 equiv) and 2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (304 mg, 1.38 mmol, 1.30 equiv) in THF (10 mL) was added Ti(OiPr) 4 (453 mg, 1.60 mmol, 1.50 equiv) was added at room temperature under a nitrogen atmosphere. After 2 h, NaBH(AcO) 3(901 mg, 4.25 mmol, 4.00 equiv) was added at 0° C. and the reaction was allowed to warm to room temperature. After 2 h, the reaction was quenched by adding water (10 mL) at 0° C. The aqueous layer was extracted with EtOAc (5×30 mL). The combined organic phases were concentrated under reduced pressure and the crude product was purified by prepHPLC to give 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile (56.1 mg, 13%). LC-MS: (ES+H,m / z):[M+H] + = 393.2; 1H NMR (300MHz, DMSO-d 6 )δ12.43(s,1H),8.48(d,1H),7.85(dd,1H),7.16-7.04(m,2H),6.93(d,1 H),3.77-3.52(m,6H),2.87-2.75(m,2H),2.50-2.43(m,4H),1.22(t,3H); 19 F NMR (282MHz, DMSO-d6) δ-125.38.

[0170] Example 12 [ka] Step 1: Preparation of methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate: To a stirred mixture of methyl 2,4-difluoro-5-nitrobenzoate (10.00 g, 46.06 mmol, 1.00 equiv.) and methyl 2-aminobutanoate, HCl salt (5.40 g, 46.06 mmol, 1.00 equiv.) in NMP (100 mL) was added DIEA (48.1 mL, 276.34 mmol, 6.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The reaction was quenched by adding water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (8×200 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate (12 g, 83%). LC-MS: (ES+H,m / z):[M+H] + =315.1; 1 H NMR (400MHz, DMSO-d 6 )δ8.80-8.56(m,2H),7.21-6.99(m,1H),4.84-4.74(m,1H),3.85-3.81(s,3H),3.77-3.74(s,3H),2.05-1.82(m,2H),0.91-0.85(m,3H).

[0171] Step 2: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate: To a stirred mixture of methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate (12.00 g, 38.18 mmol, 1.00 equiv) in MeOH (180 mL) and EtOAc (30 mL) was added Pd(OH) 2 HCl (2.40 g) was added portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. Upon completion, the resulting mixture was filtered and the filter cake was washed with EtOAc (3×300 mL). The filtrate was concentrated and purified by silica gel column chromatography (Pet. Ether / EtOAc) to give methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (8 g, 83%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1 H NMR (400MHz, DMSO-d 6 )δ10.44(s,1H),7.25-7.20(m,1H),7.19-7.14(s,1H),4.00-3.91(m,1H),3.75(s,3H),1.76-1.60(m,2H),0.94-0.86(m,3H).

[0172] Step 3: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate: To a stirred mixture of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (7.00 g, 27.75 mmol, 1.00 equiv.) in DCM (70 mL) at room temperature was added DDQ (7.56 g, 33.30 mmol, 1.20 equiv.) in DCM (70 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The residue was then dissolved in saturated NaHCO 3 The precipitated solid was collected by filtration and dissolved in saturated NaHCO 3 The solid was purified by trituration with EtOAc (30 mL) / hexanes (100 mL). The resulting mixture was filtered and the filter cake was washed with hexanes (3×100 mL). The filter cake was dried under reduced pressure to give methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate (6 g, 86%). LC-MS: (ES+H, m / z): [M+H] + =251.1; 1 H NMR (400MHz, DMSO-d 6 )δ12.44(s,1H),7.78(d,1H),7.63(d,1H),3.89(s,3H),2.82(q,2H),1.23(t,3H).

[0173] Step 4: Preparation of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one: To a stirred mixture of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate (5.00 g, 19.98 mmol, 1.00 equiv) in THF (100 mL) was added LiAlH 4(40 mL, 39.96 mmol, 2.00 equiv, 1 mol / L in THF) was added dropwise at 0° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding water (1.5 mL), 15% NaOH (1.5 mL), and water (4.5 ml) at 0° C. The precipitated solid was collected by filtration and washed with water (3×30 mL). The solid was dissolved in water (500 mL) and EtOAc (200 mL). The resulting mixture was extracted with EtOAc (8×200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeOH (5 mL) and EtOAc (20 ml). The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The solid was dried under reduced pressure to give 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (1.2 g, 27%). LC-MS: (ES+H, m / z): [M+H] + = 223.2; 1 H NMR (400MHz, DMSO-d 6 )δ12.38(s,1H),7.48(d,1H),7.41(d,1H),5.52(brs,1H),4.64(s,2H),2.80(q,2H),1.18(t,3H).

[0174] Step 5: Preparation of 7-(bromomethyl)-3-ethyl-6-fluoro-1H-quinoxalin-2-one: To a stirred solution of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (150 mg, 0.68 mmol, 1.00 equiv) in HBr (4 mL, 33 wt% in AcOH) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =285.0.

[0175] Step 6: Preparation of 6-{4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A mixture of 7-(bromomethyl)-3-ethyl-6-fluoro-1H-quinoxalin-2-one (190 mg, 0.67 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-carbonitrile (150 mg, 0.80 mmol, 1.20 equiv), and DIEA (431 mg, 3.33 mmol, 5.00 equiv) in NMP (5 mL) was stirred at 80° C. for 1 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction mixture was poured into water (30 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. The crude product (200 mg) was purified by prepHPLC to give 6-{4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (100.2 mg, 38%). LC-MS: (ES+H, m / z): [M+H] + =393.1; 1 H NMR (300MHz, DMSO-d 6 )δ12.31(s,1H),8.48(d,1H),7.85(dd,1H),7.54(d,1H),7.38(d,1H),6.9 4(d,1H),3.75-3.67(m,6H),2.81(q,2H),2.56-2.51(m,4H),1.21(t,3H); 19 F NMR(282MHz,DMSO-d6)δ-124.28.

[0176] Example 16 [ka] Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate: To a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in THF (100 mL) was added LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M in THF) dropwise at -78 °C under nitrogen atmosphere. The reaction was stirred for 1 h, then TMSCl (8.48 g, 78.02 mmol, 1.00 equiv) was added dropwise and the reaction was warmed to room temperature and stirred for 3 h. The reaction was cooled to -78 °C and NBS (15.28 g, 85.82 mmol, 1.10 equiv) in 50 mL of THF was added dropwise. The reaction was then stirred for 2 h and warmed to room temperature. The reaction was monitored by LCMS. Saturated NH 4 The reaction was quenched by adding Cl(aq) (50 mL) at 0° C. The resulting mixture was diluted with Et 2 The combined organic layers were washed with brine (3×200 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase Combi-Flash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 31%). 1 H NMR (300 MHz, chloroform-d) δ 4.25(q, 2H), 3.58(d, 1H), 1.65-1.55(m, 1H), 1.31(t, 3H), 0.92-0.76(m, 2H), 0.61-0.53(m, 1H), 0.48-0.40(m, 1H).

[0177] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate: A solution of ethyl 2-bromo-2-cyclopropyl acetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred under nitrogen atmosphere for 24 h at 130° C. The residue was purified by reverse-phase Combiflash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 38%). 1H NMR (300 MHz, chloroform-d) δ 4.26-4.07(m, 6H), 2.19(dd, 1H), 1.30(dt, 10H), 0.71(dddd, 1H), 0.60(ddddd, 1H), 0.47-0.37(m, 1H), 0.24(ddtd, 1H).

[0178] Step 3: Preparation of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate: To a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv, 60 wt%) in THF (20 mL) was added ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 10 min, then warmed to 40° C. and stirred under nitrogen atmosphere for 10 min. The resulting mixture was cooled to −78° C., followed by the dropwise addition of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv) in THF (20 mL). The resulting mixture was stirred at −78° C. for 30 min under nitrogen atmosphere. The reaction was monitored by LCMS. Saturated NH 4 The reaction was quenched by adding Cl(aq) (5 mL) at 0° C. The resulting mixture was added with 20 mL of water and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (700 mg, 46%). LC-MS: (ES+H,m / z):[M+H] + =320.8.

[0179] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv.) and Fe (1.04 g, 18.73 mmol, 10.00 equiv.) in EtOH (10 mL) was added CaCl 2 (1.24 g, 11.24 mmol, 6.00 equiv) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (2×50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (200 mg, 41%). LC-MS: (ES+H, m / z): [M+H] + =259.0.

[0180] Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv.) was added LiAlH 4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5 M in THF) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (100 mg, 75%). LC-MS: (ES+H, m / z): [M+H]+ =217.2.

[0181] Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equiv) and DMF (3 mg, 0.04 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl 2 (264 mg, 2.22 mmol, 6.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =235.0.

[0182] Step 7: Preparation of 3-cyclopropyl-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one: To a stirred solution of 1-(5-fluoropyridin-2-yl)piperazine (100 mg, 0.55 mmol, 1.00 equiv.) and 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (130 mg, 0.55 mmol, 1.00 equiv.) in ACN (3 mL) was added DIEA (357 mg, 2.76 mmol, 5.00 equiv.) and KI (18 mg, 0.11 mmol, 0.20 equiv.) at room temperature. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and then diluted with H 22H-1,5-naphthyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one (122.8 mg, 58%). LC-MS: (ES+H,m / z):[M+H] + = 380.3; 1 H NMR (300MHz, DMSO-d 6 )δ11.88(s,1H),8.38(d,1H),8.09(d,1H),7.61(d,1H),7.55-7.45(m,1H),7.42(s,1H),6.86(dd,1H),3. 62(s,2H),3.49-2.38(m,4H),2.50-2.45(m,4H),2.20-2.08(m,1H),1.02-0.92(m,2H),0.86-0.78(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-143.41.

[0183] Examples 28 and 29 [ka] Step 1: Preparation of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred mixture of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one (3.00 g, 12.54 mmol, 1.00 equiv.) and tributyl(1-ethoxyethenyl)stannane (13.60 g, 37.64 mmol, 3.00 equiv.) in 1,4-dioxane (20 mL) was added Pd(PPh 3 ) 2 Cl 2 (0.44 g, 0.62 mmol, 0.05 equiv) was added at room temperature. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 2 h. Upon completion, the reaction was cooled to room temperature and the resulting solution was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =231.1

[0184] Step 2: Preparation of 7-acetyl-3-methyl-1,5-naphthyridin-2(1H)-one: The solution of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one from step 1 was cooled to 0° C. and treated dropwise with concentrated HCl (4 mL). The resulting reaction mixture was stirred at room temperature for 1 h and then washed with saturated NaHCO 3 (aqueous) to pH 8. The resulting mixture was then diluted with water (100 mL) and 2 Cl 2 (3×200 mL). The combined organic layers were washed with brine (1×300 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100° C., filtered and concentrated. The crude product was purified by silica gel column chromatography to give 7-acetyl-3-methyl-1,5-naphthyridin-2(1H)-one (1.39 g, 55% for two steps). LC-MS: (ES+H, m / z): [M+H] + =203.2

[0185] Step 3: Preparation of 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile: 7-Acetyl-3-methyl-1H-1,5-naphthyridin-2-one (350 mg, 1.73 mmol, 1.00 equiv.) was dissolved in CH 2 Cl 2 To a solution of 6-[(2R)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile (455 mg, 2.25 mmol, 1.30 equiv.) in 10 mL of 1,000 ml of 1 ... 4 (4.6 mL, 15.58 mmol, 9.00 equiv) was added dropwise at room temperature. The resulting mixture was stirred at 80° C. for an additional 4 h and then cooled to room temperature. To the above mixture, EtOH (5 mL) and NaBH 3CN (217 mg, 3.46 mmol, 2.00 equiv) was added portionwise at room temperature. The resulting mixture was stirred at 80° C. for an additional 2 h and then cooled to room temperature. The reaction mixture was poured into water (100 mL), stirred for 1 h, filtered through a plug of Celite, and washed with DCM / MeOH (3 / 1, 300 mL). The aqueous layer was extracted with DCM / i-PrOH (5 / 1, 2×100 mL) and the combined organic layers were washed with brine (2×50 mL) and diluted with Na 2 SO 4. The mixture was dried over 1000 ml, filtered and concentrated. The residue was purified by silica gel column chromatography to give 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (280 mg, 41.6%). LC-MS: (ES-H, m / z): [M+H] + =389.1. The diastereomers were separated by chiral-HPLC to give rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (Example 28, 90.6 mg, de=100%) and rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (Example 29, 69.5 mg, de=100%). Data for Example 28: LC-MS: (ES+H, m / z): [M+H] + =389.2; 1 H NMR (300MHz, DMSO-d 6 )δ11.90(s,1H),8.48-8.43(dd,2H),7.85-7.82(m,2H),7.65-7.64(d, 1H),6.86-6.83(d,1H),4.51(s,1H),4.26-4.22(d,1H),3.59-3.57(q, 1H),3.14-3.11(m,2H),2.58-2.50(d,1H),2.18-2.06(m,5H),1.36-1.34(d,3H),1.18-1.15(d,3H).Data regarding Example 29: LC-MS:(ES+H,m / z):[M+H]+ =389.1; 1 H NMR (300MHz, DMSO-d 6 ) δ 11.85 (s, 1H), 8.48-8.46 (dd, 2H), 7.85-7.81 (m, 2H), 7.66 (d, 1H), 6.86-6.83 (d, 1H), 4.62 (s, 1H), 4.16-4.12 (d, 1H), 3.70-3.64 (q, 1H), 3.11-3.01 (td, 1H), 2.88-2.76 (dd, 2H), 2.26-2.03 (m, 5H), 1.34 (d, 3H), 1.22 (d, 3H). The relative stereochemistry of Examples 28 and 29 has been arbitrarily assigned.

[0186] Example 36 [ka] Step 1: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: A mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equiv.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.52 g, 92.34 mmol, 2.00 equiv.), K2CO3 (12.76 g, 92.34 mmol, 2.00 equiv.), and Pd(dppf)Cl2 (3.38 g, 4.62 mmol, 0.10 equiv.) in dioxane (150 mL) and water (15 mL) was stirred at 100° C. for 3 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtoAc (3×300 mL). The combined organic layers were washed with saturated NaCl(aq) (3×100 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 49%) as a pale yellow oil. LC-MS: (ES+H,m / z):[M+H] + =222.95.

[0187] Step 2: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) was added NH 4 Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv.) were added. The reaction was stirred at 80° C. under nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature and then concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 The organic layer was diluted with 1:1 ethanol / 2-propanol (200 mL) and washed with water (250 mL) and brine (250 mL). 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure to give methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90%), which was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + =193.15. 1 H NMR (300MHz, DMSO-d 6 )δ8.29(d,1H),7.60(d,1H),5.51-5.47(m,1H),5.41(s,2H),5.39-5.36(m,1H),3.84(s,3H),2.08(t,3H).

[0188] Step 3: Preparation of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was diluted with methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et 3To a solution of N (6.16 g, 60.87 mmol, 3.00 equiv) was added at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 60° C. overnight under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with MeOH (30 mL) at 0° C. The resulting mixture was diluted with water (200 mL) and diluted with CH 2 Cl 2 The combined organic layers were washed with water (3×100 mL) and extracted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.80 g, 41%). LC-MS: (ES+H, m / z): [M+H] + =219.1; 1 H NMR (400MHz, DMSO-d 6 )δ11.92(s,1H),8.92(d,1H),8.15(d,1H),6.79(s,1H),3.93(s,3H),2.48(s,3H).

[0189] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: CH 3 To a solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv.) and NCS (587 mg, 4.40 mmol, 1.60 equiv.) in COOH (7 mL), 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. overnight and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 94%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1 H NMR (300MHz, DMSO-d 6)δ8.90(d,1H),8.13(d,1H),3.93(s,3H),2.60(s,3H).

[0190] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL) was added LiAlH 4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (1 mL, 12 M) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43%). LC-MS: (ES+H, m / z): [M+H] + = 225.1; 1 H NMR (300MHz, DMSO-d6) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.63 (s, 3H).

[0191] Step 6: Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv.) and DMF (7 mg, 0.09 mmol, 0.10 equiv.) in DCM (10 mL), SOCl2 (318 mg, 2.67 mmol, 3.00 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (98 mg, 45%). LC-MS: (ES+H, m / z): [M+H] + =243.0.

[0192] Step 7: Preparation of 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: To a stirred mixture of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (85 mg, 0.35 mmol, 1.00 equiv.) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equiv.) in ACN (1 mL) was added DIEA (136 mg, 1.05 mmol, 3.00 equiv.) and KI (1 mg, 0.01 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (90 mg), which was further purified by prepHPLC to give 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (52.5 mg, 28%). LC-MS: (ES+H,m / z):[M+H] + = 395.10; 1 H NMR (300MHz, DMSO-d 6)δ12.30(br,1H),8.50(m,2H),7.85(dd,1H),7.69(d,1H),6.94(d,1H),3.67-3.62(m,6H),2.65(s,3H),2.50-2.49(m,4H).

[0193] Example 42 [ka] Step 1: Preparation of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A mixture of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (800 mg, 3.67 mmol, 1.00 equiv.), sodium difluoromethanesulfinate (1012 mg, 7.33 mmol, 2.00 equiv.), 2-methylpropane-2-peroxol (991 mg, 11.00 mmol, 3.00 equiv.), and TFA (418 mg, 3.67 mmol, 1.00 equiv.) in CHCl / HO (2.5:1, 120 mL) was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was then diluted with water (100 mL) and eluted in CH. 2 Cl 2 The combined organic layers were washed with water (3×50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure to give methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 66%). LC-MS: (ES+H, m / z): [M+H] + =269.1; 1 H NMR (400MHz, DMSO-d 6 )δ12.39(s,1H),8.99(d,1H),8.19(m,1H),7.26(t,1H),3.94(s,3H),2.72(s,3H).

[0194] Step 2: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 2.42 mmol, 1.00 equiv) in THF (65 mL) was added LiAlH 4 A solution (2.5M in THF, 3.9 mL, 9.75 mmol, 4.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. Saturated NH 4 The reaction was quenched by adding aqueous Cl (10 mL) at 0° C. and anhydrous Na 2 SO 4 The mixture was filtered and dried over CH 2 Cl 2 / MeOH (10:1, 100 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (520 mg, 89%). LC-MS: (ES+H, m / z): [M+H] + =241.1. 1 H NMR (400MHz, Methanol-d4) δ8.58(d,1H), 7.73(d,1H), 7.20(t,1H), 4.79(s,2H), 2.81(t,3H).

[0195] Step 3: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one: CH 2 Cl 2 To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (320 mg, 1.33 mmol, 1.00 equiv) and DMF (5 mg, 0.07 mmol, 0.05 equiv) in DMF (32 mL) was added SOCl 2(475 mg, 4.00 mmol, 3.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 50° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature and then concentrated under reduced pressure to give 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (crude, 400 mg). LC-MS: (ES+H, m / z): [M+H] + =259.1

[0196] Step 4: Preparation of 6-(4-{[7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile: A mixture of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (380 mg, 1.47 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-carbonitrile (415 mg, 2.20 mmol, 1.50 equiv), KI (365 mg, 2.20 mmol, 1.50 equiv), and DIEA (569 mg, 4.40 mmol, 3.00 equiv) in MeCN (4 mL) was stirred at 80° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×10 mL) and diluted with anhydrous Na 2 SO 4 Dry on a rack. The mixture was filtered, washed with EtOAc (50 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by prepHPLC to give 6-(4-{[7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (31 mg, 5%). LC-MS: (ES+H,m / z):[M+H] + =411.2; 1 H NMR (300MHz, DMSO-d 6)δ12.17(br,1H),8.57(d,1H),8.41(d,1H),7.85(dd,1H),7.68(d,1H),7. 24(t,1H),6.94(d,1H),3.80-3.60(m,6H),2.72(s,3H),2.60-2.40(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-115.51.

[0197] Example 47 [ka] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine: To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv.) in MeOH (50 mL), NaOMe (15.76 g, 87.49 mmol, 1.10 equiv., 30 wt%) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (Pet. Ether: EtOAc = 1:1, R f =0.4). Upon completion, the reaction was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL) and diluted with anhydrous Na 2 SO 4 It was dried over water, filtered and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d 6 )δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0198] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine: A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was monitored by TLC (Pet. Ether: EtOAc = 1:1, R f = 0.5). The mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give crude (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine. The crude product was used directly in the next step without further purification.

[0199] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: THF (100 mL) and H 2 To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in 2O (100 mL) was added NaIO 4 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by TLC (Pet. Ether: EtOAc = 5:1, R f =0.2). The reaction was quenched by adding saturated sodium hyposulfite (aq) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 )δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0200] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL) was added SnCl 2 (26.25 g, 134.09 mmol, 5.00 equiv) was added portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, in three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0

[0201] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv) in DMF (10 mL) was added CuCl (0.57 g, 5.78 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120° C. overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was diluted with 3×30 mL of water (10% NH 3 H 2 2H). The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 77.78%). LC-MS: (ES+H,m / z):[M+H] + =267.0; 1H NMR (300MHz, DMSO-d 6 )δ9.27(d,1H),8.63(d,1H),8.57(s,1H),4.41(q,2H),4.12(s,3H),1.37(t,3H).

[0202] Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate: CH 3 To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CN (8 mL) was added TMSI (1.80 g, 9.00 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was washed with 3×50 mL of water (10% Et 3 The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml, filtered and concentrated. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 97.64%). LC-MS: (ES+H, m / z): [M+H] + = 252.9; 1 H NMR (300MHz, DMSO-d 6 )δ12.61(s,1H),8.94(d,1H),8.37(d,1H),8.20(s,1H),4.39(q,2H),1.36(t,3H).

[0203] Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL) was added LiAlH 4(2.5mL, 5.85mmol, 2.00eq) was added dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for an additional 2h. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1M HCl (aq). The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250mg, 40.53%). LC-MS: (ES+H,m / z):[M+H] + =211.0; 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H), 8.45(d,1H), 8.28(s,1H), 7.69(d,1H), 5.53(t,1H), 4.64(d,2H).

[0204] Step 4: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: CH 2 Cl 2 To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv) in 1 mL of SOCl 2 (423 mg, 3.56 mmol, 3.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) were added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =228.95.

[0205] Step 9: Preparation of 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one: CH 3To a stirred mixture of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (200 mg, 0.87 mmol, 1.00 equiv.) and 1-(5-fluoropyridin-2-yl)piperazine (126 mg, 0.69 mmol), 0.80 equiv.) in CN (5 mL) was added DIEA (564 mg, 4.36 mmol, 5 equiv.) and KI (14 mg, 0.08 mmol, 0.10 equiv.) at room temperature. The resulting mixture was stirred at 50° C. for 2 h. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 20 mL of water. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prepHPLC to give 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one (42.7 mg, 13.08%). LC-MS: (ES+H,m / z):[M+H] + =374.0; 1 1H NMR (300MHz, DMSO-d 6 )δ12.48(s,1H),8.48(d,1H),8.29(s,1H),8.09(d,1H),7.70(d,1H),7.55-7 .47(m,1H),6.87(dd,1H),3.66(s,2H),3.46-3.42(m,4H),2.53-2.50(m,4H); 19 F NMR (282MHz, DMSO-d 6 )δ-143.39.

[0206] Example 48 [ka] Step 1: Preparation of ethyl 7-difluoromethyl-6-methoxy-1,5-naphthyridine-3-carboxylate: A solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (300 mg, 0.96 mmol, 1.00 equiv.), [1,3-bis[2,6-bis(i-propyl)phenyl]-2-imidazolidinylidene]difluoromethylsilver(I) (97 mg, 0.17 mmol, 1.10 equiv.), [2-[2-(diphenylphosphanyl)phenoxy]phenyl]diphenylphosphane (181 mg, 0.33 mmol, 0.35 equiv.), and Pd(dba)2 (177 mg, 0.30 mmol, 0.32 equiv.) in toluene (5 ml) was stirred at 80° C. for 1.5 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (Pet. Ether / EtOAc 5:1) to give ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate (235 mg, 86%). LC-MS: (ES+H, m / z): [M+H] + =283.1; 1 H NMR (300MHz, DMSO-d 6 )δ9.25(d,1H),8.59(d,1H),8.53(s,1H),7.24(t,1H),4.42(q,2H),4.12(s,3H),1.40(t,3H); 19 F NMR (282MHz, DMSO-d 6 )δ-117.83.

[0207] Step 2: Preparation of ethyl 7-difluoromethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a solution of ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate (240 mg, 0.85 mmol, 1.00 equiv.) in ACN (7 mL) was added TMSI (680 mg, 3.40 mmol, 4.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The reaction mixture was then stirred at 50° C. for 5 h under nitrogen atmosphere, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, (Pet. ether / EtOAc) to give ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate (225 mg, 99%). LC-MS: (ES+H, m / z): [M+H] + =269.1.

[0208] Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate (230 mg, 0.85 mmol, 1.00 equiv) in THF (5 ml) was added LiAlH 4 (0.69 mL, 2.5 mol / L in THF, 2.00 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with MeOH (10 mL) and then DCM (50 mL) was added. The solution was filtered and the filter cake was washed with DCM / MeOH (5:1) (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH) to give 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (50 mg, 26%). LC-MS: (ES+H, m / z): [M+H] + =227.0; 1 H NMR (400MHz, DMSO-d 6 )δ12.36(s,1H),8.50(d,1H),8.16(d,1H),7.70(s,1H),6.98(t,1H),5.57(t,1H),4.67(d,2H).

[0209] Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.35 mmol, 1.00 equiv.) and DMF (1 mg, 0.02 mmol, 0.05 equiv.) in DCM (4 ml), was added SOCl 2 (126 mg, 1.06 mmol, 3.00 equiv) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =245.0.

[0210] Step 5: Preparation of 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile: To a stirred solution of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (86 mg, expected yield 100%, 0.35 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equiv), KI (11 mg, 0.07 mmol, 0.20 equiv) in ACN (5 ml) was added dropwise at room temperature DIEA (227 mg, 1.76 mmol, 5.00 equiv). The resulting solution was stirred at 80° C. for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (80 mg). The crude product was purified by prepHPLC to give 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (42.9 mg, 33% over two steps). LC-MS: (ES+H,m / z):[M+H] + =397.1; 1 H NMR (300MHz, DMSO-d 6 )δ12.33(s,1H),8.54(d,1H),8.48(d,1H),8.16(s,1H),7.85(dd,1H),7.71( d,1H),7.20-6.73(m,2H),3.72-3.68(m,4H),3.67(s,2H),2.51-2.49(m,4H); 19 F NMR (282MHz, DMSO-d 6 )δ-119.30.

[0211] Example 49 [ka] Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate: To a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.01 mmol, 1.00 equiv.) and methyl 2-aminopropanoate hydrochloride (2.93 g, 21.00 mmol, 1.00 equiv.) in NMP (200 mL) was added DIEA (27.15 g, 210.09 mmol, 5.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 2 h. The reaction was monitored by TLC (Pet. Ether / EtOAc=10 / 1). The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (1 L). The resulting mixture was washed with water (3×300 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate (7.5 g, 56%) as a red oil. 1 H NMR (400MHz, DMSO-d 6 )δ8.08(t,1H),7.87(dd,1H),7.77(dd,1H),4.67-4.55(m,1H),3.68(s,3H),1.48(dd,3H); 19 F NMR(377MHz,DMSO-d6)δ-122.19.

[0212] Step 2: Preparation of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one: To a stirred solution of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate (6.00 g, 18.68 mmol, 1.00 equiv) in HOAc (200 mL) was added Fe (5.22 g, 93.43 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was filtered and the filter cake was washed with DCM:MeOH=4:1 (3×100 mL). The filtrate was concentrated under reduced pressure. The pH of the residue was adjusted to 100% by adding saturated NaHCO 3The pH was adjusted to 7 with (aqueous). The resulting mixture was then diluted with CH 2 Cl 2 (3×300 mL). The combined organic layers were washed with brine (1×100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.2 g, 87%). LC-MS: (ES-H, m / z): [MH] - =257.1; 1 H NMR (400MHz, DMSO-d 6 )δ10.54(s,1H),7.01(dd,1H),6.76(t,1H),6.20(s,1H),3.90-3.80(m,1H),1.28(d,3H). 19 F NMR (377MHz, DMSO-d 6 )δ-132.99.

[0213] Step 3: Preparation of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one: To a stirred solution of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.50 g, 17.36 mmol, 1.00 equiv.) in DCM (500 mL) was added DDQ (4.34 g, 19.10 mmol, 1.10 equiv.) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with saturated NaHCO 3 (aqueous) (500 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting mixture was filtered and the filter cake was washed with saturated NaHCO 3 (aqueous) (3×100 mL). The filter cake was dried under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one (3 g, 67%). LC-MS: (ES-H, m / z): [MH] - =255.0; 1 H NMR (400MHz, DMSO-d 6)δ12.52(s,1H),7.49-7.40(m,1H),7.24(q,1H),2.40(q,3H).

[0214] Step 4: Preparation of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde: To a solution of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one (500 mg, 1.94 mmol, 1.00 equiv.) in toluene (100 mL), bis(adamantan-1-yl)(butyl)phosphane (349 mg, 0.97 mmol, 0.50 equiv.), TMEDA (1.13 g, 9.72 mmol, 5.00 equiv.), and Pd(OAc)2 (218 mg, 0.97 mmol, 0.50 equiv.) were added in a pressure tank. The mixture was purged with nitrogen for 5 minutes and then pressurized to 30 Mpa with CO2:H2=1:1 at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (300 mg, 74.8%). LC-MS: (ES-H, m / z): [MH] - = 205.2; 1 H NMR (400MHz, DMSO-d 6 )δ12.75(s,1H),10.02(q,1H),7.67-7.52(m,2H),2.49-2.44(m,3H).

[0215] Step 5: Preparation of 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: To a stirred mixture of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (200 mg, 0.97 mmol, 1.00 equiv.) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (274 mg, 1.45 mmol, 1.50 equiv.) in THF (20 mL) was added tetrakis(propan-2-yloxy)titanium (551 mg, 1.94 mmol, 2.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. To the above mixture was added NaBH(OAc) 3 (822 mg, 3.88 mmol, 4.00 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 4 h. The reaction was monitored by LCMS. The reaction was quenched by adding water (80 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×50 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, followed by trituration with MeCN (5 mL) to give 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (51.1 mg, 14%). LC-MS: (ES+H,m / z):[M+H] + =379.2; 1 H NMR (400MHz, DMSO-d 6 )δ12.44(s,1H),8.48(d,1H),7.85(dd,1H),7.09(d,2H),6.93(d,1H),3.68(t,4H),3.60-3.55(m,2H),2.47(d,4H),2.41(s,3H); 19 F NMR (377MHz, DMSO-d 6 )δ-125.51.

[0216] Example 60 [ka] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine: To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv.) in MeOH (50 mL), NaOMe (15.76 g, 87.49 mmol, 1.10 equiv., 30 wt%) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=1:1, R f =0.4). The resulting mixture was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d 6 )δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0217] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine: A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g, 60.72 mmol, 1.00 equiv) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=1:1, R f =0.5). The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0218] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: THF (100 mL) and H 2To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in 2O (100 mL) was added NaIO 4 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise under nitrogen atmosphere at 0° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by TLC (PE:EA=5:1, R f =0.2). The reaction was quenched by adding saturated sodium hyposulfite (aq) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 )δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0219] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL) was added SnCl 2(26.25 g, 134.09 mmol, 5.00 equiv) was added portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% yield for three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0 / 313.0; 1 H NMR (400MHz, DMSO-d 6 )δ9.22(s,1H),8.78(s,1H),8.58(s,1H),4.42(q,2H),4.12(s,3H),1.39(t 3H).

[0220] Step 5: Preparation of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv.) in ACN (400 mL) was added TMSI (13.8 mL, 96.42 mmol, 6.00 equiv.) dropwise at room temperature. The final reaction mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using the following conditions: column, silica gel; mobile phase, EA in DCM, gradient 45% to 60% in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (3.8 g, 79.5%). LC-MS: (ES+H, m / z): [M+H] + =296.95 / 298.95

[0221] Step 6: Preparation of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (450 mg, 1.51 mmol, 1.00 equiv) in THF (8 mL) was added LiAlH 4 (1.21 mL, 3.03 mmol, 2.00 equiv, 2.5 M in THF) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (3.03 mL, 3.03 mmol, 2.00 equiv) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (220 mg, 56.9%). LC-MS: (ES+H, m / z): [M+H] + =255.0 / 257.0.

[0222] Step 7: Preparation of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (230 mg, 0.90 mmol, 1.00 equiv) and DMF (6 mg, 0.09 mmol, 0.10 equiv) in DCM (7 mL) was added SOCl 2 (321 mg, 2.70 mmol, 3.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (220 mg, 89.2%). LC-MS: (ES+H, m / z): [M+H] + =272.9 / 274.9.

[0223] Step 8: Preparation of 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: To a stirred mixture of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (150 mg, 0.54 mmol, 1.00 equiv), DIEA (354 mg, 2.74 mmol, 5.00 equiv), and 6-(piperazin)-1-yl)pyridine-3-carbonitrile (113 mg, 0.60 mmol, 1.10 equiv) in MeCN (7 mL) was added KI (18 mg, 0.11 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC, and the pure fractions were concentrated and then lyophilized to give 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (25.6 mg, 10.9%). LC-MS: (ES+H, m / z): [M+H] + =425.00 / 427.00; 1 H NMR (400MHz, DMSO-d 6 )δ12.41(s,1H),8.47(s,3H),7.85(dd,J=9.1,2.4Hz,1H),7.68(s,1H),6.93(d,J=9.1Hz,1H),3.78-3.59(m,6H),2.48(d,J=4.7Hz,4H).

[0224] Examples 68 and 69 [ka] Step 1: Preparation of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate: To a stirred solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv) and (4-methoxyphenyl)[4-(trifluoromethyl)phenyl]methanone (1.12 g, 4.01 mmol, 0.25 equiv) in THF was added 5,5'-dimethyl-2,2'-bipyridine (0.74 g, 4.01 mmol, 0.25 equiv), nickel acetylacetonate (1.03 g, 4.01 mmol, 0.25 equiv), and Na 2 CO 3 (1.70 g, 16.07 mmol, 1.00 equiv) was added at room temperature under nitrogen atmosphere. The resulting mixture was placed approximately 3 cm away from two 40 W blue LEDs and stirred at room temperature under nitrogen atmosphere for 7 days. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate (1.6 g, 32.93%). LC-MS: (ES+H, m / z): [M+H] + =303.15; 1 H NMR (400MHz, DMSO-d 6 )δ9.20(d,J=2.0Hz,1H),8.57(dd,J=2.1,0.8Hz,1H),8.27-8.10(m,1H),5.13-5.04(m,1H),4.41(q,J=7.1Hz,2H),4.18-4. 09(m,1H),4.09(s,3H),3.95-3.85(m,1H),2.49-2.39(m,1H),2.05-1.82(m,2H),1.79-1.67(m,1H),1.39(t,J=7.1Hz,3H).

[0225] Step 2: Preparation of methyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate: To a stirred solution of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate (1.30 g, 4.30 mmol, 1.00 equiv) in MeCN was added HBr in AcOH (0.25 ml, 33 wt%, 2.00 equiv) under nitrogen atmosphere at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL) and diluted with Et 3 The mixture was basified to pH 8 with N. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate (730 mg, 58.89%). LC-MS: (ES+H,m / z):[M+H] + =289.10; 1 H NMR (400MHz, DMSO-d 6 )δ12.14(s,1H),8.91(d,J=1.9Hz,1H),8.18(d,J=1.9Hz,1H),7.84(d,J=1.1Hz,1H),4.96-4.87(m,1H),4.39(q,J=7.1Hz, 2H),4.12-4.04(m,1H),3.91-3.79(m,1H),2.48-2.32(m,1H),1.99-1.81(m,2H),1.74-1.63(m,1H),1.36(t,J=7.1Hz,3H).

[0226] Step 3: Preparation of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate (730 mg, 2.53 mmol, 1.00 equiv) in THF (8 mL) was added LiAlH 4(192 mg, 5.06 mmol, 2.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M HCl (1 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (280 mg, 44.90%). LC-MS: (ES+H, m / z): [M+H] + =247.00; 1 H NMR (300MHz, DMSO-d 6 )δ11.97(s,1H),8.40(d,J=1.9Hz,1H),7.80(s,1H),7.64(d,J=1.9Hz,1H),5.48(t,J=5.6Hz,1H),4.98-4.84(m,1H), 4.63(d,J=5.3Hz,2H),4.18-4.01(m,1H),3.91-3.75(m,1H),2.45-2.31(m,1H),2.02-1.78(m,2H),1.74-1.58(m,1H).

[0227] Step 4: Preparation of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one: To a stirred solution of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (280 mg, 1.13 mmol, 1.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) in DCM was added SOCl 2 (0.25 mL, 3.41 mmol, 3.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (300 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =265.05.

[0228] Step 5: Preparation of 6-(4-{[6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile: To a stirred mixture of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (150 mg, 0.56 mmol, 1.00 equiv.) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (106 mg, 0.56 mmol, 1.00 equiv.) in MeCN (10 mL) was added DIEA (292 mg, 2.26 mmol, 4.00 equiv.) and KI (18 mg, 0.11 mmol, 0.20 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous NaCl. 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give 6-(4-{[6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (88 mg, 37.29%). LC-MS: (ES+H,m / z):[M+H] + = 417.10. The racemate (88 mg) was separated by prep-chiral-HPLC with the following conditions: Column: CHIRALPAK IH, 2 x 25 cm, 5 μm; Mobile phase A: Hex (10 mM NH 3 -MeOH), mobile phase B: EtOH:ACN=5:1; flow rate: 20 mL / min; gradient: 50%B to 50%B in 12 min; wavelength: 218 / 282 nm; RT1 (min): 4.62; RT2 (min): 6.76; sample solvent: MeOH:DCM=1:1-HPLC; injection volume: 0.75 mL; run number: 6, the pure fractions were concentrated under vacuum and then lyophilized to give Example 68 (34.2 mg, purity 99.7%, ee=100%) and Example 69 (34.1 mg, purity 99.3%, ee=99.7%). Example 68: LC-MS: (ES+H, m / z): [M+H] + =417.10;1 H NMR (300MHz, DMSO-d 6 )δ11.95(s,1H),8.47(d,J=2.4Hz,1H),8.43(d,J=1.8Hz,1H),7.84(dd,J=9.1,2.4Hz,1 H),7.80(d,J=1.3Hz,1H),7.64(d,J=1.9Hz,1H),6.93(d,J=9.2Hz,1H),4.89(t,J=6.8H z,1H),4.10-4.03(m,1H),3.87-3.79(m,1H),3.73-3.62(m,6H),2.58-2.49(m,4H),2.4 3-2.30(m,1H),2.02-1.77(m,2H),1.73-1.57(m,1H).Example 69: LC-MS:(ES+H,m / z):[M+H] + =417.10; 1 H NMR (300MHz, DMSO-d 6 )δ11.95(s,1H),8.48(d,J=2.4Hz,1H),8.43(d,J=1.8Hz,1H),7.85(dd,J=9.1 ,2.4Hz,1H),7.82-7.77(m,1H),7.64(d,J=1.9Hz,1H),6.93(d,J=9.1Hz,1H), 4.90(t,J=6.8Hz,1H),4.15-4.00(m,1H),3.92-3.76(m,1H),3.74-3.59(m,6H ),2.50-2.45(m,4H),2.44-2.31(m,1H),2.02-1.78(m,2H),1.74-1.57(m,1H).

[0229] Example 71 [ka] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide: A solution of α-methylcinnamic acid (2.56 g, 15.78 mmol, 1.00 equiv.) in DCM (30 mL) was stirred at room temperature under nitrogen for 5 min with DIEA (8.16 g, 63.15 mmol, 4.00 equiv.), T 3The mixture was treated with P (15.07 g, 23.68 mmol, 1.50 equiv, 50 wt% in DCM) followed by the addition of 3-bromo-2-fluoroaniline (3.00 g, 15.78 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide (2.00 g, 37.9%). LC-MS: (ES+H, m / z): [M+H] + =333.95 / 335.95; 1 H NMR (400MHz, DMSO-d 6 )δ9.89(s,1H),7.62-7.41(m,7H),7.21-7.13(m,1H),6.85-6.69(m,1H),2.12(d,J=1.4Hz,3H).

[0230] Step 2: Preparation of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one: To a stirred solution of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide (2.00 g, 5.98 mmol, 1.00 equiv) in chlorobenzene (20 mL) was added AlCl 3 (2.39 g, 17.95 mmol, 3.00 equiv) was added at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 120° C. for 3 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-8-chloro-3-methyl-1H-quinolin-2-one (1.00 g, 65.2%). LC-MS: (ES+H, m / z): [M+H] + = 255.80 / 257.80; 1H NMR (400MHz, DMSO-d 6 )δ11.94(s,1H),7.82(s,1H),7.44-7.34(m,2H),2.09(s,3H).

[0231] Step 3: Preparation of 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one: A solution of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one (800 mg, 3.12 mmol, 1.00 equiv.) and (tributylstannyl)methanol (1.10 g, 3.43 mmol, 1.10 equiv.), XPhos precatalyst 2nd generation (123 mg, 0.15 mmol, 0.05 equiv.) in 1,4-dioxane (10 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one (400 mg, 61.7%). LC-MS: (ES+H, m / z): [M+H] + =208.15

[0232] Step 4: Preparation of 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one: To a stirred solution of 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one (400 mg, 1.93 mmol, 1.00 equiv) and DMF (14 mg, 0.19 mmol, 0.10 equiv) in DCM (5 mL) was added SOCl 2 (2.30 g, 19.30 mmol, 10.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (400 mg, 91.8%). LC-MS: (ES+H, m / z): [M+H] + =226.3

[0233] Step 5: Preparation of 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A solution of 6-(piperazin-1-yl)pyridine-3-carbonitrile hydrochloride (229 mg, estimated yield 100%, 0.88 mmol, 1.00 equiv) in MeCN (10 mL) was treated with DIEA (573 mg, 4.43 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere for 5 min, followed by the addition of KI (17 mg, 0.10 mmol, 0.10 equiv) and 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (200 mg, 0.88 mmol, 1.00 equiv). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (92.1 mg, 23.8%). LC-MS: (ES+H,m / z):[M+H] + =378.10; 1 H NMR (400MHz, DMSO-d 6 )δ11.77(s,1H),8.47(d,J=4.0Hz,1H),7.87-7.76(m,2H),7.38(d,J=8.1Hz,1H),7.18(dd,J=8.1 ,6.4Hz,1H),6.91(d,J=8.0Hz,1H),3.66-3.65(m,6H),2.51-2.48(m,4H),2.10(d,J=1.3Hz,3H). 19 F NMR (377MHz, DMSO-d 6 )δ-135.84.

[0234] Example 82 [ka] Step 1: Preparation of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate: To a stirred solution of potassium tert-butoxide (21.27 g, 189.52 mmol, 1.50 equiv) in THF (500 ml) was added 1-tert-butyl 3-ethylpropanedioate (35.67 g, 189.52 mmol, 1.50 equiv) dropwise at room temperature under nitrogen atmosphere. To the above mixture was added 5-bromo-2-chloro-3-nitropyridine (30.00 g, 126.34 mmol, 1.00 equiv) in THF (50 ml) dropwise over 15 min at 60° C. The resulting solution was stirred at 60° C. for an additional 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with HCl (1M in water) (200 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×200 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl) malonate (45 g, 91.5%). LC-MS: (ES-H, m / z): [MH] - =387.1

[0235] Step 2: Preparation of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate: CH 2 Cl 2 To a stirred solution of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl) malonate (45.00 g, 115.62 mmol, 1.00 equiv) in (300 ml) was added TFA (200 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (100 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 200 mL) and diluted with anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35 g, crude). LC-MS: (ES+H, m / z): [M+H] + =290.9

[0236] Step 3: Preparation of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate: To a stirred solution of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35.00 g, 121.07 mmol, 1.00 equiv) and Fe (79.72 g, 1219.36 mmol, 7.50 equiv) in EtOH (250 ml) was added saturated NH 4 Aqueous Cl (250 mL) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was filtered and the filter cake was washed with EtOAc (3×70 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×200 mL) and then with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (9.3 g, 29.7%) as a pale yellow oil. LC-MS: (ES+H,m / z):[M+H] + =259.1

[0237] Step 4: Preparation of ethyl 2-(5-bromo-3-(2,2-dimethoxypropanamido)pyridin-2-yl)acetate: To a stirred solution of methyl 2,2-diethoxypropanoate (12.00 g, 80.99 mmol, 1.00 equiv) in MeOH (120 mL) was added H 2NaOH (9.72 g, 242.98 mmol, 3.00 equiv) in 2O (120 mL) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 h. The reaction was monitored by TLC. The mixture was acidified to pH 8 with HCl (2 M in water). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOH (500 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered and the filter cake was washed with EtOH (3×100 mL). The filtrate was concentrated under reduced pressure to give sodium 2,2-dimethoxypropanoate (8.5 g, 78.2%). 1 H NMR (300MHz, D 2 O) δ3.12(d,J=1.7Hz,6H),1.33(s,3H).

[0238] To a stirred solution of sodium 2,2-dimethoxypropanoate (7.59 g, 48.63 mmol, 1.50 equiv.) in dioxane (100 ml) was added DIEA (12.57 g, 97.26 mmol, 3.00 equiv.) and T 3 P (30.95 g, 97.26 mmol, 3.00 equiv, 50 wt% in EtOAc) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. To the above mixture, methyl 2-(3-amino-5-bromopyridin-2-yl)acetate (8.40 g, 32.42 mmol, 1.00 equiv) was added at room temperature. The resulting mixture was stirred at 100° C. overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×100 mL) and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-(5-bromo-3-(2,2-dimethoxypropanamido)pyridin-2-yl)acetate (9.3 g, 79.4%). LC-MS: (ES+H,m / z):[M+H] + =375.1

[0239] Step 5: Preparation of ethyl 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxylate: To a stirred solution of ethyl 2-(5-chloro-3-(2,2-dimethoxypropanamido)pyridin-2-yl)acetate (7.00 g, 18.65 mmol, 1.00 equiv) in TFA (100 ml) was added H 2 0 (7 mL) was added followed by 2 drops of fresh I2 solution (30 mg of I2 suspended in TFA (10 mL)) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 °C overnight under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in toluene (100 mL) and piperidine (6 mL). The resulting mixture was refluxed at 120 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-naphthyridine-4-carboxylate (3.3 g, 56.9%). LC-MS: (ES+H, m / z): [M+H] + =313.0; 1 H NMR (400MHz, DMSO-d 6 )δ12.20(s,1H),8.55(d,J=2.1Hz,1H),7.86(d,J=2.1Hz,1H),4.42(q,J=7.1Hz,2H),2.06(s,3H),1.33(t,J=7.1Hz,3H). Step 6: Preparation of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred solution of ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-naphthyridine-4-carboxylate (3.00 g, 9.64 mmol, 1.00 equiv) in THF (50 ml) was added LiEt 3 BH (30 ml, 1M in THF) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding water / ice (6 mL) at 0° C. The resulting mixture was concentrated under vacuum. The residue was purified by HPLC using HCl. 2 Cl 2Purification by silica gel column chromatography eluting with 1,2-dichloro-1,3-dimethyl-2,4-dimethyl-1,5-naphthyridin-2(1H)-one (1.8 g, 69.4%) was obtained. LC-MS: (ES-H, m / z): [MH] - = 267.0 / 269.0; 1 H NMR (300MHz, DMSO-d 6 )δ11.95(s,1H),8.57(d,J=2.1Hz,1H),7.83(d,J=2.1Hz,1H),5.04(t,J=5.5Hz,1H),4.90(d,J=5.2Hz,2H),2.21(s,3H).

[0240] Step 7: Preparation of 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde: To a stirred mixture of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (1.80 g, 6.68 mmol, 1.00 equiv) in THF (20 ml) was added 1,1-bis(acetyloxy)-3-oxo-3H-1l^[5],2-benziodaokiol-1-yl acetate (3.40 g, 8.02 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with water (3 x 5 mL). The residue was purified by reverse-phase Combiflash chromatography to give 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (760 mg, 42.5%). LC-MS: (ES-H, m / z): [MH] - = 264.9; 1 H NMR (300MHz, DMSO-d 6 )δ12.28(s,1H),10.88(s,1H),8.62(d,J=2.1Hz,1H),7.89(d,J=2.1Hz,1H),2.25(s,3H).

[0241] Step 8: Preparation of 7-bromo-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred solution of 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (750 mg, 2.80 mmol, 1 equiv.) in THF (5 ml), BAST (2.49 g, 11.23 mmol, 4 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 50° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. Saturated NH 4 The reaction was quenched with Cl(aq) (3 ml) at 0° C. The resulting mixture was extracted with EtOAc (3×20 mL) and diluted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (320 mg, 39.4%). LC-MS: (ES-H, m / z): [MH] - =287.0

[0242] Step 9: Preparation of 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred solution of 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (360 mg, 1.24 mmol, 1.00 equiv.) and XPhos precatalyst 2nd generation (195 mg, 0.24 mmol, 0.20 equiv.) in dioxane (5 ml), (tributylstannyl)methanol (959 mg, 2.98 mmol, 2.40 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography to give 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (195 mg, 65.2%). LC-MS: (ES+H, m / z): [M+H] + =241.1.

[0243] Step 10: Preparation of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: CH 2 Cl 2 To a stirred solution of 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (185 mg, 0.25 mmol, 1.00 equiv.) and DMF (2 mg, 0.02 mmol, 0.10 equiv.) in DMF (3 mL) was added SOCl 2 (183 mg, 1.54 mmol, 6.00 equiv) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (195 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =259.0

[0244] Step 11: Preparation of 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile: To a stirred solution of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (104 mg, 0.40 mmol, 1.00 equiv.) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (91 mg, 0.48 mmol, 1.20 equiv.) in MeCN (5 ml), DIEA (260 mg, 2.01 mmol, 5.00 equiv.) and KI (13 mg, 0.08 mmol, 0.20 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (crude). The crude product was further purified by trituration with MeOH (6 mL) to give 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (28.3 mg, 16.6%). LC-MS: (ES+H,m / z):[M+H] + =411.10; 1 H NMR (300MHz, DMSO-d 6 )δ12.25(s,1H),8.48(t,J=1.8Hz,2H),8.14-7.74(m,2H),7.70(d,J=1.9Hz,1H),6 .94(d,J=9.1Hz,1H),3.39-3.67(m,6H),2.50-2.48(m,4H),2.33(t,J=2.8Hz,3H). 19 F NMR (282MHz, DMSO-d 6 )δ-117.71.

[0245] Example 83 [ka] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide: To a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 equiv) in DCM (300 mL) was added pyridine (14.99 g, 189.45 mmol, 1.80 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 min under nitrogen atmosphere. To the above mixture was added (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 equiv) dropwise over 5 min at room temperature. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with water (3×500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (24.6 g, 81.1%). LC-MS: (ES+H, m / z): [M+H] + =288.0 / 290.0.

[0246] Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one: H 2 SO 4 A mixture of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (17.00 g, 59.00 mmol, 1.00 equiv) in (85 mL) was stirred at room temperature under nitrogen atmosphere for 3 h. The resulting mixture was added dropwise to ice water (1 L) and stirred for 1 h. The precipitated solid was collected by filtration and washed with water (3×200 mL). The resulting mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-quinolin-2-one (14.30 g, crude). LC-MS: (ES+H, m / z): [M+H] + =242.0 / 244.0.

[0247] Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one: CH 3To a stirred mixture of 7-bromo-8-fluoro-1H-quinolin-2-one (3.00 g, 12.39 mmol, 1.00 equiv.) and NCS (2.65 g, 19.83 mmol, 1.60 equiv.) in COOH (50 mL), 2,2-dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude). LC-MS: (ES+H, m / z): [M+H] + = 275.9 / 277.9; 1 H NMR (400MHz, DMSO-d 6 )δ12.52(s,1H),8.38(d,J=1.6Hz,1H),7.52-7.42(m,2H).

[0248] Step 4: Preparation of 3-chloro-7-ethyl-8-fluoro-1H-quinolin-2-one: 7-Bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, 8.97 mmol, 1.00 equiv.), CsF (4.09 g, 26.91 mmol, 3.00 equiv.), Pd(dppf)Cl in dioxane (50 mL). 2 (0.33 g, 0.44 mmol, 0.05 equiv.), and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 8.97 mmol, 1.00 equiv.) were added to a stirred mixture of 1,2-dimethyl-2,4-dimethyl-1,2-dioxaborolane (1.02 g, 1.00 equiv.) and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.02 g, 1.00 equiv.). 2 O (5 mL) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES+H, m / z): [M+H] + =224.0; 1H NMR (300MHz, DMSO-d 6 )δ12.38(s,1H),8.34(d,J=1.6Hz,1H),7.53-7.46(m,2H),6.95(dd,J=17.7,11.2Hz,1H),6.07(dd,J=17.7,1.0Hz,1H),5.57(dd,J=11.2,1.0Hz,1H).

[0249] Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde: 3-Chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv) in THF (15 mL), K 2 OsO 2 (OH) 4 (123mg, 0.33mmol, 0.10eq), NaIO 4 (2.87 g, 13.41 mmol, 4.00 equiv.), and 2,6-dimethylpyridine (718 mg, 6.70 mmol, 2.00 equiv.) were added to a stirred mixture of 1,2-dichlorophenylpyridine (1.0 mg, 1.0 mmol, 0.5 equiv.) and 2,6-dimethylpyridine (1.0 mg, 1.0 mmol, 0.5 equiv.) in H 2 O (1.5 mL) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (630 mg, 83.2%). LC-MS: (ES-H, m / z): [MH] - =224.1.

[0250] Step 6: Preparation of 6-{4-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (150 mg, 0.66 mmol, 1.00 equiv.) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (137 mg, 0.73 mmol, 1.10 equiv.) in DCM (2 ml) was stirred at room temperature for 10 min. The resulting mixture was concentrated under reduced pressure. To the resulting mixture was added HOAc (19 mg, 0.33 mmol, 0.50 equiv.) in EtOH (3 mL) and stirred at 50° C. under nitrogen atmosphere for 4 h. The mixture was allowed to cool to room temperature. The above mixture was diluted with NaBH 3 CN (83 mg, 1.33 mmol, 2.00 equiv) was added portionwise under nitrogen atmosphere at 0° C. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The precipitated solid was collected by filtration and washed with EtOH (3×2 mL). The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure to give 6-{4-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (69.3 mg, 26.2%). LC-MS: (ES+H, m / z): [M+H] + =398.10; 1 H NMR (400MHz, DMSO-d 6 )δ12.46(s,1H),8.47(d,J=2.0Hz,1H),8.36(d,J=1.5Hz,1H),7.85(dd,J=9.1,2.4Hz,1H),7.49(d, J=8.1Hz,1H),7.28(dd,J=8.1,6.3Hz,1H),6.97-6.87(m,1H),3.71-3.63(m,6H),2.50-2.44(m,4H); 19 F NMR (282MHz, DMSO-d6) δ-134.50.

[0251] The following compounds were synthesized as described above: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0252] Example A: Cell proliferation inhibition assay Cell proliferation was measured by cell viability assays using DLD-1 BRCA2(- / -) and parental isogenic pairs as well as MDA-MB-436 (mutated BRCA1) cell lines. The CellTiter-Glo (CellTiter-Glo, CTG) based cell viability assay is designed to determine the number of viable cells in culture due to compound effects by quantifying ATP, which indicates the presence of metabolically active cells.

[0253] DLD-1 BRCA2(- / -) and parental isogenic pairs were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both were incubated at 37 °C for 24 h at 5% CO 2 The cells were cultured at 37°C at 4°C for 10 min. Compounds of the invention were dispensed into 384-well plates (Corning, 3764) using an Echo acoustic liquid handler to form 1:3 serially diluted final concentrations with a top dose of 10 or 30 μM. Cells were seeded into the plates at a density of 50 cells / well (DLD-1 parental), 200 cells / well (DLD-1 BRCA2- / -), or 500 cells / well (MDA-MB-436). After a brief rotation, the cells were incubated at 37°C at 4°C for 10 min in a fully humidified incubator at 5% CO 2The cells were cultured at 37 °C for 7 days without disturbance. Cell viability was measured by CellTiter Glo2.0 assay kit (Promega, G9243), and the percentage of growth inhibition was calculated and plotted against the final compound concentration, and the data was fitted with Xfit to obtain IC 50 Generated a value.

[0254] Example B: Biochemical (FP) Assay Fluorescent polarization (FP)-based assays are used to generate homogeneous The compound has been widely used in drug discovery due to its rapid, robust performance and lack of interference seen in other assays. The compound was assayed against a commercially available fluorescently labeled PARP1 / 2 inhibitor (PARPi-FL, Tocris) as exemplified in the assays performed in WO 2014 / 064149 and WO 2021 / 013735(A1). The antibodies were characterized using an assay that measures the displacement of IgG1 from IgG1 (Biosciences, No. 6461) using the following method.

[0255] Compounds were dissolved in DMSO and serially diluted in the desired concentration range in Optiplate-384F plates utilizing an Echo550 liquid handler. 100% DMSO was used for high (with protein) and low (without protein) control samples. 20 nL of compound or DMSO alone was added to individual assay plate wells.

[0256] PARP1 and PARP2 proteins were expressed, purified, and incubated in 50 mM Tris, pH 8.0, 0.001% Triton® X-100, 10 mM MgCl 2 The antibodies were diluted in assay buffer containing 150 mM NaCl to a final concentration of 20 nM. PARPi-FL was then added to a final concentration of 3 nM.

[0257] The assay plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0258] Fluorescence polarization was read using an Envision plate reader using the following settings: Excitation Filter-FITC FP480-Ex Slot 3 Emission Filter-FITC FP P-pol535-Em Slot 4 Second Emission Filter - FITC FP S-pol535-Em Slot 3 Mirror Module - FITC FP Dual Enhance - Slot 1

[0259] The inhibition rate was calculated using the percentage of the permuted Mahalanobis distance greater than the control sample (mP value) according to the following formula: [Table 5]

number

[0260] IC reported for each compound using XLFit (Eq. 201) 50 Calculate.

[0261] Data from Examples A and B are provided in Table 3. [Table 3-1] [Table 3-2]

[0262] Example C: Human Transporter Efflux In Vitro Madin-Darby canine kidney (MDCKII) cells expressing MDR1 and BCRP were seeded at a density of 545,000 cells / cm2 on Corning HTS Transwell® 96-well polycarbonate permeable (0.4 μm pore) supports. Cells were incubated for 4-8 days before the assay and monolayer integrity was assessed by measuring transepithelial electrical resistance (TEER). Test and reference compounds were diluted in transport buffer (HBSS HEPES pH 7.4) to concentrations of 10 and 1 μM, respectively. The final organic solvent concentration was 0.5% (v / v). Bidirectional (apical to basolateral and basolateral to apical) flux of test and reference compounds was determined over a 2-h incubation at 37°C and 5% CO2 at 95% relative humidity. At the end of the incubation, samples from the apical and basolateral sides were taken and then precipitated with acetonitrile containing an internal standard. After centrifugation at 3200 × g, the supernatant was diluted 1:1 (v / v) with water and subjected to analysis by HPLC-MS / MS.

[0263] The apparent permeability (Papp, in units of ×10-6 cm / s) was calculated using the following formula: Papp = (dQ / dt) / (A × D0) where dQ / dt is the drug transport rate (pmol / s) and A is the membrane surface area (0.143 cm 2 ), and D0 was the initial donor concentration (nM or pmol / cm3). Outflow ratio=Papp(B→A) / Papp(A→B) where Papp(B→A) is the apparent permeability in the basolateral to apical direction and Papp(A→B) is the apparent permeability in the apical to basolateral direction.

[0264] Example D: In vivo determination of rat Kp,uu Determination of the unbound fraction (Pu) in plasma.

[0265] The equilibrium dialysis method was used to study the in vitro binding of test and reference compounds to plasma proteins. Plasma samples containing 5 μM test article or blank dialysis buffer solution (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) device. The dialysis plate was sealed and incubated at 5% CO. 2 The plates were placed in an incubator with a 37° C. filter and shaken at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Ketoconazole (5 μM) was used as a reference compound. After incubation, the seals were removed and 50 μL of post-dialysis samples were pipetted from both the buffer and plasma chambers into a fresh 96-well plate. Samples were equimatrilyzed by the addition of either blank samples to the buffer samples or blank buffer to the plasma samples. Subsequently, 400 μL (4 volumes) of acetonitrile containing internals was added to all samples to precipitate the proteins, which were then analyzed by UPLC-MS / MS to determine the relative concentrations of the test article. The unbound fraction in plasma was calculated using the concentrations of the test article in the buffer and plasma samples according to the following formula:

number

[0266] Determination of the unbound fraction in brain homogenates (Bu)

[0267] The equilibrium dialysis method was used to study the in vitro binding of test articles and reference compounds to rodent brain homogenates. Brains collected from naive animals were weighed and homogenized in 4 volumes of PBS, pH 7.4. Brain homogenate samples containing 1 μM of test article or blank dialysis buffer solution (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) apparatus. The dialysis plate was sealed and incubated at 37 °C for 24 h at 5% CO. 2The plates were placed in an incubator with a 37°C filter and shaken at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Telmisartan (5 μM) was used as a reference compound. After incubation, the seals were removed and 50 μL of the dialyzed samples were pipetted from both the buffer and brain homogenate chambers into a new 96-well plate. Samples were isomatrixed by either adding blank homogenate to the buffer samples or adding blank buffer to the homogenate samples. Subsequently, 400 μL (4 volumes) of acetonitrile containing internals were added to all samples to precipitate proteins and then analyzed by UPLC-MS / MS to determine the relative concentrations of the test articles. The unbound fraction in the diluted brain homogenate was calculated using the concentrations of the test article in the buffer and homogenate samples according to the following formula:

number

[0268] Correction for the percentage unbound in undiluted brain was achieved using the following formula:

number

[0269] Determination of drug brain-to-plasma partition coefficient (Kp) and drug unbound Kp (Kp,uu) in rats

[0270] Compounds were formulated individually or in cassettes (as a mixture) at a concentration of 0.1 mg / mL / compound in sterile water containing 0.5% (w / v) methylcellulose 400 cP and administered to male Sprague-Dawley rats by oral gavage at a dose volume of 10 mL / kg. One animal was sacrificed at each time point 0.5, 1, 2, 4, 8, and 24 hours after dosing, and brain and blood samples were collected. Plasma was prepared from the blood via refrigerated centrifugation, and plasma samples were stored frozen at -80°C until bioanalysis. Brain samples were rinsed with saline to remove residual blood and blotted dry with paper wipes. Brain samples were then weighed, homogenized in 3 volumes (v / w) of water, and stored frozen at -80°C until bioanalysis.

[0271] Prior to bioanalysis, plasma and brain samples were extracted with 4 volumes of acetonitrile containing an internal standard and centrifuged for 15 min. The supernatant was diluted with 2 constant volumes of water and injected for analysis by HPLC-MS / MS. Plasma and brain homogenate drug concentrations were determined against a calibration curve constructed by spiking blank rat plasma or brain homogenate with drug over an appropriate concentration range. Brain homogenate concentrations were corrected for the homogenization buffer dilution factor to obtain total brain drug concentrations.

[0272] Brain-to-plasma partition coefficients (Kp) were determined for each compound, calculated as AUC brain:AUC plasma, where t was the same in each matrix. If the drug concentration versus time profile for one matrix fell below the lower limit of quantification at an earlier time point than the other, the brain Kp was calculated as the average ratio of the total brain drug concentration to the total plasma drug concentration measured at each time point where drug concentrations in both matrices were quantifiable.

[0273] Kp,uu was then calculated from Kp using the following formula: Kp,uu=Kp×(unbound fraction in brain homogenate / unbound fraction in plasma).

[0274] Data from Examples C and D are provided in Table 4. [Table 4]

Claims

1. 【Chemical 45】 or a pharma- ceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound of claim 1 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

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