PARP1 inhibitors and their uses

Abstract

Described herein are PARP1 inhibitors and pharmaceutical compositions comprising the inhibitors. The subject compounds and compositions are useful for the treatment of cancer.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 304,345, filed January 28, 2022, and U.S. Provisional Patent Application No. 63 / 381,456, filed October 28, 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 a key 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 and degenerative diseases, protection from the adverse effects of cytotoxic compounds, and enhancement of cytotoxic cancer therapy. PARP has also been implicated in retroviral infection, and therefore 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, intestine, 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 its complications) and Parkinson's disease. PARP inhibitors can ameliorate liver toxicity after acetaminophen overdose, cardiac and renal toxicity from doxorubicin and platinum-based antitumor drugs, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cancer cell death, 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 incisions 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, auto-PARylation of PARP releases it from DNA, allowing it access to other DNA repair proteins to complete the repair. Thus, PARP binding to the damage site, its catalytic activity, and its eventual release from DNA are all critical steps for cancer cell response to DNA damage caused by chemotherapy drugs and radiation therapy.

[0005] Inhibition of PARP family enzymes has been utilized 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 via homologous recombination (HR), are selectively sensitive to small-molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors are defective in the homologous recombination repair (HRR) pathway and depend on PARP enzyme function for survival. While PARP inhibitor therapy primarily targets SRCA-mutated cancers, PARP inhibitors are also being tested in clinical trials for non-SRCA-mutated tumors, i.e., tumors exhibiting homologous recombination deficiency (HRD).

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

[0007] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -ORa , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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 dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0008] Also disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; X is N, C, or CH; [ka] is a single or double bond, Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; however, X is N, and [ka] is a single bond, n is 1 to 4; or X is C or CH, and [ka] is a single bond or a double bond, n is 0 to 4; R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0009] Also disclosed herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R; or R 1 is cycloalkyl or heterocycloalkyl, R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -ORa , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is a C1-C6 haloalkyl, a C1-C6 deuteroalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, or a heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 7 is C1-C6 alkyl substituted with one or more R, Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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 dare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0010] Also disclosed herein is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Y is N or CR 8 and R 8 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 9 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0011] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0012] Also disclosed herein are methods of treating cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein are methods of treating cancer comprising a mutation in a gene that results in a homologous repair deficiency in a subject in need thereof, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in a gene that results in a homologous repair deficiency includes 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, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0013] Also disclosed herein is a method of treating brain cancer in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0014] Also disclosed herein are methods of treating brain cancer in a subject in need thereof, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0015] 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 pharmaceutically acceptable salt, solvate, or stereoisomer thereof, [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR 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 2 is a 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 said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 are hydrogen, deuterium, halogens, 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 said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 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 is alkynyl, Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 5 represents hydrogen, deuterium, halogens, -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 6 represents hydrogen, deuterium, halogens, -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 7 is 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, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R a independently, 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 C1 ~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), wherein 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, or -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 is heteroalkyl, or a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom are taken together to form oxo. (Item 2) R 2 But C 1 ~C 6 2. The compound according to item 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 3) R 3 3. The compound according to item 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen. (Item 4) R 2 and R 3 taken together form a cycloalkyl, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. (Item 5) Each R 4 But independently, C 1 ~C 6 5. The compound according to any one of items 1 to 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl. (Item 6) 6. The compound according to any one of items 1 to 5, wherein n is 0 to 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. (Item 7) A compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

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[0016] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present 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, throughout the following specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be interpreted in an open and inclusive sense, i.e., "including, but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. 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 phrase "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, 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. Also, please note that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0017] As used herein, the following terms have the following meanings unless otherwise indicated.

[0018] "Oxo" refers to =O.

[0019] "Carboxyl" refers to --COOH.

[0020] "Cyano" refers to -CN.

[0021] "Alkyl" refers to a straight- or branched-chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 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. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means 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 a C1- 10In some embodiments, the alkyl is an alkyl. In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH2, or —NO2. In some embodiments, the alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0022] "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. This group can be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH), 1-propenyl (-CHCH=CH), isopropenyl [-C(CH=CH], butenyl, 1,3-butadienyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless specifically stated otherwise in this specification, an alkenyl group can be any group, including, for example, For example, alkenyl may be optionally substituted with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkenyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH, or —NO. In some embodiments, alkenyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, alkenyl is optionally substituted with halogen.

[0023] "Alkynyl" refers to a straight- or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Wherever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkynyl" without a specified numerical range. Unless stated otherwise specifically in the specification, alkynyl groups may 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, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0024] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, alkylene groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkylene is optionally substituted with halogen.

[0025] "Alkoxy" means a group of the formula -OR a refers to the radical of R a is an alkyl radical as defined above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0026] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, an aryl is a 6- to 10-membered aryl. In some embodiments, an aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. 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, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0027] "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, a cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3 to C6). 15 Cycloalkyl or C3-C 15Cycloalkenyl), 3 to 10 carbon atoms (C3 to C 10 Cycloalkyl or C3-C 10Examples of cycloalkyls include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 6 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), 3 to 5 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl), or 3 to 4 carbon atoms (C-C cycloalkyl or C-C cycloalkenyl). In some embodiments, a cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, a cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, a 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 cycloalkyl 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 cycloalkyl 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 oxo, halogen, methyl, ethyl, —CN, —COOH, COOMe, —CF, —OH, —OMe, —NH, or —NO.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0029] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0030] "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.

[0031] "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.

[0032] "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, CD3, CHD, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0033] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0034] "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 can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and can include fused ring systems (when fused to an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2 to C6). 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 to C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl). 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, pyrrolidinyl, and pyrrolidinyl. 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 (including heteroatoms) of atoms comprising the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, a heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, a heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a 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, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0035] "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, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains 1-3 nitrogens. In some embodiments, a heteroaryl contains 1 or 2 nitrogens. In some embodiments, a heteroaryl contains 1 nitrogen. A heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and can include fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can 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, benzoindolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl nyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl can 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, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF, -OH, -OMe, -NH, or -NO. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0036] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances when the event or circumstance occurs and instances when the event or circumstance does not. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CHCH), fully substituted (e.g., -CFCF), monosubstituted (e.g., -CHCHF), or substituted at any level between fully and monosubstituted (e.g., -CHCHF, -CHCF, -CFCH, -CFHCHF, etc.). Those of skill in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., a substituted alkyl may include an optionally substituted cycloalkyl group, which may continue indefinitely as defined to include an optionally substituted alkyl group). Thus, any substituent 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.

[0037] The term "one or more" when referring to optional substituents means that the group of interest is optionally substituted with 1, 2, 3, 4, or more substituents. In some embodiments, the group of interest is optionally substituted with 1, 2, 3, or 4 substituents. In some embodiments, the group of interest is optionally substituted with 1, 2, or 3 substituents. In some embodiments, the group of interest is optionally substituted with 1 or 2 substituents. In some embodiments, the group of interest is optionally substituted with 1 substituent. In some embodiments, the group of interest is optionally substituted with 2 substituents.

[0038] 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, effective to produce a desired therapeutic effect.

[0039] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogen, and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0040] "Synergistic" or "synergizing" refers to an effect of the combination that is greater than the additive effect of each component alone at the same dose.

[0041] 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.

[0042] 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. compound

[0043] Described herein are compounds, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that are useful in the treatment of cancer.

[0044] Disclosed herein are compounds of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SRa , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R aare independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0045] In some embodiments of the compounds of Formula (I), R 1 is deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl, wherein the alkyl, alkynyl, and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 1 is a C1-C6 alkyl or cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 1 is C1-C6 alkyl or cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 1 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compounds of Formula (I), R 1 is cyclopropyl substituted with one or more R. In some embodiments of the compounds of Formula (I), R 1is cyclopropyl. In some embodiments of the compounds of Formula (I), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (I), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (I), R 1 is C1-C6 alkyl or cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 1 is C1-C6 alkyl. In some embodiments of the compounds of Formula (I), R 1 is methyl or ethyl. In some embodiments of the compound of Formula (I), R 1 is methyl. In some embodiments of the compounds of Formula (I), R 1 is ethyl. In some embodiments of the compounds of Formula (I), R 1 is C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), R 1 is difluoromethyl.

[0046] In some embodiments of the compounds of Formula (I), R 2 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (I), R 2 is C1-C6 alkyl. In some embodiments of the compound of Formula (I), R 2 is methyl.

[0047] In some embodiments of the compounds of Formula (I), R 3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (I), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), R 3is C1-C6 alkyl. In some embodiments of the compound of Formula (I), R 3 is methyl. In some embodiments of the compounds of Formula (I), R 3 is hydrogen.

[0048] In some embodiments of the compounds of Formula (I), R 2 and R 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 2 and R 3 taken together form a cycloalkyl. In some embodiments of the compounds of Formula (I), R 2 and R 3 together to form a cyclopropyl.

[0049] In some embodiments of the compound of Formula (I), each R 4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (I), each R 4 is independently C1-C6 alkyl. In some embodiments of the compound of Formula (I), each R 4 In some embodiments of the compounds of Formula (I), two R on the same or different carbons are 4 In some embodiments of the compounds of Formula (I), two R on the same or different carbons may be joined to form a cycloalkyl. 4 together to form a cyclopropyl.

[0050] In some embodiments of the compound of Formula (I), n is 0 or 1. In some embodiments of the compound of Formula (I), n is 0 to 2. In some embodiments of the compound of Formula (I), n is 1 or 2. In some embodiments of the compound of Formula (I), n is 1. In some embodiments of the compound of Formula (I), n is 2.

[0051] In some embodiments of the compounds of Formula (I), R 5 is hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (I), R 5 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), R 5 is halogen, —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), R 5 is hydrogen or halogen. In some embodiments of the compounds of Formula (I), R 5 is halogen. In some embodiments of the compounds of Formula (I), R 5 is hydrogen.

[0052] In some embodiments of the compounds of Formula (I), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (I), R 6 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), R 6 is hydrogen or halogen. In some embodiments of the compounds of Formula (I), R 6 is hydrogen. In some embodiments of the compounds of Formula (I), R 6 is a halogen.

[0053] In some embodiments of the compounds of Formula (I), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I), R 7is a C1-C6 alkyl or cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 7 is C1-C6 alkyl. In some embodiments of the compound of Formula (I), R 7 is methyl. In some embodiments of the compounds of Formula (I), R 7 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compounds of Formula (I), R 7 is cyclopropyl or cyclobutyl, each optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 7 is cyclopropyl optionally substituted with one or more R. In some embodiments of the compound of Formula (I), R 7 is cycloalkyl. In some embodiments of the compounds of Formula (I), R 7 is cyclopropyl.

[0054] Disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; X is N, C, or CH; [ka] is a single or double bond, Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; however, X is N, and [ka] is a single bond, n is 1 to 4; or X is C or CH, and [ka] is a single bond or a double bond, n is 0 to 4; R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R aare independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0055] In some embodiments of the compound of Formula (II), R 1 is deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (II), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl, where alkyl, alkynyl, and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (II), R 1 is a C1-C6 alkyl or cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (II), R 1 is C1-C6 alkyl or cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of formula (II), R 1 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of Formula (II), R 1 is cyclopropyl substituted with one or more R. In some embodiments of the compound of Formula (II), R 1is cyclopropyl. In some embodiments of the compound of Formula (II), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (II), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (II), R 1 is C1-C6 alkyl or cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of formula (II), R 1 is C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 1 is methyl or ethyl. In some embodiments of the compound of Formula (II), R 1 is methyl. In some embodiments of the compound of Formula (II), R 1 is ethyl. In some embodiments of the compound of Formula (II), R 1 is C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), R 1 is difluoromethyl.

[0056] In some embodiments of the compound of Formula (II), R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (II), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 2 is hydrogen. In some embodiments of the compound of Formula (II), R 2 is C1-C6 alkyl.

[0057] In some embodiments of the compound of Formula (II), R 2 is methyl. In some embodiments of the compound of Formula (II), R 3is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (II), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 3 is C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 3 is methyl. In some embodiments of the compound of Formula (II), R 3 is hydrogen.

[0058] In some embodiments of the compound of Formula (II), R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of the compound of Formula (II), R 2 and R 3 taken together form a cycloalkyl. In some embodiments of the compound of Formula (II), R 2 and R 3 together to form a cyclopropyl.

[0059] In some embodiments of the compound of Formula (II), X is N; [ka] is a single bond and n is 1 to 4. In some embodiments of compounds of Formula (II), X is N; [ka] is a single bond and n is 1 or 2. In some embodiments of compounds of Formula (II), X is N; [ka] is a single bond and n is 1. In some embodiments of compounds of Formula (II), X is N; [ka] is a single bond and n is 2.

[0060] In some embodiments of the compound of Formula (II), X is CH or C; [ka] is a single bond or a double bond, and n is 0 to 4. In some embodiments of compounds of Formula (II), X is CH or C; [ka] is a single bond or a double bond, and n is 0 to 2. In some embodiments of the compound of Formula (II), X is CH or C; [ka] is a single or double bond and n is 0 or 1. In some embodiments of compounds of Formula (II), X is CH or C; [ka] is a single bond or a double bond, and n is 1 or 2. In some embodiments of the compound of Formula (II), X is CH or C; [ka] is a single bond or a double bond, and n is 0. In some embodiments of compounds of Formula (II), X is CH or C; [ka] is a single bond or a double bond, and n is 1. In some embodiments of the compound of Formula (II), X is CH or C; [ka] is a single or double bond, and n is 2.

[0061] In some embodiments of the compound of Formula (II), X is CH; [ka] is a single bond and n is 0 to 4. In some embodiments of the compound of Formula (II), X is CH; [ka] is a single bond and n is 0 to 2. In some embodiments of compounds of Formula (II), X is CH; [ka] is a single bond and n is 0 or 1. In some embodiments of the compound of Formula (II), X is CH; [ka] is a single bond and n is 1 or 2. In some embodiments of the compound of Formula (II), X is CH; [ka] is a single bond and n is 0. In some embodiments of the compound of Formula (II), X is CH; [ka] is a single bond and n is 1. In some embodiments of the compound of Formula (II), X is CH; [ka] is a single bond and n is 2.

[0062] In some embodiments of the compound of Formula (II), X is C; [ka] is a double bond and n is 0 to 4. In some embodiments of compounds of Formula (II), X is C; [ka] is a double bond and n is 0 to 2. In some embodiments of compounds of Formula (II), X is C; [ka] is a double bond and n is 0 or 1. In some embodiments of the compound of Formula (II), X is C; [ka] is a double bond and n is 1 or 2. In some embodiments of the compound of Formula (II), X is C; [ka] is a double bond and n is 0. In some embodiments of compounds of Formula (II), X is C; [ka] is a double bond and n is 1. In some embodiments of compounds of Formula (II), X is C; [ka] is a double bond and n is 2.

[0063] In some embodiments of the compound of Formula (II), each R 4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (II), each R 4 is independently C1-C6 alkyl. In some embodiments of the compound of Formula (II), each R 4 In some embodiments of the compound of Formula (II), two R on the same or different carbons are 4 In some embodiments of the compound of Formula (II), two R on the same or different carbons are taken together to form a cycloalkyl. 4together to form a cyclopropyl.

[0064] In some embodiments of the compound of Formula (II), R 5 is hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (II), R 5 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), R 5 is halogen, —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), R 5 is hydrogen or halogen. In some embodiments of the compound of Formula (II), R 5 is halogen. In some embodiments of the compound of Formula (II), R 5 is hydrogen.

[0065] In some embodiments of the compound of Formula (II), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (II), R 6 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), R 6 is hydrogen or halogen. In some embodiments of the compound of Formula (II), R 6 is hydrogen. In some embodiments of the compound of Formula (II), R 6 is a halogen.

[0066] In some embodiments of the compound of Formula (II), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (II), R7 is a C1-C6 alkyl or cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (II), R 7 is C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 7 is methyl. In some embodiments of the compound of Formula (II), R 7 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of Formula (II), R 7 is cyclopropyl or cyclobutyl, each optionally substituted with one or more R. In some embodiments of the compound of Formula (II), R 7 is cyclopropyl optionally substituted with one or more R. In some embodiments of the compound of Formula (II), R 7 is cycloalkyl. In some embodiments of the compound of Formula (II), R 7 is cyclopropyl.

[0067] Disclosed herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R; or R 1 is cycloalkyl or heterocycloalkyl, R 2is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 5 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is a C1-C6 haloalkyl, a C1-C6 deuteroalkyl, a C1-C6 hydroxyalkyl, a C1-C6 aminoalkyl, a C1-C6 heteroalkyl, a C2-C6 alkenyl, a C2-C6 alkynyl, a cycloalkyl, or a heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 7 is C1-C6 alkyl substituted with one or more R, Each R aare independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0068] In some embodiments of the compound of Formula (III), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, wherein alkyl and alkynyl are optionally substituted with one or more R, or R 1 is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (III), R 1 is C1-C6 alkyl optionally substituted with one or more R; or R 1 is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (III), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of Formula (III), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (III), R 1 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compound of Formula (III), R 1 is C1-C6 alkyl. In some embodiments of the compound of Formula (III), R 1 is methyl or ethyl. In some embodiments of the compound of Formula (III), R 1is methyl. In some embodiments of the compound of Formula (III), R 1 is ethyl. In some embodiments of the compound of Formula (III), R 1 is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (III), R 1 is cycloalkyl. In some embodiments of the compound of Formula (III), R 1 is cyclopropyl. In some embodiments of the compound of Formula (III), R 1 is C1-C6 haloalkyl. In some embodiments of the compound of Formula (III), R 1 is difluoromethyl.

[0069] In some embodiments of the compound of Formula (III), R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (III), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (III), R 2 is hydrogen. In some embodiments of the compound of Formula (III), R 2 is C1-C6 alkyl.

[0070] In some embodiments of the compound of Formula (III), R 2 is methyl. In some embodiments of the compound of Formula (III), R 3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (III), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (III), R 3 is C1-C6 alkyl. In some embodiments of the compound of Formula (III), R 3 is methyl. In some embodiments of the compound of Formula (III), R 3 is hydrogen.

[0071] In some embodiments of the compound of Formula (III), R 2 and R 3 taken together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of the compound of Formula (III), R 2 and R 3 taken together form a cycloalkyl. In some embodiments of the compound of Formula (III), R 2 and R 3 together to form a cyclopropyl.

[0072] In some embodiments of the compound of Formula (III), each R 4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (III), each R 4 is independently C1-C6 alkyl. In some embodiments of the compound of Formula (III), each R 4 In some embodiments of the compound of Formula (III), two R on the same or different carbons are 4 In some embodiments of the compound of Formula (III), two R on the same or different carbons are taken together to form a cycloalkyl. 4 together to form a cyclopropyl.

[0073] In some embodiments of the compound of Formula (III), n is 0 or 1. In some embodiments of the compound of Formula (III), n is 0 to 2. In some embodiments of the compound of Formula (III), n is 1 or 2. In some embodiments of the compound of Formula (III), n is 1. In some embodiments of the compound of Formula (III), n is 2.

[0074] In some embodiments of the compound of Formula (III), R 5 is hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (III), R5 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III), R 5 is halogen, —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III), R 5 is hydrogen or halogen. In some embodiments of the compound of Formula (III), R 5 is halogen. In some embodiments of the compound of Formula (III), R 5 is hydrogen.

[0075] In some embodiments of the compound of Formula (III), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (III), R 6 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III), R 6 is hydrogen or halogen. In some embodiments of the compound of Formula (III), R 6 is hydrogen. In some embodiments of the compound of Formula (III), R 6 is a halogen.

[0076] In some embodiments of the compound of Formula (III), R 7 is a C1-C6 haloalkyl, a C1-C6 deuteroalkyl, a cycloalkyl, or a heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (III), R 7 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of Formula (III), R 7 is cyclopropyl or cyclobutyl, each optionally substituted with one or more R. In some embodiments of the compound of Formula (III), R 7is cyclopropyl optionally substituted with one or more R. In some embodiments of the compound of Formula (III), R 7 is cycloalkyl. In some embodiments of the compound of Formula (III), R 7 is cyclopropyl or cyclobutyl. In some embodiments of the compound of Formula (III), R 7 is cyclopropyl. In some embodiments of the compound of Formula (III), R 7 is a C1-C6 alkyl substituted with one or more R.

[0077] Disclosed herein is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -SR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; Or, two R on the same carbon 4 together to form oxo, or Or, two R on the same carbon or different carbons 4 together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4, R 6 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Y is N or CR 8 and R 8 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 9 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R aare independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 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, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein 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, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same atom together form oxo.

[0078] In some embodiments of the compound of Formula (IV), R 1 is deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of formula (IV), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl, where the alkyl, alkynyl, and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 1 is a C1-C6 alkyl or cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 1 is C1-C6 alkyl or cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 1 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 1 is cyclopropyl substituted with one or more R. In some embodiments of the compound of formula (IV), R 1is cyclopropyl. In some embodiments of the compound of Formula (IV), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (IV), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compound of Formula (IV), R 1 is C1-C6 alkyl or cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 1 is C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 1 is methyl or ethyl. In some embodiments of the compound of Formula (IV), R 1 is methyl. In some embodiments of the compound of Formula (IV), R 1 is ethyl. In some embodiments of the compound of Formula (IV), R 1 is C1-C6 haloalkyl. In some embodiments of the compound of formula (IV), R 1 is difluoromethyl.

[0079] In some embodiments of the compound of Formula (IV), R 2 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of formula (IV), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 2 is hydrogen. In some embodiments of the compound of Formula (IV), R 2 is C1-C6 alkyl.

[0080] In some embodiments of the compound of Formula (IV), R 2 is methyl. In some embodiments of the compound of Formula (IV), R 3is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of formula (IV), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 3 is C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 3 is methyl. In some embodiments of the compound of Formula (IV), R 3 is hydrogen.

[0081] In some embodiments of the compound of Formula (IV), R 2 and R 3 together form a cycloalkyl or heterocycloalkyl, each optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 2 and R 3 together form a cycloalkyl. In some embodiments of the compound of Formula (IV), R 2 and R 3 together to form a cyclopropyl.

[0082] In some embodiments of the compound of Formula (IV), each R 4 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (IV), each R 4 is independently C1-C6 alkyl. In some embodiments of the compound of Formula (IV), each R 4 In some embodiments of the compound of Formula (IV), two R on the same or different carbons are 4 In some embodiments of the compound of Formula (IV), two R on the same or different carbons are taken together to form a cycloalkyl. 4 together to form a cyclopropyl.

[0083] In some embodiments of the compound of Formula (IV), n is 0 or 1. In some embodiments of the compound of Formula (IV), n is 0 to 2. In some embodiments of the compound of Formula (IV), n is 1 or 2. In some embodiments of the compound of Formula (IV), n is 1. In some embodiments of the compound of Formula (IV), n is 2.

[0084] In some embodiments of the compound of Formula (IV), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (IV), R 6 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IV), R 6 is hydrogen or halogen. In some embodiments of the compound of Formula (IV), R 6 is hydrogen. In some embodiments of the compound of Formula (IV), R 6 is a halogen.

[0085] In some embodiments of the compound of Formula (IV), Y is N. In some embodiments of the compound of Formula (IV), Y is CR 8 is.

[0086] In some embodiments of the compound of Formula (IV), R 8 is hydrogen, deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (IV), R 8 is hydrogen, halogen, —CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IV), R 8 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IV), R 8 is hydrogen or halogen. In some embodiments of the compound of Formula (IV), R 8is hydrogen. In some embodiments of the compound of Formula (IV), R 8 is a halogen.

[0087] In some embodiments of the compound of Formula (IV), R 9 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (IV), R 9 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (IV), R 9 is hydrogen or halogen. In some embodiments of the compound of Formula (IV), R 9 is hydrogen. In some embodiments of the compound of Formula (IV), R 9 is a halogen.

[0088] In some embodiments of the compound of Formula (IV), R 7 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of formula (IV), R 7 is a C1-C6 alkyl or cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 7 is C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 7 is methyl. In some embodiments of the compound of Formula (IV), R 7 is cycloalkyl optionally substituted with one or more R. In some embodiments of the compound of formula (IV), R 7 is cyclopropyl or cyclobutyl, each optionally substituted with one or more R. In some embodiments of compounds of Formula (IV), R 7is cyclopropyl optionally substituted with one or more R. In some embodiments of the compound of Formula (IV), R 7 is cycloalkyl. In some embodiments of the compound of Formula (IV), R 7 is cyclopropyl.

[0089] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 haloalkyl.

[0090] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen or C1-C6 alkyl. 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 C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently C1-C6 haloalkyl.

[0091] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0092] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC-C alkyl, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C haloalkyl, C-C deuteroalkyl, C-C hydroxyalkyl, C-C aminoalkyl, or C-C heteroalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each is independently deuterium, halogen, -CN, -OH, -OC-C alkyl, -NH, -NHC-C alkyl, -N(C-C alkyl), C-C alkyl, C-C haloalkyl, or C-C deuteroalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, —CN, —OH, —OC1-C6 alkyl, —NH2, C1-C6 alkyl, or C1-C6 haloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen.

[0093] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0094] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from the compounds set forth in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0095] The absolute label (abs) is added to the chiral center to indicate that it is a pure sample of the specifically depicted stereoisomer.

[0096] 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).

[0097] The AND symbol (and) indicates that both isomers exist at the indicated stereochemical center. Assigning different numerical values ​​to the AND symbols means that they are independent of each other. The use of AND symbols with the same value indicates that the two stereocenters are relative to each other and can only vary in concert.

[0098] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is [ka] [ka] is selected from.

[0099] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is [ka] is selected from.

[0100] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is [ka] [ka] is selected from.

[0101] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is [ka] is selected from.

[0102] 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 possess one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in either the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further 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 diastereomeric compounds, separating the diastereoisomers, 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.

[0103] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a 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 have been replaced by an atom having an atomic mass or mass number different from that 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, for example, 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, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms 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 3C is incorporated are useful in drug and / or substrate tissue distribution assays. 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 by, for example, H may confer particular therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0104] 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.

[0105] 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 a disease by administering such a pharmaceutically acceptable salt. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such a pharmaceutically acceptable salt as a pharmaceutical composition.

[0106] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically 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 the appropriate acid or base and isolating the salt thus formed.

[0107] Examples of pharmaceutically 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, 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, These include hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 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.

[0108] Additionally, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically 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. , 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, while not themselves pharmaceutically acceptable, 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.

[0109] In some embodiments, compounds described herein containing free acid groups are reacted with a suitable base, such as a hydroxide, carbonate, bicarbonate, or sulfate salt of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. 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.

[0110] 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.

[0111] 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.

[0112] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed during the process of crystallization using pharmaceutically acceptable solvents such as water, ethanol, and the like. 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. For example, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. Furthermore, 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.

[0113] tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within 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 bonding 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.

[0114] Treatment method Disclosed herein are methods for treating diseases in which inhibition of PARP is beneficial, the methods comprising administering a compound disclosed herein. Also disclosed herein are methods for treating diseases in which inhibition of PARP1 is beneficial, the methods 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, stomach cancer, thyroid cancer, or uterine cancer.

[0115] In some embodiments, the cancer is metastatic, hi some embodiments, the cancer has metastasized to the brain.

[0116] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0117] 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, stomach cancer, thyroid cancer, or uterine cancer.

[0118] In some embodiments, the cancer is a cancer with a deficiency in homologous 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 (NM_001111). A (NM_005590), and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulatory factors such as EMSY. In some embodiments, a cancer deficient in FIR-dependent DNA DSB repair comprises one or more cancer cells that have reduced or eliminated ability to repair DNA DSBs via the 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.

[0119] In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is abolished in one or more cancer cells of an individual with a cancer that is deficient in FIR-dependent DNA DSB repair.

[0120] In some embodiments, 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 BRCA1 and / or BRCA2-deficient, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, due to a mutation or polymorphism in the encoding nucleic acid, or due to amplification, mutation, or polymorphism in a gene encoding a regulator, such as 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, which encodes 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.

[0121] Also disclosed herein are methods of treating cancer in a subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in some embodiments, the mutation in a gene that results in a homologous repair deficiency includes ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof.

[0122] Also disclosed herein are methods of treating cancer in the brain, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0123] In some embodiments, the cancer in the brain arises from a primary peripheral tumor that has metastasized to the brain, hi some embodiments, the cancer in the brain arises from primary brain tissue.

[0124] Also disclosed herein are methods of treating brain cancer, the methods comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0125] In some embodiments, the brain cancer is a primary brain tumor, which tends to start and stay in the brain.

[0126] In some embodiments, the brain cancer is a secondary brain tumor. These cancers start elsewhere in the body and travel to the brain. Lung, breast, kidney, colon, and skin cancers are the most common cancers that spread to the brain.

[0127] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can penetrate 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., between 0.3 and 1) as determined in the rat kp,uu assay.

[0128] Administration In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are 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 symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous medications, the patient's health status, weight, and response to the medication, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0129] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." For this use, the precise amount will also depend on the patient's health, weight, and the like. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous medications, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0130] In certain embodiments in which the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0131] In certain embodiments where the patient's condition improves, the dose of the administered drug is temporarily reduced or temporarily stopped for a specified 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%.

[0132] Once the patient's condition has improved, a maintenance dose is administered as needed. Thereafter, in specific embodiments, the dosage or frequency of administration, or both, is 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 long-term, intermittent, or daily treatment upon any recurrence of symptoms.

[0133] 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 (e.g., weight, sex) of the subject or host requiring treatment, 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.

[0134] In general, however, doses used for adult treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, doses used for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more divided doses per day.

[0135] In one embodiment, a suitable daily dosage for a compound described herein or a pharmaceutically acceptable salt 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 a dosage form is lower or higher than the ranges set forth herein, based on a number of variables related to the particular treatment regimen. In various embodiments, the daily dosage and unit dosage amount will vary depending on several 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 judgment of the physician.

[0136] 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 therapeutically effective daily dose ranges and / or therapeutically effective unit doses for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is such that the ED 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.

[0137] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0138] 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.

[0139] In any of the foregoing aspects, further embodiments include multiple administrations 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 administered compound 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 ranges from two days to one year.

[0140] Administration route 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. Further, by way of example only, parenteral administration includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0141] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, via direct injection of the compound into an organ, often in a depot or sustained-release preparation. 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 the organ and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate-release formulation, a sustained-release formulation, or an intermediate-release formulation. In still other embodiments, the compounds described herein are administered locally.

[0142] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need thereof, in accordance with standard pharmaceutical practice, either alone or in a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, excipient, or diluent. 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.

[0143] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein or its pharmaceutically acceptable salt, solvate, or stereoisomer and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable preparation.The appropriate formulation depends on the selected route of administration. Summary summaries 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, H.A. and 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.

[0144] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0145] 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 combined immediate- and controlled-release formulations.

[0146] Pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof are manufactured by conventional means, including, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0147] Pharmaceutical compositions for oral use can be prepared by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and optionally adding suitable additives to obtain tablets or dragee cores, followed by processing the resulting granules. 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 such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0148] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin and 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 fillers 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 (e.g., fatty oils, liquid paraffin, or liquid polyethylene glycol). In some embodiments, stabilizers are added.

[0149] Pharmaceutical compositions for parenteral use are formulated for infusion or injection. In some embodiments, pharmaceutical compositions suitable for injection or infusion comprise a sterile aqueous solution or dispersion, or a sterile powder, containing a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises 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 comprises a preservative to prevent the growth of microorganisms.

[0150] combination Disclosed herein are methods of treating cancer using the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, in combination with an additional therapeutic agent.

[0151] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0152] 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 before administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. [Example]

[0153] Example 1 [ka] Step 1: Preparation of 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-6-fluoropyridine-2-carboxylic acid: A mixture of tert-butyl 4-[2-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (1.70 g, 5.01 mmol, 1.00 equiv) and LiOH (120 mg, 5.01 mmol, 1.00 equiv) in MeOH (15 mL) was stirred at 50 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The mixture was acidified to pH 3-4 with HCl (1 M). The resulting mixture was extracted with CHCl (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated to give 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-6-fluoropyridine-2-carboxylic acid (1.50 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =326.1.

[0154] Step 2: Preparation of tert-butyl 4-[6-(cyclopropylcarbamoyl)-2-fluoropyridin-3-yl]piperazine-1-carboxylate: A mixture of 5-[4-(tert-butoxycarbonyl)piperazin-1-yl]-6-fluoropyridine-2-carboxylic acid (1.50 g, 4.61 mmol, 1.00 equiv.), DIEA (2.98 g, 23.06 mmol, 5.00 equiv.), aminocyclopropane (1.32 g, 23.06 mmol, 5.00 equiv.), and T3P (14.67 g, 23.06 mmol, 5.00 equiv., 50 wt. % in EtOAc) in ethyl acetate (10 mL) was stirred at 80° C. overnight under a nitrogen atmosphere. 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 (3×100 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography eluting with PE / EA (10% to 50% gradient in 30 min) to give tert-butyl 4-[6-(cyclopropylcarbamoyl)-2-fluoropyridin-3-yl]piperazine-1-carboxylate (1.32 g, 72.5%). LC-MS: (ES+H, m / z): [M+H] + =365.20; 1 H NMR(300MHz,DMSO-d6)δ8.39(d,J=5.0Hz,1H),7.86(dd,J=8.0,1.4Hz,1H),7.64-7.53(m,1H) ),3.59-3.47(m,4H),3.15-3.07(m,4H),2.91-2.80(m,1H),1.43(s,9H),0.69-0.62(m,4H).

[0155] Step 3: Preparation of N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)pyridine-2-carboxamide HCl salt: A mixture of tert-butyl 4-[6-(cyclopropylcarbamoyl)-2-fluoropyridin-3-yl]piperazine-1-carboxylate (1.30 g, 3.57 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (15 mL, 4 M) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give the HCl salt of N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)pyridine-2-carboxamide (1.20 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =265.10.

[0156] Step 3: Preparation of N-cyclopropyl-6-fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-2-carboxamide: A mixture of N-cyclopropyl-6-fluoro-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (250 mg, estimated yield 100%, 0.95 mmol, 1.00 equiv.), DIEA (612 mg, 4.73 mmol, 5.00 equiv.), and 7-(bromomethyl)-8-fluoro-3-methyl-1H-quinoxalin-2-one (513 mg, 0.95 mmol, 1.00 equiv., 50% purity), KI (16 mg, 0.09 mmol, 0.10 equiv.) in MeCN (10 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CHCl / MeOH (10:1) (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 silica gel; mobile phase: MeOH (0.1% NH.H.sub.2O) in water, 20% to 60% gradient in 10 min; UV 220 nm) and then further purified by trituration with MeCN (3 mL). The precipitated solid was collected by filtration and washed with MeCN (2 × 1 mL) to give N-cyclopropyl-6-fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-2-carboxamide (57.6 mg, 13.4%). LC-MS: (ES+H, m / z): [M+H] + =455.25; 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.35(d,J=5.0Hz,1H),7.83(dd,J=8.0,1.4Hz,1H),7.58-7.50(m,2H),7.29(t,J =7.6Hz,1H),3.70(s,2H),3.20-3.12(m,4H),2.90-2.82(m,1H),2.59(t,J=4.5Hz,4H),2.42(s,3H),0.70-0.62(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-72.46;-135.50.

[0157] The following examples were prepared using procedures similar to those set forth in Example 1. [Table 8-1] [Table 8-2] Example 2 [ka]

[0158] Step 1: Preparation of rel-tert-butyl (1R,6S)-5-[2-fluoro-6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate: To a stirred mixture of methyl 5-bromo-6-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.00 equiv.) and rel-tert-butyl (1R,6S)-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.02 g, 5.12 mmol, 1.20 equiv.) in 1,4-dioxane (15 mL), Pd(dba) (195 mg, 0.21 mmol, 0.05 equiv.), XantPhos (247.25 mg, 0.43 mmol, 0.1 equiv.), and CsCO (2.78 g, 8.54 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS and NMR. 1 The reaction mixture was monitored by H NMR. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl:MeOH (10:1, 300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20-60% in 30 min) to give rel-tert-butyl (1R,6S)-5-[2-fluoro-6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (700 mg, 45.8%). 1H NMR(400MHz,DMSO-d6)δ7.90(dd,J=8.2,1.8Hz,1H),7.54(dd,J=10.6,8.2Hz,1H),3.82(s,3H),3.60- 3.57(m,1H),3.47-3.31(m,4H),3.14-3.01(m,1H),1.43(s,9H),1.11-1.03(m,1H),0.50-0.40(m,1H). 19 F NMR(400MHz,DMSO-d6)δ-71.58.

[0159] Step 2: Preparation of rel-tert-butyl (1R,6S)-5-[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate: A solution of rel-tert-butyl (1R,6S)-5-[2-fluoro-6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (700 mg, 1.99 mmol, 1.00 equiv) in MeCN (5 mL) was treated with CH3NH2 (5 mL, 25-30 wt % in water) at room temperature under a nitrogen atmosphere for 10 minutes. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (100 mL), washed with saturated NH4Cl(aq) (2 × 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give rel-tert-butyl (1R,6S)-5-[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (690 mg, 98.8%). LC-MS: (ES+H, m / z): [M+H] + =351.2.

[0160] Step 3: Preparation of rel-5-[(1R,6S)-2,5-diazabicyclo[4.1.0]heptan-2-yl]-6-fluoro-N-methylpyridine-2-carboxamide, HCl (salt): A solution of rel-tert-butyl (1R,6S)-5-[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (650 mg, 1.85 mmol, 1.00 equiv.) in MeOH (5 mL) was treated with HCl (gas) in 1,4-dioxane (3 mL, 4 M in dioxane) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtO (10 mL). The resulting mixture was filtered, and the filter cake was washed with EtO (30 mL). The filter cake was dried under reduced pressure to give rel-5-[(1R,6S)-2,5-diazabicyclo[4.1.0]heptan-2-yl]-6-fluoro-N-methylpyridine-2-carboxamide, HCl salt (500 mg, crude), which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =251.2.

[0161] Step 4: Preparation of rel-6-fluoro-5-[(1R,6S)-5-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide: To a stirred mixture of rel-5-[(1R,6S)-2,5-diazabicyclo[4.1.0]heptan-2-yl]-6-fluoro-N-methylpyridine-2-carboxamide (60 mg, 0.24 mmol, 1.00 equiv.) and 7-(bromomethyl)-8-fluoro-3-methyl-1H-quinoxalin-2-one (129 mg, 0.48 mmol, 2.00 equiv.) in MeCN (3 mL), KI (8 mg, 0.04 mmol, 0.20 equiv.) and DIEA (154 mg, 1.20 mmol, 5.00 equiv.) were added at room temperature. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. 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 then washed with CH2Cl2:H2O (10:1, 100 mL). The filtrate was concentrated under reduced pressure, and the crude product (80 mg) was purified by prep-HPLC (column: XSelect CSH Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.1% NH4HCO3 and 0.1% NH4OH), mobile phase B: MeOH (preparative); flow rate: 25 mL / min; gradient: 12% B to 39% B, 39% B in 11 min; wavelength: 254 / 220 nm) to give rel-6-fluoro-5-[(1R,6S)-5-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (8.6 mg, 7.9%, in two steps). LC-MS: (ES+H, m / z): [M+H] + =441.05; 1 H NMR(400MHz,DMSO-d6)δ12.45(br s,1H),8.27(q,J=4.7Hz,1H),7.79(dd,J=8.2,1.8Hz,1H),7.54-7.43(m,2H),7.30(t,J=7.7Hz,1H),3.85(q,J=3.4Hz,2H),3.62 -3.53(m,1H),3.29-3.22(m,1H),2.89-2.80(m,1H),2.79-2.69(m,4H),2.65-2.56(m,1H),2.44-2.35(m,4H),0.69-0.56(m,2H). 19F NMR(400MHz,DMSO-d6)δ-73.65,-135.60.

[0162] The following examples were prepared using procedures similar to those set forth in Example 2. [Table 9] Example 5 [ka]

[0163] Step 1: Preparation of 1'-tert-butyl 6-methyl 2-fluoro-3',6'-dihydro-2'H-[3,4'-bipyridine]-1',6-dicarboxylate: To a stirred mixture of methyl 5-bromo-6-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.00 equiv.) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.32 g, 4.27 mmol, 1.00 equiv.) in dioxane (20 mL) and HO (1 mL), Pd(dppf)Cl (313 mg, 0.43 mmol, 0.10 equiv.) and CsF (1.95 g, 13 mmol, 3.00 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude residue was purified by silica gel column chromatography eluting with PE / EA (20% to 28% gradient in 30 min) to give 1'-tert-butyl 6-methyl 2-fluoro-3',6'-dihydro-2'H-[3,4'-bipyridine]-1',6-dicarboxylate (1.3 g, 90.5%). LC-MS: (ES+H, m / z): [M+H] + =337.15.

[0164] Step 2: Preparation of tert-butyl 2-fluoro-6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'-carboxylate: To a stirred solution of 1'-tert-butyl 6-methyl 2-fluoro-3',6'-dihydro-2'H-[3,4'-bipyridine]-1',6-dicarboxylate (1.00 g, 2.97 mmol, 1.00 equiv.) in MeCN (10 mL) was added aqueous methylamine (10 mL, 30% wt.-40% wt.) portionwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with saturated NH4Cl (aqueous solution 50 mL). The resulting mixture was extracted with CHCl2 (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave tert-butyl 2-fluoro-6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'-carboxylate (956 mg, 95.9%). LC-MS: (ES+H, m / z): [M+H] + =336.10.

[0165] Step 3: Preparation of tert-butyl 4-[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]piperidine-1-carboxylate: To a stirred mixture of tert-butyl 2-fluoro-6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'-carboxylate (300 mg, 0.90 mmol, 1.00 equiv.) in MeOH (10 mL), Pd / C (30 mg, 0.28 mmol, 0.32 equiv.) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was then washed with MeOH (5 x 5 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]piperidine-1-carboxylate (290 mg, 96.1%). LC-MS: (ES+H, m / z): [M+H-tBu]+ =282.10.

[0166] Step 4: Preparation of 6-fluoro-N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide hydrochloride: To a stirred mixture of tert-butyl 4-[2-fluoro-6-(methylcarbamoyl)pyridin-3-yl]piperidine-1-carboxylate (200 mg, 0.59 mmol, 1.00 equiv.) in DCM (10 mL), HCl (gas) in 1,4-dioxane (10.00 mL, 40.02 mmol, 67.48 equiv., 4 M) was added in portions at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give 6-fluoro-N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide hydrochloride (180 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H+MeCN] + =279.10.

[0167] Step 5: Preparation of 6-fluoro-5-{1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperidin-4-yl}-N-methylpyridine-2-carboxamide: To a stirred mixture of 6-fluoro-N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide hydrochloride (160 mg, 0.58 mmol, estimated yield 100%, 1.00 equiv.), 7-(bromomethyl)-8-fluoro-3-methyl-1H-quinoxalin-2-one (158 mg, 0.58 mmol, 1.00 equiv.), and KI (19 mg, 0.12 mmol, 0.20 equiv.) in MeCN (8 mL) was added DIEA (377 mg, 2.920 mmol, 5.00 equiv.) portionwise at room temperature. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. 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 resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified by silica gel column chromatography eluting with CHCl / MeOH (0-10% gradient in 30 min) to give 6-fluoro-5-{1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperidin-4-yl}-N-methylpyridine-2-carboxamide (87.0 mg, 34.8%). LC-MS: (ES+H, m / z): [M+H] + =428.10; 1 H NMR(300MHz,DMSO-d6)δ12.45(s,1H),8.61(d,J=5.0Hz,1H),8.07(dd,J=9.7,7.7Hz,1H),7.89(dd,J=7.6,1.6Hz,1H),7.52(d,J=8.3H) z,1H),7.33-7.23(m,1H),3.66(s,2H),2.96(d,J=11.2Hz,2H),2.79-2.75(m,4H),2.42(s,3H),2.21-2.10(m,2H),1.83-1.64(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-73.33,-135.62.

[0168] The following examples were prepared using procedures similar to those set forth in Example 5. [Table 4] Example 7 [ka]

[0169] Step 1: Preparation of 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride: To a stirred mixture of tert-butyl 2-fluoro-6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'-carboxylate (300 mg, 0.90 mmol, 1.00 equiv.) in DCM (5 mL) was added HCl (gas) in 1,4-dioxane (5 mL, 20.00 mmol, 22.36 equiv., 4 M) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (300 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H+MeCN] + =277.05.

[0170] Step 2: Preparation of 2-fluoro-1'-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-N-methyl-3',6'-dihydro-2'H-[3,4'-bipyridine]-6-carboxamide: To a stirred mixture of 2-fluoro-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide hydrochloride (150 mg, 0.64 mmol, estimated yield 100%, 1.00 equiv.) and 7-(bromomethyl)-8-fluoro-3-methyl-1H-quinoxalin-2-one (207 mg, 0.77 mmol, 1.20 equiv.) in MeCN (8 mL) was added KI (21 mg, 0.13 mmol, 0.20 equiv.) and DIEA (412 mg, 3.19 mmol, 5.00 equiv.) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by prep-HPLC (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: MeOH-HPLC; flow rate: 60 mL / min; gradient: 38% B to 68% B, 68% B in 8 min; wavelength: 254 / 220 nm) to give 2-fluoro-1'-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-N-methyl-3',6'-dihydro-2'H-[3,4'-bipyridine]-6-carboxamide (76.4 mg, 28.2%). LC-MS: (ES+H, m / z): [M+H] + =426.10; 1 H NMR(300MHz,DMSO-d6)δ12.46(s,1H),8.63(q,J=4.7Hz,1H),8.07(dd,J=9.9,7.7Hz,1H),7.92(dd,J=7.7,1.9Hz,1H),7.51(d,J=8.4Hz,1H),7.31(dd ,J=8.3,7.0Hz,1H),6.24(brs,1H),3.76(s,2H),3.17(q,J=3.0Hz,2H),2. 79(d,J=4.8Hz,3H),2.70(t,J=5.6Hz,2H),2.52-2.50(m,2H),2.42(s,3H).

[0171] The following examples were prepared using procedures similar to those set forth in Example 7. [Table 5] Examples 15 and 16 [ka]

[0172] Step 1: Preparation of 7-(1-ethoxyethenyl)-3-ethyl-8-fluoro-1H-quinoxalin-2-one: To a stirred solution of 7-bromo-3-ethyl-8-fluoro-1H-quinoxalin-2-one (1.00 g, 3.69 mmol, 1.00 equiv.) and tributyl(1-ethoxyethenyl)stannane (1.60 g, 4.42 mmol, 1.20 equiv.) in 1,4-dioxane (10 mL), Pd(PPh3)2Cl2 (0.26 g, 0.36 mmol, 0.10 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =263.1.

[0173] Step 2: Preparation of 7-acetyl-3-ethyl-8-fluoroquinoxalin-2(1H)-one: To the above mixture, concentrated HCl (5 mL, 4 mol / L) was added dropwise at room temperature. The resulting mixture was stirred at 50° C. for an additional 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was washed with EtOAc (10 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3×20 mL). The filtrate was concentrated under reduced pressure to give 7-acetyl-3-ethyl-8-fluoroquinoxalin-2(1H)-one (810 mg, 81.0% two steps). LC-MS: (ES+H, m / z): [M+H] + =235.1.

[0174] Step 3: Preparation of 5-{4-[1-(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide: A stirred mixture of 7-acetyl-3-ethyl-8-fluoro-1H-quinoxalin-2-one (150 mg, 0.64 mmol, 1.00 equiv) and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (211 mg, 0.96 mmol, 1.50 equiv) in DCM (2 mL) was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under reduced pressure. To the above mixture, titanium(IV) isopropoxide (1.5 mL) was added at room temperature. The resulting mixture was stirred at 50° C. for an additional 4 hours. The mixture was allowed to cool to room temperature. To the above mixture, NaBHCN (60 mg, 0.96 mmol, 1.50 equiv) was added at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was poured into stirred water (10 mL) for 10 minutes and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl / MeOH (gradient 0% to 10% over 30 min)) to give 5-{4-[1-(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (120 mg, 42.7%). LC-MS: (ES+H, m / z): [M+H] + =439.1.

[0175] Step 4: Preparation of rel-5-{4-[(1R)-1-(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide and rel-5-{4-[(1R)-1-(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide: The crude product (120 mg) was purified by Prep-Chiral-HPLC (column: CHIRALPAK IA, 2*25 cm, 5 μm; mobile phase A: MTBE:DCM=1:1 (10 mM NH3), mobile phase B: MeOH--HPLC; flow rate: 20 mL / min; gradient: 50% B to 50% B in 13 min; wavelength: 220 / 290 nm; RT1 (min): 7; RT2 (min): 10.5; sample solvent: MeOH:DCM=1:1--HPLC; injection volume: 1 mL; run number: 5) to give rel-5-{4-[(1R)-1-(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (Example 15, Isomer 1, 33.4 mg, 27.8%, ee=100%) and rel-5-{4-[(1R)-1-(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (Example 16, Isomer 2, 32.6 mg, 27.2%, ee=99.7%) were obtained.

[0176] Example 15: LC-MS:(ES+H,m / z):[M+H] + =439.20; 1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.38(q,J=4.7Hz,1H),8.23(d,J=2.9Hz,1H),7.81(d,J=8.8Hz,1H),7.56(d,J=8.5Hz,1H),7.38-7.28(m,2H), 3.95(q,J=6.7Hz,1H),3.30(t,J=5.1Hz,4H),2.84-2.76(m,5H),2.62-2.5 2(m,2H),2.49-2.45(m,2H),1.40(d,J=6.8Hz,3H),1.21(t,J=7.5Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-136.15.

[0177] Example 16: LC-MS:(ES+H,m / z):[M+H] + =439.20; 1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.38(q,J=4.8Hz,1H),8.23(d,J=2.9Hz,1H),7.81(d,J=8.8Hz,1H),7.56(d,J=8.5Hz,1H),7.39-7.28(m,2H), 3.95(q,J=6.8Hz,1H),3.29(t,J=5.1Hz,4H),2.84-2.74(m,5H),2.62-2.5 4(m,2H),2.49-2.45(m,2H),1.40(d,J=6.8Hz,3H),1.21(t,J=7.4Hz,3H). 19 F NMR(377MHz,DMSO-d6)δ-136.15.

[0178] The following examples were prepared using procedures similar to those set forth in Examples 15 and 16. [Table 6-1] [Table 6-2]

[0179] Example A: Cell proliferation inhibition assay Cell proliferation was measured by cell viability assay using DLD-1 BRCA2(- / -) and parental isogenic cell lines and MDA-MB-436 (mutated BRCA1) cell line. The 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.

[0180] 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 cultured at 37°C and 5% CO2. Compounds of the present invention were dispensed into 384-well plates (Corning, 3764) using an Echo acoustic liquid handler to form 1:3 serial dilutions with final concentrations at the highest dose of 10 or 30 μM. Cells were seeded into plates at a density of 200 cells / well (DLD-1 BRCA2- / -) or 500 cells / well (MDA-MB-436). After a brief rotation, the cells were cultured undisturbed in a well-humidified incubator at 37°C and 5% CO2 for 7 days. 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. Data were fitted with Xfit to obtain IC 50 Generated a value.

[0181] Example B: Biochemical (FP) Assay Fluorescent polarization (FP)-based assays are widely used in drug discovery due to their homogeneous format, robust performance, and lack of interference seen in other assays. Compounds were characterized using an assay measuring the displacement of a commercially available fluorescently labeled PARP1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, #6461), as exemplified in the assays performed in WO 2014 / 064149 and WO 2021 / 013735(A1). The assay was performed using the following method.

[0182] Compounds were dissolved in DMSO and serially diluted over the desired concentration range in Optiplate-384F plates using 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.

[0183] PARP1 and PARP2 proteins were expressed, purified, and diluted to a final concentration of 20 nM in assay buffer containing 50 mM Tris, pH 8.0, 0.001% Triton® X-100, 10 mM MgCl2, 150 mM NaCl, and PARPi-FL was then added to a final concentration of 3 nM.

[0184] The assay plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0185] 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 Enhancer - Slot 1

[0186] The inhibition rate was calculated using the percentage of permutation Mahalanobis distance greater than the control sample (mP value) according to the following formula: [Table 7]

number

[0187] XLFit (Equation 201) is used to calculate the reported IC50 for each compound.

[0188] The data from Examples A and B are shown in Table 2. [Table 3]

[0189] Example C: In vitro human transporter efflux Madin-Darby canine kidney (MDCKII) cells expressing either MDR1 or 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 to 8 days before 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 μM and 1 μM, respectively. The final organic solvent concentration was 0.5% (v / v). Bidirectional (apical-basolateral and basolateral-apical) flux of test and reference compounds was measured over a 2-hour incubation at 37°C and 5% CO2 with 95% relative humidity. At the end of the incubation, samples were taken from the apical and basolateral sides 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. The integrity of the cell monolayer during the assay was confirmed by using the marker Lucifer Yellow at a final concentration of 100 μM.

[0190] Apparent permeability (Papp, 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). Emission 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.

[0191] Example D: In vivo measurement of Kp,uu in rats Measurement of plasma unbound fraction (Pu)

[0192] The in vitro binding of test and reference compounds to plasma proteins was investigated using equilibrium dialysis. Plasma samples containing 5 μM test substance 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 placed in a 37°C incubator with 5% CO2 and shaking at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Ketoconazole (5 μM) was used as the reference compound. After incubation, the seals were removed, and 50 μL of post-dialysis sample from both the buffer and plasma chambers was pipetted into a fresh 96-well plate. Samples were equimatrilyzed by either adding blank plasma to the buffer sample or blank buffer to the plasma sample. Subsequently, 400 μL (4 volumes) of acetonitrile containing an internal standard was added to all samples to precipitate proteins before analysis by UPLC-MS / MS, and the relative concentrations of the test substances were then measured. The unbound fraction in plasma was calculated using the concentrations of the test substance in the buffer and plasma samples according to the following formula:

number

[0193] Measurement of unbound fraction (Bu) in brain homogenate

[0194] Equilibrium dialysis was used to examine the in vitro binding of test and reference compounds to rodent brain homogenates. Brains collected from naive animals were weighed and homogenized in four volumes of PBS (pH 7.4). Brain homogenate samples containing 1 μM test substance 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 placed in a 37°C incubator with 5% CO2 and shaking at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Telmisartan (5 μM) was used as the reference compound. After incubation, the seals were removed, and 50 μL of post-dialysis samples from both the buffer and brain homogenate chambers were pipetted into a fresh 96-well plate. Samples were equilibrated by either adding blank homogenate to the buffer sample or blank buffer to the homogenate sample. Subsequently, 400 μL (4 volumes) of acetonitrile containing an internal standard was added to all samples to precipitate proteins before analysis by UPLC-MS / MS, and the relative concentrations of the test substances were measured. The unbound fraction in the diluted brain homogenate was calculated using the concentrations of the test substance in the buffer and homogenate samples according to the following formula:

number

[0195] Correction for the percentage unbound in undiluted brain was achieved using the following formula:

number

[0196] Determination of brain-to-plasma drug partition coefficient (Kp) and drug-unbound Kp (Kp,uu) in rats

[0197] 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 0.5, 1, 2, 4, 8, and 24 hours post-dose, 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 three volumes (v / w) of water, and stored frozen at -80°C until bioanalysis.

[0198] Prior to bioanalysis, plasma and brain samples were extracted with four volumes of acetonitrile containing an internal standard and centrifuged for 15 minutes. The supernatant was diluted with two volumes of water and injected for analysis by HPLC-MS / MS. Plasma and brain homogenate drug concentrations were determined against a calibration curve generated 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.

[0199] The brain-to-plasma partition coefficient (Kp) was determined for each compound and calculated as AUCbrain:AUCplasma, where t last was the same for 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 matrix, 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.

[0200] Kp,uu was then calculated from Kp using the following formula: Kp,uu=Kp*(unbound fraction in brain homogenate / unbound fraction in plasma).

[0201] The data from Examples C and D are shown in Table 3. Table 9

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, 【Chemistry 51】 During the ceremony, R １ represents hydrogen, deuterium, halogen, -CN, -OR ａ , -SR 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 ２ is a 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 said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ３ is 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 said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R ２ and R ３ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R ４ 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 is alkynyl, Or, two R on the same carbon ４ together to form oxo, or Or, two R on the same carbon or different carbons ４ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; n is 0 to 4; R ５ represents 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 ６ represents 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 ７ is 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, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R ａ are 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 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), wherein 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 is heteroalkyl, or a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom are taken together to form oxo.

2. R ２ But C １ ~C ６ alkyl, or R ３ is hydrogen, or R ２ and R ３ together form a cycloalkyl, 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

3. Each R ４ But independently, C １ ~C ６ 3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is alkyl or n is 0 to 2.

4. A compound of formula (II) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: 【Chemistry 52】 During the ceremony, R １ represents hydrogen, deuterium, halogen, -CN, -OR ａ , -SR 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 ２ is 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 said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ３ is 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 said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R ２ and R ３ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; X is N, C, or CH; 【Chemistry 53】 is a single or double bond, Each R ４ 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 is alkynyl, Or, two R on the same carbon ４ together to form oxo, or Or, two R on the same carbon or different carbons ４ together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; however, X is N, and 【Chemistry 54】 is a single bond, n is 1 to 4; or X is C or CH, and 【Transformation 55】 is a single bond or a double bond, n is 0 to 4; R ５ represents 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 ６ represents 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 ７ is 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, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R ａ are 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 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), wherein 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 is heteroalkyl, or a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on the same atom are taken together to form oxo.

5. R ２ is hydrogen or C １ ~C ６ alkyl, or R ３ is hydrogen or C １ ~C ６ alkyl, or R ２ and R ３ together form a cycloalkyl, 5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

6. X is N; 【Transformation 56】 is a single bond and n is 1 or 2, or X is CH; 【Chemistry 57】 is a single bond and n is 0 to 2, or X is C; 【Chemistry 58】 is a double bond and n is 0 to 2; 6. The compound according to any one of claims 4 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

7. Each R ４ But independently, C １ ~C ６ alkyl, or Two R on the same or different carbons ４ The compound of any one of claims 4 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

8. R １ C optionally substituted with one or more R １ ~C ６ alkyl or cycloalkyl, or R １ is C １ ~C ６ alkyl, or R １ is cycloalkyl optionally substituted with one or more R; 6. The compound according to any one of claims 4 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

9. R ５ But halogen, -CN, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl, or R ６ is hydrogen or halogen; 6. The compound according to any one of claims 4 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. R ７ But C １ ~C ６ 6. The compound of any one of claims 4 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is alkyl or cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with one or more R. 【Request Item 11】 【Table 10-1】 Table 10-2 Table 10-3 Table 10-4 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 2, 4 to 5 and 11, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

13. 12. A composition for treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1-2, 4-5 and 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; optionally, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, or lung cancer; optionally, the cancer comprises a BRCA1 and / or BRCA2 mutation; Optionally, 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, stomach cancer, thyroid cancer, or uterine cancer.

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