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 TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 176,610, filed April 19, 2021, U.S. Provisional Patent Application No. 63 / 183,563, filed May 3, 2021, and U.S. Provisional Patent Application No. 63 / 254,832, filed October 12, 2021, which are incorporated by reference 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 also has applications in retroviral infection, and thus inhibitors have potential use in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurotrauma, organ transplantation, and reperfusion of the eye, kidney, gut, and skeletal muscle. PARP 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 cells to respond to DNA damage caused by chemotherapy 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, particularly those with selectivity for PARP1. Summary of the Invention [Means for solving the problem]

[0007] Disclosed herein are compounds of formula (III"), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] (In the formula, R C1 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b, -C(=O)NR c R d , C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R Ca and Each R Ca are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Ca together to form oxo, R C2represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)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; R C3 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; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -ORa , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, R 12is C1-C6 alkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl).

[0008] 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.

[0009] 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 cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, or lung cancer.

[0010] Also disclosed herein are methods of treating a BRCA1 and / or BRCA2 mutation-containing cancer in a subject in need thereof, the method comprising administering a compound of any one of claims 1-70, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

[0011] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0012] 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.

[0013] References throughout this specification to "some embodiments" or "embodiments" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the 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. Note also that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

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

[0015] "Oxo" refers to =O.

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

[0017] "Cyano" refers to -CN.

[0018] "Alkyl" refers to 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. Whenever appearing herein, "C1-C6 alkyl" or "C 1~6 Numerical ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is defined as any of the C 1~10 In some embodiments, alkyl is C 1~6 In some embodiments, alkyl is C 1~5 In some embodiments, alkyl is C 1~4 In some embodiments, alkyl is C 1~3and alkyl. Unless stated otherwise specifically in the specification, alkyl groups 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, alkyl is optionally substituted with oxo, halogen, —CN, —COOH, —COOMe, —OH, —OMe, —NH, or —NO. In some embodiments, alkyl is optionally substituted with halogen, —CN, —OH, or —OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0019] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) 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. Whenever appearing herein, "C2-C6 alkenyl" or "C 2~6Numerical ranges such as "alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, alkenyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH, or -NO. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0020] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Whenever it appears herein, "C2-C6 alkynyl" or "C 2~6Numerical ranges such as "alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless stated otherwise specifically in the specification, alkynyl groups can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. 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.

[0021] "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.

[0022] "Alkoxy" means a group of the formula -OR a refers to the radical of R ais 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.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. 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.

[0024] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which can 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.

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

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

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

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

[0029] "Cyanoalkyl" refers to an alkyl radical, as defined above, that is substituted with one or more cyano groups. In some embodiments, the alkyl is substituted with one cyano. In some embodiments, the alkyl is substituted with one or two cyano. Cyanoalkyl includes, for example, cyanomethyl.

[0030] "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.

[0031] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., 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, e.g., 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.

[0032] "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 10heterocycloalkyl having 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-C7 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 of atoms (including heteroatoms) that make up 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 can be optionally substituted as described below with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0033] "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, benzodioxolyl, 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, indazolyl, isoi Examples include, but are not limited to, indolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyranidyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, 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, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF, -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0034] 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.

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

[0036] "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.

[0037] "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.

[0038] 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.

[0039] As used herein, "PARP1-associated disease or disorder" or "PARP1-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.

[0040] compound Described herein are compounds of Formulas (I), (I'), (II), (III), (III'), (III"), (IV), and (V), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, that are useful for the treatment of cancer.

[0041] Disclosed herein are compounds of formula (I'), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)Ra , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Z is N or CR 4 and R 4 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)Ra , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NRc R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, R 12is cycloalkyl or heterocycloalkyl, wherein cycloalkyl and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0042] 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, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR bC(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R 2 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is selected from the group consisting of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR 4 and R 4 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c Rd , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, Ring A is a 3-16 membered monocyclic, bicyclic, or tricyclic ring optionally containing 1-5 heteroatoms selected from the group consisting of O, N, S, P, or B; Each R A are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R Aa and Or, two R on the same atom A together to form oxo, Each R Aa are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Aatogether to form oxo, m is 0 to 6; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; However, at least one of X and Y is N, If n is 0, [ka] teeth, [ka] isn't it.

[0043] In some embodiments of compounds of Formula (I) or (I'), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl.

[0044] In some embodiments of compounds of Formula (I) or (I'), R 1 is halogen or cycloalkyl.

[0045] In some embodiments of compounds of Formula (I) or (I'), R 1 is cycloalkyl.

[0046] In some embodiments of compounds of Formula (I) or (I'), R 1 is a C1-C6 alkyl.

[0047] In some embodiments of the compound of Formula (I) or (I'), X is N and Y is CR 5 is.

[0048] In some embodiments of compounds of Formula (I) or (I'), R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (I'), R 5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (I'), R 5 is hydrogen.

[0049] In some embodiments of compounds of Formula (I) or (I'), X is CR 2 and Y is N.

[0050] In some embodiments of compounds of Formula (I) or (I'), R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (I'), R 2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (I'), R 2 is hydrogen. In some embodiments of compounds of Formula (I) or (I'), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (I'), R 2 is a C1-C6 alkyl.

[0051] In some embodiments of the compounds of Formula (I) or (I'), X is N and Y is N. In some embodiments of the compound of Formula (I) or (I'), Z is N. In some embodiments of the compound of Formula (I) or (I'), Z is CR 4 is.

[0052] In some embodiments of compounds of Formula (I) or (I'), R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (I'), R 4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (I'), R 4 is hydrogen.

[0053] In some embodiments of compounds of Formula (I) or (I'), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (I) or (I'), R 6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I) or (I'), R 6 is hydrogen.

[0054] In some embodiments of compounds of Formula (I) or (I'), each R 7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (I) or (I'), each R 7 is hydrogen. In some embodiments of compounds of Formula (I) or (I'), two R 7 together form a cycloalkyl.

[0055] In some embodiments of compounds of Formula (I) or (I'), each R 8 is a C1-C6 alkyl, or two R 8 In some embodiments of compounds of Formula (I) or (I'), two R on opposite carbons form oxo. 8 In some embodiments of the compounds of Formula (I) or (I'), two R on the same carbon 8 In some embodiments of the compounds of Formula (I) or (I'), two R on adjacent carbons 8 together form a cycloalkyl.

[0056] In some embodiments of a compound of Formula (I) or (I'), n is 0. In some embodiments of a compound of Formula (I) or (I'), n is 1. In some embodiments of a compound of Formula (I) or (I'), n is 2. In some embodiments of a compound of Formula (I) or (I'), n is 3. In some embodiments of a compound of Formula (I) or (I'), n is 4. In some embodiments of a compound of Formula (I) or (I'), n is 5. In some embodiments of a compound of Formula (I) or (I'), n is 6. In some embodiments of a compound of Formula (I) or (I'), n is 0 to 3. In some embodiments of a compound of Formula (I) or (I'), n is 1 to 3. In some embodiments of a compound of Formula (I) or (I'), n is 1 or 2. In some embodiments of a compound of Formula (I) or (I'), n is 1 to 4. In some embodiments of the compounds of Formula (I) or (I'), n is 2-4.

[0057] In some embodiments of compounds of Formula (I), ring A is a 3-7 membered monocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0058] In some embodiments of the compounds of Formula (I), ring A is phenyl.

[0059] In some embodiments of the compounds of Formula (I), ring A is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0060] In some embodiments of the compounds of Formula (I), ring A is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0061] In some embodiments of compounds of Formula (I), ring A is a 6-membered heteroaryl containing 1-3 heteroatoms that are N.

[0062] In some embodiments of the compounds of Formula (I), ring A is pyridinyl.

[0063] In some embodiments of the compounds of Formula (I), ring A is not pyridinyl.

[0064] 27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring A is a 3- to 7-membered cycloalkyl.

[0065] In some embodiments of the compounds of Formula (I), ring A is a 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0066] In some embodiments of compounds of Formula (I), ring A is a 6-12 membered bicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0067] In some embodiments of the compounds of Formula (I), ring A is a 6-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0068] In some embodiments of the compounds of Formula (I), ring A is a 6-12 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0069] In some embodiments of compounds of Formula (I), ring A is a 6-12 membered bicyclic partially saturated ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0070] In some embodiments of the compound of Formula (I), each R A are independently deuterium, halogen, -CN, -OH, -OR a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a, -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R Aa or two R on the same atom A together form oxo. In some embodiments of the compounds of Formula (I), each R A are independently deuterium, halogen, -S(=O)R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R Aa or two R on the same atom A together form oxo. In some embodiments of the compounds of Formula (I), each R A are independently halogen, -C(=O)NR c R d or C1-C6 alkyl. In some embodiments of the compound of Formula (I), each R A are independently -C(=O)NR c R d In some embodiments of the compounds of Formula (I), R A is -C(=O)NR c R d In some embodiments of the compound of Formula (I), each RA may independently be one or more R Aa is heteroaryl optionally and independently substituted with

[0071] In some embodiments of the compound of Formula (I), each R Aa are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or two R on the same atom Aa together form oxo. In some embodiments of the compounds of Formula (I), each R Aa 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, or two R on the same atom Aa together to form oxo.

[0072] In some embodiments of the compound of Formula (I), m is 0-4. In some embodiments of the compound of Formula (I), m is 0 or 1. In some embodiments of the compound of Formula (I), m is 2 or 3. In some embodiments of the compound of Formula (I), m is 1 or 2. In some embodiments of the compound of Formula (I), m is 0. In some embodiments of the compound of Formula (I), m is 1. In some embodiments of the compound of Formula (I), m is 2. In some embodiments of the compound of Formula (I), m is 3. In some embodiments of the compound of Formula (I), m is 4. In some embodiments of the compound of Formula (I), m is 5. In some embodiments of the compound of Formula (I), m is 6.

[0073] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] is.

[0074] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] is.

[0075] In some embodiments of the compounds of Formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] In some embodiments of the compound of formula (I), [ka] teeth, [ka] is.

[0076] In some embodiments of the compound of Formula (I'), each R 11 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (I'), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (I'), each R 11 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I'), each R 11 are independently halogen.

[0077] In some embodiments of the compound of Formula (I'), q is 0 or 1. In some embodiments of the compound of Formula (I'), q is 1 or 2. In some embodiments of the compound of Formula (I'), q is 0. In some embodiments of the compound of Formula (I'), q is 1. In some embodiments of the compound of Formula (I'), q is 2. In some embodiments of the compound of Formula (I'), q is 3.

[0078] In some embodiments of the compound of Formula (I'), R 12 is cycloalkyl. In some embodiments of the compounds of Formula (I'), R 12 is cycloalkyl.

[0079] In some embodiments of the compound of Formula (I), the compound has the formula: [ka] is a compound of R 1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Y is N, CH, or CF; and each A 1 are independently CH, CD, CMe, CCF, CCl, CF, or N, and each R A are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, NHMe, or NHCD3.

[0080] In some embodiments of the compound of Formula (I), the compound has the formula: [ka] is a compound of R 1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Y is N, CH, or CF; and each A 1 are independently CH, CD, CMe, CCF, CCl, CF, or N, and each R Aare independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, NHMe, or NHCD3.

[0081] In some embodiments of the compound of Formula (I), the compound has the formula: [ka] is a compound of R 1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Y is N, CH, or CF; and each A 1 are independently CH, CD, CMe, CCF, CCl, CF, or N, and each R A are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, NHMe, or NHCD3; A 2 is O, NH, NMe, or NCD3, and A 3 is N, CH, CF, or CD.

[0082] In some embodiments of the compound of Formula (I), the compound has the formula: [ka] is a compound of R 1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Y is N, CH, or CF; and each A 1 are independently CH, CD, CMe, CCF, CCl, CF, or N, and each R A are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, NHMe, or NHCD3; A 2 is O, NH, NMe, or NCD3, and A 3 is N, CH, CF, or CD.

[0083] In some embodiments of the compound of Formula (I), the compound has the formula: [ka] is a compound of R 1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CCl, CF, or N; W is CH2, CF2, CD2, CHF, or CHD; and each R 11 are independently hydrogen, deuterium, or halogen; R 12 is C1-C6 alkyl or C1-C6 deuteroalkyl.

[0084] Also disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R 2 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is selected from the group consisting of deuterium, halogen, —CN, —OH, —OR a , -NR c R d, optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR 4 and R 4 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)Ra , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 6 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; W 1 does not exist or is -C(R 7 )2-, -O-, -S-, -NR W1 -, -C(R 7 )2C(R 7 )2-, -C(R 7 )2NR W1 -, -NR W1 C(R 7 )2-, -C(R 7 )2O-, -OC(R 7 )2-, -C(R 7 )2S- or -SC(R 7 )2- and Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R W1 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Ring B is a 3-16 membered monocyclic, bicyclic, or tricyclic ring optionally containing 1-5 heteroatoms selected from the group consisting of O, N, S, P, or B; Each RB are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R Ba and Or, two R on the same atom B together to form oxo, Each R Ba are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2Ra , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Ba together to form oxo, p is 0 to 6; W 2 does not exist or is -C(R 9 )2-, -O-, -S-, -NR W2 -, -C(R 9 )2C(R 9 )2-, -C(R 9 )2NR W2 -, -NR W2 C(R 9 )2-, -C(R 9 )2O-, -OC(R 9 )2-, -C(R 9 )2S- or -SC(R 9 )2- and Each R 9 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 9 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R W2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; however, [ka] teeth, [ka] No.

[0085] In some embodiments of the compound of Formula (II), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of Formula (II), R 1 is a C1-C6 alkyl.

[0086] In some embodiments of the compound of Formula (II), X is CR 2 and Y is CR 5 is.

[0087] In some embodiments of the compound of Formula (II), X is N and Y is CR 5 is.

[0088] In some embodiments of the compound of Formula (II), R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (II), R 5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 5 is hydrogen.

[0089] In some embodiments of the compound of Formula (II), X is CR 2 and Y is N.

[0090] In some embodiments of the compound of Formula (II), R 2is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (II), R 2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 2 is hydrogen.

[0091] In some embodiments of the compound of Formula (II), X is N and Y is N.

[0092] In some embodiments of the compound of Formula (II), Z is N. In some embodiments of the compound of Formula (II), Z is CR 4 is.

[0093] In some embodiments of the compound of Formula (II), R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (II), R 4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R 4 is hydrogen.

[0094] In some embodiments of the compound of Formula (II), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (II), R 6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R6 is hydrogen.

[0095] In some embodiments of the compound of Formula (II), W 1 is -C(R 7 )2-, -NR W1 -, -C(R 7 )2C(R 7 )2-, -C(R 7 )2NR W1 - or -NR W1 C(R 7 In some embodiments of the compound of Formula (II), W 1 is -C(R 7 )2-, -NR W1 - or -C(R 7 )2NR W1 In some embodiments of the compound of Formula (II), W 1 is -C(R 7 )2-.

[0096] In some embodiments of the compound of Formula (II), each R 7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), each R 7 is hydrogen. In some embodiments of the compound of Formula (II), two R 7 together form a cycloalkyl.

[0097] In some embodiments of the compound of Formula (II), R W1 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R W1 is hydrogen.

[0098] In some embodiments of the compound of Formula (II), W 2 does not exist or is -C(R 9 )2-, -NR W2 -, -C(R 9 )2C(R 9 )2-, -C(R 9 )2NR W2 - or -NRW2 C(R 9 )2-.

[0099] In some embodiments of the compound of Formula (II), W 1 is absent or -NR W2 In some embodiments of the compound of Formula (II), W 2 In some embodiments of the compound of Formula (II), W is absent. 2 is -O-.

[0100] In some embodiments of the compound of Formula (II), each R 9 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (II), each R 9 is hydrogen. In some embodiments of the compound of Formula (II), two R 799 together form a cycloalkyl.

[0101] In some embodiments of the compound of Formula (II), R W2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (II), R W2 is hydrogen.

[0102] 82. The compound of any one of claims 50 to 81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring B is a 3-7 membered monocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0103] In some embodiments of compounds of Formula (II), Ring B is a 3- to 7-membered cycloalkyl.

[0104] In some embodiments of compounds of Formula (II), Ring B is a 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0105] In some embodiments of the compound of Formula (II), Ring B is piperazinyl.

[0106] In some embodiments of the compound of Formula (II), ring B is not piperazinyl.

[0107] In some embodiments of compounds of Formula (II), Ring B is a 6-12 membered bicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0108] In some embodiments of compounds of Formula (II), Ring B is a 6-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0109] In some embodiments of compounds of Formula (II), Ring B is a 6-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms that are N.

[0110] In some embodiments of compounds of Formula (II), ring B is a 6-16 membered tricyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0111] In some embodiments of compounds of Formula (II), Ring B is a 6-16 membered tricyclic heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0112] In some embodiments of compounds of Formula (II), Ring B is a 6-16 membered tricyclic heterocycloalkyl containing 1-3 heteroatoms that are N.

[0113] In some embodiments of the compound of Formula (II), each R B 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, cycloalkyl, heterocycloalkyl, or two R on the same atom B together to form oxo.

[0114] In some embodiments of the compound of Formula (II), each R B are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or two R on the same atom B together to form oxo.

[0115] In some embodiments of the compound of Formula (II), p is 0 to 4. In some embodiments of the compound of Formula (II), p is 0 or 1. In some embodiments of the compound of Formula (II), p is 1 or 2. In some embodiments of the compound of Formula (II), p is 1. In some embodiments of the compound of Formula (II), p is 2. In some embodiments of the compound of Formula (II), p is 3. In some embodiments of the compound of Formula (II), p is 4.

[0116] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] is.

[0117] In some embodiments of the compound of Formula (II), [ka] teeth, [ka] is.

[0118] In some embodiments of the compound of Formula (II), each R 11 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of Formula (II), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (II), each R 11 is independently halogen or C1 to C6 alkyl.

[0119] In some embodiments of the compound of Formula (II), q is 0 or 1. In some embodiments of the compound of Formula (II), q is 1 or 2. In some embodiments of the compound of Formula (II), q is 1. In some embodiments of the compound of Formula (II), q is 0. In some embodiments of the compound of Formula (II), q is 2. In some embodiments of the compound of Formula (II), q is 3.

[0120] Also disclosed herein is a compound of formula (III"), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R C1 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c Rd , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally joined by one or more R Ca and Each R Ca are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)ORb , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Ca together to form oxo, R C2 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)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; R C3 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; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, R 12 is C1-C6 alkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NRc R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0121] In some embodiments of the compound of Formula (III"), R C1 is deuterium, halogen, -CN, -OH, -OR a , -NR c R d, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are each independently selected from the group consisting of one or more R Ca In some embodiments of the compound of Formula (III"), R C1 is halogen, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (III"), R C1 is halogen, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of Formula (III"), R C1 is halogen, or cycloalkyl. In some embodiments of the compound of Formula (III"), R C1 is halogen. In some embodiments of the compound of Formula (III"), R C1 is cycloalkyl.

[0122] In some embodiments of the compound of Formula (III"), each R Ca are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of formula (III"), each R Ca are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1 to C6 alkyl, or C1 to C6 haloalkyl.

[0123] In some embodiments of the compound of Formula (III"), R C2 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III"), R C2 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III"), R C2 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III"), R C2 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III"), R C2 is hydrogen. In some embodiments of the compound of Formula (III"), R C2 is a C1-C6 alkyl.

[0124] In some embodiments of the compound of Formula (III"), R C3 represents hydrogen, deuterium, halogens, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of formula (III"), R C3 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III"), R C3 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III"), R C3 is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III"), R C3 is hydrogen. In some embodiments of the compound of Formula (III"), R C3 is a C1-C6 alkyl.

[0125] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] is.

[0126] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] In some embodiments of the compound of formula (III"), [ka] teeth, [ka] is.

[0127] In some embodiments of the compound of Formula (III"), each R 7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compound of Formula (III"), each R 7 is hydrogen. In some embodiments of the compound of Formula (III"), two R 7 together form a cycloalkyl.

[0128] In some embodiments of the compound of Formula (III"), each R 8 is a C1-C6 alkyl, or two R 8 together form oxo. In some embodiments of the compound of Formula (III"), two R on opposite carbons 8 together form a cycloalkyl. In some embodiments of the compound of Formula (III"), two R on the same carbon 8 together form a cycloalkyl. In some embodiments of the compound of Formula (III"), two R on adjacent carbons 8 together form a cycloalkyl.

[0129] In some embodiments of a compound of Formula (III"), n is 0. In some embodiments of a compound of Formula (III"), n is 1. In some embodiments of a compound of Formula (III"), n is 2. In some embodiments of a compound of Formula (III"), n is 3. In some embodiments of a compound of Formula (III"), n is 4. In some embodiments of a compound of Formula (III"), n is 5. In some embodiments of a compound of Formula (III"), n is 6. In some embodiments of a compound of Formula (III"), n is 0-3. In some embodiments of a compound of Formula (III"), n is 1-3. In some embodiments of a compound of Formula (III"), n is 1 or 2. In some embodiments of a compound of Formula (III"), n is 1-4. In some embodiments of a compound of Formula (III"), n is 2-4.

[0130] In some embodiments of the compound of Formula (III"), each R 11 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of formula (III"), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (III"), each R 11 is independently halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (III"), each R 11 are independently halogen.

[0131] In some embodiments of a compound of Formula (III"), q is 0 or 1. In some embodiments of a compound of Formula (III"), q is 1 or 2. In some embodiments of a compound of Formula (III"), q is 0. In some embodiments of a compound of Formula (III"), q is 1. In some embodiments of a compound of Formula (III"), q is 2. In some embodiments of a compound of Formula (III"), q is 3.

[0132] In some embodiments of the compound of Formula (III"), R 12 is C1-C6 alkyl, or cycloalkyl. In some embodiments of the compound of formula (III"), R 12 is C1-C6 alkyl. In some embodiments of the compound of formula (III"), R 12 is cycloalkyl.

[0133] Also disclosed herein is a compound of formula (III'), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, Ring C is a 3-16 membered monocyclic, bicyclic, or tricyclic ring optionally containing 1-5 heteroatoms selected from the group consisting of O, N, S, P, or B; Each R C are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R Ca and Or, two R on the same atom C together to form oxo, Each R Ca are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Ca together to form oxo, r is 0 to 6, W 3 does not exist or is -C(R 7 )2-, or C2 alkynylene; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, A is N or CR 11 or CH, R 12 is C1-C6 alkyl or C1-C6 deuteroalkyl, Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; However, if n is 0, [ka] teeth, [ka] No.

[0134] Also disclosed herein is a compound of formula (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, Ring C is a 3-16 membered monocyclic, bicyclic, or tricyclic ring optionally containing 1-5 heteroatoms selected from the group consisting of O, N, S, P, or B; Each R C are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally selected from the group consisting of one or more R Caand Or, two R on the same atom C together to form oxo, Each R Ca are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Ca together to form oxo, r is 0 to 6, W 3 does not exist or is -C(R 7 )2-, or C2 alkynylene; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; However, if n is 0, [ka] teeth, [ka] No.

[0135] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 3-7 membered monocyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0136] In some embodiments of the compounds of Formula (III) or (III'), Ring C is phenyl.

[0137] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 5-6 membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0138] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of O, N, or S.

[0139] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 6-membered heteroaryl containing 1-3 heteroatoms that are N.

[0140] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 3- to 7-membered cycloalkyl.

[0141] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 3-7 membered heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0142] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 6-12 membered bicyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0143] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 6-12 membered bicyclic heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0144] In some embodiments of compounds of Formula (III) or (III'), Ring C is a 6-12 membered bicyclic heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0145] In some embodiments of compounds of Formula (III) or (III'), Ring C is an 8-16 membered tricyclic ring optionally containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0146] In some embodiments of compounds of Formula (III) or (III'), Ring C is an 8-16 membered tricyclic heterocycloalkyl containing 1-3 heteroatoms selected from the group consisting of O, N, or S.

[0147] In some embodiments of compounds of Formula (III) or (III'), each R C 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 alkynyl, cycloalkyl, or heterocycloalkyl, or two R on the same atom C together form oxo. In some embodiments of compounds of Formula (III) or (III'), each R C are independently deuterium, halogen, —CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or two R C together form oxo. In some embodiments of compounds of Formula (III) or (III'), each R Cis independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of a compound of Formula (III) or (III'), each R C is independently C1-C6 alkyl. In some embodiments of compounds of formula (III) or (III'), R C is not C1-C6 alkyl. In some embodiments of compounds of formula (III) or (III'), R C is not a C1-C6 haloalkyl.

[0148] In some embodiments of a compound of Formula (III) or (III'), r is 0 to 4. In some embodiments of a compound of Formula (III) or (III'), r is 1 to 3. In some embodiments of a compound of Formula (III) or (III'), r is 0 or 1. In some embodiments of a compound of Formula (III) or (III'), r is 0 to 3. In some embodiments of a compound of Formula (III) or (III'), r is 1 or 2. In some embodiments of a compound of Formula (III) or (III'), r is 1 or 2. In some embodiments of a compound of Formula (III) or (III'), r is 1. In some embodiments of a compound of Formula (III) or (III'), r is 2. In some embodiments of a compound of Formula (III) or (III'), r is 3. In some embodiments of a compound of Formula (III) or (III'), r is 4.

[0149] In some embodiments of compounds of Formula (III) or (III'), [ka] teeth, [ka] is.

[0150] In some embodiments of compounds of Formula (III) or (III'), [ka] teeth, [ka] is.

[0151] In some embodiments of compounds of Formula (III) or (III'), W 3 In some embodiments of compounds of formula (III) or (III'), W 3 is C2 alkynylene. In some embodiments of compounds of formula (III) or (III'), W 3 is -C(R 7 )2-.

[0152] In some embodiments of compounds of Formula (III) or (III'), each R 7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (III) or (III'), each R 7 is hydrogen. In some embodiments of compounds of formula (III) or (III'), two R 7 together form a cycloalkyl.

[0153] In some embodiments of compounds of Formula (III) or (III'), each R 8 is a C1-C6 alkyl, or two R 8 In some embodiments of compounds of Formula (III) or (III'), two R on opposite carbons form oxo. 8 In some embodiments of the compounds of Formula (III) or (III'), two R on the same carbon 8 In some embodiments of the compounds of Formula (III) or (III'), two R on adjacent carbons are8 together form a cycloalkyl.

[0154] In some embodiments of a compound of Formula (III) or (III'), n is 0. In some embodiments of a compound of Formula (III) or (III'), n is 1. In some embodiments of a compound of Formula (III) or (III'), n is 2. In some embodiments of a compound of Formula (III) or (III'), n is 3. In some embodiments of a compound of Formula (III) or (III'), n is 4. In some embodiments of a compound of Formula (III) or (III'), n is 5. In some embodiments of a compound of Formula (III) or (III'), n is 6. In some embodiments of a compound of Formula (III) or (III'), n is 0-3. In some embodiments of a compound of Formula (III) or (III'), n is 1-3. In some embodiments of a compound of Formula (III) or (III'), n is 1 or 2. In some embodiments of a compound of Formula (III) or (III'), n is 1-4. In some embodiments of the compound of Formula (III) or (III'), n is 2-4.

[0155] In some embodiments of compounds of Formula (III) or (III'), each R 11 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of formula (III) or (III'), each R 11is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of a compound of Formula (III) or (III'), each R 11 is independently halogen or C1 to C6 alkyl.

[0156] In some embodiments of a compound of Formula (III) or (III'), q is 0 or 1. In some embodiments of a compound of Formula (III) or (III'), q is 1 or 2. In some embodiments of a compound of Formula (III) or (III'), q is 0. In some embodiments of a compound of Formula (III) or (III'), q is 1. In some embodiments of a compound of Formula (III) or (III'), q is 2. In some embodiments of a compound of Formula (III) or (III'), q is 3.

[0157] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 1 are CH2, CF2, CHF, CHCH3, and C(CH3)2, and B 1 are CH2, CF2, CHF, CHCH3, C(CH3)2, and C 1 is O or S), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0158] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 2 are CH2, CF2, CHF, CHCH3, and C(CH3)2, and B 2 are CH2, CF2, CHF, CHCH3, C(CH3)2, and C 2are CH2, CF2, CHF, CHCH3, C(CH3)2, and D 2 is O or S), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0159] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 3 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl optionally substituted with halogen; B 3 is O or S, C 3 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl optionally substituted with halogen), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0160] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 4 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, and B 4 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C 4 is O or S), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0161] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 5 is O or S, and B 5is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, and C 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0162] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 6 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, and B 6 is O or S), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0163] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 7 is O or S, and B 7 are CH2, CF2, CHF, CHCH3, C(CH3)2, and C 7 is CH2, CF2, CHF, CHCH3, C(CH3)2), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0164] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 8 is O or S, and B 8 are CH2, CF2, CHF, CHCH3, C(CH3)2, and C 7 are CH2, CF2, CHF, CHCH3, C(CH3)2, and D 8is CH2, CF2, CHF, CHCH3, C(CH3)2), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0165] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] (Wherein, Y is N, CH, or CF; A 9 is O or S, and B 9 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl optionally substituted with halogen, and C 9 is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl optionally substituted with halogen), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0166] In some embodiments of the compound of Formula (III) or (III'), the compound has the formula [ka] wherein Y is N, CH, or CF; A is CH, CMe, CCF, CCl, CF, or N; and R 12 is C1-C6 alkyl, C1-C6 deuteroalkyl, and each R 11 are independently hydrogen, deuterium, or halogen; A 10 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl).

[0167] Disclosed herein is a compound of formula (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -ORa , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)Ra , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R 2 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is selected from the group consisting of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR 4 and R 4 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NRb C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R6 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 7a is 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, cycloalkyl, or heterocycloalkyl; R 7b 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, cycloalkyl, or heterocycloalkyl; Or R 7a and R 7b taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 0 to 6, Each R 11 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c Rd , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; q is 0 to 3; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0168] In some embodiments of the compound of Formula (IV), R 1is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of compounds of Formula (IV), R 1 is a C1-C6 alkyl.

[0169] In some embodiments of the compound of Formula (IV), X is CR 2 and Y is CR 5 is.

[0170] In some embodiments of the compound of Formula (IV), X is N and Y is CR 5 is.

[0171] In some embodiments of the compound of Formula (IV), R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (IV), R 5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IV), R 5 is hydrogen.

[0172] In some embodiments of the compound of Formula (IV), X is CR 2 and Y is N.

[0173] In some embodiments of the compound of Formula (IV), R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (IV), R 2is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IV), R 2 is hydrogen.

[0174] In some embodiments of the compound of Formula (IV), X is N and Y is N.

[0175] In some embodiments of the compound of Formula (IV), Z is N. In some embodiments of the compound of Formula (IV), Z is CR 4 is.

[0176] In some embodiments of the compound of Formula (IV), R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (IV), R 4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IV), R 4 is hydrogen.

[0177] In some embodiments of the compound of Formula (IV), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (IV), R 6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compound of Formula (IV), R 6 is hydrogen.

[0178] In some embodiments of the compound of Formula (IV), R 7ais deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of formula (IV), R 7a is deuterium or C1-C6 alkyl. In some embodiments of the compound of formula (IV), R 7a is deuterium.

[0179] In some embodiments of the compound of Formula (IV), R 7b is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (IV), R 7b is hydrogen, deuterium, or C1-C6 alkyl.

[0180] In some embodiments of the compound of Formula (IV), R 7a and R 7b taken together form a cycloalkyl. In some embodiments of the compound of Formula (IV), R 7a and R 7b is deuterium.

[0181] In some embodiments of the compound of Formula (IV), each R 8 is a C1-C6 alkyl, or two R 8 In some embodiments of the compound of Formula (IV), two R on opposite carbons form oxo. 8 In some embodiments of the compound of Formula (IV), two R on the same carbon 8 In some embodiments of the compound of Formula (IV), two R on adjacent carbons are taken together to form a cycloalkyl. 8 together form a cycloalkyl.

[0182] In some embodiments of a compound of Formula (IV), n is 0. In some embodiments of a compound of Formula (IV), n is 1. In some embodiments of a compound of Formula (IV), n is 2. In some embodiments of a compound of Formula (IV), n is 3. In some embodiments of a compound of Formula (IV), n is 4. In some embodiments of a compound of Formula (IV), n is 5. In some embodiments of a compound of Formula (IV), n is 6. In some embodiments of a compound of Formula (IV), n is 0-3. In some embodiments of a compound of Formula (IV), n is 1-3. In some embodiments of a compound of Formula (IV), n is 1 or 2. In some embodiments of a compound of Formula (IV), n is 1-4. In some embodiments of a compound of Formula (IV), n is 2-4.

[0183] In some embodiments of the compound of Formula (IV), each R 11 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (IV), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (IV), each R 11 is independently halogen or C1 to C6 alkyl.

[0184] In some embodiments of the compound of Formula (IV), q is 0 or 1. In some embodiments of the compound of Formula (IV), q is 1 or 2. In some embodiments of the compound of Formula (IV), q is 0. In some embodiments of the compound of Formula (IV), q is 1. In some embodiments of the compound of Formula (IV), q is 2. In some embodiments of the compound of Formula (IV), q is 3.

[0185] Disclosed herein is a compound of formula (V), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, R 1 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; X is N or CR 2 and R 2 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Or R 1 and R 2 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is selected from the group consisting of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Z is N or CR4 and R 4 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Y is N or CR 5 and R 5 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d, -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; R 6 are hydrogen, deuterium, halogens, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl; Each R 7 are independently hydrogen, 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, cycloalkyl, or heterocycloalkyl; Or two R 7 taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R 8 are independently deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR bS(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon 8 together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons 8 taken together to form a cycloalkyl or heterocycloalkyl, each of which may be one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; n is 1 to 6, Each R 11 are independently hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NRb S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, However, one R 11 and one R 8 taken together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which may be substituted with one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each A is independently N or CR 11 and R 12 is C1-C6 alkyl or C1-C6 deuteroalkyl, 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the aryl and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Each R bare 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; 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 alkyl(cycloalkyl), C1-C6 alkyl(heterocycloalkyl), C1-C6 alkyl(aryl), or C1-C6 alkyl(heteroaryl), and each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, the alkyl, aryl, and heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0186] In some embodiments of compounds of Formula (V), R 1is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, or cycloalkyl.

[0187] In some embodiments of compounds of Formula (V), R 1 is a C1-C6 alkyl.

[0188] In some embodiments of the compound of Formula (V), X is N and Y is CR 5 is.

[0189] In some embodiments of compounds of Formula (V), R 5 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (V), R 5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V), R 5 is hydrogen.

[0190] In some embodiments of the compound of Formula (V), X is CR 2 and Y is N.

[0191] In some embodiments of compounds of Formula (V), R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (V), R 2 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V), R 2 is hydrogen.

[0192] In some embodiments of the compound of Formula (V), X is N and Y is N. In some embodiments of the compound of Formula (V), Z is N. In some embodiments of the compound of Formula (V), Z is CR 4 is.

[0193] In some embodiments of compounds of Formula (V), R 4 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (V), R 4 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V), R 4 is hydrogen.

[0194] In some embodiments of compounds of Formula (V), R 6 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 heteroalkyl, or cycloalkyl. In some embodiments of compounds of Formula (V), R 6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (V), R 6 is hydrogen.

[0195] In some embodiments of the compound of Formula (V), each R 7 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of Formula (V), each R 7 is hydrogen. In some embodiments of the compound of Formula (V), two R 7 together form a cycloalkyl.

[0196] In some embodiments of the compound of Formula (V), each R 8 is a C1-C6 alkyl, or two R 8 In some embodiments of the compound of Formula (V), two R on opposite carbons form oxo. 8 In some embodiments of the compound of Formula (V), two R on the same carbon 8 In some embodiments of the compound of Formula (V), two R on adjacent carbons are 8 together form a cycloalkyl.

[0197] In some embodiments of a compound of Formula (V), n is 0. In some embodiments of a compound of Formula (V), n is 1. In some embodiments of a compound of Formula (V), n is 2. In some embodiments of a compound of Formula (V), n is 3. In some embodiments of a compound of Formula (V), n is 4. In some embodiments of a compound of Formula (V), n is 5. In some embodiments of a compound of Formula (V), n is 6. In some embodiments of a compound of Formula (V), n is 0-3. In some embodiments of a compound of Formula (V), n is 1-3. In some embodiments of a compound of Formula (V), n is 1 or 2. In some embodiments of a compound of Formula (V), n is 1-4. In some embodiments of a compound of Formula (V), n is 2-4.

[0198] In some embodiments of the compound of Formula (V), each R 11 are independently deuterium, halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formula (V), each R 11 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of compounds of Formula (V), each R 11 is independently halogen or C1 to C6 alkyl.

[0199] In some embodiments of the compound of Formula (V), one A is CR 11 and one is N. In some embodiments of compounds of Formula (V), both A are CR 11 In some embodiments of the compound of Formula (V), both A are N.

[0200] In some embodiments of compounds of Formula (V), R 12 is C1-C6 alkyl. In some embodiments of compounds of Formula (V), R 12 is a C1-C6 deuteroalkyl.

[0201] In some embodiments of the compound of Formula (V), one R 11 and one R 8 taken together form a cycloalkyl or heterocycloalkyl, each of which may be substituted with one or more of deuterium, halogen, —CN, —OH, —OR a , -NR c R d , optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0202] In some embodiments of the compound of Formula (V), one R 11 and one R 8 together form one or more deuterium, halogen, -CN, -OH, -ORa , -NR c R d , forming a heterocycloalkyl optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0203] In some embodiments of the compound of Formula (V), one R 11 and one R 8 together form one or more deuterium, halogen, -CN, -OH, -OR a , -NR c R d , forming a 5-6 membered heterocycloalkyl optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0204] In some embodiments of the compound of Formula (V), one R 11 and one R 8 together form one or more deuterium, halogen, -CN, -OH, -OR a , -NR c R d , forming a 6-membered heterocycloalkyl optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0205] In some embodiments of the compound of Formula (V), one R 11 and one R 8 together form one or more deuterium, halogen, -CN, -OH, -OR a , -NR c R d , forming a 5-membered heterocycloalkyl optionally substituted with C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0206] In some embodiments of the compound of Formula (V), the compound has the following formula: [ka] wherein R 1 is C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl; Y is N, CH, or CF; each A is independently CH, CD, CMe, CCF3, CCl, CF, or N; B 1 is O, S, NH, NMe, NCD, CH, CHF, CD, or CDH; R is hydrogen, deuterium, or halogen; R 12 is C1-C6 alkyl or C1-C6 deuteroalkyl.

[0207] In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, —CN, —OH, —OCH3, — and optionally substituted with S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1 to C6 alkyl.

[0208] In some embodiments of the compounds disclosed herein, each R bare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, -CN, -OH, -OCH3 , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R bare independently hydrogen or C1-C6 alkyl.

[0209] 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 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently contains one or more of oxo, deuterium, halogen, -CN, -OH, -OCH3 , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —S(═O)CH3, —S(═O)2CH3, —S(═O)2NH2, —S(═O)2NHCH3, —S(═O)2N(CH3)2, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or 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 are independently hydrogen or C1-C6 alkyl.

[0210] In some embodiments of the compounds disclosed herein, R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more oxo, deuterium, halogen, —CN, —OH, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl.

[0211] In some embodiments of the compounds disclosed herein, each R A , R B , R C , R a , R b , R c , R d , 2 R 7 a cycloalkyl or heterocycloalkyl formed when two R 8 taken together, a cycloalkyl or heterocycloalkyl formed, and R c and R d taken together, the heterocycloalkyl formed is independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R a , Rb , R c , R d , 2 R 7 a cycloalkyl or heterocycloalkyl formed when two R 8 taken together, a cycloalkyl or heterocycloalkyl formed, and R c and R d taken together, the heterocycloalkyl formed is independently substituted with 1, 2, or 3 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R a , R b , R c , R d , 2 R 7 a cycloalkyl or heterocycloalkyl formed when two R 8 taken together, a cycloalkyl or heterocycloalkyl formed, and R c and R d taken together, the heterocycloalkyl formed is independently substituted with 1 or 2 substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A , R B , R C , R a , R b , R c , R d , 2 R 7 a cycloalkyl or heterocycloalkyl formed when two R 8 taken together, a cycloalkyl or heterocycloalkyl formed, and R c and R d taken together form a heterocycloalkyl, which is independently substituted with one substituent as defined herein.

[0212] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, such groups and substituents are chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0213] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from the compounds in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21]

[0214] In some embodiments, the compound is [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0215] In some embodiments, the compound is [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0216] In some embodiments, the compound is [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0217] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0218] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0219] 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.

[0220] 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 Substitutions such as H may confer particular therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate Examples of suitable salts include mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate, and xylenesulfonate.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. For example, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures 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.

[0230] 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.

[0231] 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, blood 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.

[0232] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0233] 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.

[0234] In some embodiments, the cancer is a cancer with a deficiency in Flomologous Recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via a homologous mechanism and reforms a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), and MRE1 (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.

[0235] 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.

[0236] 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.

[0237] To minimize the risk of off-target effects, it is desirable for drug molecules to be selective for particular targets.

[0238] Avoiding inhibition of PARP family isoforms other than PARP1 may be important to minimize toxicity that can result from inhibition of non-PARP1 isoforms. Pharmacological inhibition of PARP isoforms other than PARP1 may lead to toxicity that reduces the therapeutic index of drugs with lower selectivity for PARP1 over PARP isoforms. PARP3, like PARP1, is involved in DNA damage, but it has also been shown to play an important role in mitotic spindle integrity and telomerase integrity (Boehler, C., Gauthier, L.R., Mortusewicz, O. et al. Poly(ADP-ribose) polymerase 3 (PARP3), a novel component in the cellular response to DNA damage and mitotic progression. PNAS, January 26, 2011, 108(7)2783-2788). PARP5A, also known as Tankyrase 1, plays a key role in Wnt signaling and telomere length (Kulak, O., Chen, H., Holohan B. et al. Disruption of Wnt / β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells. Mol Cell Biol. 2015 Jul;35(14),2425-2435). PARP6 is an essential microtubule-regulating gene in mice, and germline mutations in PARP6 that abrogate its catalytic activity adversely affect neuronal function in humans (Vermehren-Schmaedick, A., Huang JY, Levinson, M. et al. Characterization of PARP6 Function in Knockout Mice and Patients with Developmental Delay. Cells, 2021 Jun;10(6),1289).PARP7 catalytic inhibition leads to hyperstimulatory responses to type I interferon, resulting in an autoimmune phenotype (Gozgit, JM, Vasbinder, MM, Abo, RP et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. Volume 39, Issue 9, September 13, 2021, Pages 1214-1226). Although the precise function of PARP8 has not been established, its knockout has been shown to induce defects in mitosis and nuclear morphology and reduced cell viability (Vyas, S., Chesarone-Cataldo, M., Todorova, T., et al. A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell Physiology. Nat. Commun. 2013, 4(1), 2240). PARP10 has been described as a MYC-interacting protein with tumor suppressor activity (Yu, M., Schreek, S., Cerni, C. et al. PARP-10, a novel Myc-interacting protein with poly(ADP-ribose) polymerase activity, inhibits transformation. Oncogene, 2005 volume 24, pages 1982-1993).

[0239] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over other members of the PARP family, including PARP2, PARP3, PARP6, PARP7, PARP8, PARP10, PARP11, PARP14, PARP15, TNKS1 (PARP5A), and TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP6. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP7. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP10. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP14. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over PARP15. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over TNKS1 (PARP5A).In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selective for PARP1 over TNKS2 (PARP5B).

[0240] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 10,000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 9,000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 8,000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 7,000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 6,000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 5000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 4000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 3000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 2000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 1000-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 100-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein are at least 400-600-fold selective for PARP1 over PARP2.In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are at least 400-fold selective for PARP1 over PARP2. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are at least 500-fold selective for PARP1 over PARP2.

[0241] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 100-fold selective for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are more than 200-fold selective for PARP1 over PARP3.

[0242] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are at least 200-700-fold selective for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are at least 200-fold selective for PARP1 over PARP3. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are at least 650-fold selective for PARP1 over PARP3.

[0243] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 1000-fold selectivity for PARP1 over PARP6. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 2000-3000-fold selectivity for PARP1 over PARP6. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 2400-fold selectivity for PARP1 over PARP6. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 3000-fold selectivity for PARP1 over PARP6.

[0244] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 500-fold selectivity for PARP1 over PARP7. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 600-900-fold selectivity for PARP1 over PARP7. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 600-fold selectivity for PARP1 over PARP7. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 800-fold selectivity for PARP1 over PARP7.

[0245] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 3,000-fold selectivity for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 5,000-9,000-fold selectivity for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 8,000-fold selectivity for PARP1 over PARP8. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 5,000-fold selectivity for PARP1 over PARP8.

[0246] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 200-fold selectivity for PARP1 over PARP10. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 300-400-fold selectivity for PARP1 over PARP10. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 350-fold selectivity for PARP1 over PARP10. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 300-fold selectivity for PARP1 over PARP10.

[0247] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 5-fold selectivity for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 5- to 270-fold selectivity for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 6-fold selectivity for PARP1 over PARP11. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 270-fold selectivity for PARP1 over PARP11.

[0248] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 2000-fold selectivity for PARP1 over PARP14. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 1400-2600-fold selectivity for PARP1 over PARP14. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 1400-fold selectivity for PARP1 over PARP14. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 2600-fold selectivity for PARP1 over PARP14.

[0249] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 1000-fold selectivity for PARP1 over PARP 15. In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 1600-fold selectivity for PARP1 over PARP15.

[0250] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 100-fold selectivity for PARP1 over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 100-250-fold selectivity for PARP1 over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 100-fold selectivity for PARP1 over TNKS1 (PARP5A). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 230-fold selectivity for PARP1 over TNKS1 (PARP5A).

[0251] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have greater than 100-fold selectivity for PARP1 over TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 100- to 150-fold selectivity for PARP1 over TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 140-fold selectivity for PARP1 over TNKS2 (PARP5B). In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, have at least 130-fold selectivity for PARP1 over TNKS2 (PARP5B).

[0252] dosage In certain embodiments, compositions containing a compound(s) 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 drugs, 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.

[0253] 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.

[0254] 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.

[0255] 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%.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0276] 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]

[0277] Example 1 [ka] Step 1: Preparation of tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.00 g, 2.50 mmol, 1.00 equiv.) and Zn(CN) (0.44 g, 3.76 mmol, 1.50 equiv.) in DMF (10 mL) was added Pd(PPh) (0.29 g, 0.25 mmol, 0.10 equiv.) at room temperature under a N atmosphere. The resulting mixture was stirred at 120 °C under a N atmosphere for 3 h. The reaction was monitored by LCMS. The resulting mixture was diluted with H0 (50 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fractions were concentrated in vacuo to give tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (460 mg, 53.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =346.2. 1H NMR (300MHz, DMSO-d6) δ8.60(q,1H), 8.13(d,1H), 7.76(d,1H), 3.52(dd,4H), 3.33(d,4H), 2.80(d,3H), 1.43(s,9H).

[0278] Step 2: Preparation of 6-cyano-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt: To a stirred solution of tert-butyl 4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (260 mg, 0.75 mmol, 1.00 equiv) in dioxane (2 mL), HCl (gas) in 1,4-dioxane (2 mL, 4 M in 1,4-dioxane) was added dropwise in an ice bath. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 6-cyano-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt (180 mg, 97.4%). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =245.9.1H NMR(300MHz,DMSO-d6)δ9.32(brs,2H),8.65(d,1H),8.16(d,1H),7.86(d,1H),3.58(dd,4H),3.29(s,4H),2.80(d,3H). Step 3: Preparation of 6-cyano-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide: To a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (50 mg, 0.22 mmol, 1.00 equiv.), 6-cyano-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (60 mg, 0.25 mmol, 1.10 equiv.), and KI (7 mg, 0.04 mmol, 0.20 equiv.) in MeCN (3 mL) was added DIEA (145 mg, 1.12 mmol, 5.00 equiv.) dropwise at room temperature under a N atmosphere. The resulting mixture was stirred at 80° C. under a N atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (3 mL). The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 6-cyano-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (12.9 mg, 13.11%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =431.9.1H NMR(300MHz,DMSO-d6)δ11.87(s,1H),8.58(d,1H),8.42(s,1H),8.11(d,1H),7.74(d,2) H),7.62(s,1H),3.68(s,2H),3.37(d,4H),2.79(d,3H),2.60-2.56(m,6H),1.19(t,3H). The following examples were prepared using procedures similar to those set forth in Example 1. [Table 4]

[0279] Example 2 [ka] Step 1: Preparation of tert-butyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate: tert-Butyl (3R)-3-methylpiperazine-1-carboxylate (5.00 g, 24.96 mmol, 1.00 equiv., [α]) in 1,4-dioxane (50 mL) 26 A mixture of D (c = 1.0, CHCl3): +14.75), methyl 5-bromopyridine-2-carboxylate (5.66 g, 26.21 mmol, 1.05 equiv.), Cs2CO3 (16.27 g, 49.93 mmol, 2.00 equiv.), and RuPhos Palladacycle Gen. 3 (1.04 g, 1.25 mmol, 0.05 equiv.) was stirred overnight at 120 °C 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) and then extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (5.00 g, 59.71%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =336.1.

[0280] Step 2: Preparation of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: A solution of tert-butyl (3R)-4-[6-(methoxycarbonyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (2.00 g, 5.96 mmol, 1.00 equiv.) and methanamine (8 mL, 25-30 wt % solution in water) in CHOH (7 mL) was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The reaction was quenched with saturated NH4Cl (30 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.70 g, 85.25%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =335.3.

[0281] Step 3: Preparation of N-methyl-5-[(2R)-2-methylpiperazin-1-yl]pyridine-2-carboxamide, HCl salt: A mixture of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (500 mg, 1.50 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (3.7 mL, 14.95 mmol, 10.00 equiv., 4.0 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 N-methyl-5-[(2R)-2-methylpiperazin-1-yl]pyridine-2-carboxamide, HCl salt (400 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =234.9.

[0282] Step 4: Preparation of 5-[(2R)-4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-1-yl]-N-methylpyridine-2-carboxamide: A mixture of N-methyl-5-[(2R)-2-methylpiperazin-1-yl]pyridine-2-carboxamide, HCl salt (128 mg, crude), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv.), KI (15 mg, 0.09 mmol, 0.20 equiv.), and DIEA (290 mg, 2.24 mmol, 5.00 equiv.) in MeCN (10 mL) 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 extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (2×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by preparative HPLC. Pure fractions were concentrated under reduced pressure and lyophilized to give 5-[(2R)-4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-1-yl]-N-methylpyridine-2-carboxamide (90 mg, 46.89%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =421.2. 1 H NMR(400MHz,DMSO-d6)δ11.90(s,1H),8.42(d,1H),8.37(d,1H),8.21(d,1H), 7.82(d,1H),7.76(s,1H),7.67(d,1H),7.33(dd,1H),4.23(s,1H),3.71(d,1H) ,3.65-3.52(m,2H),3.14-3.03(m,1H),2.93(d,1H),2.78(d,3H),2.72(d,1H), 2.58-2.53(m,2H),2.33(dd,1H),2.29-2.15(m,1H),1.19(t,3H),1.13(d,3H). The following examples were prepared using procedures similar to those set forth in Example 2. [Table 5-1] [Table 5-2] [Table 5-3]

[0283] Example 3A and Example 3B [ka] Step 1: Preparation of tert-butyl 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate: To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (2.5 g, 11.57 mmol, 1 equiv.) and tert-butyl 2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (2.41 g, 12.15 mmol, 1.05 equiv.) in dioxane (25 mL), RuPhos Palladacycle Gen. 3 (0.48 g, 0.57 mmol, 0.05 equiv.) and CsCO (7.54 g, 23.14 mmol, 2.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with saturated NaCl (aq) (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.1 g, Y=28.4%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =334.1

[0284] Step 2: Preparation of tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate: A mixture of tert-butyl 5-[6-(methoxycarbonyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1 g, 3.00 mmol, 1 equiv.) and CH3NH2 (2.33 g, 75.03 mmol, 25.01 equiv., 40% in HO) in MeOH (15 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 mL). The mixture was acidified to pH 6 with saturated NH4Cl (aq.). The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.2 g, crude) as a crude yellow oil. LC-MS: (ES+H, m / z): [M+H] + =333.1

[0285] Step 3: Preparation of 5-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide: To a stirred mixture of tert-butyl 5-[6-(methylcarbamoyl)pyridin-3-yl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (1.2 g, 3.61 mmol, 1 equiv.) in MeOH (10 mL) was added HCl (gas) in 1,4-dioxane (6 mL) dropwise 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 diethyl ether (40 mL). The resulting mixture was concentrated under reduced pressure to give 5-{2,5-diazabicyclo[4.1.0]heptane-2-yl}-N-methylpyridine-2-carboxamide (1 g, crude) as a crude yellow oil. LC-MS: (ES+H, m / z): [M+H] + =232.9

[0286] Step 4: Preparation of 5-{5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide: To a stirred mixture of 5-{2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide (547.67 mg, 2.35 mmol, 1.5 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (350 mg, 1.57 mmol, 1.00 equiv.) in acetonitrile (5 mL), KI (52.19 mg, 0.31 mmol, 0.20 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. 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 silica gel column chromatography to give 5-{5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl}-N-methylpyridine-2-carboxamide (180 mg, Y=21.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =419.0

[0287] Step 5: Preparation of rel-5-[(1R,6S)-5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3A) and rel-5-[(1R,6S)-5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3B): rel-5-[(1R,6S)-5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide was purified by PREP_CHIRAL_HPLC to give rel-5-[(1R,6S)-5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide.

[0049] 1,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3A, 54.8 mg, Y = 30.4%, ee = 99.28%) and rel-5-[(1R,6S)-5-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2,5-diazabicyclo[4.1.0]heptan-2-yl]-N-methylpyridine-2-carboxamide (Example 3B, 39.0 mg, Y = 21.6%, ee = 98.42%) were obtained. Note: The stereochemical assignments of Examples 3A and 3B are arbitrary.

[0288] Example 3A: LC-MS: (ES+H, m / z): [M+H] + =419.2.1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.44(d,1H),8.37-8.32(m,1H),8.19(d,1H),7.85(d,1H),7.75(s,1H),7.69-7.65(m,1H),7.27(dd,1H) ,3.89(q,2H),3.54-3.46(m,1H),3.24-3.16(m,1H),2.81-2.69(m,5H) ,2.57-2.52(m,4H),1.18(t,3H),0.83-0.74(m,1H),0.44-0.34(m,1H).

[0289] Example 3B: LC-MS: (ES+H, m / z): [M+H] +=419.1.1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.46-8.40(m,1H),8.38-8.31(m,1H),8.19(d,1H),7.85(d,1H),7.75(s,1H),7.67(s,1H),7.27(dd,1H),3 .99-3.81(m,2H),3.56-3.47(m,1H),3.24-3.18(m,1H),2.85-2.70(m,5H ),2.58-2.52(m,4H),1.18(t,3H),0.83-0.74(m,1H),0.44-0.34(m,1H). The following examples in Table 3 were made using procedures similar to those set forth for Examples 3A and 3B. [Table 3-1] [Table 3-2]

[0290] Example 4 [ka] Step 1: Preparation of tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate: To a stirred solution of tert-butyl (3R)-3-methyl-4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (2.20 g, 6.58 mmol, 1.00 equiv.) in DMF (30 mL) was added NBS (1.29 g, 7.24 mmol, 1.10 equiv.) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The desired product could be detected by LCMS. The reaction was quenched by adding saturated NaHCO (aq.) (30 mL) at 0° C. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (1.77 g, 65%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =413.0 / 415.0. 1 H NMR(300MHz,DMSO-d6)δ8.47(d,1H),7.97(d,1H),7.75(d,1H),3.66-3.48(m,4H ),3.27-3.18(m,2H),2.80(d,3H),2.73-2.60(m,1H),1.43(s,9H),0.84(d,3H).

[0291] Step 2: Preparation of tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate: A mixture of tert-butyl (3R)-4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (500 mg, 1.21 mmol, 1.00 equiv.), Zn(CN) (156 mg, 1.33 mmol, 1.10 equiv.), and Pd(PPh) (140 mg, 0.12 mmol, 0.10 equiv.) in DMF (8 mL) was stirred overnight at 120 °C under a nitrogen atmosphere. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (428 mg, 98%) as a yellow solid. LC-MS: (ES-H, m / z): [MH] - =358.1. 1 H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.12(d,1H),7.81(d,1H),3.41-3.33(m ,4H),3.21(d,2H),2.80(d,3H),2.52-2.51(m,1H),1.43(s,9H),1.02(d,3H).

[0292] Step 3: Preparation of 6-cyano-N-methyl-5-[(2R)-2-methylpiperazin-1-yl]pyridine-2-carboxamide, HCl salt: A solution of tert-butyl (3R)-4-[2-cyano-6-(methylcarbamoyl)pyridin-3-yl]-3-methylpiperazine-1-carboxylate (135 mg, 0.38 mmol, 1.00 equiv.) and HCl (gas) in 1,4-dioxane (5 mL, 4 M) in DCM (5 mL) was stirred at room temperature under a nitrogen atmosphere for 3 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 6-cyano-N-methyl-5-[(2R)-2-methylpiperazin-1-yl]pyridine-2-carboxamide, HCl salt (310 mg, crude) as a pale yellow solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =260.2

[0293] Step 4: Preparation of 6-cyano-5-[(2R)-4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-1-yl]-N-methylpyridine-2-carboxamide: To a stirred mixture of 6-cyano-N-methyl-5-[(2R)-2-methylpiperazin-1-yl]pyridine-2-carboxamide, HCl salt (250 mg, crude) and DIEA (498 mg, 3.86 mmol, 5.00 equiv.) in MeCN (8 mL), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (172 mg, 0.77 mmol, 1.00 equiv.) and KI (26 mg, 0.15 mmol, 0.20 equiv.) were added at room temperature. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 4 hours. The desired product could be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the pure fractions were concentrated under reduced pressure to give 6-cyano-5-[(2R)-4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-2-methylpiperazin-1-yl]-N-methylpyridine-2-carboxamide (135.4 mg, 39%, ee=97.6%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + =446.1. 1H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.58(d,1H),8.42(d,1H),8.12(d,1H),7.81(d,1H),7.75(s,1H),7.65(d,1H),4.02(m,1H) ,3.74-3.58(m,2H),3.47-3.39(m,1H),3.28-3.20(m,1H)2.79(m,4H),2.58-2.53(m,4H),2.42(t,1H),1.19(t,3H),1.13(d,3H).

[0294] Example 5 [ka] Step 1: Preparation of tert-butyl 4-(5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate: A mixture of methyl 5-bromo-3-fluoropyridine-2-carboxylate (1.00 g, 4.27 mmol, 1.00 equiv.), tert-butyl piperazine-1-carboxylate (0.84 g, 4.48 mmol, 1.05 equiv.), RuPhos Palladacycle Gen. 3 (0.36 g, 0.43 mmol, 0.10 equiv.), and CsCO (2.78 g, 8.55 mmol, 2.00 equiv.) in 1,4-dioxane (16 mL) was stirred at 110 °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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (1.00 g, 68.96%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =339.9. 1 H NMR (300MHz, DMSO-d6) δ8.24 (s, 1H), 7.23 (dd, 1H), 3.81 (s, 3H), 3.56-3.36 (m, 8H), 1.43 (s, 9H).

[0295] Step 2: Preparation of tert-butyl 4-(5-fluoro-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate: To a stirred solution of ethyl 4-[5-fluoro-6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (1.20 g, 3.86 mmol, 1.00 equiv) in methanol (8 mL) was added CH3NH2 (8 mL, 25%-30% in water) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched with saturated NH4Cl (aqueous, 100 mL) at 0 °C. The resulting mixture was extracted with CHCl2 (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product (1.22 g) as a white solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =338.9. 1 H NMR (400MHz, DMSO-d6) δ8.29(q,1H),8.14(d,1H),7.23(d,1H),3.55-3.34(m,8H),2.75(d,3H),1.42(s,9H).

[0296] Step 3: Preparation of 3-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide: To a stirred solution of 3-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (1.22 g, 5.12 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added dropwise HCl (gas) in 1,4-dioxane (10 mL, 4 M) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane:ether=1:1 (10 mL×3) to give the crude product (1.22 g, HCl salt) as a white solid. The crude product was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =238.9.

[0297] Step 4: Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylpicolinamide: To a stirred solution of 3-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (80 mg, estimated yield 100%, 0.34 mmol, 1.50 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (50 mg, 0.22 mmol, 1.00 equiv.) in ACN (5 mL) was added KI (7 mg, 0.04 mmol, 0.20 equiv.) and DIEA (145 mg, 1.12 mmol, 5.00 equiv.) 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 concentrated under reduced pressure. The residue was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-3-fluoro-N-methylpicolinamide (34 mg, 34.24%, over three steps) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =424.90. 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(s,1H),8.27(q,1H),8.13(s,1H),7.75(s,1H),7.62(s ,1H),7.22(dd,1H),3.65(s,2H),3.45-3.34(m,4H),2.74(d,3H),2.58-2.51(m,6H),1.18(t,3H). 19 F NMR (377MHz, DMSO) δ-120.40.

[0298] Example 6 [ka] Step 1: Preparation of tert-butyl 4-(2-bromo-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (2.00 g, 6.24 mmol, 1.00 equiv) in DMF (10 mL) was added NBS (1.22 g, 6.87 mmol, 1.10 equiv) in portions at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NaHCO (aq) (5 mL) at 0° C. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 4-(2-bromo-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (2.40 g, 96.29%) as a colorless oil. LC-MS: (ES+H, m / z): [M+H] + =399.1 / 401.1. 1 H NMR (400MHz, DMSO-d6) δ8.44(q,1H),7.96(d,1H),7.65(d,1H),3.60-3.41(m,4H),3.10-2.98(m,4H),2.80(d,3H),1.43(s,9H).

[0299] Step 2: Preparation of tert-butyl 4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate: A mixture of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.20 g, 3.00 mmol, 1.00 equiv.), Pd(dppf)Cl (0.22 g, 0.30 mmol, 0.10 equiv.), CsCO (1.96 g, 6.01 mmol, 2.00 equiv.), and cyclopropylboronic acid (0.26 g, 3.00 mmol, 1.00 equiv.) in toluene / HO (10 mL / 1 mL) was stirred at 100 °C under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 4-(2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate (900 mg, 83.08%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =361.1. 1 H NMR(300MHz,DMSO-d6)δ8.28(q,1H),7.71(d,1H),7.44(d,1H),3.64-3.43(m,4H),3.06-2.8 9(m,4H),2.80(d,3H),2.45-2.32(m,1H),1.43(s,9H),1.22-1.13(m,2H),1.07-0.88(m,2H).

[0300] Step 3: Preparation of 6-cyclopropyl-N-methyl-5-(piperazin-1-yl)picolinamide, HCl salt: To a stirred solution of tert-butyl 4-[2-cyclopropyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (900 mg, 2.50 mmol, 1.00 equiv) in 1,4-dioxane (3 mL) was added dropwise HCl (gas) in 1,4-dioxane (10.00 mL, 4 M) at 0° C. 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 in vacuo. The residue was purified by trituration with hexane:ether=1:1 (10 mL×3) to give 6-cyclopropyl-N-methyl-5-(piperazin-1-yl)picolinamide, HCl salt (900 mg, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =261.2.

[0301] Step 4: Preparation of 6-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide: To a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv.) and 6-cyclopropyl-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt (200 mg, 0.67 mmol, 1.50 equiv.) in MeCN (10 mL) was added KI (15 mg, 0.09 mmol, 0.20 equiv.) and DIEA (290 mg, 2.25 mmol, 5.00 equiv.) 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 concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 6-cyclopropyl-5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (31 mg, 15.51%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =447.0. 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.41(d,1H),8.32-8.21(m,1H),7.75(s,1H),7.70(d,1H),7.62(s,1H),7.43(d,1H) ,3.68(s,2H),3.15-2.90(m,4H),2.78(d,3H),2.69-2.54(m,6H),2.36-2.29(m,1H),1.22-1.10(m,5H),1.01-0.91(m,2H).

[0302] Example 7 [ka] Step 1: Preparation of tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate: To a stirred mixture of methyl 4-bromo-2-fluorobenzoate (1.00 g, 4.29 mmol, 1.00 equiv.) and tert-butyl piperazine-1-carboxylate (0.84 g, 4.51 mmol, 1.05 equiv.) in dioxane (100 mL), CsCO (2.80 g, 8.58 mmol, 2.00 equiv.) and RuPhos Palladacycle Gen. 3 (0.18 g, 0.22 mmol, 0.05 equiv.) were added at room temperature. The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 6 hours. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1.30 g, 89%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =339.2. 1 H NMR (300MHz, DMSO-d6) δ7.72(t,1H), 6.84-6.69(m,2H), 3.77(s,3H), 3.48-3.33(m,8H), 1.43(s,9H).

[0303] Step 2: Preparation of tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate: To a mixture of tert-butyl 4-[3-fluoro-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1.3 g, 3.84 mmol, 1.00 equiv.) in MeOH (5 mL) was added dropwise methylamine (3.5 mL, 25–30 wt % in water). The mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography. The resulting mixture was concentrated under reduced pressure to give tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate (1.00 g, 77%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =338.2. 1 H NMR (300MHz, DMSO-d6) δ7.78(d,1H),7.58(t,1H),6.85-6.68(m,2H),3.45-3.40(m,4H),3.27(dd,4H),2.76(d,3H),1.43(s,9H).

[0304] Step 3: Preparation of 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt: To a stirred mixture of tert-butyl 4-[3-fluoro-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate (500 mg, 1.48 mmol, 1.00 equiv.) in DCM (4 mL) was added dropwise HCl (gas) in 1,4-dioxane (2 mL, 4 M) at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane / ethyl ether:ethyl ether=1:1 (4 mL). The resulting mixture was concentrated under reduced pressure to give 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt (500 mg, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =237.9. 1 H NMR (400MHz, DMSO-d6) δ9.46(s,2H), 7.92-7.79(m,1H), 7.60(t,1H), 6.91-6.72(m,2H), 3.54(m,4H), 3.17(m,4H), 2.75(d,3H).

[0305] Step 4: Preparation of 4-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-2-fluoro-N-methylbenzamide: To a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one, HCl salt (100 mg, 0.45 mmol, 1.00 equiv.) and 2-fluoro-N-methyl-4-(piperazin-1-yl)benzamide hydrochloride (123 mg, 0.45 mmol, 1.00 equiv.) in MeCN (5 mL), KI (15 mg, 0.09 mmol, 0.20 equiv.) and DIEA (290 mg, 2.24 mmol, 5.00 equiv.) were added. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC, and the pure fractions were concentrated and lyophilized to give 4-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-2-fluoro-N-methylbenzamide (14 mg, 7%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =423.90. 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,1H),7.76(d,2H),7.66-7.48(m,2H),6.86-6.6 6(m,2H),3.64(s,2H),3.30(d,4H),3.28(d,4H),2.74(d,3H),2.56-2.53(m,2H),1.18(t,3H). 19 F NMR (377MHz, DMSO) δ-111.58.

[0306] Example 8 [ka] Step 1: Preparation of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate: A solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (859 mg, 2.78 mmol, 1.20 equiv.), methyl 5-bromopyridine-2-carboxylate (500 mg, 2.31 mmol, 1.00 equiv.), KCO (640 mg, 4.63 mmol, 2.00 equiv.), and Pd(dppf)Cl (339 mg, 0.46 mmol, 0.2 equiv.) in 1,4-dioxane (10 mL) and HO (2 mL) was stirred at 80 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with HO (50 mL). The resulting mixture was extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (260 mg, 29.41%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =319.1. 1 H NMR (300MHz, DMSO-d6) δ 8.82 (dd, 1H), 8.02 (t, 2H), 6.46 (s, 1H), 4.06 (d, 2H), 3.88 (s, 3H), 3.57 (t, 2H), 2.54 (s, 2H), 1.44 (s, 9H).

[0307] Step 2: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate: To a stirred solution of 1'-(tert-butyl) 6-methyl 3',6'-dihydro-[3,4'-bipyridine]-1',6(2'H)-dicarboxylate (210 mg, 0.66 mmol, 1.00 equiv.) in methanol (3 mL) was added CH3NH2 (3 mL, 25-30 wt % in water) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl(aq) (50 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were concentrated under reduced pressure to give tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (190 mg, 90.76%) as a purple solid. LC-MS: (ES+H, m / z): [M+H] + =318.2. 1 H NMR (400MHz, DMSO-d6) δ8.76-8.68(m,2H),8.08-7.86(m,2H),6.34(d,1H),4.05(d,2H),3.56(t,2H),2.82(d,4H),2.54(d,1H),1.43(s,9H).

[0308] Step 3: Preparation of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide, TFA salt: To a stirred solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-2'H-[3,4'-bipyridine]-1'-carboxylate (170 mg, 0.54 mmol, 1 equiv.) in DCM (5 mL) was added TFA (1 mL) dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =218.1

[0309] Step 4: Preparation of 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide: To a stirred mixture of N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (101 mg, 0.50 mmol, 1.00 equiv.) and 7-(chloromethyl)-3-ethyl-1,5-naphthyridin-2(1H)-one (111 mg, 0.50 mmol, 1.00 equiv.) in MeCN (5 mL) was added KI (17 mg, 0.10 mmol, 0.20 equiv.) and DIEA (323 mg, 2.50 mmol, 5.00 equiv.) at room temperature. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 1'-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide (39.6 mg, 18.49%, over two steps) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + =404.2. 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.70(t,2H),8.42(s,1H),8.05-7.93(m,2H),7.76(s,1H),7.65(s ,1H),6.42(s,1H),3.73(s,2H),3.16(s,2H),2.81(d,3H),2.71(s,2H),2.60-2.52(m,4H),1.19(t,3H). The following examples were prepared using procedures similar to those set forth in Example 8. [Table 6]

[0310] Example 9 [ka] Step 1: Preparation of 7-(chloromethyl)-3-ethyl-1H-quinolin-2-one: To a stirred mixture of 3-ethyl-7-(hydroxymethyl)-1H-quinolin-2-one (1.00 g, 4.92 mmol, 1.00 equiv.) and DMF (18 mg, 0.25 mmol, 0.05 equiv.) in DCM (20 mL) was added SOCl (1.76 g, 14.76 mmol, 3.00 equiv.) dropwise at 0° C. 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 to give 7-(chloromethyl)-3-ethyl-1H-quinolin-2-one (1.00 g, 91.68%) as an off-white solid. MS: (ES+H, m / z): [M+H] + =222.1

[0311] Step 2: Preparation of 6-{4-[(3-ethyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: To a stirred mixture of 7-(chloromethyl)-3-ethyl-1H-quinolin-2-one (100 mg, 0.45 mmol, 1.20 equiv.), 6-(piperazin-1-yl)pyridine-3-carbonitrile (71 mg, 0.38 mmol, 1.00 equiv.), and KI (12 mg, 0.08 mmol, 0.20 equiv.) in MeCN (5 mL) was added DIEA (243 mg, 1.88 mmol, 5.00 equiv.) 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 resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to give 6-{4-[(3-ethyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (35.2 mg, 25.07%) as an off-white solid. MS: (ES+H, m / z): [M+H] +=374.2.1H NMR(300MHz,DMSO-d6)δ11.68(s,1H),8.48(d,1H),7.84(dd,1H),7.70(s,1H),7.57(d,1H),7. 27(s,1H),7.13(d,1H),6.92(d,1H),3.67(s,4H),3.57(s,2H),2.50-2.47(m,6H),1.16(t,3H).

[0312] Example 10 [ka] Step 1: Preparation of N-(3-bromophenyl)-2-oxocyclopentane-1-carboxamide: A solution of 4-(cyclopent-1-en-1-yl)morpholine (3.60 g, 23.49 mmol, 1.00 equiv.) and 1-bromo-3-isocyanatobenzene (5.58 g, 28.19 mmol, 1.20 equiv.) in CHCl3 (100 mL) was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated in vacuo to give N-(3-bromophenyl)-2-oxocyclopentane-1-carboxamide (3.9 g, 58.8%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =281.9 / 283.9. 1 H NMR (300 MHz, chloroform-d) δ 8.83 (s, 1H), 7.84 (t, 1H), 7.45-7.41 (m, 1H), 7.29-7.15 (m, 2H), 3.20-3.11 (m, 1H), 2.51-2.33 (m, 4H), 2.17-2.05 (m, 1H), 1.96-1.83 (m, 1H).

[0313] Step 2: Preparation of 7-bromo-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one: To a stirred solution of H2SO4 (10 mL) was added N-(3-bromophenyl)-2-oxocyclopentane-1-carboxamide (3.3 g, 11.69 mmol, 1.00 equiv) slowly at 0 °C. The resulting mixture was stirred at room temperature for 4 h. The reaction was monitored by LCMS. The mixture was basified with aqueous Na2CO3 (200 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (2.10 g, 67.9%) as a white solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =264.0 / 266.0. 1 H NMR (300MHz, DMSO-d6) δ11.66(s,1H),7.52-7.43(m,2H),7.33(dd,1H),3.06(t,2H),2.74(t,2H),2.14-1.99(m,2H).

[0314] Step 3: Preparation of ethyl 4-oxo-1H,2H,3H,5H-cyclopenta[c]quinoline-7-carboxylate: To a solution of 7-bromo-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (1.50 g, 5.67 mmol, 1.00 equiv.) and EtN (1.15 g, 11.35 mmol, 2.00 equiv.) in EtOH (20 mL) was added Pd(PPh)Cl (797 mg, 1.13 mmol, 0.20 equiv.) in a pressure tank. The mixture was purged with nitrogen for 3 minutes and then pressurized to 40 atm with carbon monoxide at 120 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated in vacuo to give ethyl 4-oxo-1H,2H,3H,5H-cyclopenta[c]quinoline-7-carboxylate (750 mg, 51.33%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + =258.2

[0315] Step 4: Preparation of 7-(hydroxymethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one: To a stirred solution of ethyl 4-oxo-1H,2H,3H,5H-cyclopenta[c]quinoline-7-carboxylate (650 mg, 2.52 mmol, 1.00 equiv.) in THF (3 mL) was added under a nitrogen atmosphere at 0 °C. To the above mixture, LiAlH (2.02 mL, 5.05 mmol, 2.00 equiv., 2.5 M in THF) was added dropwise over 3 min at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. The reaction was quenched at 0 °C by the addition of HO (0.3 mL). NaOH (15 wt%, 1.4 mL) was then added and stirred at room temperature for 10 min. HO (0.3 mL) was added to the reaction and stirred for an additional 10 min. The resulting mixture was filtered, and the filter cake was washed with THF (3 × 5 mL) and dried over anhydrous NaSO. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated in vacuo to give 7-(hydroxymethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (300 mg, 55.1%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =216.2. 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),7.47(d,1H),7.33(s,1H),7.12-7.08(m ,1H),5.34(t,1H),4.57(d,2H),3.07(t,2H),2.75(t,2H),2.13-2.06(m,2H).

[0316] Step 5: Preparation of 7-(chloromethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one: To a stirred solution of 7-(hydroxymethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (350 mg, 1.62 mmol, 1.00 equiv.) and DMF (12 mg, 0.16 mmol, 0.10 equiv.) in DCM (2 mL) was added SOCl (967 mg, 8.13 mmol, 5.00 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The resulting mixture was washed with DCM (3 × 30 mL). The resulting mixture was concentrated in vacuo to give 7-(chloromethyl)-3-ethyl-4-fluoro-1H-quinolin-2-one (390 mg, crude) as an orange solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =234.0

[0317] Step 6: Preparation of N-methyl-5-[4-({4-oxo-1H,2H,3H,5H-cyclopenta[c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide: To a stirred solution of 7-(chloromethyl)-1H,2H,3H,5H-cyclopenta[c]quinolin-4-one (150 mg, 0.64 mmol, 1.00 equiv.) and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (148 mg, 0.67 mmol, 1.05 equiv.) in MeCN (3 mL) was added dropwise DIEA (415 mg, 3.21 mmol, 5.00 equiv.) 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 in vacuo. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated in vacuo to give N-methyl-5-[4-({4-oxo-1H,2H,3H,5H-cyclopenta[c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (34.1 mg, 12.1%) as a light brown solid. LC-MS: (ES+H, m / z): [M+H] + =418.2. 1H NMR(300MHz,DMSO-d6)δ11.55(s,1H),8.41(d,1H),8.27(d,1H),7.83(d,1H),7.50(d,1H),7.42-7.30(m,2H),7. 17(d,1H),3.59(s,2H),3.34-3.32(m,4H)3.08(t,2H),2.78-2.74(m,5H),2.55-2.54(d,4H),2.15-2.05(m,2H).

[0318] Example 11 [ka] Step 1: Preparation of methyl 3-(furan-3-amido)-4-iodobenzoate: A mixture of methyl 3-amino-4-iodobenzoate (10.00 g, 36.09 mmol, 1.00 equiv.), 3-furoic acid (8.09 g, 72.18 mmol, 2.00 equiv.), T3P (114.84 g, 180.46 mmol, 5.00 equiv., 50 wt. % in EA), and DIEA (23.32 g, 180.46 mmol, 5.00 equiv.) in DCM (100 mL) was stirred overnight at 60° C. 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 (150 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3-(furan-3-amido)-4-iodobenzoate (6.80 g, 50.76%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =372.0.

[0319] Step 2: Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate: A solution of methyl 3-(furan-3-amido)-4-iodobenzoate (6.00 g, 16.167 mmol, 1.00 equiv.), (Boc)O (7.06 g, 32.34 mmol, 2.00 equiv.), and DMAP (1.98 g, 16.17 mmol, 1.00 equiv.) in DCE (100 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (250 mL) and washed with water (2 × 200 mL). The combined organic layers were washed with brine (2 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (5.00 g, 65.63%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.31(dd,1H),8.13(d,1H),7.90(d,1H),7.79(t,1H),7.69(dd,1H),6.79(dd,1H),3.87(s,3H),1.34(s,9H).

[0320] Step 3: Preparation of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate: To a mixture of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (400 mg, 0.85 mmol, 1.00 equiv.) and PCy3 (48 mg, 0.17 mmol, 0.20 equiv.) in DMF (12 mL) was added Pd(OAc)2 (38 mg, 0.17 mmol, 0.20 equiv.) and K2CO3 (235 mg, 1.70 mmol, 2.00 equiv.) at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation at 100 °C for 2 h. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (2 × 25 mL). The combined organic layers were washed with brine (2 × 25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (120 mg, 58.13%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =244.0.

[0321] Step 4: Preparation of 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one: To a stirred mixture of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (300 mg, 1.23 mmol, 1.00 equiv.) in THF (2 mL) was added LiAlH (0.99 mL, 2.47 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1.2 mL) at 0° C. The residue was purified by silica gel column chromatography to give 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (220 mg, 82.88%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =216.1.

[0322] Step 5: Preparation of 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one: To a stirred mixture of 7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (300 mg, 1.39 mmol, 1.00 equiv.) and DMF (10 mg, 0.14 mmol, 0.10 equiv.) in DCM (5 mL) was added SOCl (995 mg, 8.36 mmol, 6.00 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at 0° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one (240 mg, 73.69%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =234.0.

[0323] Step 6: Preparation of N-methyl-5-[4-({4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide: A mixture of 7-(chloromethyl)-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.43 mmol, 1.00 equiv.), N-methyl-5-(piperazin-1-yl)picolinamide, HCl salt (110 mg, 0.43 mmol, 1.00 equiv.), KI (14 mg, 0.09 mmol, 0.20 equiv.), and DIEA (276 mg, 2.14 mmol, 5.00 equiv.) in MeCN (10 mL) 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-methyl-5-[4-({4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (95 mg, 51.63%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =418.20. 1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.40(q,1H),8.27(d,1H),8.08(d,1H),7.89(d,1H),7.83(d,1H),7.46 (s,1H),7.39(dd,1H),7.28(dd,1H),7.06(d,1H),3.63(s,2H),3.39-3.34(m,4H),2.78(d,3H),2.56(m,4H).

[0324] Example 12 [ka] Step 1: Preparation of 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylic acid: To a stirred solution of methyl 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylate (120 mg, 0.29 mmol, 1.00 equiv) in EtOH / THF (1:1, 5 mL) was added aqueous NaOH (3.0 mL, 1N) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. 1(N) aqueous HCl (3.0 mL) was then added. The reaction was concentrated under reduced pressure to give 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylic acid (150 mg) as a white solid (used without further purification). LC-MS: (ES+H, m / z): [M+H] + =394.2.

[0325] Step 2: Preparation of N-cyclopropyl-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxamide: To a stirred solution of 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylic acid (120 mg, 0.30 mmol, 1.00 equiv.) and DIEA (158 mg, 1.22 mmol, 4.00 equiv.) in DMF (4 mL) was added HATU (174 mg, 0.46 mmol, 1.50 equiv.) at room temperature under a nitrogen atmosphere. Aminocyclopropane (35 mg, 0.61 mmol, 2.00 equiv.) was added to the above mixture and stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography, and the pure fractions were concentrated and lyophilized to give N-cyclopropyl-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxamide (23.1 mg, 17%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =433.2. 1 H NMR(300MHz,DMSO-d6)δ11.85(s,1H),8.41(s,1H),8.35(s,1H),8.24(s,1H),7.83(d,1H),7.75(s,1H),7.63(s,1 H),7.40(d,1H),3.65(s,2H),3.30-3.14(m,6H),2.85(s,1H),2.65-2.53(m,4H),1.18(t,3H),0.69-0.57(m,4H).

[0326] Example 13 [ka] Step 1: Preparation of methyl 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylate: To a stirred mixture of methyl 5-(piperazin-1-yl)pyridine-2-carboxylate (280 mg, 1.26 mmol, 1.00 equiv.) and DIEA (818 mg, 6.32 mmol, 5.00 equiv.) in MeCN (6 mL), 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (282 mg, 1.26 mmol, 1.00 equiv.) and KI (42 mg, 0.25 mmol, 0.20 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give methyl 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylate (300 mg, 58%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 408.1.

[0327] Step 2: Preparation of 5-(4-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)picolinic acid: To a stirred solution of methyl 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylate (200 mg, 0.49 mmol, 1.00 equiv.) in EtOH / THF (5 mL / 5 mL), 5.0 mL of 1(N) aqueous NaOH solution was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction solution was neutralized with 1 mol / L hydrochloric acid, and then the organic solvent was evaporated under reduced pressure. The resulting residue was filtered, washed with water, and concentrated under reduced pressure to give the title compound (140 mg, 73%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =394.2.

[0328] Step 3: Preparation of N-(2,2-difluoroethyl)-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxamide: To a stirred solution of 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylic acid (220 mg, 0.56 mmol, 1.00 equiv.) and DIEA (361 mg, 2.80 mmol, 5.00 equiv.) in DMF (5 mL), EDCI (536 mg, 2.80 mmol, 5.00 equiv.) and HOBT (227 mg, 1.68 mmol, 3.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (1×5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (80 mg, purity 94%) as a white solid. The crude product was purified by reverse-phase Combiflash chromatography, and the pure fractions were concentrated and lyophilized to give N-(2,2-difluoroethyl)-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxamide (46 mg, 18%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =457.2. 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.70(t,1H),8.41(s,1H),8.30(d,1H),7.86(d,1H),7.76(s,1H),7.6 3(s,1H),7.41(dd,1H),6.25-5.97(m,1H),3.73-3.60(m,4H),3.37(s,4H),2.61-2.52(m,6H),1.18(t,3H). The following examples were prepared using procedures similar to those set forth in Example 13. [Table 7-1] [Table 7-2]

[0329] Example 14 [ka] Step 1: Preparation of tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[2-bromo-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.73 g, 4.33 mmol, 1.00 equiv.) and TMEDA (604 mg, 5.20 mmol, 1.20 equiv.) in toluene (60 mL), bis(adamantan-1-yl)(butyl)phosphane (311 mg, 0.87 mmol, 0.20 equiv.) and Pd(OAc) (97 mg, 0.43 mmol, 0.10 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100° C. under a CO / H atmosphere (1:1, 30 atm). The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.50 g, crude) as a yellow solid. LC-MS: (ES-H, m / z): [MH] - =346.8.

[0330] Step 2: Preparation of tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[2-formyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.50 g, 4.29 mmol, 1.00 equiv.) in DCM (8 mL) was added BAST (1.20 mL, 6.44 mmol, 1.50 equiv.) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The reaction was quenched with ice water (40 mL) at room temperature. The resulting mixture was extracted with CHCl (3×40 mL). The combined organic layers were washed with brine (3×20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (580 mg, 36.05%, 2 steps) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =371.1. 1 H NMR (300 MHz, chloroform-d) δ 8.29 (d, 1H), 7.94 (d, 1H), 7.63 (d, 1H), 7.21-6.80 (m, 1H), 3.69-3.61 (m, 4H), 3.06 (d, 3H), 3.03-2.98 (m, 4H), 1.51 (s, 9H). 19 F NMR (282MHz, CDCl3) δ-116.99,

[0331] Step 3: Preparation of 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt: To a stirred solution of tert-butyl 4-[2-(difluoromethyl)-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (570 mg, 1.54 mmol, 1.00 equiv.) was added HCl (gas) in 1,4-dioxane (4 mL, 4 M) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This afforded 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt (610 mg, crude) as a red solid. LC-MS: (ES+H, m / z): [M+H] + =270.9. 1 H NMR(300MHz,DMSO-d6)δ9.39(s,2H),8.50-8.40(m,1H),8.14(d,1H),7.93(d ,1H),7.52-7.06(m,1H),3.31-3.27(m,4H),3.22-3.18(m,4H),2.84(d,3H).

[0332] Step 4: Preparation of 6-(difluoromethyl)-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide: To a stirred solution of 6-(difluoromethyl)-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide, HCl salt (250 mg, 0.82 mmol, 1.40 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (130 mg, 0.58 mmol, 1.00 equiv.) in MeCN (5 mL), DIEA (377 mg, 2.92 mmol, 5.00 equiv.) and KI (2 mg, 0.01 mmol, 0.02 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (366 mg) was purified by preparative HPLC to give 6-(difluoromethyl)-5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (76.0 mg, 29.92%, 2 steps) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =457.2. 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.44-8.36(m,2H),8.10(d,1H),7.86(d,1H),7.75(s,1H),7.62(d,1) H),7.32-6.99(m,1H),3.68(s,2H),3.06-2.98(m,4H),2.83(d,3H),2.66-2.53(m,6H),1.22-1.15(m,3H). 19 F NMR (377MHz, DMSO) δ-115.95.

[0333] Example 15 [ka] Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate: To a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in THF (100 mL) was added LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M in THF) dropwise at −78° C. under a nitrogen atmosphere. The reaction was stirred for 1 hour, then TMSCl (8.48 g, 78.02 mmol, 1.00 equiv) was added dropwise, and the reaction was stirred for 3 hours while warming to room temperature. The reaction was cooled to −78° C., and NBS (15.28 g, 85.82 mmol, 1.10 equiv) in 50 mL of THF was added dropwise. The reaction was then stirred for 2 hours while warming to room temperature. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl (aq) (50 mL) at 0° C. The resulting mixture was extracted with EtO (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 30.95%) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 4.25 (q, 2H), 3.58 (d, 1H), 1.65-1.55 (m, 1H), 1.31 (t, 3H), 0.92-0.76 (m, 2H), 0.61-0.53 (m, 1H), 0.48-0.40 (m, 1H).

[0334] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate: A solution of ethyl 2-bromo-2-cyclopropyl acetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred under a nitrogen atmosphere at 130° C. for 24 hours. The residue was purified by reverse-phase Combiflash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 37.61%) as a yellow liquid. 1H NMR (300 MHz, chloroform-d) δ 4.26-4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (ddddd, 1H), 0.47-0.37 (m, 1H), 0.24 (ddtd, 1H).

[0335] Step 3: Preparation of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate: To a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv., 60 wt%) in THF (20 mL) was added ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 10 minutes, then warmed to 40° C. and stirred under a nitrogen atmosphere for 10 minutes. The resulting mixture was cooled to −78° C., followed by the dropwise addition of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv.) in THF (20 mL). The resulting mixture was stirred at −78° C. for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl(aq.) (5 mL) at 0° C. The resulting mixture was added with 20 mL of water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (700 mg, 45.93%) as a brown oil. LC-MS: (ES+H, m / z): [M+H] + =320.8.

[0336] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv.) and Fe (1.04 g, 18.73 mmol, 10.00 equiv.) in EtOH (10 mL), CaCl (1.24 g, 11.24 mmol, 6.00 equiv.) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 × 50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture, which was then extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (200 mg, 41.34%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =259.0.

[0337] Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv.) was added LiAlH (0.50 mL, 1.23 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (100 mg, 74.65%) as a pale yellow solid. LC-MS: (ES+H, m / z): [M+H] + =217.2.

[0338] Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equiv.) and DMF (3 mg, 0.04 mmol, 0.10 equiv.) in DCM (10 mL) was added SOCl (264 mg, 2.22 mmol, 6.00 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =235.0.

[0339] Step 7: Preparation of 5-{4-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide: A mixture of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (80 mg, 0.34 mmol, 1.00 equiv.), N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (75 mg, 0.34 mmol, 1.00 equiv.), KI (11 mg, 0.07 mmol, 0.20 equiv.), and DIEA (220 mg, 1.71 mmol, 5.00 equiv.) in MeCN (10 mL) 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) and extracted with EtOAc (2×50 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 silica gel column chromatography to give 5-{4-[(7-cyclopropyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (85 mg, 58.57%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =419.3. 1 H NMR(300MHz,DMSO-d6)δ11.89(s,1H),8.43-8.36(m,2H),8.26(d,1H),7.83(d,1H),7.61(d,1H),7.44-7.35(m,2H) ),3.64(s,2H),3.34-3.28(m,4H),2.78(d,3H),2.56(d,4H),2.21-2.07(m,1H),0.97(dt,2H),0.86-0.77(m,2H).

[0340] Example 16 [ka] Step 1: Preparation of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate: To a stirred mixture of 5-bromo-N-methylpyridine-2-carboxamide (300 mg, 1.40 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 (518 mg, 1.67 mmol, 1.20 equiv.) in 1,4-dioxane / HO (4 / 1, 5 mL), Pd(dppf)Cl (102 mg, 0.14 mmol, 0.10 equiv.) and KCO (386 mg, 2.79 mmol, 2.00 equiv.) were added 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (330 mg, 74.53%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =318.2. 1 H NMR (400MHz, DMSO-d6) δ8.75-8.67(m,2H),8.04-7.95(m,2H),6.41(s,1H),4.08-4.00(m,2H),3.56(t,2H),2.82(d,3H),2.53(d,2H),1.43(s,9H).

[0341] Step 2: Preparation of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate: To a stirred solution of tert-butyl 6-(methylcarbamoyl)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (330 mg, 1.04 mmol, 1.00 equiv.) in methanol (20 mL) was added Pd / C (33 mg, 10 wt%) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (5 x 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate (320 mg, 96.36%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =320.2. 1 H NMR (400MHz, DMSO-d6) δ8.70(d,1H),8.53(d,1H),7.95(d,1H),7.86(dd,1H),4.09(d,2H),2.81(d,6H),1.78(d,2H),1.55(qd,2H),1.42(s,9H).

[0342] Step 3: Preparation of N-methyl-5-(piperidin-4-yl)picolinamide, TFA salt: To a stirred solution of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperidine-1-carboxylate (310 mg, 0.97 mmol, 1.00 equiv) in DCM (5 mL) was added TFA (2 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product N-methyl-5-(piperidin-4-yl)picolinamide, TFA salt (510 mg, crude) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =220.2.

[0343] Step 4: Preparation of 5-(1-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperidin-4-yl)-N-methylpicolinamide: To a stirred mixture of N-methyl-5-(piperidin-4-yl)pyridine-2-carboxamide, TFA salt (294 mg, estimated yield 50%, 1.35 mmol, 2.00 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (150 mg, 0.67 mmol, 1.00 equiv.) in MeCN (3 mL), KI (112 mg, 0.67 mmol, 1.00 equiv.) and DIEA (435 mg, 3.37 mmol, 5.00 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 5-{1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperidin-4-yl}-N-methylpyridine-2-carboxamide (24.6 mg, 9.01%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =406.2. 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.69(d,1H),8.53(d,1H),8.40(d,1H),7.95(d,1H),7.86(dd,1H),7.75(s,1H),7.61( s,1H),3.62(s,2H),2.94(d,2H),2.81(d,3H),2.68(m,1H),2.59-2.53(m,2H),2.13(m,2H),1.82-1.68(m,4H),1.18(t,3H).

[0344] Example 17 [ka] Step 1: Preparation of tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate: To a stirred solution of methyl 4-bromo-3-cyanobenzoate (1.00 g, 4.17 mmol, 1.00 equiv.) and tert-butyl piperazine-1-carboxylate (770 mg, 4.17 mmol, 1.00 equiv.) in dioxane (10 mL), CsCO (2.70 g, 8.33 mmol, 2.00 equiv.) and RuPhos Palladacycle Gen. 3 (350 mg, 0.42 mmol, 0.10 equiv.) were added under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (5 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1.00 g, 69.50%) as a dark oil. LC-MS: (ES+H, m / z): [M+H-tBu] + =289.8. 1 H NMR (400 MHz, chloroform-d) δ 8.24 (d, 1H), 8.11 (dd, 1H), 6.97 (d, 1H), 3.91 (s, 3H), 3.68-3.59 (m, 4H), 3.36-3.28 (m, 4H), 1.39 (s, 9H).

[0345] Step 2: Preparation of tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate: To a stirred solution of tert-butyl 4-[2-cyano-4-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (1.00 g, 2.90 mmol, 1.00 equiv.) and methylamine (5 mL, 25 wt%-30 wt% in water) in methanol (5 mL) was added. The resulting mixture was stirred overnight at 50° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate (900 mg, 90.26%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H-tBu]+ = 288.9. 1 H NMR (300 MHz, chloroform-d) δ 8.01 (d, 1H), 7.98-7.87 (m, 1H), 7.01 (d, 1H), 6.41 (s, 1H), 3.65 (t, 4H), 3.28 (t, 4H), 3.02 (d, 3H), 1.50 (s, 9H).

[0346] Step 3: Preparation of 3-cyano-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt: To a stirred solution of tert-butyl 4-[2-cyano-4-(methylcarbamoyl)phenyl]piperazine-1-carboxylate (900 mg, 2.61 mmol, 1.00 equiv.) in dichloromethane (3 mL) was added dropwise HCl (gas) in 1,4-dioxane (7 mL) at 0° C. 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 residue was purified by trituration with n-hexane and ether (1:1) (12 mL × 3). The precipitated solid was collected by filtration and washed with ether (3 × 5 mL) to give 3-cyano-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt (580 mg) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =244.9.

[0347] Step 4: Preparation of 3-cyano-4-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylbenzamide: To a stirred solution of 3-cyano-N-methyl-4-(piperazin-1-yl)benzamide, HCl salt (150 mg, crude), 7-(chloromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (128 mg, 0.61 mmol, 1.00 equiv.) in acetonitrile (8 mL), DIEA (238 mg, 1.84 mmol, 3.00 equiv.) and KI (20 mg, 0.12 mmol, 0.20 equiv.) were added under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The residue was purified by trituration with MeOH (3 mL). The resulting mixture was stirred at 50° C. under a nitrogen atmosphere for 1 hour. The precipitated solid was collected by filtration and washed with MeOH (2 × 1 mL). Pure fractions were concentrated in vacuo to give 3-cyano-4-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylbenzamide (125.5 mg, 46.53%) as a white solid. LC-MS: (ES+H, m / z): [MH]+ = 431.30. 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.49-8.39(m,2H),8.12(d,1H),8.01(dd,1H),7.75(s,1H), 7.62(s,1H),7.19(d,1H),3.68(s,2H),3.29(m,4H),2.77(d,3H),2.61-2.51(m,6H),1.18(t,3H).

[0348] Example 18 [ka] Step 1: Preparation of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate: To a solution of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (480 mg, 1.97 mmol, 1.00 equiv.) in MeOH / DCM (80 mL / 20 mL) was added Pd / C (200 mg, 10 wt%) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 days. The reaction was monitored by LCMS. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash chromatography to give methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (170 mg, 35%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =246.2.

[0349] Step 2: Preparation of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one: To a stirred solution of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (170 mg, 0.69 mmol, 1.00 equiv.) in THF (8 mL) was added LiAlH (0.55 mL, 1.39 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (10 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (150 mg, 100%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =218.0. 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),7.53(d,1H),7.34(s,1H),7.09(dd,1H),5.40-5.36(m,1H),4.79(t,2H),4.56(s,2H),3.03(t,2H).

[0350] Step 3: Preparation of 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one: To a stirred solution of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (170 mg, 0.78 mmol, 1.00 equiv.) and DMF (29 mg, 0.39 mmol, 0.50 equiv.) in DCM (6 mL) was added thionyl chloride (744 mg, 6.26 mmol, 8.00 equiv.) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (160 mg, 87%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =236.0.

[0351] Step 4: Preparation of N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide: To a stirred solution of N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (200 mg, crude) and DIEA (351 mg, 2.72 mmol, 4.00 equiv.) in MeCN (6 mL) was added 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (160 mg, 0.68 mmol, 1.00 equiv.) and KI (22 mg, 0.14 mmol, 0.20 equiv.) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 h. The residue was purified by silica gel column chromatography to give N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (56.5 mg, 19%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =420.1. 1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.40(s,1H),8.27(s,1H),7.83(d,1H),7.56(d,1H),7.43-7.28(m,2H), 7.16(d,1H),4.79(t,2H),3.60(s,2H),3.43-3.31(m,4H),3.05(t,2H),2.84-2.73(m,3H),2.61-2.52(m,4H). The following examples were made using procedures similar to those set forth in Example 18. [Table 8]

[0352] Example 19 [ka] Step 1: Preparation of 5-bromo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridine: A solution of 5-bromo-2-(1H-imidazol-2-yl)pyridine (1.00 g, 4.46 mmol, 1.00 equiv) and NaH (0.23 g, 5.80 mmol, 1.30 equiv, 60 wt%) in DMF (10 mL) was stirred at 0° C. for 0.5 h. Then, SEMCl (0.97 g, 5.80 mmol, 1.30 equiv) was added dropwise to the above solution at room temperature. The mixture was stirred for 2 h. The reaction was monitored by LCMS. The reaction was quenched with water (50 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridine (1.20 g, 75.88%) as a brown oil. LC-MS: (ES+H, m / z): [M+H]+ = 353.8 / 355.8. 1H NMR (300 MHz, chloroform-d) δ 8.65 (d, 1H), 8.14 (d, 1H), 7.91 (d, 1H), 7.24 (d, 1H), 7.20 (d, 1H), 6.01 (s, 2H), 3.59-3.53 (m, 2H), 0.93-0.87 (m, 2H), 0.00 (s, 9H).

[0353] Step 2: Preparation of tert-butyl 4-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine-1-carboxylate: To a stirred solution of 5-bromo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridine (900 mg, 2.54 mmol, 1.00 equiv.) and tert-butyl piperazine-1-carboxylate (426 mg, 2.29 mmol, 1.00 equiv.) in dioxane (10 mL), RuPhos Palladacycle Gen. 3 (118 mg, 0.25 mmol, 0.10 equiv.) and CsCO (1.66 g, 5.08 mmol, 2.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with CHCl / MeOH (3:1) (5 × 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine-1-carboxylate (900 mg, 77.08%) as an orange oil. LC-MS: (ES+H, m / z): [M+H] + =460.2. 1 H NMR (400 MHz, chloroform-d) δ 8.33 (d, 1H), 8.15 (d, 1H), 7.37-7.34 (m, 1H), 7.24 (d, 1H), 7.21 (d, 1H), 6.08 (s, 2H), 3.74-3.64 (m, 4H), 3.63-3.57 (m, 2H), 3.32 (t, 4H), 1.58 (s, 9H), 0.99-0.92 (m, 2H), 0.00 (s, 9H).

[0354] Step 3: Preparation of 1-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine: To a stirred solution of tert-butyl 4-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine-1-carboxylate (1.00 g, 2.17 mmol, 1.00 equiv) and DIEA (5.62 g, 43.50 mmol, 20.00 equiv) in dioxane (20 mL) was added TMSOTf (4.84 g, 21.75 mmol, 10.00 equiv) dropwise at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by adding MeOH (3 mL) at room temperature. The residue was purified by silica gel column chromatography to give 1-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine (530 mg, 67.76%) as an orange oil. LC-MS: (ES+H, m / z): [M+H]+ = 360.2. 1 H NMR (300MHz, chloroform-d) δ8.26(d,1H),8.09-7.97(m,1H),7.28(d,1H),7.16(d,1H),7.12(d,1H),5. 99(s,2H),3.56-3.46(m,2H),3.35-3.26(m,4H),3.15-3.08(m,4H),0.93-0.83(m,2H),0.00(s,9H).

[0355] Step 4: Preparation of 3-ethyl-7-({4-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazin-1-yl}methyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of 1-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazine (160 mg, 0.44 mmol, 1.00 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.44 mmol, 1.00 equiv.) in acetonitrile (8 mL), DIEA (172 mg, 1.34 mmol, 3.00 equiv.) and potassium iodide (15 mg, 0.09 mmol, 0.20 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-7-({4-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazin-1-yl}methyl)-1H-1,5-naphthyridin-2-one (300 mg, crude) as a brown solid. LC-MS: (ES+H, m / z): [M+H] + =546.0.

[0356] Step 5: Preparation of 3-ethyl-7-({4-[6-(1H-imidazol-2-yl)pyridin-3-yl]piperazin-1-yl}methyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of 3-ethyl-7-({4-[6-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)pyridin-3-yl]piperazin-1-yl}methyl)-1H-1,5-naphthyridin-2-one (300 mg, 0.55 mmol, 1.00 equiv) in DCM (7 mL) was added TFA (3 mL) dropwise at 0° C. under a nitrogen atmosphere. 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 residue was purified by trituration with ether (10 mL×3). The residue was basified with NH4OH. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fractions were concentrated in vacuo to give 3-ethyl-7-({4-[6-(1H-imidazol-2-yl)pyridin-3-yl]piperazin-1-yl}methyl)-1H-1,5-naphthyridin-2-one (80.3 mg, 33.78%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =416.30. 1 H NMR(300MHz,DMSO-d6)δ12.45(s,1H),11.87(s,1H),8.42(d,1H),8.27(d,1H),7.87(d,1H),7.76(s,1H) ,7.64(s,1H),7.44(q,1H),7.05(s,2H),3.66(s,2H),3.34(m,4H),2.59-2.51(m,6H),1.23-1.17(t,3H).

[0357] Examples 20 and 21 [ka] Step 1: Preparation of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid: To a solution of methyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.15 g, 4.95 mmol, 1.00 equiv.) in MeOH (15 mL) and HO (3 mL) was added NaOH (0.59 g, 14.86 mmol, 3.00 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The residue was acidified to pH 4 with 6N HCl (aq.). The resulting mixture was filtered, and the solid was concentrated under reduced pressure to give 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800.0 mg, crude) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =218.9. 1 H NMR (400MHz, DMSO-d6) δ13.43(s,1H),12.08(s,1H),8.89(d,1H),8.15(d,1H),7.82(s,1H),2.62-2.54(m,2H),1.20(t,3H).

[0358] Step 2: Preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide: To a solution of 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid (800 mg, crude) and N,O-dimethylhydroxylamine (336 mg, 5.50 mmol, 1.50 equiv.) in DMF (8 mL) was added EDCI (2.10 g, 11.00 mmol, 3.00 equiv.) portionwise 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 diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide (540 mg, 45.44%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =262.1. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),8.64(d,1H),7.89(dd,1H),7.80(s,1H),3.58(s,3H),3.31(s,3H),2.57(q,2H),1.20(t,3H).

[0359] Step 3: Preparation of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one: To a solution of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxamide (540 mg, 2.07 mmol, 1.00 equiv) in THF (5 mL) was added CHMgBr (1.4 mL, 4.13 mmol, 2.00 equiv, 3 M in THF) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The reaction was quenched with water at 0° C. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×60 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (397 mg, 88.83%) as an off-white solid. LC-MS: (ES+H, m / z): [M+H] + =217.1. 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),8.98(s,1H),8.09(d,1H),7.84(d,1H),2.67(s,3H),2.58(q,2H),1.20(t,3H).

[0360] Step 4: Preparation of 3-ethyl-7-(1-hydroxyethyl)-1H-1,5-naphthyridin-2-one: To a solution of 7-acetyl-3-ethyl-1H-1,5-naphthyridin-2-one (398 mg, 1.84 mmol, 1.00 equiv) in MeOH (5 mL) was added NaBH (174 mg, 4.59 mmol, 2.50 equiv) portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched with saturated NH Cl (aq) at 0 °C. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na SO . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-7-(1-hydroxyethyl)-1H-1,5-naphthyridin-2-one (335.0 mg, 83.60%) as a brown solid. LC-MS: (ES+H, m / z): [M+H] + =219.2.

[0361] Step 5: Preparation of 7-(1-chloroethyl)-3-ethyl-1H-1,5-naphthyridin-2-one: To a solution of 3-ethyl-7-(1-hydroxyethyl)-1H-1,5-naphthyridin-2-one (335 mg, 1.54 mmol, 1.00 equiv.) in DCM (10 mL) was added SOCl2 (457 mg, 3.84 mmol, 2.50 equiv.) dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was used directly in the next step. LC-MS: (ES+H, m / z): [M+H] + =237.0.

[0362] Step 6: Preparation of 5-{4-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide: To a solution of 7-(1-chloroethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (280 mg, 1.18 mmol, 1.00 equiv.) and N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (350 mg, crude) in MeCN (6 mL) was added KI (785 mg, 4.73 mmol, 4.00 equiv.) and DIEA (917 mg, 7.10 mmol, 6.00 equiv.) in portions at room temperature under a nitrogen atmosphere. 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{4-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (303.1 mg, 60.91%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =421.2.

[0363] Step 7: Preparation of rel-5-{4-[(1R)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (Example 20) and rel-5-{4-[(1R)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (Example 21): 5-{4-[1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (300 mg, 0.71 mmol, 1.00 equiv) was isolated by preparative chiral HPLC. This gave rel-5-{4-[(1R)-1-(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (Example 20, 130.0 mg, 43.33%, ee=100%) as a white solid and rel-5-(4-{[(1aR)-1a-ethyl-2-oxo-1H,3H,7bH-cyclopropa[c]quinolin-5-yl]methyl}piperazin-1-yl)-N-methylpyridine-2-carboxamide (Example 21, 122.4 mg, 40.80%, ee=99.5%) as a white solid. Note: The stereochemical assignments of Examples 20 and 21 are arbitrary.

[0364] Example 20: LC-MS: (ES+H, m / z): [M+H] + =421.3. 1 H NMR(300MHz,DMSO-d6)δ11.83(s,1H),8.45(s,1H),8.39(q,1H),8.25(d,1H),7.82(d,1H),7.75(s,1H),7.62(s,1H),7.42-7.3 3(m,1H),3.67-3.64(m,1H),3.35-3.33(m,4H),2.78(dd,3H),2.63-2.59(m,4H),2.55-2.50(m,2H),1.38(d,3H),1.18(t,3H).

[0365] Example 21: LC-MS: (ES+H, m / z): [M+H] + =421.3. 1H NMR(300MHz,DMSO-d6)δ11.83(s,1H),8.45(s,1H),8.39(q,1H),8.25(d,1H),7.82(d,1H),7.75(s,1H),7.62(s,1H),7.42-7.3 3(m,1H),3.67-3.64(m,1H),3.35-3.33(m,4H),2.78(dd,3H),2.63-2.59(m,4H),2.55-2.50(m,2H),1.38(d,3H),1.18(t,3H).

[0366] Example 22A [ka] Step 1: Preparation of 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate: tert-Butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (5.00 g, 23.11 mmol, 1.00 equiv., [α]) in DCM (80 mL) 26 To a stirred mixture of D (c=0.1, MeOH):+54.50) and EtN (7.02 g, 69.35 mmol, 3.00 equiv.) was added Cbz-Cl (7.89 g, 46.23 mmol, 2.00 equiv.) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with CHCl (3 × 150 mL). The combined organic layers were washed with brine (1 × 150 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (7.40 g, Y=91.35%) as a colorless oil. LC-MS: (ES+H, m / z): [M-(t-Bu)+H] + =294.9. 1H NMR(300MHz,DMSO-d6)δ7.44-7.26(m,5H),5.09(s,2H),4.80-4.70(m,1H),4.18-3 .85(m,2H),3.80-3.60(m,2H),3.50-3.35(m,2H),3.15-2.75(m,3H),1.41(s,9H).

[0367] Step 2: Preparation of 4-benzyl 1-(tert-butyl)(R)-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate: A mixture of PPh3 (19.76 g, 75.34 mmol, 6.00 equiv.) and DEAD (10.93 g, 62.78 mmol, 5.00 equiv.) in THF (200 mL) was stirred at 0° C. for 1 hour under a nitrogen atmosphere. The mixture was added dropwise to 4-benzyl 1-tert-butyl (2R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (4.40 g, 12.55 mmol, 1.00 equiv.) and methyl 5-bromo-6-hydroxypyridine-2-carboxylate (2.91 g, 12.55 mmol, 1.00 equiv.) in THF (50 mL) at 0° C. over 10 minutes. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give 4-benzyl 1-(tert-butyl)(R)-2-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1,4-dicarboxylate (5.80 g, Y=81.84%) as a colorless oil. LC-MS: (ES+H, m / z): [M+Na] + =586.0 / 588.0.

[0368] Step 3: Preparation of benzyl (R)-3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate: To a stirred mixture of 4-benzyl 1-tert-butyl 2-({[3-bromo-6-(methoxycarbonyl)pyridin-2-yl]oxy}methyl)piperazine-1,4-dicarboxylate (5.60 g, 9.62 mmol, 1.00 equiv) in DCM (100 mL) was added HCl (gas) in 1,4-dioxane (50 mL, 4 M) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane / diethyl ether (1 / 1, 3 × 50 mL). The precipitated solid was collected by filtration and washed with hexane (3 × 50 mL). The residue was basified to pH 8-9 with saturated Na2CO3 (aq) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (1 x 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give benzyl (R)-3-(((3-bromo-6-(methoxycarbonyl)pyridin-2-yl)oxy)methyl)piperazine-1-carboxylate (3.7 g, Y = 80.32%) as a pale yellow oil. LC-MS: (ES + H, m / z): [M + H] + =463.9 / 465.9. 1 H NMR (300MHz, DMSO-d6) δ8.23(d,1H),7.60(d,1H),7.45-7.25(m,5H),5.08(s,2H),4.45-3.99(m,4H),3.92-3.68(m,4H),3.04-2.54(m,4H).

[0369] Step 4: Preparation of 3-benzyl 8-methyl (R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate: To a stirred mixture of benzyl 3-({[3-bromo-6-(methoxycarbonyl)pyridin-2-yl]oxy}methyl)piperazine-1-carboxylate (1.20 g, 2.58 mmol, 1.00 equiv.) and CsCO (2.53 g, 7.75 mmol, 3.00 equiv.) in THF (60 mL) was added dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (740 mg, 1.03 mmol, 0.40 equiv.) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated under reduced pressure to give 3-benzyl 8-methyl(R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (560 mg, Y=56.52%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =384.1.1H NMR(300MHz,DMSO-d6)δ7.63(d,1H),7.46-7.22(m,6H),5.13(s,2H),4.56-4.47(m,1H),4.13-4.06(m,5H),3.78(s,3H),3.17(d,2H).

[0370] Step 5: Preparation of benzyl (R)-8-(methylcarbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate: To a stirred mixture of 3-benzyl 8-methyl (R)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3,8(4H)-dicarboxylate (560 mg, 1.46 mmol, 1.00 equiv.) in MeOH (15 mL), methylamine (10 mL, 25–30 wt % in water) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Saturated NH4Cl (100 mL) was added to the resulting mixture, which was then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave benzyl (R)-8-(methylcarbamoyl)-1,2,4a,5-tetrahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-3(4H)-carboxylate (530 mg, Y=94.89%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =383.2.

[0371] Step 6: Preparation of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide: To a stirred mixture of benzyl 5-(methylcarbamoyl)-8-oxa-1,6,12-triazatricyclo[8.4.0.0^{2,7}]tetradeca-2,4,6-triene-12-carboxylate (500 mg, 1.30 mmol, 1.00 equiv.) and NH3.HO (3 mL) in i-PrOH (15 mL) was added Pd / C (100 mg, 10 wt%) at room temperature under a hydrogen atmosphere. The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (5 × 50 mL). The filtrate was concentrated under reduced pressure. This gave (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (290 mg, Y=89.33%) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ =249.0.

[0372] Step 7: Preparation of (R)-3-((7-ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide: To a stirred mixture of (R)-N-methyl-1,2,3,4,4a,5-hexahydropyrazino[1,2-d]pyrido[2,3-b][1,4]oxazine-8-carboxamide (123 mg, 0.49 mmol, 1.10 equiv.) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (100 mg, 0.45 mmol, 1.00 equiv.) in ACN (4 mL) was added DIEA (290 mg, 2.24 mmol, 5.00 equiv.) and KI (7 mg, 0.04 mmol, 0.10 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was cooled...

Claims

1. A compound of formula (III"), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. 【Chemistry 118】 [In the formula, R Ｃ１ is hydrogen, deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)NR ｃ R ｄ , 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, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently selected from one or more R Ｃａ and Each R Ｃａ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same atom Ｃａ together to form oxo, R Ｃ２ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)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; R Ｃ３ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, or heterocycloalkyl; Each R ７ are independently 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, cycloalkyl, or heterocycloalkyl; Or, two R ７ taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from deuterium, halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is optionally substituted with heteroalkyl; Each R ８ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)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, heterocycloalkyl, aryl, or heteroaryl; Or, two R on the same carbon ８ together to form oxo, or Or, two R on the same carbon, adjacent carbons, or opposite carbons ８ taken together form a cycloalkyl or heterocycloalkyl, each of which is selected from the group consisting of one or more deuterium, halogen, —CN, —OH, —OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, or C １ ~C ６ is optionally substituted with heteroalkyl; n is 0 to 6; R １２ is C １ ~C ６ Alkyl, C １ ~C ６ deuteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are each independently one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , 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 optionally substituted with heteroalkyl; Each R １１ are independently deuterium, halogen, -CN, -NO ２ , -OH, -OR ａ , -OC(=O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ N.R. ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (=O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , -C(=O)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, cycloalkyl, or heterocycloalkyl; q is 0 to 3; Each R ａ is independently １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently may be one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , 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 optionally substituted with heteroalkyl; Each R ｂ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ ~C ６ Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently may be one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , 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 optionally substituted with heteroalkyl; 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 Alkyl (cycloalkyl), C １ ~C ６ Alkyl (heterocycloalkyl), C １ ~C ６ Alkyl (aryl), or C １ ~C ６ alkyl(heteroaryl), where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl independently may be one or more of oxo, deuterium, halogen, —CN, —OH, —OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , 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 optionally substituted with heteroalkyl; Or, R ｃ and R ｄ together with the atom to which they are attached, represent one or more of oxo, deuterium, halogen, -CN, -OH, -OCH ３ , -S(=O)CH ３ , -S(=O) ２ CH ３ , -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C.H. ３ , -S(=O) ２ N (CH ３ ) ２ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -C(=O)CH ３ , -C(=O)OH, -C(=O)OCH ３ , 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 forming a heterocycloalkyl, optionally substituted with a heteroalkyl.

2. R Ｃ１ is halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is deuteroalkyl, cycloalkyl, or heterocycloalkyl.

3. R Ｃ１ is halogen, cycloalkyl, or heterocycloalkyl, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

4. R Ｃ１ is halogen or cycloalkyl, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

5. R Ｃ１ is halogen, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

6. R Ｃ１ is cycloalkyl, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

7. R Ｃ２ is hydrogen, deuterium, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

8. R Ｃ２ is hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

9. R Ｃ２ is hydrogen, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

10. R Ｃ２ is C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

11. R Ｃ３ is hydrogen, deuterium, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

12. R Ｃ３ is hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

13. R Ｃ３ is hydrogen or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

14. R Ｃ３ is hydrogen, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

15. 【Catalogue 119】 teeth, 【Chemistry 120】 2. The compound of claim 1, wherein:

16. 【Chemical 121】 teeth, 【Chemistry 122】 2. The compound of claim 1, wherein:

17. 【Chemical 123】 teeth, 【Chemistry 124】 2. The compound of claim 1, wherein:

18. 【Chemical 125】 teeth, 【Chemistry 126】 2. The compound of claim 1, wherein:

19. Each R ７ are independently hydrogen, deuterium, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

20. Each R ７ is hydrogen, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

21. Each R ８ is C １ ~C ６ alkyl or two R on the same carbon ８ The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

22. Two R on opposite carbons ８ The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

23. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 to 3.

24. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.

25. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.

26. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

27. Each R １１ are independently deuterium, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is deuteroalkyl.

28. Each R １１ are independently halogen or C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

29. Each R １１ is independently a halogen, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

30. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 or 1.

31. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1.

32. 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0.

33. R １２ is C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is 1, 2, 3, 4, 5, 6, or 7;

34. R １２ is C １ ~C ６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

35. R １２ is cycloalkyl, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

36. The compound is 【Chemistry 127】 【Chemistry 128】 【Chemistry 129】 The compound of claim 1 selected from the group consisting of: or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

37. The compound is 【Chemistry 130】 37. The compound of claim 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

38. The compound is 【Chemistry 131】 37. The compound of claim 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

39. The compound is 【Chemistry 132】 37. The compound of claim 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

40. The compound is 【Chemistry 133】 37. The compound of claim 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

41. The compound is 【Chemistry 134】 37. The compound of claim 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

42. The compound is 【Chemistry 135】 37. The compound of claim 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

43. 43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

44. 43. A composition for use in the treatment of cancer, comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

45. 45. The composition of claim 44, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, or lung cancer.

46. 43. A composition for use in the treatment of cancer involving BRCA1 and / or BRCA2 mutations, comprising a compound according to any one of claims 1 to 42, or a pharma- ceutically acceptable salt, solvate or stereoisomer thereof.

47. 47. The composition of claim 46, wherein the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, renal cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

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